Conditions: Triple-Negative Breast Cancer
Keywords: Breast Neoplasms Triple Negative Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Paclitaxel Atezolizumab Ipatasertib Antibodies, Monoclonal Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 242
Healthy volunteers: no

Brief summary:
This study evaluated the efficacy and safety of ipatasertib in combination with atezolizumab and paclitaxel in locally advanced or metastatic Triple-Negative Breast Cancer (TNBC) previously untreated in this setting.

Detailed description:

Arms:
arm 1: TNBC participants with programmed death-ligand 1 (PD-L1) non-positive received a combination of paclitaxel, 80 milligrams per meter square (mg/m\^2), intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, 400 mg, orally (PO), once daily (QD), from Day 1 to Day 21 of each 28-day cycle and atezolizumab, 840 mg, IV infusion on Day 1 and 15 of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent, whichever occurred first. arm 2: TNBC participants with PD-L1 non-positive received a combination of paclitaxel, 80 mg/m\^2, IV infusion on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, 400 mg, PO, QD, from Day 1 to Day 21 of each 28-day cycle and atezolizumab-matching placebo, IV infusion on Day 1 and 15 of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent, whichever occurred first. arm 3: TNBC participants with PD-L1 non-positive received a combination of paclitaxel, 80 mg/m\^2, IV infusion on Days 1, 8, and 15 of each 28-day cycle and ipatasertib-matching placebo, PO, QD, from Day 1 to Day 21 of each 28-day cycle and atezolizumab-matching placebo, IV infusion on Day 1 and 15 of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent, whichever occurred first. arm 4: TNBC participants with PD-L1 positive received a combination of paclitaxel, 80 mg/m\^2, IV infusion on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, 400 mg, PO, QD, from Day 1 to Day 21 of each 28-day cycle and atezolizumab, 840 mg, IV infusion on Day 1 and 15 of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent, whichever occurred first. arm 5: TNBC participants with PD-L1 positive received a combination of paclitaxel, 80 mg/m\^2, IV infusion on Days 1, 8, and 15 of each 28-day cycle and ipatasertib-matching placebo, PO, QD, from Day 1 to Day 21 of each 28-day cycle and atezolizumab, 840 mg, IV infusion on Day 1 and 15 of each 28-day cycle until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent, whichever occurred first.

Interventions: intervention 1: Atezolizumab intervention 2: Ipatasertib intervention 3: Paclitaxel intervention 4: Placebo for Atezolizumab intervention 5: Placebo for Ipatasertib
Intervention descriptions: intervention 1: Atezolizumab was administered as per the dosage regimen mentioned in arm descriptions. intervention 2: Ipatasertib was administered as per the dosage regimen mentioned in arm descriptions. intervention 3: Paclitaxel was administered as per the dosage regimen mentioned in arm descriptions. intervention 4: Placebo was administered as per the dosage regimen mentioned in arm descriptions. intervention 5: Placebo was administered as per the dosage regimen mentioned in arm descriptions.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol CO41101, Version 6 
PROTOCOL 
TITLE: 
A PHASE III, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED STUDY 
OF IPATASERTIB IN COMBINATION WITH 
ATEZOLIZUMAB AND PACLITAXEL AS 
A TREATMENT FOR PATIENTS WITH LOCALLY 
ADVANCED UNRESECTABLE OR METASTATIC 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: CO41101 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2019-000810-12 
IND NUMBER: 
133823 
NCT NUMBER: 
NCT04177108 
TEST PRODUCTS: 
Ipatasertib (RO5532961, GDC0068) 
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)
25-Feb-2022 20:48:14


 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol CO41101, Version 6 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
6 
See electronic date stamp above. 
 
 
 
5 
21 December 2020 
 
 
 
4 
18 August 2020 
 
 
 
3 
20 September 2019 
 
 
 
1 
27 June 2019 
VHP 
2 
13 September 2019 
 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol CO41101, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol CO41101 has been amended to primarily align the protocol with the most 
recent Investigator’s Brochures for Ipatasertib (Version 13) and Atezolizumab 
(Version 17) and to reduce study assessments for long-term follow-up.  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. 
• 
Benefit-risk assessment and guidance on concomitant administration of severe 
acute respiratory syndrome coronavirus 2 vaccines with atezolizumab has been 
added (Sections 1.5 and 4.4.1). 
• 
Text has been added to clarify that long-term follow-up assessments will no longer 
be collected (Sections 3.1.1, 4.6.1, and Appendix 1).  
• 
The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility have been clarified (Sections 4.1.1.2, 4.3.2.3, 4.3.3, 
4.4.1, 4.4.2.2, 4.4.2.3, 4.4.3, 4.5.7, 4.5.8, Appendices 1, 4, 13, and 14). 
• 
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 4). 
• 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 18 (Appendices 13 and 14). 
 
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 and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol CO41101, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 13 
PROTOCOL SYNOPSIS ....................................................................................... 14 
1. 
BACKGROUND .............................................................................................. 35 
1.1 
Background on Triple-Negative Breast Cancer ...................... 35 
1.2 
Background on Ipatasertib ....................................................... 36 
1.3 
Background on Atezolizumab .................................................. 38 
1.4 
Background on Studies in TNBC Combining 
Ipatasertib and Atezolizumab .................................................. 40 
1.5 
Study Rationale and Benefit−Risk Assessment ...................... 41 
2. 
OBJECTIVES AND ENDPOINTS .................................................................. 44 
2.1 
Efficacy Objectives ................................................................... 45 
2.1.1 
Primary Efficacy Objective ....................................................... 45 
2.1.2 
Exploratory Efficacy Objectives ............................................... 45 
2.2 
Safety Objectives ..................................................................... 47 
2.3 
Exploratory Pharmacokinetic Objectives ................................. 47 
2.4 
Exploratory Immunogenicity Objectives .................................. 48 
2.5 
Exploratory Biomarker Objectives ........................................... 48 
3. 
STUDY DESIGN ............................................................................................. 48 
3.1 
Description of the Study ........................................................... 48 
3.1.1 
Overview of Study Design ........................................................ 48 
3.1.2 
Assessments and Monitoring ................................................... 51 
3.1.3 
Safety Data Monitoring............................................................. 51 
3.2 
End of Study and Length of Study ........................................... 52 
3.3 
Rationale for Study Design ...................................................... 52 
3.3.1 
Rationale for Ipatasertib Dose and Schedule.......................... 52 
3.3.2 
Rationale for Atezolizumab Dose and Schedule ..................... 53 
3.3.3 
Rationale for Paclitaxel Dose and Schedule ........................... 53 
3.3.4 
Rationale for Patient Population .............................................. 54 
3.3.5 
Rationale for Control Group ..................................................... 55 
3.3.6 
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints .............................. 55 


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3.3.7 
Rationale for Biomarker Assessments .................................... 56 
3.3.8 
Rationale for the Pharmacokinetic Evaluation 
Schedule ................................................................................... 57 
3.3.9 
Rationale for Collection of DNA (Blood) for 
Exploratory Whole Genome Sequencing ................................ 58 
3.3.10 
Rationale for Patient-Reported Outcome 
Assessments ............................................................................ 59 
4. 
MATERIALS AND METHODS ....................................................................... 60 
4.1 
Patients ..................................................................................... 60 
4.1.1 
Inclusion Criteria ....................................................................... 60 
4.1.1.1 
General Inclusion Criteria ........................................................ 61 
4.1.1.2 
Disease-Specific Inclusion Criteria .......................................... 63 
4.1.2 
Exclusion Criteria ..................................................................... 64 
4.1.2.1 
General Exclusion Criteria ....................................................... 64 
4.1.2.2 
Disease-Specific Exclusion Criteria ......................................... 66 
4.1.2.3 
Paclitaxel-Specific Exclusion Criteria ...................................... 68 
4.1.2.4 
Ipatasertib-Specific Exclusion Criteria ..................................... 68 
4.1.2.5 
Atezolizumab-Specific Exclusion Criteria ................................ 68 
4.2 
Method of Treatment Assignment and Blinding ...................... 69 
4.2.1 
Treatment Assignment ............................................................. 69 
4.2.2 
Blinding ..................................................................................... 70 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design .................................................................. 72 
4.3.1 
Study Treatment Formulation, Packaging, 
and Handling ............................................................................ 72 
4.3.1.1 
Ipatasertib and Placebo ........................................................... 72 
4.3.1.2 
Atezolizumab and Placebo ...................................................... 72 
4.3.1.3 
Paclitaxel .................................................................................. 73 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................... 73 
4.3.2.1 
Ipatasertib and Placebo ........................................................... 73 
4.3.2.2 
Atezolizumab and Placebo ...................................................... 74 
4.3.2.3 
Paclitaxel .................................................................................. 75 
4.3.3 
Other Treatments:  Premedications and 
Prophylactic Treatment ............................................................ 76 


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4.3.4 
Investigational Medicinal Product Accountability .................... 77 
4.3.5 
Continued Access to Ipatasertib and 
Atezolizumab ............................................................................ 77 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions.............................................................. 78 
4.4.1 
Permitted Therapy .................................................................... 78 
4.4.2 
Cautionary Therapy .................................................................. 80 
4.4.2.1 
Corticosteroidsand Tumor Necrosis Factor−α 
Inhibitors ................................................................................... 80 
4.4.2.2 
Surgery and Palliative Radiotherapy ....................................... 80 
4.4.2.3 
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes .................................. 80 
4.4.2.4 
Herbal Therapies ...................................................................... 81 
4.4.3 
Prohibited Therapy ................................................................... 82 
4.4.4 
Prohibited Food ........................................................................ 82 
4.4.5 
Additional Restrictions.............................................................. 83 
4.5 
Study Assessments .................................................................. 83 
4.5.1 
Informed Consent Forms and Screening Log ......................... 83 
4.5.2 
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data .................. 84 
4.5.3 
Physical Examinations ............................................................. 84 
4.5.4 
Weight and Height .................................................................... 85 
4.5.5 
Vital Signs ................................................................................. 85 
4.5.6 
ECOG Performance Status...................................................... 86 
4.5.7 
Tumor and Response Evaluations .......................................... 86 
4.5.8 
Electrocardiograms and Cardiac Function 
Assessment .............................................................................. 87 
4.5.9 
Laboratory, Biomarker, and Other Biological 
Samples .................................................................................... 88 
4.5.10 
Patient-Reported Outcome Assessments ............................... 92 
4.5.10.1 
EORTC QLQ-C30 .................................................................... 93 
4.5.10.2 
PRO-CTCAE ............................................................................ 93 
4.5.10.3 
EQ-5D-5L.................................................................................. 94 
4.5.11 
Blood Samples for Whole Genome Sequencing 
(Patients at Participating Sites)................................................ 94 


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7/Protocol CO41101, Version 6 
4.5.12 
Optional Samples for Research Biosample 
Repository................................................................................. 95 
4.5.12.1 
Overview of the Research Biosample Repository................... 95 
4.5.12.2 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 96 
4.5.12.3 
Sample Collection .................................................................... 96 
4.5.12.4 
Confidentiality ........................................................................... 97 
4.5.12.5 
Consent to Participate in the Research 
Biosample Repository .............................................................. 97 
4.5.12.6 
Withdrawal from the Research Biosample 
Repository................................................................................. 98 
4.5.12.7 
Monitoring and Oversight ......................................................... 98 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ......................................................................... 99 
4.6.1 
Study Treatment Discontinuation ............................................ 99 
4.6.2 
Patient Discontinuation from the Study ................................. 100 
4.6.3 
Study Discontinuation ............................................................ 100 
4.6.4 
Site Discontinuation ............................................................... 100 
5. 
ASSESSMENT OF SAFETY........................................................................ 101 
5.1 
Safety Plan ............................................................................. 101 
5.1.1 
Risks Associated with Ipatasertib .......................................... 102 
5.1.2 
Risks Associated with Paclitaxel............................................ 102 
5.1.3 
Risks Associated with Ipatasertib in Combination 
with Paclitaxel ......................................................................... 102 
5.1.4 
Risks Associated with Atezolizumab ..................................... 103 
5.1.5 
Risks Associated with Combination Use of 
Atezolizumab and Ipatasertib ................................................ 104 
5.1.6 
Risks Associated with Atezolizumab in 
Combination with Paclitaxel ................................................... 104 
5.1.7 
Risks Associated with Ipatasertib in Combination 
with Atezolizumab and Paclitaxel .......................................... 104 
5.2 
Safety Parameters and Definitions ........................................ 104 
5.2.1 
Adverse Events ...................................................................... 104 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ....................................................................... 105 


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5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 106 
5.2.4 
Selected Adverse Events ....................................................... 107 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 107 
5.3.1 
Adverse Event Reporting Period ........................................... 107 
5.3.2 
Eliciting Adverse Event Information ....................................... 108 
5.3.3 
Assessment of Severity of Adverse Events .......................... 108 
5.3.4 
Assessment of Causality of Adverse Events......................... 109 
5.3.5 
Procedures for Recording Adverse Events ........................... 110 
5.3.5.1 
Infusion-Related Reactions .................................................... 110 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................ 111 
5.3.5.3 
Adverse Events That Are Secondary to 
Other Events........................................................................... 111 
5.3.5.4 
Persistent or Recurrent Adverse Events ............................... 111 
5.3.5.5 
Abnormal Laboratory Values ................................................. 112 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 113 
5.3.5.7 
Abnormal Vital Sign Values ................................................... 113 
5.3.5.8 
Deaths .................................................................................... 113 
5.3.5.9 
Preexisting Medical Conditions.............................................. 114 
5.3.5.10 
Lack of Efficacy or Worsening of Triple-Negative 
Breast Cancer......................................................................... 114 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ......................... 114 
5.3.5.12 
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse........................................................... 115 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 117 
5.3.5.14 
Safety Biomarker Data ........................................................... 117 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 117 
5.4.1 
Emergency Medical Contacts ................................................ 118 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest .................... 118 
5.4.2.1 
Events That Occur prior to Study Treatment 
Initiation .................................................................................. 118 
5.4.2.2 
Events That Occur after Study Treatment 
Initiation .................................................................................. 119 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol CO41101, Version 6 
5.4.3 
Reporting Requirements for Pregnancies ............................. 119 
5.4.3.1 
Pregnancies in Female Patients ............................................ 119 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................ 120 
5.4.3.3 
Abortions................................................................................. 120 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 120 
5.5 
Follow-Up of Patients after Adverse Events .......................... 121 
5.5.1 
Investigator Follow-Up ........................................................... 121 
5.5.2 
Sponsor Follow-Up ................................................................. 121 
5.6 
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 121 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees .......................................................... 121 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...................... 122 
6.1 
Determination of Sample Size ............................................... 122 
6.1.1 
Type I Error Control ................................................................ 122 
6.1.2 
Sample Size Consideration for Cohort 1 ............................... 123 
6.1.3 
Sample Size Consideration for Cohort 2 ............................... 125 
6.2 
Summaries of Conduct of Study ............................................ 126 
6.3 
Summaries of Treatment Group Comparability .................... 126 
6.4 
Efficacy Analyses ................................................................... 126 
6.4.1 
Co-Primary Efficacy Endpoints .............................................. 126 
6.4.2 
Exploratory Efficacy Endpoints .............................................. 127 
6.4.2.1 
Objective Response Rate ...................................................... 127 
6.4.2.2 
Duration of Response ............................................................ 127 
6.4.2.3 
Clinical Benefit Rate ............................................................... 127 
6.4.2.4 
Patient Subgroup Analysis in Each Cohort ........................... 128 
6.4.2.5 
Patient-Reported Outcomes of Role and Physical 
Function and GHS/QoL and EORTC Data ............................ 128 
6.4.2.6 
Progression-Free Survival 2 (PFS2)...................................... 128 
6.4.2.7 
Patient-Reported Outcomes of Disease- and 
Treatment-Related Symptoms, and Cognitive, 
Emotional, and Social Function:  EORTC Data .................... 129 
6.4.2.8 
Health Economic EQ-5D-5L Data .......................................... 129 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol CO41101, Version 6 
6.5 
Safety Analyses ...................................................................... 129 
6.5.1 
Analyses of Exposure, Adverse Events, 
Laboratory Data, and Vital Signs ........................................... 129 
6.5.2 
Exploratory Safety Analysis of Patient-Reported 
Symptomatic Adverse Events:  PRO-
CTCAE Data ........................................................................... 129 
6.6 
Exploratory Pharmacokinetic Analyses ................................. 130 
6.7 
Exploratory Immunogenicity Analyses .................................. 130 
6.8 
Exploratory Biomarker Analyses............................................ 131 
6.9 
Interim Analyses ..................................................................... 131 
6.9.1 
Planned Interim Safety Analyses ........................................... 131 
6.9.2 
Planned Interim Analysis of OS at the Primary 
Analysis of PFS ...................................................................... 132 
6.9.2.1 
Planned Interim OS Analysis for Cohort 1............................. 132 
6.9.2.2 
Planned Interim OS Analysis for Cohort 2............................. 133 
6.10 
China Subpopulation Analyses .............................................. 133 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 134 
7.1 
Data Quality Assurance ......................................................... 134 
7.2 
Electronic Case Report Forms ............................................... 134 
7.3 
Source Data Documentation .................................................. 135 
7.4 
Use of Computerized Systems .............................................. 135 
7.5 
Retention of Records ............................................................. 135 
8. 
ETHICAL CONSIDERATIONS .................................................................... 136 
8.1 
Compliance with Laws and Regulations................................ 136 
8.2 
Informed Consent ................................................................... 136 
8.3 
Institutional Review Board or Ethics Committee ................... 137 
8.4 
Confidentiality ......................................................................... 138 
8.5 
Financial Disclosure ............................................................... 139 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................................... 139 
9.1 
Study Documentation ............................................................. 139 
9.2 
Protocol Deviations ................................................................ 139 
9.3 
Management of Study Quality ............................................... 139 
9.4 
Site Inspections ...................................................................... 140 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol CO41101, Version 6 
9.5 
Administrative Structure ......................................................... 140 
9.6 
Dissemination of Data and Protection of 
Trade Secrets ......................................................................... 140 
9.7 
Protocol Amendments ............................................................ 141 
10. REFERENCES ............................................................................................. 142 
 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent 
Atezolizumab/Placebo Infusions ................................................... 75 
Table 2 
Timing for Vital Sign Measurements for First and 
Subsequent Infusions .................................................................... 85 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 109 
Table 4 
Causal Attribution Guidance ........................................................ 110 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ................................................................................ 50 
Figure 2 
Type I Error Control ..................................................................... 123 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities................................................................... 150 
Appendix 2 
Schedule of Pharmacokinetic and Immunogenicity Samples .... 166 
Appendix 3 
Eastern Cooperative Oncology Group Performance Status 
Scale............................................................................................. 167 
Appendix 4 
Preexisting Autoimmune Diseases and Immune Deficiencies ... 168 
Appendix 5 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) .......................................................... 169 
Appendix 6 
Example of Treatment Cycle and Tumor Assessment 
Calendar  ...................................................................................... 179 
Appendix 7 
Anaphylaxis Precautions ............................................................. 180 
Appendix 8 
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations ...................................................... 181 
Appendix 9 
ASCO/CAP HER2 Test Guideline Recommendations ............... 182 
Appendix 10 European Organisation for Research and Treatment of 
Cancer Quality of Life−Core 30 Questionnaire (EORTC 
QLQ-C30) ..................................................................................... 185 
Appendix 11 EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) ........ 187 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
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Appendix 12 Selected Items from the Patient-Reported Outcomes Version 
of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE).............................................................................. 190 
Appendix 13 Overall Guidelines for Management of Patients Who 
Experience Adverse Events ........................................................ 192 
Appendix 14 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab................................................................................ 223 
Appendix 15 Drugs with Known Risk of TdP; 
https://www.crediblemeds.org ..................................................... 249 


Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol CO41101, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED STUDY 
OF IPATASERTIB IN COMBINATION WITH 
ATEZOLIZUMAB AND PACLITAXEL AS 
A TREATMENT FOR PATIENTS WITH LOCALLY 
ADVANCED UNRESECTABLE OR METASTATIC 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: CO41101 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2019-000810-12 
IND NUMBER: 
133823 
NCT NUMBER: 
NCT04177108 
TEST PRODUCTS: 
Ipatasertib (RO5532961, GDC0068) 
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 retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 
 


 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol CO41101, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED STUDY OF IPATASERTIB IN COMBINATION WITH 
ATEZOLIZUMAB AND PACLITAXEL AS A TREATMENT FOR 
PATIENTS WITH LOCALLY ADVANCED UNRESECTABLE OR 
METASTATIC TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
CO41101 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2019-000810-12 
IND NUMBER: 
133823 
NCT NUMBER: 
NCT04177108 
TEST PRODUCTS: 
Ipatasertib (RO5532961, GDC0068) 
Atezolizumab (RO5541267) 
PHASE: 
Phase III 
INDICATION: 
Metastatic triple-negative breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of ipatasertib in combination 
with atezolizumab and paclitaxel in locally advanced unresectable or metastatic triple-negative 
breast cancer (TNBC) previously untreated in this setting.  Patients with programmed 
death-ligand-1 (PD-L1)−non-positive and PD-L1−positive tumors will be independently enrolled 
in Cohorts 1 and 2, respectively.  The combination of ipatasertib, atezolizumab, and paclitaxel 
will be evaluated in two independently enrolled cohorts (Cohorts 1 and 2) and the combination 
of ipatasertib and paclitaxel will be evaluated in Cohort 1.   
Specific objectives and corresponding endpoints are outlined in the following sections.  
In this protocol, "study treatment" refers to the combination of treatments assigned to any 
individual patient as part of this study (e.g., ipatasertib/placebo [for ipatasertib], 
atezolizumab/placebo [for atezolizumab], and paclitaxel). 
As of protocol Version 5, the following objectives and the corresponding statistical 
considerations and analyses will no longer be applicable to the study.  Due to the early 
termination of the enrollment, data from enrolled patients will only be summarized descriptively 
for endpoints that are deemed appropriate and necessary. 
Efficacy Objectives 
Primary Efficacy Objective 
The primary efficacy objective for this study is to independently evaluate the efficacy of the 
experimental arm treatment compared with control arm treatment in each cohort (i.e., Arm A vs. 
Arm C and Arm B vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2), on the basis of the 
following co-primary endpoints: 


 
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• 
Investigator-assessed progression-free survival (PFS) after randomization, defined as the 
time from randomization to the first occurrence of disease progression, as determined 
locally according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), or death from any cause, whichever occurs first 
• 
Overall survival (OS) after randomization, defined as the time from randomization to death 
from any cause 
 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are as follows: 
• 
To independently evaluate the efficacy of experimental arm treatment compared with 
control arm treatment in each cohort (i.e., Arm A vs. Arm C in Cohort 1 and Arm B vs. 
Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2) on the basis of the following endpoints: 
− Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, 
as determined by the investigator according to RECIST v1.1 
− Duration of response (DOR), defined as the time from the first occurrence of 
a documented objective response to the first occurrence of disease progression, as 
determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first  
− Clinical benefit rate (CBR), defined as the proportion of patients who have a CR, PR, or 
stable disease for ≥24 weeks, as determined by the investigator according to RECIST 
v1.1 
• 
To evaluate patient-reported outcomes (PROs) of function (role, physical), global health 
status (GHS)/quality of life (QoL) associated with the following: 
− Ipatasertib plus paclitaxel compared with paclitaxel in patients with PD-L1−non-positive 
tumors (Arm B vs. Arm C in Cohort 1) 
− The addition of atezolizumab to ipatasertib plus paclitaxel compared with ipatasertib plus 
paclitaxel alone in patients with PD-L1−non-positive tumors (Arm A vs. Arm B in 
Cohort 1) 
− Ipatasertib plus paclitaxel plus atezolizumab compared with control arm treatments 
(Arm A vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2) as measured by the 
Functional and GHS/QoL scales of the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire−Core 30 (EORTC QLQ-C30) on the 
basis of the following endpoint: 
– 
Mean and mean changes from baseline score in function (role, physical) and GHS/QoL 
by assessment timepoint and between treatment arms, as measured using the Functional 
and the GHS/QoL scales of the EORTC QLQ-C30 
• 
To evaluate the efficacy of atezolizumab when combined with ipatasertib and paclitaxel in 
patients with PD-L1−non-positive tumors (Arm A vs. Arm B in Cohort 1) on the basis of 
PFS, OS, and ORR 
• 
To independently evaluate the efficacy of experimental arm treatment compared with 
control arm treatment in patients with PIK3CA/AKT1/PTEN-altered tumors in each cohort, 
on the basis of PFS, OS, ORR, DOR, and CBR 
• 
To evaluate PROs of function (cognitive, emotional, social) and disease- and 
treatment-related symptoms associated with: 
− Ipatasertib plus paclitaxel compared with paclitaxel in patients with PD-L1-non-positive 
tumors (Arm B vs. Arm C in Cohort 1). 
− The addition of atezolizumab to ipatasertib plus paclitaxel compared with ipatasertib plus 
paclitaxel alone in patients with PD-L1-non-positive tumors (Arm A vs. Arm B in 
Cohort 1) 


 
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− Ipatasertib plus paclitaxel plus atezolizumab compared with control arm treatments 
(Arm A vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2) as measured by the 
Functional and Symptom scales of the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) on the 
basis of the following endpoint: 
Mean and mean change from baseline scores in functional (cognitive, emotional, 
social) and disease- and treatment-related symptoms by cycle and between treatment 
arms, as assessed using the Functional and Symptom scales of the EORTC QLQ-C30 
• 
To evaluate patients’ health utility, as measured by the EuroQol 5-Dimension 
Questionnaire, 5-Level Version (EQ-5D-5L) to generate utility scores for 
pharmacoeconomic modeling, on the basis of the following endpoint:  
Utility scores of the EQ-5D-5L Questionnaire  
• 
To independently evaluate the clinical benefit in each cohort, on the basis of the following 
endpoint: 
PFS2 after randomization, defined as the time from randomization to second 
occurrence of objective disease progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause (whichever occurs first)  
 
Safety Objectives 
The safety objective for this study is to independently evaluate the safety of experimental arm 
treatment in each cohort, on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined by the investigator 
according to the NCI Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0) 
• 
Change from baseline in targeted vital signs 
• 
Change from baseline in targeted clinical laboratory test results 
 
The exploratory safety objective for this study is to independently evaluate key patient-reported 
symptomatic adverse events associated with ipatasertib plus paclitaxel plus atezolizumab 
compared with control arm treatment in each cohort, on the basis of the following endpoint:  
Selected items from the NCI’s PRO Version of the CTCAE (PRO-CTCAE) capturing 
patients' rating of the presence, severity, frequency, and/or activity interference of diarrhea, 
nausea, vomiting, decreased appetite, fatigue, neuropathy, mouth sores, and rash 
symptoms, as well as an additional item regarding bother associated with side effects of 
treatment   
 
Exploratory Pharmacokinetic Objectives 
The exploratory PK objective for this study are as follows:  
• 
To evaluate the pharmacokinetics of atezolizumab, ipatasertib, and its metabolite 
(G-0377720) in each cohort, on the basis of the following endpoints: 
– 
Plasma concentrations of ipatasertib and its metabolite (G-037720) at specified 
timepoints  
– 
Serum concentrations of atezolizumab at specified timepoints  
• 
To evaluate potential relationships between ipatasertib and/or atezolizumab exposure, 
efficacy, and safety of ipatasertib plus paclitaxel plus atezolizumab in each cohort, on the 
basis of the following endpoints: 
– 
Relationship between ipatasertib and/or atezolizumab PK and efficacy endpoints, as 
appropriate based on the data 
– 
Relationship between ipatasertib and/or atezolizumab PK and safety endpoints, as 
appropriate based on the data 


 
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Exploratory Immunogenicity Objectives 
The exploratory immunogenicity objectives of this study are as follows: 
• 
To independently evaluate the immune response to atezolizumab in each cohort, on the 
basis of the following endpoint: 
– 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study 
• 
To evaluate the potential effects of ADAs in each cohort, on the basis of the following 
endpoint: 
– 
Relationship between ADA status and efficacy, safety, PK, or biomarker endpoints 
 
Exploratory Biomarker Objectives 
The exploratory biomarker objectives for this study are as follows: 
• 
To independently evaluate predictive or prognostic biomarkers (plasma or tissue) 
associated with disease activity status or response to treatment in each cohort, on the basis 
of the following endpoint: 
Relationship between tissue and blood-based biomarkers and patient clinical features 
(e.g., baseline features) and outcome (e.g., duration of PFS) 
• 
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 in each cohort, on the basis of the following endpoints: 
− 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 (IHC)  
 
Study Design 
Description of Study 
Overview of Study Design  
This study will enroll approximately 1155 patients (approximately 525 patients in Cohort 1 and 
approximately 630 patients in Cohort 2) with advanced TNBC across up to 350 sites globally.  
The study will compare the efficacy of the combination of ipatasertib, atezolizumab, and 
paclitaxel against paclitaxel in patients with PD-L1−non-positive tumors (Cohort 1, Arm A vs. 
Arm C) and against atezolizumab and paclitaxel in patients with PD-L1−positive tumors 
(Cohort 2, Arm A vs. Arm B).  Cohort 1 will also evaluate the combination of paclitaxel and 
ipatasertib against paclitaxel in patients with PD-L1−non-positive tumors (Arm B vs. Arm C).  In 
Cohort 1, approximately 525 patients with PD-L1−non-positive tumors will be enrolled and 
randomized in a 1:1:1 ratio to treatment Arms A, B, and C, respectively.  In Cohort 2, 
approximately 630 patients with PD-L1−positive tumors will be enrolled and randomized in a 1:1 
ratio to treatment Arms A and B, respectively.  Patients with PD-L1 unknown tumors will be 
assigned to Cohort 1.  It is anticipated that owing to the prevalence of PD-L1 positivity and 
negativity by the SP142 assay that Cohort 1 will be fully enrolled before Cohort 2. 
As of 6 August 2020, further enrollment in Cohort 2 has been terminated; treatment 
assignments for Cohort 2 were unblinded on 7 August 2020.  Patients may continue current 
study treatment if considered clinically appropriate and if deriving benefit as assessed by the 
investigator.  However, patients in Arm B of Cohort 2 will no longer receive placebo for 
ipatasertib.  No crossover will be permitted for patients in Arm B of Cohort 2.  For patients who 
choose to continue in the study, assessments will proceed as specified in the protocol.  
As of 18 September 2020, further enrollment in Cohort 1 has been terminated; treatment 
assignments for Cohort 1 were unblinded on 21 September 2020.  Patients may continue 
current study treatment if considered clinically appropriate and if deriving benefit as assessed 
by the investigator.  However, patients in Arm B of Cohort 1 will no longer receive placebo for 
atezolizumab; patients in Arm C of Cohort 1 will no longer receive placebo for ipatasertib nor 


 
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placebo for atezolizumab.  No crossover will be permitted for patients in Arm B or Arm C of 
Cohort 1.  Assessments will proceed as specified in the protocol. 
Ipatasertib or placebo will be administered to patients at a starting dose of 400 mg QD PO for 
21 days of each 28-day cycle on Days 1−21 unless held for management of adverse events.  
Atezolizumab or placebo will be administered to patients by IV infusion at a fixed dose of 
840 mg on Days 1 and 15 of each 28-day cycle.  Paclitaxel will be administered to patients at 
a starting dose of 80 mg/m2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day 
cycle unless deferred to Day 22 because of an adverse event.   
Any study treatment may be continued until disease progression, intolerable toxicity, elective 
withdrawal from the study or study treatment, or study completion or termination.  
After treatment discontinuation, patients will be followed every 3 months for survival, PROs, as 
well as follow-up anti-cancer therapy and related outcomes (therapy and procedures, doses, 
start and stop dates, best response, most recent tumor assessment date, and progression 
date).  As of protocol Version 6, these long-term follow-up assessments are no longer 
required. 
In each cohort, a permuted block randomization scheme will be used to ensure an appropriate 
allocation of patients to each arm (at an approximately 1:1:1 ratio to Arms A, B, and C in 
Cohort 1 and approximately a 1:1 ratio to Arms A and B in Cohort 2) with respect to the 
following stratification factors: 
• 
Geographic region (Asia-Pacific vs. western Europe/North America vs. rest of the world) 
• 
Prior (neo)adjuvant taxane (yes vs. no) 
• 
Prior cancer immunotherapy (CIT) in the (neo)adjuvant setting (yes vs. no) 
 
Assessments and Monitoring 
All patients will be closely monitored for adverse events throughout the study, and adverse 
events will be graded according to the NCI CTCAE v5.0.   
Tumor assessments should be performed based on a schedule calculated from Day 1 of 
Cycle 1, with the first assessment performed at Week 8 and approximately every 8 weeks 
thereafter, regardless of treatment administration timing or prior early or late tumor 
assessments.  For estimation of PFS, ORR, DOR, and CBR, 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 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.  As of protocol Version 5, 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.  Such 
tumor tissue will be collected by biopsy, unless not clinically feasible as assessed and 
documented by the investigator, at the time of first evidence of radiographic disease 
progression per RECIST v1.1 (within 40 days after radiographic progression or prior to the start 
of new anti-cancer treatment, whichever is sooner).  These samples will enable analysis of 
tumor tissue biomarkers related to resistance, disease progression, and clinical benefit of the 
study treatments.   
Safety Data Monitoring  
An independent Data Monitoring Committee (iDMC) will evaluate safety data during the study.  
The analysis supporting iDMC review will be conducted by an independent Data Coordinating 
Center (iDCC) and provided to the iDMC.  Sponsor affiliates will be excluded from iDMC 
membership.  The iDMC will follow a charter that outlines the iDMC roles and responsibilities. 
Unblinded safety data will be reviewed by the iDMC on a periodic basis, approximately every 
6 months from the time of the first patient’s enrollment until the time of the primary analysis of 
PFS.  All summaries and analyses for the iDMC review will be prepared by the iDCC.   
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as described 
in the iDMC Charter.  Final decisions will rest with the Sponsor. 


 
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Due to the early termination of the enrollment and unblinding of patients, the iDMC’s review of 
the ongoing safety summary data will be discontinued after the unblinding, and the study team 
will be responsible for the ongoing monitoring of patient safety in the study.  As unblinded data 
will now be available to the study team, aggregate safety data will be reviewed by the study 
team at the regular frequency interval previously defined by the iDMC Charter (approximately 
every 6 months).  These safety reviews are perfomed in addition to the ongoing assessment of 
the incidence, nature, and severity of adverse events; serious adverse events; deaths; and 
laboratory abnormalities. 
Any outcomes of these data reviews that affect study conduct will be communicated in a timely 
manner to the investigators for notification of their respective Institutional Review Boards/Ethics 
Committees. 
Number of Patients 
This study will enroll approximately 1155 patients (approximately 525 patients in Cohort 1 and 
approximately 630 patients in Cohort 2) with advanced TNBC across up to 350 sites globally.  
As of 6 August 2020, further enrollment in Cohort 2 has been terminated.  As of 18 September 
2020, further enrollment in Cohort 1 has been terminated.  
Target Population 
Inclusion Criteria 
Women or men with locally advanced unresectable or metastatic triple-negative 
adenocarcinoma of the breast who have not received prior systemic chemotherapy in this 
setting may be eligible for this study.  In patients with BRCA-associated tumors, platinum 
chemotherapy as potentially the preferred treatment option should be taken into consideration 
when determining whether this study may be appropriate for these patients.  Patients may have 
received prior chemotherapy in the neoadjuvant or adjuvant setting if treatment was completed 
at least 12 months prior to randomization.  Locally advanced unresectable disease must not be 
amenable to resection with curative intent.  Patients must have sufficient tumor tissue 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)  
• 
Women or men, age ≥ 18 years at the time of signing the Informed Consent Form 
• 
Willingness and ability to complete all study-related assessments, including 
PRO assessments, in the investigator’s judgment 
• 
Measurable disease according to RECIST v1.1  
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since radiation. 
• 
Eastern Cooperative Oncology Group (ECOG) 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, as defined by the following: 
− 
Neutrophils (ANC ≥ 1500/µL) 
− 
Hemoglobin ≥ 9 g/dL 
− 
Platelet count ≥ 100,000/µL 
− 
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. 


 
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− 
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 a patient’s value before starting heparin treatment).  
Patients receiving coumarin derivatives should have an INR between 2.0 and 3.0 
assessed in two consecutive measurements performed 1−4 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 hemoglobin A1C ≤ 7.5% 
• 
Life expectancy of at least 6 months 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as described below: 
Women must remain abstinent or use contraceptive methods with a failure rate of < 1% 
per year during the treatment period and for at least 28 days after the final dose of 
ipatasertib/placebo, 5 months after the final dose of atezolizumab/placebo, and 
6 months after the final 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 is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  Per this definition, a woman with a tubal 
ligation is considered to be of childbearing potential.  The definition of childbearing 
potential may be adapted for alignment with local guidelines or regulations. 
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 intrauterine 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 abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods, and agreement to refrain from donating sperm, as defined below: 
With 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 final dose of 
ipatasertib/placebo, or 6 months after the final dose of paclitaxel, whichever occurs later.  
Men must refrain from donating sperm during this same period. 


 
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With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 28 days after the final dose of ipatasertib/placebo or 6 months 
after the final 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 intrauterine 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.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
• 
For 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: 
• 
Appropriate candidate for paclitaxel monotherapy if tumor PD-L1 status is unknown or non-
positive; appropriate candidate for paclitaxel and atezolizumab if tumor PD-L1 status is 
positive 
• 
Histologically documented triple-negative 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 centrally, if not 
available locally) according to the American Society of Clinical Oncology/College of 
American Pathologists 2018 guidelines: 
TNBC is defined as HER2 negative, estrogen receptor (ER) negative, and 
progesterone receptor (PgR) negative. 
ER or PgR positivity is defined as ≥ 1% of tumor cell nuclei immunoreactive to the 
respective hormonal receptor. 
HER2 positivity is defined as one of the following:  3+, as assessed on IHC or 
in situ hybridization positive).   
− 
Submittal of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 
a minimum of 10−15 slides at least (15 slides preferred) containing freshly 
cut unstained, serial tumor slides from the most recently collected tumor tissue (for 
central analysis of PD-L1 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.    
− 
Tumor tissue must be evaluated centrally for PD-L1 expression prior to enrollment.  
Patients will be assigned to the appropriate cohort with a centrally determined PD-L1 
result. 
− 
If multiple tumor specimens are submitted (e.g., an archival specimen and tissue from 
relapsed disease), patients may be eligible if at least one specimen is evaluable for 
PD-L1.  For the purpose of cohort assignment, the PD-L1 score of the patient will be 
the maximum PD-L1 score among the samples. 
If a more recent specimen is either insufficient or unavailable, a patient may still be 
eligible if the patient can provide a tissue block (preferred) or a minimum of 
15 unstained serial slides from an older archival tumor tissue or undergo an additional 
pretreatment core or excisional biopsy of a non-target lesion (a non-target lesion is 


 
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preferred if it is accessible and the biopsy can be safely obtained).  In general, 
a minimum of three core biopsies is required. 
If a patient already has results available from Foundation Medicine, Inc.’s commercial 
tissue-based next-generation sequencing (NGS) assay known as the FoundationOne 
CDx, 10 freshly cut unstained, serial tumor slides from the most recently collected 
tumor tissue are acceptable for central analysis of PD-L1 status and other 
protocol-mandated secondary and exploratory assessments. 
 
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  
• 
Severe infection within 4 weeks prior to initiation of study treatment (including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia) 
as well as those who have received treatment with therapeutic oral or IV antibiotics within 
2 weeks prior to initiation of study treatment are not eligible for the study.  Patients receiving 
prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive 
pulmonary disease exacerbation) are eligible for the study.  Known HIV infection (there 
must be a negative HIV test at screening)  
• 
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.  
• 
Current treatment with anti-viral therapy for HBV 
• 
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 study  
Placement of a vascular access device is not considered major surgery.  
• 
Pregnancy or breastfeeding, or intention to become pregnant during the study or within 
28 days after the final dose of ipatasertib/placebo, 5 months after the final dose of 
atezolizumab/placebo, and 6 months after the final 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 through use Fridericia's 
formula (QTcF) > 480 ms  
• 
Current treatment with medications used at doses known to cause clinically relevant 
prolongation of QT/QTc interval  
• 
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) 


 
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• 
Requirement for chronic corticosteroid therapy of > 10 mg of prednisone per day 
or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressant 
agents for a chronic disease  
No chronic corticosteroid use is permitted at baseline with rare exceptions.  Refer to the 
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 renders 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 spinal cord metastases, as determined by computed 
tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or prior 
radiographic assessments 
• 
Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the 
following criteria are met: 
– 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord) 
– 
No ongoing requirement for corticosteroids as therapy for CNS disease 
– 
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization 
– 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
– 
Note: Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional brain 
scan prior to enrollment, if all other criteria are met. 
Patients with leptomeningeal carcinomatosis will be excluded. 
• 
Known germline BRCA1/2 deleterious mutation, unless the patient is not an appropriate 
candidate for a PARP-inhibitor  
• 
Any previous systemic therapy for inoperable locally advanced or metastatic triple-negative 
adenocarcinoma of the breast 
Patients may have received prior neoadjuvant and/or adjuvant chemotherapy, prior 
neoadjuvant and/or adjuvant CIT, and/or radiotherapy for breast adenocarcinoma, 
provided all chemotherapy and CIT were completed ≥ 12 months prior to randomization. 
The 12-month treatment-free minimum interval in these cases begins with the last 
administration of chemotherapy in the early breast cancer setting and is not meant to 
encompass HER2-targeted therapy, such as trastuzumab, ado-trastuzumab emtansine, 
pertuzumab, neratinib, or endocrine therapies.  
Previous systemic therapies for TNBC include, but are not limited to, chemotherapy, 
immune checkpoint inhibitors, or targeted agents. 
• 
Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 
peripheral neuropathy  


 
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• 
Patients who have received palliative radiotherapy 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 radiotherapy. 
− 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 (i.e., > 1.5 mmol/L ionized calcium, > 12 mg/dL calcium, or 
corrected serum calcium greater than 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 
 
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 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:  Prior treatment with PI3K or mTOR inhibitors is allowed. 
 


 
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Atezolizumab-Specific Exclusion Criteria  
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 syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
Patients with a history of autoimmune-mediated 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: 
− 
Rash must cover < 10% of body surface area. 
− 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
− 
There has been 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 final 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-α agents) within 2 weeks prior to initiation of study treatment, or anticipation 
of need for systemic immunosuppressive medication during 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. 
In addition, the Sponsor may decide to terminate the study at any time. 


 
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Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2-3 years.  
Investigational Medicinal Products 
Test Products (Investigational Drugs) 
The investigational medicinal products for this study are ipatasertib, matching ipatasertib 
placebo, atezolizumab, matching atezolizumab placebo, and paclitaxel.   
Ipatasertib and Placebo 
Patients will be randomly assigned to a treatment arm through the IxRS.  Ipatasertib/placebo 
will be administered at the starting dosage of 400 mg PO QD, beginning at 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 ipatasertib/placebo prior to the IV infusions 
of paclitaxel and atezolizumab/placebo. 
Following unblinding of treatment assignments, placebo for ipatasertib will no longer be 
administered to patients in Arm B of Cohort 2 and to patients in Arm C of Cohort 1.  
Atezolizumab and Placebo 
Atezolizumab/placebo will be administered to patients by IV infusion at a fixed dose of 840 mg 
on Days 1 and 15 of each 28-day cycle until the patient experiences disease progression, 
intolerable  toxicity orwithdraws consent.  Although a ± 1-day window is permitted for 
atezolizumab/placebo administration, it is discouraged to dose on days other than on Day 1 
or 15 because of the risk that atezolizumab doses may fall too close together. 
Following unblinding of treatment assignments, placebo for atezolizumab will no longer be 
administered to patients in Arm B and Arm C of Cohort 1. 
Paclitaxel  
The dose of paclitaxel in this study is 80 mg/m2 administered to patients by IV infusion on 
Days 1, 8, and 15 of each 28-day cycle.   
 
Non-Investigational Medicinal Products 
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.  Ranitidine and famotidine are 
recommended H2-receptor blockers for prophylactic treatment of paclitaxel infusion-related 
reactions.  However, in cases when ranitidine and famotidine are not available, cimetidine may 
be used with caution.  Cimetidine is a moderate CYP3A inhibitor, which can increase the 
exposure of ipatasertib up to approximately 2-fold.  It can take up to 3 days for ipatasertib 
concentration to return to typical steady state levels.  
Only applicable while the patient is receiving ipatasertib: 
• 
For visits without PK sample collection, intravenous cimetidine can be administered 
irrespective of timing with the oral dose of ipatasertib.  For visits that include PK sample 
collection, intravenous cimetidine can be administered after ipatasertib sampling is 
complete or 2 hours after ipatasertib dosing, whichever is later.  
• 
For sites needing use of oral cimetidine, cimetidine should be administered at least 2 hours 
after ipatasertib or after completion of PK sampling, whichever is later. 
Diarrhea is a common adverse event associated with ipatasertib and/or paclitaxel treatment.  
In this study, to improve diarrhea management and patient burden, loperamide (racecadotril as 
used in Europe) will be administered to patients daily as prophylaxis for diarrhea.  Prophylactic 
use is mandated in the first cycle (if allowed by local guidance), 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.  The Medical Monitor is 
available to advise as needed.   
Patients should be educated/reminded to be cognizant of the onset, duration, severity, and 
frequency of symptoms and the medications administered.  If side effects of loperamide are not 


 
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tolerated, doses may be reduced (or if necessary, discontinued) at any time.  Investigators are 
encouraged to continue prophylactic- and/or treatment-dose loperamide for the remainder of the 
study at their discretion based on clinical judgment. 
Owing to the risk of rash in Cycle 1, patients should receive the following prophylaxis during the 
first cycle when all three study treatments will be given: 
• 
Unless contraindicated, daily PO antihistamine prophylaxis should be used for at least the 
first cycle.  It is suggested that a non-sedating longer-acting oral antihistamine be used 
(such as 10 mg of cetirizine PO QD or comparable dose of other antihistamines, 
e.g., loratadine, fexofenadine).  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. 
• 
On days when patients will receive atezolizumab/placebo (typically, Days 1 and 15), 
patients should receive at least 10 mg/day of 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 of prednisone on the day of paclitaxel, then the additional 10 mg of prophylactic 
prednisone should not be given on that day to prevent rash.  If the investigator determines 
that administration of the steroid immediately prior to paclitaxel, rather than prior to 
atezolizumab/placebo, is more appropriate, this is acceptable.  
 
As of protocol Versions 4 and 5, rash and antidiarrheal prophylaxis is no longer applicable to 
patients in Arm C of Cohort 1 and Arm B of Cohort 2. 
Statistical Methods 
As of protocol Versions 4 and 5, statistical considerations and the analyses outlined in Section 6 
are no longer applicable to the study as indicated in the respective sections.  Due to the early 
termination of the enrollment, data from enrolled patients will only be summarized descriptively 
for endpoints that are deemed appropriate and necessary (e.g., demographics, disposition, and 
adverse events). 
Efficacy analyses will be performed independently for each cohort.  All efficacy analyses will be 
based on the intent-to-treat population within each cohort according to the treatment arm to 
which patients are allocated.  The analysis of DOR will include all patients with an objective 
response. 
All primary and exploratory endpoints based on tumor burden will be based on radiological 
(or photographic, if applicable) assessments by the local radiologist or investigator, unless 
otherwise specified. 
Primary Analysis 
The co-primary efficacy endpoints are investigator-assessed PFS and OS. 
Investigator-assessed PFS, defined as the time from randomization to the first occurrence of 
disease progression, as determined locally by the investigator using RECIST v1.1, or death 
from any cause, whichever occurs first.  Data for patients without the occurrence of disease 
progression or death as of the clinical data cutoff date will be censored at the time of the last 
tumor assessment (or at the time of randomization plus 1 day if no tumor assessment was 
performed after the baseline visit). 
OS is defined as the time from randomization to death from any cause.  Data for patients who 
have not died as of the clinical data cutoff date will be censored at the last date they are known 
to be alive.  Data for patients who do not have postbaseline information will be censored at the 
randomization plus 1 day. 
Both PFS and OS 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.  For each treatment arm, Kaplan-Meier methodology will be used to estimate the 
median PFS and OS, and the Brookmeyer-Crowley method will be used to construct the 95% CI 


 
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for the median PFS and OS (Brookmeyer and Crowley 1982).  Kaplan-Meier curves will be 
produced as well. 
Determination of Sample Size   
Type I Error Control 
Cohort 1 (patients with PD-L1−non-positive tumors) and Cohort 2 (patients with PD-L1 positive 
tumors) are two independent cohorts and will be analyzed separately for all endpoints unless 
otherwise specified.  Each cohort will be tested independently with an overall 5% type I error 
control.  
For Cohort 1, the overall type I error (α) is 0.05 (two sided) and is split among the co-primary 
efficacy endpoints 0.01 for PFS for Arm A versus Arm C, 0.01 for PFS for Arm B versus Arm C, 
and 0.03 for OS.  PFS for Arm A versus Arm C and Arm B versus Arm C will be tested 
independently, whereas OS will be tested in a hierarchical sequence of Arm A versus Arm C 
followed by Arm B versus Arm C.  The PFS data will mature earlier and PFS will be firstly tested 
with α of 0.01 for Arm A versus Arm C and 0.01 for Arm B versus Arm C.  When a PFS test is 
passed at an α level of 0.01, that 0.01 α assigned will be recycled to OS (i.e., OS will be tested 
at the significance level of 0.05 [if both PFS tests are passed] or 0.04 [if only one PFS test is 
passed]; otherwise, OS will be tested at the significance level of 0. 03[when neither PFS tests is 
passed] to control the overall type I error at 0.05). 
For Cohort 2, the overall type I error (α) is 0.05 (two sided) and is split between the two co-
primary efficacy endpoints PFS and OS.  The PFS data will mature earlier and PFS will be firstly 
tested with α of 0.01.  If the PFS test is passed at the significance level of 0.01, the 0.01 α 
assigned to PFS will be recycled to OS (i.e., OS will be tested at the significance level of 0.05; 
otherwise, OS will be tested at the significance level of 0.04 to control the overall type I error at 
0.05).  
Sample Size Consideration for Cohort 1 
The following statistical considerations were applicable prior to the termination of enrollment on 
18 September 2020 and subsequent unblinding of Cohort 1 on 21 September 2020.  At that 
time, a total of 127 patients had been enrolled in Cohort 1. 
Approximately 525 patients will be enrolled and randomized in a 1:1:1 ratio to Arm A (ipatasertib 
plus atezolizumab plus paclitaxel), Arm B (ipatasertib plus paclitaxel plus placebo) and Arm C 
(paclitaxel plus placebo plus placebo).  The sample size is determined by the co-primary 
endpoints: PFS comparing Arm A versus Arm C, PFS comparing Arm B versus Arm C, and OS 
comparing Arm A versus Arm C. 
The primary analysis of PFS will be conducted when approximately 239 PFS events from all 
three arms (including approximately 171 PFS events for the comparison of Arm B versus Arm C 
and approximately 166 PFS events for the comparison of Arm A vs. Arm C) are observed or 
when the last patient has been randomized, whichever occurs later.   
With 172 PFS events for the comparison of Arm B versus Arm C, this allows for 80% power to 
detect an improvement in median PFS from 5.6 months to approximately 9.4 months (hazard 
ratio = 0.593) at the 1% level of significance (two sided).  The largest hazard ratio deemed to be 
statistically significant at the 1% level will be approximately 0.675 (with median improvement in 
PFS from 5.6 to 8.3 months).  With 166 PFS events for the comparison of Arm A vs. C, this 
allows for 94% power to detect an improvement in median PFS from 5.6 months to 
approximately 10.6 months (hazard ratio = 0.528) at the 1% level of significance (two sided).  
The largest hazard ratio deemed to be statistically significant at the 1% level will be 
approximately 0.670 (with median improvement in PFS from 5.6 to 8.4 months). 
If the 0.02 α assigned to PFS is recycled, the co-primary endpoint, OS, will be tested at the 5% 
level of significance (two sided).  The final OS analysis will be conducted when approximately 
216 OS events for the comparison of Arm A vs. Arm C) are observed.  With α spending to the 
interim analyses of OS, at the OS final analysis, 216 OS events for the comparison of Arm A vs. 
Arm C will allow for 80% power to detect an improvement in median OS from 18.4 to 27.1 
months (hazard ratio = 0.680) at the 5% level of significance (two sided).  The largest OS hazard 
ratio deemed to be statistically significant will be approximately 0.759 (with median OS 
improvement from 18.4 to 24.2 months). 
If the 0.02 α assigned to PFS is not recycled or only 0.01 α is recycled, the co-primary endpoint, 
OS, will be tested at the 3% or 4% level of significance (two sided), respectively.  The final OS 


 
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analysis timing and the require number of OS events will be adjusted accordingly to allow 80% 
power to detect an improvement in median OS from 18.4 to 27.1 months (hazard ratio = 0.680) 
at the 3% or 4% level of significance (two sided).  Further details will be provided in the 
Statistical Analysis Plan. 
The enrollment duration is projected to be approximately 22 months (from the first patient 
randomized).  For all three arms, an annual loss to follow-up rate of 5% and 2% are assumed 
for PFS and OS, respectively.  Based on these, it is projected that the primary PFS analysis will 
occur when the last patient is randomized, and the final OS analysis is projected to occur 
approximately 49 months after the first patient is enrolled, if the 0.02 α assigned to PFS is 
recycled for OS. 
Sample Size Consideration for Cohort 2 
The following statistical considerations were applicable prior to the termination of enrollment on 
6 August 2020 and subsequent unblinding of Cohort 2 on 7 August 2020.  At that time, a total of 
115 patients had been enrolled in Cohort 2. 
Approximately 630 patients will be enrolled and randomized in a 1:1 ratio to Arm A (ipatasertib 
plus atezolizumab plus paclitaxel) and Arm B (atezolizumab plus paclitaxel plus placebo).  
The primary analysis of PFS will be conducted when approximately 228 PFS events are 
observed or when the last patient has been randomized, whichever occurs later.  Based on the 
enrollment assumption, it is most likely driven by the last patient’s randomization. 
With 228 PFS events, this allows for 80% power to detect an improvement in median PFS from 
7.5 to approximately 11.8 months (hazard ratio = 0.636) at the 1% level of significance (two 
sided).  The largest hazard ratio deemed to be statistically significant at the 1% level will be 
approximately 0.711 (with median improvement in PFS from 7.5 to 10.5 months). 
If the 0.01 α assigned to PFS is recycled, the co-primary endpoint, OS, will be tested at the 5% 
level of significance (two sided).  The final OS analysis will be conducted when approximately 
417 OS events are observed.  With α spending to the interim analyses of OS (see details in 
Section 6.9.2.2), at the OS final analysis, it will allow for 80% power to detect a hazard ratio of 
0.758 (median OS improvement from 25 to 33 months) at the 5% level of significance (two 
sided).  The largest OS hazard ratio deemed to be statistically significant will be approximately 
0.820 (with median OS improvement from 25 to 30.5 months). 
If the 0.01 α assigned to PFS is not recycled, the co-primary endpoint, OS, will be tested at the 
4% level of significance (two sided).  The final OS analysis will be conducted when 
approximately 444 OS events are observed.  With α spending to the interim analyses of OS, at 
the OS final analysis, it will allow for 80% power to detect a hazard ratio of 0.758 (median OS 
improvement from 25 to 33 months) at the 4% level of significance (two sided).  The largest OS 
hazard ratio deemed to be statistically significant will be approximately 0.818 (with median OS 
improvement from 25 to 30.6 months). 
The enrollment duration is projected to be approximately 36 months (from the first patient 
randomized).  For both arms, an annual loss to follow-up rate of 5% and 2% are assumed for 
PFS and OS, respectively.  Based on these, it is projected that the primary PFS analysis will 
occur when the last patient is randomized, and it is predicted that there will be approximately 
372 PFS events.  With 372 PFS events, the largest hazard ratio deemed to be statistically 
significant at the 1% level will be approximately 0.766 (with median PFS improvement from 
7.5 to 9.8 months).  The final OS analysis is projected to occur approximately 70 months after 
the first patient is enrolled, if the 0.01 α assigned to PFS is recycled for OS. 
Interim Analyses 
Planned Interim Safety Analysis 
An external iDMC will be formed to evaluate safety data in Cohorts 1 and 2 on a periodic basis, 
approximately every 6 months from the time of the first patient’s enrollment until the time of the 
primary analysis of PFS for both cohorts are complete.  All summaries/analyses by treatment 
arm for the iDMC's review will be prepared by an external iDCC for each cohort.  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. 


 
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In the absence of extenuating circumstances, accrual will not be halted while the interim 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.  The final decision will rest with the Sponsor.  In addition, the Sponsor 
may request ad-hoc meetings of the iDMC at any time during the study to review ongoing safety 
summary data. 
Due to the early termination of enrollment and unblinding of patients, the iDMC’s review of the 
ongoing safety summary data will be terminated after the unblinding.  The study team will be 
responsible for the ongoing monitoring of patient safety in the study. 
Planned Interim OS Analysis for Cohort 1 
The following statistical considerations were applicable prior to the early termination of 
enrollment on 18 September 2020 and subsequent unblinding of Cohort 1 on 21 September 
2020, and they are not appliacable as of protocol V5. 
There are two planned OS interim analyses for the comparisons across the three treatment 
arms.  The first OS interim analysis will be performed at the time of PFS analysis.  The second 
OS interim analysis will be performed when around 80% of the OS events required for the final 
OS analysis for the comparison of Arm A versus Arm C is reached.  OS will be tested in 
a hierarchical testing sequence of Arm A versus Arm C followed by Arm B versus Arm C, and 
the Lan-DeMets α-spending function with an O’Brien-Fleming boundary will be used to control 
the type I error accounting for the interim and final analyses of OS.  The comparison of Arm A 
versus Arm B will be conducted for descriptive purposes only with no type I error control.  
If the 0.02 α assigned to PFS is recycled, the final OS will be analyzed when 216 OS events for 
the comparison of Arm A vs. Arm C occur at approximately 49 months after the first patient has 
been enrolled.  It is estimated that there will be approximately (76, 176, 216) OS events at the 
first interim, the second interim, and the final OS analyses for the comparison of Arm A versus 
Arm C, with corresponding p-value boundaries of (0.0003, 0.0259, 0.0424) and hazard ratio 
boundaries of (0.438, 0.715, 0.759) at the first interim, the second interim, and the final OS 
analysis for the comparison of Arm A versus Arm C, respectively.  The actual boundaries will be 
adjusted according to the actual information fractions at the interim analyses using the 
Lan-DeMets α−spending function with an O’Brien-Fleming boundary. 
If the 0.02 α assigned to PFS is not recycled or only 0.01 α is recycled, the final OS analysis for 
timing, the required number of OS events, the p-value, and the hazard ratio boundaries for the 
interim and final analyses will be adjusted accordingly.  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.  
At the time of each OS analysis, OS test comparing Arm B versus Arm C will be formally 
performed only if the OS test comparing Arm A versus Arm C is passed with statistical 
significance; otherwise, OS test for Arm B versus C will be descriptive only.  When comparison 
of Arm B versus Arm C is formally tested, the same p-value and hazard ratio boundaries used 
by Arm A versus Arm C comparison will be used, so that the overall type I error of 5% is 
controlled.  The OS test for Arm A versus Arm B will be performed descriptively only.  Further 
details will be provided in the Statistical Analysis Plan. 
Planned Interim OS Analysis for Cohort 2 
The following statistical considerations were applicable prior to the termination of enrollment on 
6 August 2020 and subsequent unblinding of Cohort 2 on 7 August 2020, and they are not 
applicable as of protocol Version 4. 
There are two planned OS interim analyses for the comparisons between the two treatment 
arms.  The first OS interim analysis will be performed at the time of PFS analysis.  The second 
OS interim analysis will be performed when 80% of the OS events required for the final OS 
analysis is reached.  The Lan-DeMets α-spending function with an O’Brien-Fleming boundary 
will be used to control the type I error accounting for the interim and final analyses of OS.  
If the 0.01 α assigned to PFS is recycled, the final OS will be analyzed when 417 OS events 
occur at approximately 70 months after the first patient has been enrolled.  It is estimated that 
there will be approximately (184, 334, 417) OS events at the first interim, the second interim and 
the final OS analyses, with corresponding p-value boundaries of (0.0015, 0.0204, 0.0427) and 


 
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corresponding hazard ratio boundaries of (0.626, 0.781, 0.820) at the first interim, the second 
interim, and the final OS analysis, respectively.  The actual boundaries will be adjusted 
according to the actual information fractions at the interim analyses using the Lan-DeMets 
α-spending function with an O’Brien-Fleming boundary. 
If the 0.01 α assigned to PFS is not recycled, the final OS will be analyzed when 444 OS events 
occur at approximately 76 months after the last patient has been enrolled.  It is estimated that 
there will be approximately (184, 355, 444) OS events at the first interim, the second interim and 
the final OS analysis, with corresponding p-value boundaries of (0.0006, 0.0183, 0.0345) and 
corresponding hazard ratio boundaries of (0.603, 0.779, 0.818) at the first interim, the second 
interim, and the final OS analysis, respectively.   
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ASCO 
American Society of Clinical Oncology  
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CI 
confidence interval 
CIT 
cancer immunotherapy 
CLIA 
Clinical Laboratory Improvement Amendments 
COVID-19 
coronavirus 2019 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
ctDNA 
circulating-tumor DNA 
CYP 
cytochrome P  
DOR 
duration of response 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30  
EQ-5D-5L 
EuroQol 5 Dimension Questionnaire, 5-Level Version 
ER 
estrogen receptor 
Fc 
fragment crystallizable  
FDA 
(U.S.) Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded  
FMI 
Foundation Medicine, Inc.  
FNA 
fine-needle aspiration  
GHS 
global health status 
HbA1C 
hemoglobin A1C 
HBcAb 
hepatitis B core antibody 
HBsAG 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor 2 
HIPAA 
Health Insurance Portability and Accountability Act 


 
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Abbreviation 
Definition 
HR 
hormone receptor 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
iDCC 
independent Data Coordinating Center  
iDMC 
independent Data Monitoring Committee 
IFN 
interferon 
IL 
interleukin 
IRR 
infusion-related reaction 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE, v5 
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5 
NGS 
next-generation sequencing  
NMPA 
National Medical Products Administration  
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD-1 
programmed death receptor−1 
PD-L1 
programmed death-ligand−1 
PFS 
progression-free survival 
PgR 
progesterone receptor  
PIK3CA 
phosphatidylinositol-4, 5−bisphosphate 3-kinase, 
catalytic subunit, alpha 
PK 
pharmacokinetic 
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  
Q2W 
every 2 weeks 


 
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Abbreviation 
Definition 
Q3W 
every 3 weeks 
QoL 
quality of life 
QW 
once a week 
QLQ-C30 
Quality of Life Questionnaire for Cancer 
RBR 
Research Biosample Repository 
QTcF 
QT interval corrected through use of 
Fridericia’s formula 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SITC 
Society for Immunotherapy of Cancer 
TNF-α 
tumor necrosis factor−α  
WES 
whole exome sequencing  
WGS 
whole genome sequencing 
ULN 
upper limit of normal 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON TRIPLE-NEGATIVE 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 HER2 expression per the 
American Society of Clinical Oncology (ASCO) and College of American Pathologists 
(CAP) guidelines (ASCO/CAP 2010, 2013, 2018).  Patients with metastatic TNBC exhibit 
a particularly poor clinical outcome, generally with rapid progression and a median 
overall survival (OS) of approximately 16 months in a diagnostically unselected 
population (Rodler et al. 2010; Miles et al. 2013) and up to approximately 25 months in 
patients with tumors expressing PD-L1 (Schmid et al. 2018b).  The TNBC phenotype 
has been associated with black race, younger age, and more advanced tumor stage at 
presentation (Millikan et al. 2008; Lund et al. 2009; Trivers et al. 2009; Lin et al. 2012; 
Danforth 2013).  Although TNBC may respond to chemotherapy, including taxanes, 
there are no approved first-line regimens or targeted therapies for an all-comer 
population.  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; National Comprehensive Cancer Network 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, 2017).  There is 
a pressing need for clinically active agents for the treatment of triple-negative subtype of 
metastatic breast cancer. 
The 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).  


 
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Large-scale comprehensive genomic analyses have characterized the heterogeneous 
nature of TNBC, including a subgroup of patients 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 hormone receptor (HR)-positive and 
HER2-negative 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 indicating 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, 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 and mitotic 
stress (Xu et al. 2012).  Activation of Akt signaling following chemotherapy (including 
taxanes) may promote cell survival and chemoresistance across several cancer models, 
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-positive and 
HER2-negative tumors (Cancer Genome Atlas Network 2012), clinical trials evaluating 


 
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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 
(PAM4983g; Arm C), with an expansion cohort of patients with HER2-negative breast 
cancer, and a Phase II randomized study (GO29227; LOTUS) comparing ipatasertib plus 
paclitaxel versus placebo plus 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-positive patients/HER2-negative patients: 
n = 2; TNBC: n = 1), and 4 partial responses included patients who had prior exposure to 
paclitaxel or investigational PI3K inhibitors (HR-positive patients/HER2-negative 
patients: n = 2; TNBC: n = 2). 
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 intent-to-treat (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.  This study showed improvement in median 
PFS in the ITT population (hazard ratio:  0.60; 6.2 months in the ipatasertib arm 
compared with 4.9 months in the control arm), and in the prespecified patient population 
with PIK3CA/AKT1/PTEN-altered tumors (hazard ratio: 0.44; 9 vs. 4.9 months).   
The ongoing Phase III, randomized, double-blind, placebo-controlled study CO40016 
(IPATunity130) uses an identical treatment assignment for first-line therapy for patients 
with inoperable locally advanced or metastatic TNBC with PIK3CA/AKT1/PTEN-altered 
tumors and was designed to confirm the results seen in the preplanned efficacy analysis 
in the GO29227 study population with PIK3CA/AKT1/PTEN-altered tumors.  The primary 
endpoint for Cohort A of the IPATunity130 study was not met: ipatasertib in combination 
with paclitaxel did not significantly reduce the risk of investigator-assessed PFS events 
compared with paclitaxel alone in patients with mTNBC who have PIK3CA/AKT/PTEN 
alterations.  The primary analysis results for Cohort A show that the safety profile of 
ipatasertib in combination with paclitaxel was consistent with the known risks of each 
individual study drug and no new safety signal was identified. 
In addition, the clinical safety profile of ipatasertib has been evaluated in multiple clinical 
trials 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.  As a single 
agent, ipatasertib has a predictable pharmacokinetic (PK) profile, with a half-life of 


 
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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 experience 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, decreased 
neutrophil count, 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 events.  The onset of diarrhea was 
most common during the first cycle of treatment; 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 
(3%) discontinuation of ipatasertib treatment because of 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. 
Because of the high incidence of diarrhea seen in Study GO29227, loperamide 
prophylaxis has been implemented in the Phase III study CO40016.  The primary 
analysis results for Cohort A of study CO40016, show that the safety profile of 
ipatasertib in combination with paclitaxel was consistent with the known risks of each 
individual study drug and no new safety signal was identified. 
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and 
clinical studies. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 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 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to fragment crystallizable (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.  


 
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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). 
The safety findings of single-agent atezolizumab across multiple tumor types in the 
clinical development program are consistent with the known mechanism of action of 
atezolizumab and the underlying disease.  Currently, no maximum tolerated dose, no 
dose-limiting toxicities, and no clear dose-related trends related to the incidence of 
adverse events have been observed.  
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.  .   
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. 2018a). 
No new safety signals were identified.  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. 2018a). 


 
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Also in metastatic TNBC, the Phase III IMpassion131 (MO39196) study (clinical cutoff 
date of 15 November 2019; data as of 29 July 2020) did not meet its primary endpoint of 
investigator-assessed PFS in the PD-L1−positive population.  At the primary analysis, 
atezolizumab plus paclitaxel did not significantly reduce the risk of investigator-assessed 
PFS events compared with placebo plus paclitaxel in this population.  Safety of 
atezolizumab in combination with paclitaxel appeared consistent with the known safety 
profiles of the individual medicines.  The combination was generally well-tolerated and 
toxicities were manageable.  No new safety signal was identified.  
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 
There are at present four ongoing Roche-sponsored studies with study treatments that 
include combinations of ipatasertib and atezolizumab in advanced breast cancer.  
Studies CO40115 and CO39611 are studies within a Phase Ib/II, open-label, multicenter, 
randomized umbrella study, evaluating the safety and efficacy of immunotherapy-based 
treatment combinations in patients with unresectable locally advanced or metastatic 
TNBC and HR-positive and HER2-negative breast cancer, respectively.  Both studies 
have an experimental arm with ipatasertib in combination with atezolizumab at the same 
dose and schedule used in this study, without chemotherapy.  Study CO40115 has 
enrolled 22 patients in the second-line setting in unresectable locally advanced or 
metastatic TNBC.  Study CO39611 has enrolled 15 patients in the second- and third-line 
settings for HR-positive and HER2-negative unresectable locally advanced or metastatic 
breast cancer, after progression with CDK4/6 inhibitors.  Internal and external safety 
monitoring are being performed for this study, and to date, safety evaluations have been 
conducted for 6 patients in each study.  Based on a safety analysis of data from the 
6 patients in each study, no new safety signals were identified. 
The Phase Ib study CO40151 is 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 (all-comer) advanced TNBC in the first-line 
setting.  As of the clinical cutoff date of 5 January 2019, a safety and efficacy analysis 
had been completed of the data from the first 26 patients enrolled after a median 
6.1 months in the study (18 patients treated with paclitaxel + ipatasertib + atezolizumab; 
8 patients treated with nab-paclitaxel + ipatasertib + atezolizumab) in Cohort 1 and 
enrollment is ongoing.  To date, more than 100 patients have been treated in this study, 
and more than 200 patients are anticipated to have been treated by the completion of 
the study.  The preliminary but promising response rate of > 70% (Schmid et al. 2019) 
does not seem to be dependent on tumor PIK3CA/AKT1/PTEN alterations or PD-L1 
expression.  In the safety analysis, no Grade 4 or 5 adverse events were reported and 
Grade 3 events occurred in 53.8% of patients.  Serious adverse events occurred in 


 
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46.2% of patients.  In all, 19.2% of patients discontinued any of the three individual study 
drugs because of an adverse event, but no patient discontinued study treatment 
altogether because of an adverse event.  The preliminary efficacy and tolerability of the 
combination suggest that this is a promising treatment regimen for further development 
(Schmid et al. 2019).  
Study CO40016 is a Phase III study for patients with PIK3CA/AKT1/PTEN-altered 
positive locally advanced or metastatic TNBC or HR-positive HER2-negative breast 
cancer, with the primary objective of evaluating the efficacy of the combination of 
ipatasertib and paclitaxel compared with paclitaxel.  One open-label single-treatment 
assignment cohort in this study will evaluate the combination of ipatasertib with 
atezolizumab and paclitaxel in up to approximately 100 patients with 
PIK3CA/AKT1/PTEN-altered negative locally advanced or metastatic TNBC.   
Across these studies, more than 200 patients have been treated to date with ipatasertib 
and atezolizumab in combination, with no new safety signals reported.   
1.5 
STUDY RATIONALE AND BENEFIT−RISK ASSESSMENT 
Metastatic breast cancer remains an incurable disease.  For patients with locally 
advanced unresectable and metastatic TNBC, clinical outcome for some patients has 
improved with the incorporation of atezolizumab (Schmid et al. 2018a), although the 
prospect for long-term survival remains disappointingly low.  As the biomarker-based 
segmentation of patient populations becomes more common, there are expected to be 
increasing challenges of appropriate treatment selection.  Identification of an effective 
therapeutic approach that is broadly applicable is desirable.  Study CO41101 continues 
the work of multiple Phase Ib−III clinical trials that have taken the approach of building 
on a taxane backbone with ipatasertib, atezolizumab, or the combination of the two.   
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 
identifying and targeting T-cell co-inhibitory surface receptors, such as cytotoxic 
T lymphocyte−associated protein 4 (CTLA-4) and PD-L1/PD-1.  Although CIT has 
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 
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reduced efficacy of anti−PD-1 therapy in patients with melanoma.  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.   
As noted previously, the Phase III IMpassion130 (WO29522) study met its co-primary 
endpoint investigator-assessed PFS in the ITT population and PD-L1−positive 
population.  The co-primary endpoint, OS, did not cross the interim boundary in 
ITT population.  However, the magnitude of OS benefit in PD-L1−positive population is 
clinically meaningful.  
Multiple ongoing open-label studies are evaluating the combination of ipatasertib with 
atezolizumab showing no new safety concerns.  In particular, the ongoing Phase Ib 
study CO40151, evaluating ipatasertib in combination with atezolizumab and either 
paclitaxel or nab-paclitaxel, shows promising preliminary clinical efficacy with generally 
tolerable safety profile of the triplet treatment regimen in first-line locally advanced or 
metastatic TNBC.  Because of the high incidence of rash and diarrhea observed in 
Study CO40151, the current study will take a preventative approach to the most 
common adverse events affecting patient experience, as outlined in Section 5.1. 
On the basis of the data available to date, the benefit−risk assessment for administration 
of ipatasertib in combination with atezolizumab and paclitaxel is considered positive in 
patients with locally advanced unresectable or metastatic TNBC. 
This Study CO41101 is designed to evaluate the efficacy of ipatasertib plus 
atezolizumab plus paclitaxel against an appropriate control arm treatment in two 
independent PD-L1 status-driven cohorts (Cohort 1, PD-L1 non−positive and Cohort 2 
PD-L1−positive; see Section Section 3.1.1).  Based on results from the primary analysis 
of the Phase III IMpassion131 (MO39196) study (see Section 1.3), the control arm for 
Cohort 2 of this study (atezolizumab plus paclitaxel plus placebo for ipatasertib) is no 
longer considered appropriate.  As of 6 August 2020, further enrollment in Cohort 2 has 
been suspended and all patients in Cohort 2 have been unblinded to their treatment 
assignment to allow the patients to make informed decisions in consultation with their 
investigators regarding their treatment options.   


 
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Based on results from the primary analysis of the Phase III IPATunity130 (CO40016) 
study (see Section 1.2 ), Arm B for Cohort 1 of this study (ipatsertib plus paclitaxel plus 
placebo for atezolizumab) is no longer considered appropriate.  As of 18 September 
2020, further enrollment in Cohort 1 has been terminated, and all patients in Cohort 1 
have been unblinded to their treatment assignment on 21 September 2020 to allow the 
patients to make informed decisions in consultation with their investigators regarding 
their treatment options. 
Covid-19 Benefit–Risk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear 
whether or how systemic cancer therapies, such as chemotherapy, targeted therapy, or 
immunotherapy, impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation 
of the host immune response to acute infection, which may result in immunopathology 
or dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent 
clinical data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release syndrome 
(CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)-γ (Merad and Martin 2020).  While it is not known, there may be 
a potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving atezolizumab.  At this time, there 
is insufficient evidence for causal association between atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2−related interstitial pneumonia.  Thus, investigators should 
use their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy. 


 
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Given the mechanism of action for ipatasertib, atezolizumab and paclitaxel, 
immune-mediated adverse events are potential overlapping toxicities associated with 
combination use of these agents.There are limited data concerning the possible 
interactions between cancer immunotherapy treatment and COVID-19 vaccination, and 
it is recognized that human immune responses are highly regulated and that 
immune-modifying therapies may positively or negatively impact the efficacy and safety 
of COVID-19 vaccination (Society for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19 
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.   
SITC and NCCN recommendations along with institutional guidelines should be used 
by the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1).  
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of ipatasertib in 
combination with atezolizumab and paclitaxel in locally advanced unresectable or 
metastatic TNBC previously untreated in this setting.  Patients with PD-L1−non-positive 
and PD-L1−positive tumors will be independently enrolled in Cohorts 1 and 2, 
respectively.  The combination of ipatasertib, atezolizumab, and paclitaxel will be 
evaluated in two independently enrolled cohorts (Cohorts 1 and 2) and the combination 
of ipatasertib and paclitaxel will be evaluated in Cohort 1.   
Specific objectives and corresponding endpoints are outlined in the following sections.  


 
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In this protocol, "study treatment" refers to the combination of treatments assigned to 
any individual patient as part of this study (e.g., ipatasertib/placebo [for ipatasertib], 
atezolizumab/placebo [for atezolizumab], and paclitaxel). 
As of protocol Version 5, the following objectives and the corresponding statistical 
considerations and analyses will no longer be applicable to the study.  Due to the early 
termination of the enrollment, data from enrolled patients will only be summarized 
descriptively for endpoints that are deemed appropriate and necessary (see Section 6 
for details). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to independently evaluate the efficacy of 
the experimental arm treatment compared with control arm treatment in each cohort (i.e., 
Arm A vs. Arm C and Arm B vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2; for 
a description of each arm see Figure 1 and Section 3.1.1), on the basis of the following 
co-primary endpoints: 
• 
Investigator-assessed progression-free survival (PFS) after randomization, defined 
as the time from randomization to the first occurrence of disease progression, as 
determined locally according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first 
• 
Overall survival (OS) after randomization, defined as the time from randomization to 
death from any cause 
 
2.1.2 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are as follows:  
• 
To independently evaluate the efficacy of experimental arm treatment compared 
with control arm treatment in each cohort (i.e., Arm A vs. Arm C and Arm B vs. 
Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2), on the basis of the following 
endpoints: 
– Objective response rate (ORR), defined as the proportion of patients with 
a complete response (CR) or partial response (PR) on two consecutive 
occasions ≥ 4 weeks apart, as determined by the investigator according to 
RECIST v1.1 
– Duration of response (DOR), defined as the time from the first occurrence of 
a documented objective response to the first occurrence of disease progression, 
as determined by the investigator according to RECIST v1.1, or death from any 
cause, whichever occurs first  
– Clinical benefit rate (CBR), defined as the proportion of patients who have a CR, 
PR, or stable disease for ≥24 weeks, as determined by the investigator according 
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• 
To evaluate patient-reported outcomes (PROs) of function (role, physical), global 
health status (GHS)/quality of life (QoL) associated with the following: 
– 
Ipatasertib plus paclitaxel compared with paclitaxel in patients with 
PD-L1−non-positive tumors (Arm B vs. Arm C in Cohort 1) 
– 
The addition of atezolizumab to ipatasertib plus paclitaxel compared with 
ipatasertib plus paclitaxel alone in patients with PD-L1−non-positive tumors 
(Arm A vs. Arm B in Cohort 1) 
– 
Ipatasertib plus paclitaxel plus atezolizumab compared with control arm 
treatments (Arm A vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2) as 
measured by the Functional and GHS/QoL scales of the European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire−Core 30 
(EORTC QLQ-C30) on the basis of the following endpoint: 
Mean and mean changes from baseline score in function (role, physical) and 
GHS/QoL by assessment timepoint and between treatment arms, as measured 
using the Functional and the GHS/QoL scales of the EORTC QLQ-C30 
• 
To evaluate the efficacy of atezolizumab when combined with ipatasertib and 
paclitaxel in patients with PD-L1−non-positive tumors (Arm A vs. Arm B in Cohort 1) 
on the basis of PFS, OS, and ORR 
• 
To independently evaluate the efficacy of experimental arm treatment compared 
with control arm treatment in patients with PIK3CA/AKT1/PTEN-altered tumors in 
each cohort, on the basis of PFS, OS, ORR, DOR, and CBR 
• 
To evaluate PROs of function (cognitive, emotional, social) and disease- and 
treatment-related symptoms associated with: 
– Ipatasertib plus paclitaxel compared with paclitaxel in patients with 
PD-L1-non-positive tumors (Arm B vs. Arm C in Cohort 1) 
– The addition of atezolizumab to ipatasertib plus paclitaxel compared with 
ipatasertib plus paclitaxel alone in patients with PD-L1-non-positive tumors 
(Arm A vs. Arm B in Cohort 1) 
– Ipatasertib plus paclitaxel plus atezolizumab compared with control arm 
treatments (Arm A vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2) as 
measured by the Functional and Symptom scales of the European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire‒Core 30 
(EORTC QLQ-C30) on the basis of the following endpoint: 
Mean and mean change from baseline scores in functional (cognitive, 
emotional, social) and disease- and treatment-related symptoms by cycle 
and between treatment arms, as assessed using the Functional and 
Symptom scales of the EORTC QLQ-C30 
• 
To evaluate patients’ health utility, as measured by the EuroQol 5-Dimension 
Questionnaire, 5-Level Version (EQ-5D-5L) to generate utility scores for 
pharmacoeconomic modeling, on the basis of the following endpoint:  
Utility scores of the EQ-5D-5L Questionnaire  


 
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• 
To independently evaluate the clinical benefit in each cohort, on the basis of the 
following endpoint: 
PFS2 after randomization, defined as the time from randomization to second 
occurrence of objective disease progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause (whichever occurs first)  
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to independently evaluate the safety of experimental 
arm treatment in each cohort, on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined by the 
investigator according to the NCI Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 
• 
Change from baseline in targeted vital signs 
• 
Change from baseline in targeted clinical laboratory test results 
 
Exploratory Safety Objective 
The exploratory safety objective for this study is to independently evaluate key 
patient-reported symptomatic adverse events associated with ipatasertib plus paclitaxel 
plus atezolizumab compared with control arm treatment in each cohort, on the basis of 
the following endpoint:  
Selected items from the NCI’s PRO Version of the CTCAE (PRO-CTCAE) capturing 
patients' rating of the presence, severity, frequency, and/or activity interference of 
diarrhea, nausea, vomiting, decreased appetite, fatigue, neuropathy, mouth sores, 
and rash symptoms, as well as an additional item regarding bother associated with 
side effects of treatment. 
 
2.3 
EXPLORATORY PHARMACOKINETIC OBJECTIVES 
The exploratory PK objectives for this study are as follows: 
• 
To evaluate the pharmacokinetics of atezolizumab, ipatasertib, and its metabolite 
(G-0377720) in each cohort, on the basis of the following endpoints: 
– 
Plasma concentrations of ipatasertib and its metabolite (G-037720) at specified 
timepoints  
– 
Serum concentrations of atezolizumab at specified timepoints  
 
• 
To evaluate potential relationships between ipatasertib and/or atezolizumab 
exposure, efficacy, and safety of ipatasertib plus paclitaxel plus atezolizumab in 
each cohort, on the basis of the following endpoints: 
– 
Relationship between ipatasertib and/or atezolizumab PK and efficacy 
endpoints, as appropriate based on the data 
– 
Relationship between ipatasertib and/or atezolizumab PK and safety endpoints, 
as appropriate based on the data 
 


 
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2.4 
EXPLORATORY IMMUNOGENICITY OBJECTIVES 
The exploratory immunogenicity objectives for this study are as follows: 
• 
To independently evaluate the immune response to atezolizumab in each cohort, on 
the basis of the following endpoint: 
– 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs 
during the study 
 
• 
To evaluate the potential effects of ADAs in each cohort, on the basis of the 
following endpoint: 
– 
Relationship between ADA status and efficacy, safety, PK, or biomarker 
endpoints 
2.5 
EXPLORATORY BIOMARKER OBJECTIVES 
The exploratory biomarker objectives for this study are as follows: 
• 
To independently evaluate predictive or prognostic biomarkers (plasma or tissue) 
associated with disease activity status or response to treatment in each cohort, on 
the basis of the following endpoint: 
Relationship between tissue and blood-based biomarkers and patient clinical 
features (e.g., baseline features) and outcome (e.g., duration of PFS) 
• 
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 in each cohort, on the basis of the following 
endpoints: 
– 
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 (IHC) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design  
This study will enroll approximately 1155 patients (approximately 525 patients in 
Cohort 1, and approximately 630 patients in Cohort 2) with advanced TNBC across up to 
350 sites globally.  The study will compare the efficacy of the combination of ipatasertib, 
atezolizumab, and paclitaxel against paclitaxel in patients with PD-L1−non-positive 
tumors (Cohort 1, Arm A vs. Arm C) and against atezolizumab and paclitaxel in patients 
with PD-L1−positive tumors (Cohort 2, Arm A vs. Arm B).  Cohort 1 will also evaluate the 
combination of paclitaxel and ipatasertib against paclitaxel in patients with 
PD-L1−non-positive tumors (Arm B vs. Arm C).  In Cohort 1, approximately 525 patients 
with PD-L1−non-positive tumors will be enrolled and randomized in a 1:1:1 ratio to 
treatment Arms A, B, and C, respectively.  In Cohort 2, approximately 630 patients with 
PD-L1−positive tumors will be enrolled and randomized in a 1:1 ratio to treatment 


 
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Arms A and B, respectively.  Patients with PD-L1 unknown tumors will be assigned to 
Cohort 1.  It is anticipated that owing to the prevalence of PD-L1 positivity and negativity 
by the SP142 assay that Cohort 1 will be fully enrolled before Cohort 2.  
As of 6 August 2020, further enrollment in Cohort 2 has been terminated; treatment 
assignments for Cohort 2 were unblinded on 7 August 2020.  Patients may continue 
current study treatment if considered clinically appropriate and if deriving benefit as 
assessed by the investigator.  However, patients in Arm B of Cohort 2 will no longer 
receive placebo for ipatasertib.  No crossover will be permitted for patients in Arm B of 
Cohort 2.  For patients who choose to continue in the study, assessments will proceed 
as specified in the protocol (see Appendix 1 and Appendix 2). 
As of 18 September 2020, further enrollment in Cohort 1 has been terminated; treatment 
assignments for Cohort 1 were unblinded on 21 September 2020.  Patients may 
continue current study treatment if considered clinically appropriate and if deriving 
benefit as assessed by the investigator.  However, patients in Arm B of Cohort 1 will no 
longer receive placebo for atezolizumab; patients in Arm C of Cohort 1 will no longer 
receive placebo for ipatasertib nor placebo for atezolizumab.  No crossover will be 
permitted for patients in Arm B or Arm C of Cohort 1.  Assessments will proceed as 
specified in the protocol (see Appendix 1 and Appendix 2). 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.  The PK and immunogenicity sampling schedule is presented in Appendix 2. 


 
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Figure 1 Study Schema 
 
CBR = clinical benefit rate; CIT = cancer immunotherapy; DOR = duration of response; eBC = early 
breast cancer; FMI = Foundation Medicine, Inc.; GHS = global health status; HRQoL = health-
related quality of life; ITT = intent to treat; LA = locally advanced; MBC = metastatic breast cancer; 
NA = North America; ORR = objective response rate; OS = overall survival; PD-L1 = programmed 
death-ligand− 1; PFS = progression-free survival; PO = orally; PROs=patient-reported outcomes; 
Q28D = every 28 days; QD = once a day; R = randomization; RECIST v1.1 = Response Evaluation 
Criteria in Solid Tumors, Version 1.1; RoW = rest of world. 
Note:  Following unblinding of treatment assignments, patients in Arm B of Cohort 2 will no longer 
receive placebo for ipatasertib, patients in Arm B of Cohort 1 will no longer receive placebo for 
atezolizumab, and patients in Arm C of Cohort 1 will no longer receive placebo for ipatasertib nor 
placebo for atezolizumab. 
 
Ipatasertib or placebo will be administered to patients at a starting dose of 400 mg QD 
PO for 21 days of each 28-day cycle on Days 1−21 unless held for management of 
adverse events.  Atezolizumab or placebo will be administered to patients by IV infusion 
at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.  Paclitaxel will be 
administered to patients at a starting dose of 80 mg/m2 by IV infusion for 3 of 4 weeks on 
Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an 
adverse event.   
Any study treatment may be continued until disease progression, intolerable toxicity, 
elective withdrawal from the study or study treatment, or study completion or termination.  
After treatment discontinuation, patients will be followed every 3 months for survival, 
PROs (see Section 4.5.10), as well as follow-up anti-cancer therapy and related 
outcomes (therapy and procedures, doses, start and stop dates, best response, most 
recent tumor assessment date, and progression date).  As of protocol Version 6, these 
long-term follow-up assessments are no longer required. 
In each cohort, a permuted block randomization scheme will be used to ensure an 
appropriate allocation of patients to each arm (at an approximately 1:1:1 ratio to Arms A, 


 
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B, and C in Cohort 1 and approximately a 1:1 ratio to Arms A and B in Cohort 2) with 
respect to the following stratification factors: 
• 
Geographic region (Asia-Pacific vs. western Europe/North America vs. rest of the 
world) 
• 
Prior (neo)adjuvant taxane (yes vs. no) 
• 
Prior CIT in the (neo)adjuvant setting (yes vs. no) 
 
3.1.2 
Assessments and Monitoring 
All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the NCI CTCAE v5.0.   
Tumor assessments should be performed based on a schedule calculated from Day 1 of 
Cycle 1, with the first assessment performed at Week 8 and approximately every 
8 weeks thereafter, regardless of treatment administration timing or prior early or late 
tumor assessments (see Appendix 6).  For estimation of PFS, ORR, DOR, and CBR, 
tumor response will be based on RECIST v1.1 (see Appendix 5).  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 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.  As of protocol Version 5, 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.  Such tumor tissue will be collected by biopsy, unless not clinically feasible as 
assessed and documented by the investigator, at the time of first evidence of 
radiographic disease progression per RECIST v1.1 (within 40 days after radiographic 
progression or prior to the start of new anti-cancer treatment, whichever is sooner).  
These samples will enable analysis of tumor tissue biomarkers related to resistance, 
disease progression, and clinical benefit of the study treatments. 
For additional details regarding tumor assessments, refer to Section 4.5.7. 
3.1.3 
Safety Data Monitoring  
An iDMC will evaluate safety data during the study.  The analysis supporting iDMC 
review will be conducted by an independent Data Coordinating Center (iDCC) and 
provided to the iDMC.  Sponsor affiliates will be excluded from iDMC membership.  
The iDMC will follow a charter that outlines the iDMC roles and responsibilities. 
Unblinded safety data will be reviewed by the iDMC on a periodic basis, approximately 
every 6 months from the time of the first patient’s enrollment until the time of the primary 


 
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analysis of PFS.  All summaries and analyses for the iDMC review will be prepared by 
the iDCC.   
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.  
Due to the early termination of the enrollment and unblinding of patients, the iDMC’s 
review of the ongoing safety summary data will be discontinued after the unblinding, and 
the study team will be responsible for the ongoing monitoring of patient safety in the 
study.  As unblinded data will now be available to the study team, aggregate safety data 
will be reviewed by the study teama regularly when appropriate.  These safety reviews 
are perfomed in addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events; serious adverse events; deaths; and laboratory 
abnormalities. 
Any outcomes of these data reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of their respective Institutional 
Review Boards/Ethics Committees (IRBs/ECs). 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2−3 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Ipatasertib Dose and Schedule 
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 PK data from Arm C of Study PAM4983g (a 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 of ipatasertib was better tolerated than 600 mg of ipatasertib in this combination.  
In the Phase II, randomized, placebo-controlled study (GO29227) in patients with locally 
advanced or metastatic TNBC, the combination 400 mg of ipatasertib administered QD 
on Days 1−21 of each 28-day cycle with 80 mg/m2 of paclitaxel administered QW on 
Days 1, 8, and 15 of each 28-day cycle was generally well tolerated and showed an 
improvement in PFS (refer to Section 1.2); the sparse sampling exposure results in this 


 
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study were also consistent with the known PK profiles of ipatasertib (and its metabolite 
G-037720).  
In addition, the totality of pharmacodynamic data from the Phase I study PAM4743g 
(PK/pharmacodynamic analysis) and safety and efficacy data (including exploratory 
exposure−response analyses; data on file) from Phase II randomized studies (GO29227 
and GO27983) of ipatasertib support the selected starting dose of 400 mg of 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 plus 
paclitaxel arm of Study GO29227, despite dose reduction of ipatasertib that occurred in 
21.3% of patients because of adverse events, discontinuation of ipatasertib for any 
adverse event was 6.1% and the median cumulative dose intensity of both ipatasertib 
and paclitaxel was 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 exposure similar to the exposure of ipatasertib 
powder-in-capsule and Phase II tablet formulations used in the Phase I (PAM4743g and 
PAM4983g) and Phase II (GO29227) studies, respectively. 
3.3.2 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered to patients at a fixed dose of 840 mg Q2W (840 mg 
on Days 1 and 15 of each 28-day cycle).  This is an approved dosage for atezolizumab 
(Tecentriq U.S. Package Insert).  Anti-tumor activity has been observed across doses 
ranging from 1 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).  The 840-mg Q2W dosage in the 
present study is the same atezolizumab dose and schedule used in the Phase Ib study 
CO40151 and the WO29522 (IMpassion130) study.   
3.3.3 
Rationale for Paclitaxel Dose and Schedule 
Taxanes, in particular, paclitaxel or docetaxel, are increasingly used for adjuvant 
treatment of HER2-negative breast cancers worldwide.  Many patients are expected to 
have received adjuvant chemotherapy, including taxanes, leading to a concern regarding 
re-challenge 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 re-challenge with paclitaxel in the metastatic setting after prior adjuvant 
taxane exposure, guidelines support the retreatment with 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 have relapsed 


 
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within 12 months of completing neoadjuvant or adjuvant chemotherapy treatment 
(including a taxane) will be excluded, thus selecting for patients who are likely to retain 
sensitivity to paclitaxel in the metastatic setting.   
The TNT study demonstrated superiority of carboplatin over docetaxel for the treatment 
of patients with BRCA mutation−positive breast cancer (Tutt et al. 2015).  Thus, in 
patients with BRCA-associated TNBC, 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., patients who are BRCA1/2 germline mutation positive) 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). 
Although dosing in the package insert for paclitaxel is 220 mg/m2 Q3W, the current study 
uses the equivalent of 240 mg/m2 every 4 weeks.  Clinical studies in metastatic breast 
cancer suggest that paclitaxel given QW may have a better efficacy than paclitaxel given 
Q3W (Green et al. 2005; Gonzalez-Angulo and Hortobagyi 2008; Seidman et al. 2008; 
Lu et al. 2014).  In addition, a model-based meta-analysis of 29 monotherapy paclitaxel 
trials showed that a paclitaxel regimen of 65−80 mg/m2 QW may have improved efficacy 
(based on results from breast cancer trials) and a lower incidence of neutropenia (based 
on results from breast cancer and mixed-patient population trials) than a 175-mg/m2 
paclitaxel Q3W regimen.  A lower dose and more frequent administration pattern of 
paclitaxel are also observed in clinical practice.  A recent analysis (Roche unpublished 
data) of Flatiron Health electronic medical records of 95 patients with metastatic TNBC 
treated with paclitaxel monotherapy in the first-line setting (2011−2018) in the 
United States suggested that two-thirds of the patient sample reported receiving a first 
administration dose of 80 mg/m2; furthermore, the most frequent unique administration 
pattern at the start of therapy was QW 3 of 4 weeks, which was seen in just over 
one-third of the patient population. 
3.3.4 
Rationale for Patient Population 
Tumor-cell killing by cytotoxic chemotherapy may expose the immune system to high 
levels of tumor antigens.  Boosting tumor-specific T-cell immunity in this setting by 
blocking the PD-L1 pathway may result in deeper and more durable responses than 
those observed with standard chemotherapy alone (Merritt et al. 2003; Apetoh et al. 
2007), and this may reasonably occur in tumors regardless of PD-L1 expression.   


 
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Both Studies GO29227 (LOTUS; paclitaxel, with or without ipatasertib) and WO29522 
(IMpassion130; nab-paclitaxel, with or without atezolizumab) demonstrated statistically 
significant PFS improvement at the primary PFS analysis for a first-line locally advanced 
or metastatic TNBC population.  In light of the encouraging data for TNBC seen in both 
combinations of ipatasertib with paclitaxel and atezolizumab with nab-paclitaxel, as well 
as the preliminary clinical activity and tolerability profile for the combination of 
ipatasertib, atezolizumab, and taxane chemotherapy in Study CO40151, this study 
further evaluates the combination of ipatasertib with atezolizumab and paclitaxel in the 
first-line locally advanced or metastatic TNBC population. 
3.3.5 
Rationale for Control Group 
Data from the WO29522 (IMpassion130) study suggested that patients with 
PD-L1−positive tumors may significantly benefit from the addition of atezolizumab to 
taxane chemotherapy.  Hence this study is designed with two distinct cohorts, in which 
patients with PD-L1−non-positive tumors will receive at least paclitaxel alone as 
standard-of-care treatment and patients with PD-L1−positive tumors will receive at least 
paclitaxel with atezolizumab.  The combination of paclitaxel, ipatasertib, and 
atezolizumab and the combination of ipatasertib and paclitaxel are expected to have 
significant benefit over paclitaxel alone in patients with PD-L1−non-positive tumors.  The 
combination of paclitaxel, ipatasertib, and atezolizumab is expected to have significant 
benefit over paclitaxel plus atezolizumab in patients with PD-L1−positive tumors.   
As noted in Section 1.5, the control arm for Cohort 2 of this study (atezolizumab plus 
paclitaxel plus placebo for ipatasertib) is no longer considered appropriate, based on 
results from the primary analysis of the Phase III IMpassion131 (MO39196) study.  
Disposition of patients in Cohort 2 will proceed as outlined in Section 3.1.1. 
3.3.6 
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints  
In this study, the co-primary efficacy endpoints will be investigator-assessed PFS and 
OS.  This study will test the hypothesis that treatment regimens in the experimental arms 
will prolong PFS and OS compared with treatments in the control arms.   
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents 
a direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the 
effect and the benefit−risk profile of the new treatment compared with available therapies 
(U.S. Food and Drug Administration [FDA] 2007; European Medicines Agency 2012). 
Improvement in OS is generally accepted as the best measure of clinical benefit for 
patients with advanced TNBC, but it may be confounded by therapies that follow the end 
of study treatment.  However, recent data from studies of other solid tumors suggest that 
OS may be a more appropriate endpoint for CIT than PFS.  For example, in a Phase II 


 
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randomized study (GO28753), patients with advanced non−small cell lung cancer in the 
ITT population had a significant improvement in OS when treated with atezolizumab 
compared with docetaxel, with a stratified hazard ratio of 0.73 (95% CI: 0.53% to 0.99%) 
while PFS was similar between the two arms:  hazard ratio = 0.94 (95% CI: 0.72% to 
1.23%) (Fehrenbacher et al. 2016). 
3.3.7 
Rationale for Biomarker Assessments 
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to anti−PD-1 and anti−PD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014, 
2016; Borghaei et al. 2015; Fehrenbacher et al. 2016; Rosenberg et al. 2016, 
Schmid et al. 2018a).  In the current study, archival or baseline tumor specimens will be 
collected from patients and tested for PD-L1 expression by a central laboratory during 
the screening period.  In addition to the assessment of PD-L1 status, 
PIK3CA/AKT1/PTEN-altered status and other exploratory biomarkers, such as potential 
predictive and prognostic biomarkers related to the clinical benefit of ipatasertib and/or 
atezolizumab, tumor immunobiology, mechanisms of resistance, or tumor type, may be 
analyzed. 
Archival or fresh tumor tissue will be collected at baseline.  In order to obtain the most 
accurate reflection of a patient’s current disease while minimizing burden, a specimen 
from the most recently obtained tumor tissue is requested.  Tumor tissue collected by 
biopsy will also be requested at the time of first evidence of radiographic disease 
progression per RECIST v1.1, if deemed clinically feasible by the investigator, to enable 
analysis of tumor tissue biomarkers related to resistance, disease progression, and 
clinical benefit of ipatasertib, atezolizumab, and/or paclitaxel.  This biopsy at progression 
is optional but strongly encouraged.   
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 or early termination visit to evaluate oncogenic genetic alterations at 
baseline and to assess for the possible emergence of new alteration after treatment with 
ipatasertib, atezolizumab, and/or 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 and AKT1 status between tumor 
samples and ctDNA may help clarify the prognostic and predictive significance of 
PIK3CA and AKT1 mutations in patients with breast cancer treated with ipatasertib and 
paclitaxel. 
Blood samples will be collected at baseline and during the study to evaluate changes in 
surrogate biomarkers.  Changes in biomarkers (such as ctDNA, cytokines associated 


 
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with T-cell activation, and lymphocyte subpopulations) may provide evidence of biologic 
activity of ipatasertib and/or atezolizumab in humans.  Correlations between these 
biomarkers and safety and efficacy endpoints will be explored to identify blood-based 
biomarkers that might be predictive of which patients are more likely to benefit from 
ipatasertib and/or atezolizumab.   
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 treatment arm has substantially higher 
ipatasertib plasma levels than other patients in that treatment arm, 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. 
3.3.8 
Rationale for the Pharmacokinetic Evaluation Schedule 
As of protocol Version 5, blood samples for PK and ADA analyses will no longer be 
collected. 


 
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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 Section 4.5.9.  Samples will be collected on Days 1 and 15 of Cycle 1 and on Day 15 
of Cycle 3 for ipatasertib and G-037720 analysis.  Samples will be collected on Days 1 
and 15 of Cycle 1, and on Day 1 of Cycles 2, 3, 4, 8, 12, and 16 for atezolizumab 
exposure and ADA analyses.  The sampling schedule is designed to enable 
characterization of ipatasertib and atezolizumab using population-PK methodology for 
characterization.  
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 is not expected to alter paclitaxel exposure.  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.  
Therefore, paclitaxel pharmacokinetics will not be evaluated in this study. 
In general, monoclonal antibodies do not affect 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 will also 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 Collection of DNA (Blood) for Exploratory 
Whole Genome Sequencing 
PK plasma samples will be collected for DNA extraction to enable WGS or whole exome 
sequencing (WES) to identify variants that are predictive of response to study drug, are 
associated with progression to a more severe disease state, are associated with 
acquired resistance to study drug, are associated with susceptibility to developing 
adverse events, can lead to improved adverse event monitoring or investigation, or can 
increase the knowledge and understanding of disease biology and drug safety.  
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
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develop adverse events.  Data will be analyzed in the context of this study but will also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
This sample for WGS will be collected if approved locally. 
3.3.10 
Rationale for Patient-Reported Outcome Assessments  
As of protocol Version 5, PRO assessments will no longer be collected. 
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).  PROs provide an understanding of the impact 
a treatment has on a patient.  The EORTC QLQ-C30 is a validated instrument that has 
been widely used in assessing HRQoL in patients with cancer (Anderson et al. 1993).  
The core instrument assesses GHS/QoL, functioning (physical, role, emotional, 
cognitive, and social), and general cancer symptoms, and, side effects of systemic 
chemotherapy (see Appendix 10). 
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events.  Recent research has shown that clinicians may 
underreport the incidence and severity of symptoms experienced by patients receiving 
treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; 
Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting 
adverse event information directly from patients can provide a better understanding of 
treatment characteristics and their effects.  In order to evaluate the tolerability of 
ipatasertib in combination with atezolizumab and paclitaxel, patients will be asked to 
report on their experience of breast cancer treatment−related symptoms selected from 
the validated PRO-CTCAE item bank (Basch et al. 2014) (see Appendix 12).  These 
symptoms were identified as being salient to patients' experience with ipatasertib in 
combination with atezolizumab and paclitaxel on the basis of preliminary safety data 
from the ongoing studies containing this triplet, as well as side effects pertinent to the 
individual drug classes.  
The EORTC QLQ-C30 will be administered to patients to assess disease- and 
treatment-related symptoms, functioning, and HRQoL (see Section 4.5.10).  In addition, 
selected items from the PRO-CTCAE and an additional item regarding bother owing to 
side effects will be collected to assess treatment-related symptoms and overall treatment 
burden.  The EQ-5D-5L (see Appendix 11) will be used to derive health states for use in 
economic models and therefore will not be included in the Clinical Study Report. 
The EORTC QLQ-C30, selected items from the PRO-CTCAE, and EQ-5D-5L will be 
assessed in this order (EORTC QLQ-C30 first, followed by the PRO-CTCAE second, 
and the EQ-5D-5L last), at baseline (Day 1 of Cycle 1), on Day 15 of Cycles 1 and 2, on 


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Day 1 of each subsequent cycle, and at the treatment discontinuation visit (see 
Appendix 1).  After treatment discontinuation to minimize burden on patients, only 
selected scales of the EORTC QLQ-C30 as well as the EQ-5D-5L measure will be 
administered over the telephone to patients or completed at the site during follow-up 
calls (or visits) and recorded on paper approximately every 3 months until death (see 
Appendix 1).  The selected scales of the EORTC QLQ-C30 are as follows:  the 
GHS/QoL (which consists of Questions 29 and 30), Physical Function (Questions 15), 
Role Function (Questions 6 and 7), Pain (Questions 9 and 19), Fatigue (Questions 10, 
12, and 18), and Dyspnea (Question 8). 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1155 patients with locally advanced unresectable or metastatic TNBC
with no prior systemic therapy for TNBC in the advanced setting will be enrolled during 
the global enrollment phase of this study.  After completion of the global enrollment 
phase, additional patients from mainland China may be enrolled during an extended 
China enrollment phase. 
4.1.1
Inclusion Criteria
Women or men with locally advanced unresectable or metastatic triple-negative 
adenocarcinoma of the breast who have not received prior systemic chemotherapy in 
this setting may be eligible for this study.  In patients with BRCA-associated tumors, 
platinum chemotherapy (Cardoso et al. 2017) or olaparib (Robson et al. 2019) as 
potentially the preferred treatment option should be taken into consideration when 
determining whether this study may be appropriate for these patients.  Patients may 
have received prior chemotherapy in the neoadjuvant or adjuvant setting if treatment 
was completed at least12 months prior to randomization.  Locally advanced 
unresectable disease must not be amenable to resection with curative intent.  Patients 
must have sufficient tumor tissue and comply with all eligibility criteria to be enrolled.  


 
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4.1.1.1 
General Inclusion Criteria 
Patients must meet the following general criteria for study entry: 
• 
Signed Informed Consent Form(s)  
• 
Women or men, age ≥ 18 years at the time of signing the Informed Consent Form 
• 
Willingness and ability to complete all study-related assessments, including 
PRO assessments, in the investigator’s judgment 
• 
Measurable disease according to RECIST v1.1 (see Appendix 5) 
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since 
radiation. 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see 
Appendix 3) 
• 
Adequate hematologic and organ function within 14 days before the first study 
treatment on Day 1 of Cycle 1, as defined by the following: 
– 
Neutrophils (ANC ≥ 1500/µL) 
– 
Hemoglobin ≥ 9 g/dL 
– 
Platelet count ≥ 100,000/µL 
– 
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 a patient’s value before starting heparin treatment).  
Patients receiving coumarin derivatives should have an INR between 
2.0 and 3.0 assessed in two consecutive measurements performed 1−4 days 
apart.  Patients should be on a stable anticoagulant regimen.  


 
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– 
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 hemoglobin A1C (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 contraception, and agreement to refrain from 
donating eggs, as described below: 
Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for at least 28 days after the final 
dose of ipatasertib/placebo, 5 months after the final dose of 
atezolizumab/placebo, and 6 months after the final 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 is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis).  Per this 
definition, a woman with a tubal ligation is considered to be of childbearing 
potential.  The definition of childbearing potential may be adapted for alignment 
with local guidelines or regulations. 
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 intrauterine 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 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.  If required per 
local guidelines or regulations, locally recognized acceptable methods of 
contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 


 
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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 final 
dose of ipatasertib/placebo, or 6 months after the final 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 final dose of 
ipatasertib/placebo or 6 months after the final 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 intrauterine 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.  If required per 
local guidelines or regulations, locally recognized acceptable methods of 
contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form. 
• 
For 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 
 
4.1.1.2 
Disease-Specific Inclusion Criteria 
Patients must meet the following disease-specific criteria for study entry:  
• 
Appropriate candidate for paclitaxel monotherapy if tumor PD-L1 status is unknown 
or non-positive; appropriate candidate for paclitaxel and atezolizumab if tumor 
PD-L1 status is positive 
• 
Histologically documented triple-negative 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 centrally, if not available locally) according to the ASCO/CAP 2018 guidelines 
(ASCO/CAP 2018; and Woolf et al. 2018 for HER2 testing update): 


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TNBC is defined as HER2 negative, ER negative, and PgR negative.
ER or PgR positivity is defined as 1% of tumor cell nuclei immunoreactive to 
the respective hormonal receptor (see Appendix 8).
HER2 positivity is defined as one of the following:  3, as assessed on IHC or 
in situ hybridization positive (see Appendix 9).  
– Submittal of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 
a minimum of 1015 slides at least (15 slides preferred) containing freshly 
cut unstained, serial tumor slides from the most recently collected tumor tissue 
(for central analysis of PD-L1 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. 
– Tumor tissue must be evaluated centrally for PD-L1 expression prior to 
enrollment.  Patients will be assigned to the appropriate cohort with a centrally 
determined PD-L1 result.
– If multiple tumor specimens are submitted (e.g., an archival specimen and tissue 
from relapsed disease), patients may be eligible if at least one specimen is 
evaluable for PD-L1.  For the purpose of cohort assignment, the PD-L1 score of 
the patient will be the maximum PD-L1 score among the samples.
– If a more recent specimen is either insufficient or unavailable, a patient may still 
be eligible if the patient can provide a tissue block (preferred) or a minimum of 
15 unstained serial slides from an older archival tumor tissue or undergo an 
additional pretreatment core or excisional biopsy of a non-target lesion (a 
non-target lesion is preferred if it is accessible and the biopsy can be safely 
obtained).  In general, a minimum of three core biopsies is required.
If a patient already has results available from Foundation Medicine, Inc.’s (FMI’s) 
commercial tissue-based NGS assay known as the FoundationOne CDx, 
10 freshly cut unstained, serial tumor slides from the most recently collected 
tumor tissue is acceptable for central analysis of PD-L1 status and other 
protocol-mandated secondary and exploratory assessments.
4.1.2
Exclusion Criteria
4.1.2.1
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 

Severe infection within 4 weeks prior to initiation of study treatment (including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia) as well as those who have received treatment with therapeutic oral or 
IV antibiotics within 2 weeks prior to initiation of study treatment are not eligible for 
the study. Patients receiving prophylactic antibiotics (e.g., for prevention of 


 
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a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are 
eligible for the study.  
• 
Known HIV infection (there must be a negative HIV test at screening)  
• 
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.  
• 
Current treatment with anti-viral therapy for HBV 
• 
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 study  
Placement of a vascular access device is not considered major surgery.  
• 
Pregnancy or breastfeeding, or intention to become pregnant during the study or 
within 28 days after the final dose of ipatasertib/placebo, 5 months after the final 
dose of atezolizumab/placebo, and 6 months after the final 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 through use 
Fridericia's formula (QTcF) > 480 ms  
• 
Current treatment with medications used at doses known to cause clinically relevant 
prolongation of QT/QTc interval (see list in Appendix 15) 
• 
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) 


 
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• 
Requirement for chronic corticosteroid therapy of > 10 mg of prednisone per day 
or an equivalent dose of other anti-inflammatory corticosteroids 
or immunosuppressant agents for a chronic disease  
No chronic corticosteroid use is permitted at baseline with rare exceptions.  
Refer to Section 4.1.2.5, 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 renders the patient at high risk from 
treatment complications  
 
4.1.2.2 
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 spinal cord metastases, as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during 
screening or prior radiographic assessments 
• 
Known CNS disease, except for treated asymptomatic CNS metastases, provided 
all of the following criteria are met: 
– 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord) 
– 
No ongoing requirement for corticosteroids as therapy for CNS disease 
– 
No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to randomization 
– 
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
Note:  Patients with new asymptomatic CNS metastases detected at the 
screening scan must receive radiation therapy and/or surgery for CNS 
metastases.  Following treatment, these patients may then be eligible without 
the need for an additional brain scan prior to enrollment, if all other criteria are 
met. 
Patients with leptomeningeal carcinomatosis will be excluded. 
• 
Known germline BRCA1/2 deleterious mutation, unless the patient is not an 
appropriate candidate for a PARP-inhibitor  
• 
Any previous systemic therapy for inoperable locally advanced or metastatic 
triple-negative adenocarcinoma of the breast 
Patients may have received prior neoadjuvant and/or adjuvant chemotherapy, 
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adenocarcinoma, provided all chemotherapy and CIT were completed 
≥ 12 months prior to randomization. 
The 12-month treatment-free minimum interval in these cases begins with the 
last administration of chemotherapy in the early breast cancer setting and is not 
meant to encompass HER2-targeted therapy, such as trastuzumab, 
ado-trastuzumab emtansine, pertuzumab, neratinib, or endocrine therapies.  
Previous systemic therapies for TNBC include, but are not limited to, 
chemotherapy, immune checkpoint inhibitors, or targeted agents. 
• 
Unresolved, clinically significant toxicity from prior therapy, except for alopecia and 
Grade 1 peripheral neuropathy  
• 
Patients who have received palliative radiotherapy 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 radiotherapy. 
– 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 (i.e., > 1.5 mmol/L ionized calcium, > 12 mg/dL calcium, 
or corrected serum calcium greater than 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 
 


 
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4.1.2.3 
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 
 
4.1.2.4 
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 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:  Prior treatment with PI3K or mTOR inhibitors is allowed. 
 
4.1.2.5 
Atezolizumab-Specific Exclusion Criteria  
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 syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 4 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
Patients with a history of autoimmune-mediated 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: 


 
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– 
Rash must cover < 10% of body surface area. 
– 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– 
There has been 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 final 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-α [TNF-α] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during 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 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
In this Phase III, randomized, double-blind, placebo-controlled study, patients will be 
randomized between treatment arms as follows.  In Cohort 1, patients will be 


 
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randomized in a 1:1:1 ratio to Arms A, B, and C, respectively.  In Cohort 2, patients will 
be randomized in a 1:1 ratio to Arms A and B.  
As of 6 August 2020, further enrollment in Cohort 2 has been terminated. 
There is no planned crossover in this trial.  
Patients will be allocated to each of the treatment arms through the use of 
a permuted-block randomization to ensure within-stratum balance of patient 
characteristics between treatment arms.  Randomization will be stratified according to 
the following criteria: 
• 
Geographic region (Asia-Pacific vs. western Europe/North America vs. rest of the 
world) 
• 
Prior (neo)adjuvant taxane (yes vs. no) 
• 
Prior CIT in the (neo)adjuvant setting (yes vs. no) 
 
The various stratification factors may correlate with different prognoses and differential 
responses to checkpoint inhibition, or they may reflect different regional clinical 
practices.   
To further protect the integrity of the study, the results of any patient-specific plasma 
concentration data for ipatasertib and atezolizumab will not be made known to either 
investigators or the contract research organizations, and any interim analyses done by 
iDCC and reviewed by iDMC will not be made known to the investigators or the Sponsor.  
Baseline NGS data from tumor samples will not be disclosed to the investigators or 
patients unless the report is already available in a Clinical Laboratory Improvement 
Amendments (CLIA)-certified format.  NGS data from post-progression tumor samples 
will be made available in a CLIA-certified report if and when available.  The NGS 
research report, when released, upon request by the investigator, is not intended for 
treatment decisions.  
4.2.2 
Blinding 
Study site personnel, including the investigator, and patients will be blinded to treatment 
assignment during the study.  The Sponsor and its agents will also be blinded to 
treatment assignment, with the exception of individuals who require access to patient 
treatment assignments to fulfill their job roles during a clinical trial.  These roles include 
the unblinding group responsible, clinical supply chain managers, sample handling staff, 
operational assay group personnel, Sponsor-independent PK bioanalytical personnel, 
interactive voice or web-based response system (IxRS) service provider, iDMC 
members, and the iDCC.  
As of 7 August 2020 and 21 September 2020, treatment assignments for patients in 
Cohort 2 and Cohort 1 have been unblinded to the Sponsor and study site personnel, 


 
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respectively, to allow the patients to make informed decisions in consultation with their 
investigators regarding their treatment options. 
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Baseline immunogenicity samples will be analyzed 
for all patients.  Postbaseline immunogenicity samples from patients assigned to the 
comparator arm will not be analyzed for ADAs except by request. 
To optimize timelines for delivery of PK-related analyses, unblinded PK and ADA data 
may be released to selected and appropriately documented clinical pharmacology or 
designated personnel at the clinical cutoff date prior to study unblinding. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
Non-emergency unblinding may be permitted by the Sponsor in the scenario where 
there is an approval (relevant to the patient’s country) of an in-class molecule in the 
same disease setting.   Non-emergency unblinding may be permitted by the Sponsor if 
knowledge of the treatment assignment is necessary to confirm eligibility for a clinical 
trial.  If the Medical Monitor agrees to patient unblinding, the investigator will be able to 
break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain blinded to treatment assignment. 
Unless otherwise indicated, Sponsor blinding to the treatment assignment will remain in 
place until the primary analysis (see Section 6.4.1).  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.   


 
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4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are ipatasertib, matching 
ipatasertib placebo, atezolizumab, matching atezolizumab placebo, and paclitaxel.  
Loperamide (or racecadotril, which may be more commonly used in Europe), 
prophylactic steroids and prophylactic antihistamines (see Section 4.3.3), are non-IMPs 
in this study.  
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Ipatasertib and Placebo 
Ipatasertib is intended for oral administration and will be supplied by the Sponsor 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.  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.  For information on the formulation and handling of ipatasertib/placebo, see the 
Ipatasertib Investigator’s Brochure. 
The period between re-dispensing and the 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 and Placebo 
The 840-mg atezolizumab drug product will be supplied by the Sponsor in a single-use, 
15-mL USP/Ph. Eur. Type 1 glass vial with 20-mm stoppers.  The vial is designed to 
deliver 14 mL (840 mg) of atezolizumab solution but may contain more than the stated 
volume to enable delivery of the entire 14-mL volume. 
Placebo will consist of the vehicle without the antibody.  Placebo will be supplied in 
a single-use, 15-mL USP/Ph. Eur. Type 1 glass vial with 20-mm stoppers intended for IV 
administration.  The vial contains approximately 14 mL of solution.  The formulation 
contains 20 mM histidine acetate, 120 mM sucrose, and 0.04% polysorbate 20, pH 5.8. 
Vials are filled to enable delivery of 14 mL of solution containing histidine acetate, 
sucrose, and polysorbate 20.   
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 


 
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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 3.1.1.  The sequence of drug 
administration is ipatasertib/placebo, then atezolizumab/placebo, and then paclitaxel.  
On non-atezolizumab administration days, the sequence of drug administration is 
ipatasertib/placebo and then paclitaxel. 
Refer to the pharmacy manual, supplemented by the Investigator's Brochures (for 
ipatasertib and atezolizumab) and local prescribing information (for paclitaxel) for 
detailed instructions on drug preparation, storage, and administration. 
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 Appendix 14. 
4.3.2.1 
Ipatasertib and Placebo 
Patients will be randomly assigned to a treatment arm through the IxRS.  
Ipatasertib/placebo will be administered at the starting dosage of 400 mg PO QD, 
beginning at 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 
ipatasertib/placebo prior to the IV infusions of paclitaxel and atezolizumab/placebo.  If 
ipatasertib/placebo cannot be safely administered on Days 1−21 of any 28-day cycle, it 
is permitted to make up for the missed doses on any of the Days 22−28, if safe to do so 
(refer to management guidance in Appendix 14).   
Each dose of ipatasertib/placebo should be taken in the morning 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.  Skipped or vomited doses will not 
be made up later in the day, as this risks having the following day’s dose scheduled too 
soon thereafter.  The intent is to keep the dosing at approximately the same time each 
morning.  
Following unblinding of treatment assignments, placebo for ipatasertib will no longer be 
administered to patients in Arm B of Cohort 2 and to patients in Arm C of Cohort 1 (see 
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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 at the clinic visit.  Typically, the ideal 
dosing time will be in the morning.  The 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 occurrences of vomiting within 
3 hours after study drug administration should also be recorded on the day of 
PK sampling. 
A sufficient amount of ipatasertib/placebo should be provided to the patient to last one 
treatment cycle.  Notably, there is one extra dose of ipatasertib/placebo in each bottle.  
This should be explained to the patient to minimize the risk that the patient mistakenly 
takes the extra dose.  Patients will be instructed to bring their bottles of 
ipatasertib/placebo and their medication diaries to each study visit. 
Once a decision to reduce the dose of ipatasertib/placebo is implemented, no 
re-escalation is permitted.   
4.3.2.2 
Atezolizumab and Placebo 
Atezolizumab/placebo will be administered to patients by IV infusion at a fixed dose of 
840 mg on Days 1 and 15 of each 28-day cycle until the patient experiences disease 
progression, intolerable toxicity, or withdraws consent.  Although a ± 1-day window is 
permitted for atezolizumab/placebo administration, it is discouraged to dose on days 
other than on Day 1 or 15 because of the risk that atezolizumab doses may fall too close 
together. 
Administration of atezolizumab/placebo 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 7.  
Atezolizumab infusions will be administered per the instructions outlined in Table 1. 
Following unblinding of treatment assignments, placebo for atezolizumab will no longer 
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Table 1 
Administration of First and Subsequent Atezolizumab/Placebo 
Infusions 
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/placebo 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 IRR 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 measured within 
60 minutes prior to the infusion. 
• 
Atezolizumab/placebo should be infused 
over 30 (± 10) minutes if the previous 
infusion was tolerated without an IRR, or 
60 (± 15) minutes if the patient 
experienced an infuIRRwith the previous 
infusion. 
• 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
IRR = infusion-related reaction. 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
the Appendix 13. 
No dose modification for atezolizumab/placebo is allowed. 
4.3.2.3 
Paclitaxel  
The dose of paclitaxel in this study is 80 mg/m2 administered to patients 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.  Although a ±1-day window is permitted for paclitaxel 
administration, it is discouraged to dose on days other than on Day 1, 8, 15, or 22 
because of the risk that paclitaxel doses may fall too close together.  Calculation of body 
surface area for the purposes of dosing of paclitaxel should be made according to the 
prescribing information.  If a patient's weight changes by > 10% from baseline during the 
study, the body surface area and drug doses should be recalculated.  Once recalculated, 
if the patient's weight changes by > 10% from the weight used to make the recalculation, 
the drug doses should again be recalculated.  If the local standard is to calculate 
a paclitaxel dose more often, this is acceptable.  


 
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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 and 
after the IV dose of atezolizumab/placebo.    
Patients should be monitored during paclitaxel administration per institutional policies.  
Patients may receive antiemetic and other prophylactic treatments, according to 
institutional practice. 
If the dose of paclitaxel has been reduced, it may be re-escalated (when medically 
appropriate and following management guidance in Appendix 13) by a single dose level 
at a time.  The Medical Monitor is available to advise as needed. 
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.  Ranitidine and famotidine are recommended H2-receptor blockers 
for prophylactic treatment of paclitaxel infusion-related reactions.  However, in cases 
when ranitidine and famotidine are not available, cimetidine may be used with caution.  
Cimetidine is a moderate CYP3A inhibitor, which can increase the exposure of 
ipatasertib up to approximately 2-fold.  It can take up to 3 days for ipatasertib 
concentration to return to typical steady state levels.  
Only applicable while the patient is receiving ipatasertib: 
• 
For visits without PK sample collection, intravenous cimetidine can be administered 
irrespective of timing with the oral dose of ipatasertib.  For visits that include 
PK sample collection, intravenous cimetidine can be administered after ipatasertib 
sampling is complete or 2 hours after ipatasertib dosing, whichever is later.  
• 
For sites needing use of oral cimetidine, cimetidine should be administered at least 
2 hours after ipatasertib or after completion of PK sampling, whichever is later. 
 
Diarrhea is a common adverse event associated with ipatasertib and/or paclitaxel 
treatment.  In this study, to improve diarrhea management and patient burden, 
loperamide (racecadotril as used in Europe) will be administered to patients daily as 
prophylaxis for diarrhea.  Prophylactic use is mandated in the first cycle (if allowed by 
local guidance, 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.  The Medical Monitor is available to advise as needed.   
Patients should be educated/reminded to be cognizant of the onset, duration, severity, 
and frequency of symptoms and the medications administered.  If side effects of 
loperamide are not tolerated, doses may be reduced (or if necessary, discontinued) at 


 
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any time.  Investigators are encouraged to continue prophylactic- and/or treatment-dose 
loperamide for the remainder of the study at their discretion based on clinical judgment. 
Owing to the risk of rash in Cycle 1, patients should receive the following prophylaxis 
during the first cycle when all three study treatments will be given: 
• 
Unless contraindicated, daily PO antihistamine prophylaxis should be used for at 
least the first cycle.  It is suggested that a non-sedating longer-acting oral 
antihistamine be used (such as 10 mg of cetirizine PO QD or comparable dose of 
other antihistamines, e.g., loratadine, fexofenadine).  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. 
• 
On days when patients will receive atezolizumab/placebo (typically, Days 1 and 15), 
patients should receive at least 10 mg/day of 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 of prednisone on the day of paclitaxel, 
then the additional 10 mg of prophylactic prednisone should not be given on that 
day to prevent rash.  If the investigator determines that administration of the steroid 
immediately prior to paclitaxel, rather than prior to atezolizumab/placebo, is more 
appropriate, this is acceptable.  
 
As of protocol Versions 4 and 5, rash and antidiarrheal prophylaxis is no longer 
applicable to patients in Arm C of Cohort 1 and Arm B of Cohort 2.  
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.5 
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. 


 
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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 study drug or data suggest that 
the study drug is not effective for breast cancer 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for breast cancer 
• 
Provision of the study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 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 with a failure rate of < 1% per year (see Section 4.1.1.1) 
• 
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 


 
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irradiated must not be a site of measurable disease).  Study treatment should 
be suspended during palliative radiotherapy (see Section 4.4.2.2).  
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.  The Medical Monitor is available to advise as needed.  The 
patient may continue ipatasertib treatment after the treatment hold has been 
completed and the patient has sufficiently recovered.   
• 
Prophylactic use of loperamide (racecadotril as used in Europe) as outlined in 
Section 4.3.3 
• 
Premedication with antihistamines, antipyretics, and/or analgesics for each 
paclitaxel administration 
• 
Premedications prior to administration of atezolizumab 
Premedication with corticosteroids and antihistamines prior to administration of 
atezolizumab are allowed as outlined in Section 4.3.3. 
Premedication with antipyretics and/or analgesics may be administered for the 
second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
• 
Granulocyte colony-stimulating factor treatment for patients receiving paclitaxel 
The primary prophylaxis should be administered per the ASCO, EORTC, and 
European Society for Medical Oncology guidelines; namely, in patients who 
are ≥ 60 years old and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011). 
• 
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 
osteoporosis)  
Both types of agents have potential immunomodulatory properties but may be 
used as clinically indicated. 
• 
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) 
• 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section 4.4.3) 
• 
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 


 
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• 
Low-dose corticosteroids administered for orthostatic hypotension or 
adrenocortical insufficiency  
 
4.4.2 
Cautionary Therapy  
4.4.2.1 
Corticosteroidsand Tumor Necrosis Factor−α Inhibitors 
Systemic corticosteroids are recommended, at the discretion of the investigator for the 
treatment of specific adverse events (refer to Section 4.3.3 for details).  When used for 
adverse events attributed to atezolizumab, refer to Appendix 13 and Appendix 14 for 
guidance.  Refer to Appendix 13 for instructions on holding ipatasertib/placebo and/or 
atezolizumab/placebo during systemic corticosteroid treatment (neither need to be held 
when corticosteroids are given as premedication prior to imaging studies, prior to 
paclitaxel, or as required in Cycle 1 prior to atezolizumab administration) (see 
Section 4.3.3). 
TNF-α inhibitors may attenuate potential beneficial immunologic effects of treatment with 
atezolizumab.  Therefore, in situations in which TNF-α inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, TNF-α inhibitors may be administered at the discretion of 
the investigator. 
4.4.2.2 
Surgery and Palliative Radiotherapy 
Patients who require radiotherapy or surgery as part of medical treatment in the absence 
of radiographic disease progression must exercise caution, and paclitaxel and 
ipatasertib/placebo should be temporarily withheld for at least 7 days before and after 
the procedure (at least 14 days after radiation is recommended).  While withholding 
atezolizumab is not required, caution and clinical judgment should be exercised when 
administering atezolizumab concurrently with surgery or radiotherapy.  For minor 
surgeries or single-day radiotherapy, this hold of paclitaxel and ipatasertib may be 
shorter, if discussed by the investigator.  The Medical Monitor is available to advise as 
needed.  After the temporary treatment hold is complete, study treatment may be 
re-initiated when the patient has sufficiently recovered. 
4.4.2.3 
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 at the 600-mg dose 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 
approximately 50% when co-administered with enzalutamide, a strong CYP3A inducer.  
Strong CYP3A inhibitors are expected to increase ipatasertib exposures significantly.   


 
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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  
• 
Itraconazole, a strong CYP3A4 inhibitor, increased ipatasertib area under the 
concentration−time curve and maximum concentration by approximately 5-fold and 
2-fold, respectively (drug−drug interaction study GP30057).  Given that ipatasertib is 
a substrate of CYP3A4/5, other strong inhibitors of CYP3A4/5 may also result in an 
increase in ipatasertib exposure. 
• 
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 final 
dose of strong CYP3A inhibitors and sensitive CYP3A substrates with narrow 
therapeutic window. 
• 
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 list of medications is not comprehensive.  The investigator should consult the 
prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the Medical Monitor is available to 
advise if questions arise regarding medications not listed above. 
4.4.2.4 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions are generally 


 
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unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section 4.4.3) 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) 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) 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 4.4.2.2 for details). 
• 
Hormone-replacement therapy 
• 
Chronic use of a strong CYP3A4/5 inhibitor or inducer or sensitive CYP3A 
substrates with a narrow therapeutic window.  The Medical Monitor is available to 
advise as needed . 
• 
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®) within 4 weeks prior to initiation of study 
treatment, during treatment with atezolizumab, and for 5 months after the final dose 
of atezolizumab. 
• 
Systemic immunostimulatory agents (including, but not limited to, IFNs and 
interleukin-2) 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 
4.4.4 
Prohibited Food  
Use of the following foods is prohibited as described below: 
• 
Consumption of grapefruit juice, a potent CYP3A4 enzyme inhibitor, during the 
study treatment period and for 10 days after the final dose of study treatment. 
• 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, for up to 
14 days prior to and during the study treatment period, and for 10 days after the final 
dose of study treatment. 
 
Although there is no other prohibited food for this study, patients will be provided with 
general dietary guidance aimed at minimizing any risk of hyperglycemia and diarrhea.   


 
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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 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.  
All activities must be performed and documented for each patient.   
As of protocol Version 5, patients who choose to continue in the study will continue 
assessments as specified in the protocol (see Appendix 1). 
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. 
Only essential data will be collected.  Certain assessments that are required will not be 
recorded on the eCRF (except in the case of an adverse event).  Required procedures 
should be reflected in the schedule of activities (see Appendix 1). 
It should be assumed that, other than essential protocol-specific assessments, the 
current standard of care for the TNBC will be followed; thus, parameters such as 
temperature may be measured and recorded in the source documents but not entered 
on an eCRF (unless abnormal, in which case they may be reported as adverse events). 
Study-related procedures, when required (see Appendix 1), should be performed in 
approximately the same order at each visit.  For example, if PRO assessments are 
performed after the patient has had blood and/or urine sample collection, the appropriate 
clinical assessment, and initiation of the study drug administration, then this should 
generally be repeated at each visit to minimize bias.  
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).  Alternative methods for documenting consent may be locally recognized, 
and in such cases acceptability of these methods should not be assumed.  In such 
cases, the operational lead for the study should be informed and approval must be 
obtained from the Sponsor before the patient is consented.  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 detailed record of 


 
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all patients screened, to document eligibility or record reasons for screening failure, as 
applicable. 
Patients are permitted to re-screen once, if any delay to treatment is considered clinically 
reasonable, in the investigator’s opinion.  This includes, but is not limited to, the scenario 
in which a valid tumor PD-L1 status is not yet obtained or other screening procedures 
are not completed within the 28-day screening period. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), 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. 
To further assess the actual intake of analgesic, antihistamine, and antidiarrheal 
medications taken outside of the clinic or 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, antihistamine, 
or antidiarrheal medications, including the recommended dosage and route of 
administration.  Patients should use the diary to record daily ipatasertib/placebo dosing 
and specifically any antidiarrheal, antihistamine, or analgesic medications used 
(prescribed or over the counter) taken during that cycle of treatment.  The intake of 
analgesic, antihistamine, and loperamide medications will be reported on the Analgesics 
Medication, Antihistamine, and Targeted Loperamide Concomitant Medications eCRF, 
respectively. 
Demographic data will include age, sex, and self-reported race or 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, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline 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. 


 
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4.5.4 
Weight and Height 
Weight should be recorded at each study visit, and height will be measured only at 
baseline and thereafter as clinically indicated.   
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature while the patient is sitting or supine in 
a comfortable position.  Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 
Vital signs should be measured within 60 minutes prior to each in-clinic 
ipatasertib/placebo administration, atezolizumab/placebo infusion (one set may be 
performed to cover predose vital signs for both drug administrations), and between 
atezolizumab/placebo and paclitaxel infusions (on days when both drugs are 
administered).  On days when no atezolizumab/placebo is given, one set may be 
performed as predose vital signs for both ipatasertib/placebo and paclitaxel.  On 
paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of 
the infusion.  Vital signs may be repeated if clinically indicated, during the infusion.  In 
addition, vital signs should be measured at other specified timepoints as outlined in the 
schedule of activities (see Appendix 1). 
Table 2 
Timing for Vital Sign Measurements for First and 
Subsequent Infusions 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Ipatasertib 
• Within 60 minutes prior to 
ipatasertib/placebo administration 
• Within 60 minutes prior to 
ipatasertib/placebo 
administration 
Atezolizumab 
• Within 60 minutes prior to the 
atezolizumab/placebo infusion 
• During or after the infusion if 
clinically indicated (refer to Table 1) 
• Within 60 minutes prior to the 
atezolizumab/placebo infusion 
• During or after the infusion if 
clinically indicated (refer to 
Table 1) 
Paclitaxel   
• On atezolizumab/placebo infusion 
days, after atezolizumab/placebo 
and before paclitaxel infusions 
• On non-atezolizumab/placebo 
infusion days, within 60 minutes 
prior to the paclitaxel infusion 
• After completion of paclitaxel 
• On atezolizumab/placebo 
infusion days, after 
atezolizumab and before 
paclitaxel infusions 
• On non-atezolizumab/placebo 
infusion days, within 60 
minutes prior to the paclitaxel 
infusion 
• After completion of paclitaxel 
 


 
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4.5.6 
ECOG Performance Status 
Performance status will be measured using the ECOG Performance Status Scale and 
recorded on the eCRF (see Appendix 3). 
4.5.7 
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 (see Appendix 5).  Images for tumor 
assessments will be collected to enable retrospective blinded independent central review 
when needed.  As of protocol Version 5, images for tumor assessments will no longer be 
collected for blinded independent central review. 
All measurable and evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation.  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.  Confirmation of an objective response is only 
valid when the repeat assessments are performed ≥ 4 weeks after initial documentation.  
Per study requirements, tumor assessments are due every 8th week and do not need to 
be performed sooner for the purpose of confirming a response.  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 prior to 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 prior to Day 1 of Cycle 1.   
Tumor assessments should be performed based on a schedule calculated from Cycle 1, 
Day 1 (study Day 1), with the first assessment performed at Week 8 and approximately 
every 8 weeks thereafter, regardless of treatment administration timing or prior early or 
late tumor assessments.  A sample calendar is presented in Appendix 6 .  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 at Week 16, adhering to the same 7-day window.  Bone disease 
and any changes in bone imaging should be evaluated radiographically by CT scan, 
MRI, or X-ray to ascertain the presence of bone destruction versus a healing reaction.  


 
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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 (as per 
statndard of care) until documented progressive disease per RECIST v1.1. 
A documented standard-of-care tumor assessment performed within 28 days prior to 
Day 1 of Cycle 1 (bone or head scans within 6 weeks prior to Day 1 of Cycle 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, 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.  .  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.  
• 
If a CT scan for tumor assessment is performed in a positron emission tomography 
or CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan.  The Medical Monitor is available to advise as 
needed. 
 
Objective response at a single timepoint will be determined by the investigator according 
to RECIST v1.1 (see Appendix 5).   
4.5.8 
Electrocardiograms and Cardiac Function Assessment 
A cardiac function assessment by echocardiogram or multiple-gated acquisition scan 
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 scan may be acceptable (e.g., cardiac MRI), if consistent with 
local standard practice.  The Medical Monitor is available to advise as needed. 
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.  


 
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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 post-dose 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 is available to advise as needed.  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.  The investigator should also 
evaluate the patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
concomitant medications known to prolong the QT interval, severe bradycardia). 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
Laboratory samples should be drawn according to the schedule of activities (see 
Appendix 1) 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 and reviewed prior to making the dosing decision.  The 
following tests are essential assessments for Day 1 dosing of every cycle:  hemoglobin, 
ANC, lymphocytes, and platelet count, HbA1c, glucose, creatinine, potassium, calcium, 
total bilirubin, ALP (total ALP), AST, ALT, and a pregnancy test.  Screening local 
laboratory assessments obtained within these windows prior to Day 1 of Cycle 1 do not 
have to be repeated on Day 1 of Cycle 1.  For certain laboratory values, such as ANC, 
management tables provided in Appendix 13 should be reviewed before study treatment 
administration.  Where specific guidance is not offered regarding holding study 
treatments based on a laboratory abnormality, clinical judgment should be used.  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells) 
• 
Fasting serum chemistry panel (following ≥8-hour fast):  glucose (plasma glucose is 
also acceptable per local practice), bicarbonate or total carbon dioxide (if considered 


 
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standard of care for the region), sodium, potassium, chloride, magnesium, BUN or 
urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, 
and AST 
• 
LDH 
• 
Fasting lipid profile:  total cholesterol, HDL cholesterol, LDL cholesterol, and 
triglycerides performed following a ≥ 8-hour fast 
• 
HbA1c 
• 
Amylase and lipase 
• 
Coagulation:  INR and PTT (or aPTT) 
• 
Thyroid-function testing:  TSH, free triiodothyronine (T3) (or total T3 for sites where 
free T3 is not performed), and free thyroxine (also known as T4) 
• 
HIV serology:  as per local standard, after any applicable local consenting 
requirements 
• 
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection, prior to randomization.  
• 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection, prior 
to randomization. 
• 
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 Day 1, Cycle 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 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. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a woman with a tubal ligation is 
considered to be of childbearing potential.   
• 
Urinalysis:  pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted  


 
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• 
Serum samples for C-reactive protein  
 
The following samples may be performed outside of a health care facility: 
• 
For any patients who initiate home glucose monitoring (see Appendix 13, Table 3, 
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 one or several central laboratories or to the 
Sponsor or a designee for analysis: 
• 
Blood samples for exploratory research on biomarkers  
Blood will be collected for ctDNA analysis at Day 1 of Cycle 1, at the time of the 
first tumor assessment (± 7 days), and at the study drug discontinuation visit.  
Blood should be drawn before the administration of any study drug, if 
applicable. 
• 
Most recently collected tumor tissue for evaluation of PD-L1 expression, 
PIK3CA/AKT1/PTEN-altered positivity, tumor status, and for exploratory research on 
biomarkers 
A representative FFPE tumor specimen in a paraffin block (preferred) or 10−15 
slides at least (15 preferred) containing unstained, freshly cut, serial sections 
should be submitted.  
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples collected via resection, core-needle biopsy (recommend at least three 
cores, embedded in a single paraffin block), or excisional, incisional, punch, or 
forceps biopsy are acceptable.  If less than 15 slides or only two cores are 
available, a patient may still be eligible for the study after Sponsor approval has 
been obtained and if sample contains a minimum of 50 viable tumor cells, 
regardless of needle gauge or retrieval method.  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell 
suspension and/or smears), brushing, cell pellets from pleural effusion, and 
lavage samples are not acceptable.  Tumor tissue from bone metastases that 
are subject to decalcification is not acceptable. 
If the most recently collected tumor tissue is unsuitable for required testing 
(e.g., clearly insufficient in quantity or tumor cellularity), a pretreatment tumor 
biopsy (preferred, a minimum of three core biopsies is required for NGS 
evaluation), or older archival tissue may be submitted.  If less than 15 slides or 
only two cores are available, a patient may still be eligible for the study, after 
Sponsor approval has been obtained and if sample contains a minimum of 
50 viable tumor cells, regardless of needle gauge or retrieval method. 
• 
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  


 
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Somatic mutations and copy number variations by NGS or PCR-based methods 
in tumor tissue and ctDNA 
Gene 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) 
IHC-based analysis or quantitative digital IHC of tumor suppressors, such as 
PTEN, and markers of immune infiltration and activation, such as CD8 and 
PD-L1 
• 
Serum samples for atezolizumab PK analysis  
• 
Plasma samples for ipatasertib and G-037720 PK analysis  
• 
Serum samples for assessment of ADAs to atezolizumab  
Note: As of protocol Version 5, blood samples for PK and ADA analyses will no longer 
be collected. 
 
NGS may be performed by Foundation Medicine.  For optional tumor biopsy tissues 
obtained at the time of progression, the investigator may request a NGS report if and 
when available.  If permitted by local law, the investigator may share and discuss the 
results with the patient, unless the patient chooses otherwise.  The NGS report is 
generated for research purposes and is not provided for the purpose of guiding future 
treatment decisions.  The report may be included in the participant’s medical record.  
Results will not be available for samples that do not meet criteria for testing. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11) biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions: 
• 
Serum or plasma samples collected for PK or immunogenicity analysis may be 
needed for additional immunogenicity characterization and for PK or immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
• 
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 with the exception of tissue samples that undergo WGS or WES, which 
will be stored until they are no longer needed or until they are exhausted.  
 
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. 


 
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.10 
Patient-Reported Outcome Assessments  
As of protocol Version 5, PRO assessments will no longer be collected. 
To more fully characterize ipatasertib plus atezolizumab and paclitaxel compared with 
control arm treatment as a first-line treatment in patients with metastatic breast cancer, 
PRO data will be obtained through the use of the following instruments:  EORTC 
QLQ-C30, selected items from the PRO-CTCAE (when available in the local language), 
and the EQ-5D-5L. 
Official versions of the PRO instruments in booklet format, translated as required in the 
local language, will be distributed by the investigator staff.  PROs scheduled for 
administration during a clinic visit must be completed on paper by the patient in their 
entirety at the investigational site.  To ensure instrument validity and that data standards 
meet health authority requirements, questionnaires must be completed by the patient at 
the start of the clinic visit before discussion of the patient’s health state, laboratory 
results, or health record and prior to the administration of study treatment to avoid any 
bias to patient responses.  It is common for patients to complete laboratory assessments 
before a scheduled clinic visit.  Completion of PROs after laboratory tests is permitted so 
long as there is no prior discussion of the patients’ laboratory results or health record 
with clinic staff and that the PROs are completed before drug infusion. 
For patients who are unable to complete the measures on their own, interviewer 
assessment is allowed but can only be conducted by a member of the clinic staff who 
reads the questionnaire items to the patient verbatim; no interpretation, rephrasing, or 
rewording of the questions is allowed during interview-assisted completion.   
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site and should ask the patient to rectify any response that is 
not clearly marked in the appropriate location.  If a response is missing, site staff should 
ask the patient to complete the item or confirm that the item was intentionally left blank.  
Hard copy originals of the questionnaires must be maintained as part of the patient’s 
medical record at the site for source data verification.  These originals should have the 
respondent’s initials, study patient number, visit label, and date and time of completion 
recorded in compliance with good clinical practice.  Sites will enter patient responses to 
the PRO questionnaires into the EDC system no later than 5 days after collection. 
After treatment discontinuation to minimize burden on patients, only selected scales of 
the EORTC QLQ-C30 as well as the EQ-5D-5L measure will be administered over the 
telephone to patients or completed at the site during follow-up calls (or visits) (see 
Appendix 1).  The following selected scales of the EORTC QLQ-C30 will be assessed: 
the GHS/QoL (which consists of Questions 29 and 30), Physical Function 


 
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(Questions 1−5), Role Function (Questions 6 and 7), Pain (Questions 9 and 19), Fatigue 
(Questions 10, 12, and 18), and Dyspnea (Question 8).  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.  Refer to Appendix 1 for the frequency and timing of PRO assessments. 
4.5.10.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 (see Appendix 10) is a validated, reliable self-report measure 
(Aaronson et al. 1993; Sprangers 1996; Fitzsimmons et al. 1999) consisting of 
30 questions that assess five aspects of patient functioning (physical, emotional, role, 
cognitive, and social), eight symptoms (fatigue, nausea and vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea), financial difficulties, and GHS/QoL with 
a recall period of the previous week.   The functioning and symptoms items are scored 
on a 4-point scale that ranges from "not at all" to "very much," and the global health 
status/QoL items are scored on a 7-point scale that ranges from "very poor" to 
"excellent."   
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-item scales by using a linear transformation for standardization of the calculated 
raw score.  The EORTC QLQ-C30 takes approximately 10 minutes to complete. 
4.5.10.2 
PRO-CTCAE 
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015) (see Appendix 12).  The item bank was designed and validated as a repository of 
standalone items (Basch et al. 2014). 
To evaluate the patients’ perspective of tolerability of ipatasertib in combination with 
atezolizumab and paclitaxel, patients will be asked to report on their experience of 
treatment-related symptoms selected from the validated PRO-CTCAE item bank (Basch 
et al. 2014).  A subset of 8 symptoms deemed most applicable to the current treatments 
has been selected for this study (see Appendix 12).  Symptoms selected for this study 
include those adverse events experienced at any grade that occurred in ≥ 20% of 
patients for any study drug (ipatasertib, atezolizumab, and/or paclitaxel) in previous 
studies.  These symptoms were identified as being salient to patients' experience with 
ipatasertib in combination with atezolizumab and paclitaxel on the basis of preliminary 
safety data from the ongoing studies containing this triplet, as well as side effects 
pertinent to the individual drug classes. 
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 
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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, eight symptomatic adverse events were selected from the PRO-CTCAE 
item bank (i.e., diarrhea, nausea, vomiting, decreased appetite, fatigue, neuropathy, 
mouth sores, and rash symptoms), each with a varying number of corresponding 
attribute items, for a total of 14 items.  An additional item providing an overall 
assessment of the burden of side effects will be collected in addition to the 14 selected 
items from the PRO-CTCAE.  The selected PRO-CTCAE items will be completed per the 
schedule of activities, only when available in the local language of the investigational 
site.  The PRO-CTCAE takes approximately 10 minutes to complete. 
4.5.10.3 
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 (see Appendix 11).  Utility scores will be used in this study to 
inform pharmacoeconomic evaluations and, as such, will not be included in the Clinical 
Study Report.  The EQ-5D-5L takes approximately 3 minutes to complete.   
4.5.11 
Blood Samples for Whole Genome Sequencing (Patients at 
Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  The samples may be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES 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 or 
WES, this section of the protocol (Section 4.5.11) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 


 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS or WES 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). 
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no 
identification and reporting of incidental findings to investigators or patients. 
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access these 
data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available. 
The aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication.   
Refer to Section 4.5.12.6 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.12 
Optional Samples for Research Biosample Repository  
4.5.12.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 


 
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• 
To increase knowledge and understanding of disease biology and drug safety 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.12.2 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the 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, breast cancer biology, and drug safety: 
• 
Leftover blood, serum, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides) 
• 
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 variants via WGS, WES, 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 request the FMI NGS report of the new 
biopsy; it will be provided when available through Foundation Medicine’s web portal 
(results may not be available for samples that do not meet testing criteria). 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events. 


 
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Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.12.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 


 
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global_rcr-withdrawal@roche.com 
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 samples will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 


 
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4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (ipatasertib/placebo, 
atezolizumab/placebo, and paclitaxel) if any of the following criteria are met: 
• 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
• 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
All study drugs must be discontinued for use of another non−protocol-specified 
anti-cancer therapy 
• 
All study drugs must be discontinued for pregnancy 
• 
All study drugs must be discontinued for the following:  Radiographic disease 
progression per RECIST v1.1 or symptomatic deterioration attributed to disease 
progression 
 
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 ≤ 30 (close to but 
should not exceed 30) days after the final dose of study treatment (last dose of last study 
drug).  The visit at which response assessment shows progressive disease may be used 
as the treatment discontinuation visit.  The treatment discontinuation visit must occur 
prior to initiation of new anti-cancer therapy.  Patients who discontinue study treatment 
for any reason other than progressive disease will continue to undergo tumor response 
assessments, as outlined in the schedule of activities (see Appendix 1). 
After treatment discontinuation, information on survival follow-up, 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 or the Sponsor terminates the study).  All patients will be followed for 
survival information unless the patient requests to be withdrawn from study; this request 
must be documented in the source file and signed by the investigator.  If the patient 
withdraws from the study, the study staff may use a public information source (e.g., 
county records) to obtain information about survival status only.  As of protocol 
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4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  Patients should be asked to return to the clinic for a study treatment 
discontinuation visit (if applicable).  The primary reason for discontinuation from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn 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, 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 


 
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• 
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.  Atezolizumab is approved for the treatment of urothelial carcinoma, non-small 
cell lung cancer, small-cell lung cancer, and TNBC.  Atezolizumab has received 
accelerated approval in the United States for the treatment of patients with 
PD-L1−positive locally advanced or metastatic TNBC and is under evaluation by other 
health authorities for consideration for approval in metastatic TNBC.  The safety plan for 
patients in this study is based on clinical experience with ipatasertib and atezolizumab 
(as monotherapy and in various combinations) in completed and ongoing studies.  The 
anticipated important safety risks for ipatasertib, atezolizumab, and paclitaxel are 
outlined below (see Sections 5.1.1 and 5.1.3).   
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the 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.  Administration of atezolizumab and paclitaxel will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for dosage modification and treatment interruption or discontinuation, are 
provided in Appendix 13 and Appendix 14. 
The instructions provided are intended to serve as minimal safety guidance to improve 
safety and tolerability for patients to continue receiving ongoing treatment.  Investigators 
may choose to implement dosage modification, treatment interruption, and/or 
discontinuation with a lesser degree of toxicity than instructed by the guidelines.  Dose 
reductions for ipatasertib/placebo and paclitaxel are listed in Appendix 13.  Dose 
reduction for atezolizumab/placebo is not allowed.  General guidelines for dose 
modification are provided in Appendix 13. 
The iDMC will be responsible for ongoing monitoring of patient safety.  Following the 
unblinding of Cohort 1 and Cohort 2, the study team (see Safety Data Monitoring, 
Section 3.1.3) will be responsible for the ongoing monitoring of patient safety in the 
study. 


 
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Refer to Sections 5.4−5.6 for details on safety reporting (e.g., adverse events, 
pregnancies) for this study. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-γ (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. 
5.1.1 
Risks Associated with Ipatasertib 
Ipatasertib has been associated with identified risks including the following: nausea, 
vomiting, diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, 
erythema multiforme, and rash.  Ipatasertib's potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.  
Refer to Section 6 of the Ipatasertib Investigator's Brochure for a detailed description of 
anticipated safety risks for ipatasertib.  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 anti-cancer therapies. 
5.1.2 
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, hematologic toxicity, pseudomembranous colitis, and 
cardiovascular effects such as hypotension, bradycardia, hypertension, arrhythmias, and 
other ECG abnormalities.   
To be eligible for the current study, patients must have adequate hematologic function, 
as manifested by measurements of CBC counts.  Furthermore, blood cells will be 
assessed prior to each treatment cycle.  
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. 
5.1.3 
Risks Associated with Ipatasertib in Combination with 
Paclitaxel 
Ipatasertib in combination with paclitaxel has been administered to 61 breast cancer 
patients in Study GO29227 (LOTUS) and 76 patients in Study GO29505 (FAIRLANE).  


 
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In the LOTUS study, the incidence of the following adverse events related to 
ipatasertib/placebo was ≥ 10% higher in patients receiving ipatasertib plus  paclitaxel 
versus placebo plus paclitaxel:  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) experienced by patients in the ipatasertib plus  paclitaxel arm 
relative to the placebo plus paclitaxel arm were diarrhea (reported for 14 patients 
[23.0%] for all Grade 3 events vs. no 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. 
In the FAIRLANE study, the incidence of the following adverse events related to 
ipatasertib/placebo was ≥ 10% higher in patients receiving ipatasertib plus paclitaxel 
versus placebo plus paclitaxel: diarrhea (ipatasertib plus  paclitaxel:  75.0% vs. placebo 
plus paclitaxel:  26.7%), nausea (35.5% vs. 21.3%), vomiting (17.1% vs. 4.0%), and 
abdominal pain (14.5% vs. 2.7%).  Diarrhea was the only Grade ≥ 3 adverse event 
reported in at least 5% of patients in either treatment arm (ipatasertib plus paclitaxel: 
13 patients [17.1%] vs. placebo plus paclitaxel:  1 patient [1.3%]; all Grade 3 events). 
The incidence of overall neutropenia in the LOTUS study was similar in both arms (34% 
in the ipatasertib plus paclitaxel arm vs. 39% in the placebo plus paclitaxel arm), but 
Grade ≥3 neutropenia, analyzed using grouped terms of similar medical concept, was 
higher in the ipatasertib plus paclitaxel arm (18% vs. 8%).  The incidence of overall 
neutropenia in the FAIRLANE study (by group term) of any grade was similar in the 
ipatasertib plus paclitaxel arm (11 patients [14.5%]) and in the placebo plus paclitaxel 
arm (10 patients [13.3%]).  The majority of the events were Grade 2 in severity 
(ipatasertib plus paclitaxel arm:  7 patients [9.2%]) (placebo plus paclitaxel arm 
6 patients [8.0%]).  Grade 3 neutropenia was reported in 2 patients (2.6%) in the 
ipatasertib plus paclitaxel arm and 3 patients (4.0%) in the placebo plus paclitaxel arm.  
One Grade 4 adverse event was reported in 1 patient (1.3%) in the placebo plus 
paclitaxel arm.  For recurrent Grade ≥ 3 neutropenia, ipatasertib should be reduced by 
one dose level when treatment is restarted (refer to the management guidelines in 
Appendix 13).  
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 
nonclinical and clinical safety evaluation of ipatasertib given as a single agent and in 
combination with chemotherapy. 
5.1.4 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis and severe cutaneous adverse reactions.  


 
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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 13 and Appendix 14 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab. 
5.1.5 
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. 
5.1.6 
Risks Associated with Atezolizumab in Combination 
with Paclitaxel  
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and paclitaxel:  pulmonary, gastrointestinal, cardiac, 
dermatologic, hematologic, and neurologic events (refer to the Atezolizumab 
Investigator’s Brochure for details). 
5.1.7 
Risks Associated with Ipatasertib in Combination with 
Atezolizumab and Paclitaxel  
The following adverse events are potential overlapping toxicities associated with 
combination use of ipatasertib, atezolizumab, and paclitaxel:  pulmonary, 
gastrointestinal, cardiac, hepatic, dermatologic, hematologic, and neurologic events 
(refer to the Atezolizumab Investigator’s Brochure for details). 
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 


 
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a pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
• 
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 treatment 
• 
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. 


 
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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 5.3.5.6) 
• 
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 
• 
Grade ≥ 3 diarrhea 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
• 
Grade ≥ 3 hyperglycemia  
• 
Hepatitis 
• 
Grade ≥ 3 hepatotoxicity 
• 
Grade ≥ 3 ALT/AST elevations 
• 
Colitis 
• 
Systemic lupus erythematosus 
• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 


 
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• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Grade ≥ 3 rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, 
skin exfoliation, toxic skin eruption) 
• 
Severe cutaneous reactions (e.g., erythema multiforme, 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 
• 
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) 
• 
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 
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. 


 
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Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, 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 treatment, 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 nondirective questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
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 
event reporting (see Section 5.3.5.13, Patient-Reported Outcome Data), as these 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 or an adverse event of special interest, the investigator will determine 
whether the criteria for a serious adverse event or adverse events of special interest 
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 (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htmNote:  Based on the 
most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4): 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
• 
Known association of the event with study treatment or with similar treatments 


 
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• 
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 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment 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 study treatment, 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 study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment 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 study treatment 
(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 study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as 
a diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to a single administration of study 
treatment, each reaction should be recorded as a separate event on the Adverse Event 
eCRF, with signs and symptoms also recorded separately on the dedicated Infusion-
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5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  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.   


 
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For selected adverse events, grade change will be captured in order to understand 
duration of each grade of the adverse event, as well as impact of any intervention on the 
adverse event.  Details regarding any increases or decreases in severity of selected 
adverse events (e.g., diarrhea, rash, hyperglycemia; see Section 5.3.3 will be captured 
on the Adverse Event Intensity or Grade Changes eCRF.   
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. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 × ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L 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 
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5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
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).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protoco-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of TNBC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 


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event reporting period, regardless of relationship to study treatment, 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").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Triple-Negative 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.  


 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study or insertion 
of access device for study drug administration) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
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 an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
• 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
• 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Note:  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 


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


 
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• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
• 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
• 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
5.3.5.13 
Patient-Reported Outcome Data  
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.  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.   
5.3.5.14 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 


 
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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites 
Medical Monitor/Roche Medical Responsible: 
, M.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 Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to 
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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 Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will 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 
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 after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 28 days after the final dose of ipatasertib/placebo, 5 months after the final dose of 
atezolizumab/placebo, or 6 months after the final dose of paclitaxel, whichever occurs 
later.  A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.   


 
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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 or 
within 28 days after the final dose of ipatasertib/placebo, or 6 months after the final 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 treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryo−fetal 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 
embryo−fetal 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 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 


 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, or the event is assessed as stable by the investigator, or 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 treatment or trial-related 
procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 5.3.1 ), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient's 
medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.   
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 


 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through the use of the following reference 
safety information in the documents listed below: 
Drug 
Document 
Ipatasertib 
Ipatasertib Investigator's Brochure  
Atezolizumab 
Atezolizumab Investigator’s Brochure 
Paclitaxel 
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. 
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 
This is a Phase III, two-cohort, randomized, placebo-controlled, double-blind study 
designed to evaluate the efficacy and safety of the combination of atezolizumab, 
ipatasertib, and paclitaxel in approximately 1155 patients with locally advanced 
unresectable or metastatic TNBC.  This includes approximately 525 patients with 
PD-L1−non-positive tumors in Cohort 1 and 630 patients with PD-L1−positive tumors in 
Cohort 2.  
Depending on the timing of the respective primary PFS analysis for these two cohorts, 
Cohort 1 and Cohort 2 may be unblinded separately.  In such case, the treatment codes 
of patients in the cohort whose PFS data mature earlier will be sent to the Sponsor to 
unblind only that cohort to perform the primary analysis of PFS.  The Sponsor will remain 
blinded to the treatment assignments of the other cohort. 
As of protocol Versions 4 and 5, statistical considerations and the analyses outlined in  
Section 6 are no longer applicable to the study as indicated in the respective sections.  
Due to the early termination of the enrollment, data from enrolled patients will only be 
summarized descriptively for  endpoints that are deemed appropriate and necessary 
(e.g., demographics, disposition, and adverse events). 
6.1 
DETERMINATION OF SAMPLE SIZE 
6.1.1 
Type I Error Control 
Cohort 1 (patients with PD-L1−non-positive tumors) and Cohort 2 (patients with 
PD-L1−positive tumors) are two independent cohorts and will be analyzed separately for 
all endpoints unless otherwise specified.  Each cohort will be tested independently with 
an overall 5% type I error control as illustrated in Figure 2.  


 
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Figure 2 Type I Error Control 
 
OS = overall survival; PFS = progression-free survival. 
 
For Cohort 1, the overall type I error (α) is 0.05 (two sided) and is split among the 
co-primary efficacy endpoints: 0.01 for PFS for Arm A versus Arm C, 0.01 for PFS for 
Arm B versus Arm C, and 0.03 for OS.  PFS for Arm A versus Arm C and Arm B versus 
Arm C will be tested independently, whereas OS will be tested in a hierarchical 
sequence of Arm A versus Arm C followed by Arm B versus Arm C.  The PFS data will 
mature earlier and PFS will be firstly tested with α of 0.01 for Arm A versus Arm C and 
0.01 for Arm B versus Arm C.  When a PFS test is passed at an α level of 0.01, that 0.01 
α assigned will be recycled to OS (i.e., OS will be tested at the significance level of 0.05 
[if both PFS tests are passed] or 0.04 [if only one PFS test is passed]; otherwise, OS will 
be tested at the significance level of 0.03 [when neither PFS tests is passed] to control 
the overall type I error at 0.05). 
For Cohort 2, the overall type I error (α) is 0.05 (two sided) and is split between the two 
co-primary efficacy endpoints PFS and OS.  The PFS data will mature earlier and PFS 
will be firstly tested with α of 0.01.  If the PFS test is passed at the significance level of 
0.01, the 0.01 α assigned to PFS will be recycled to OS (i.e., OS will be tested at the 
significance level of 0.05; otherwise, OS will be tested at the significance level of 0.04 to 
control the overall type I error at 0.05).  
6.1.2 
Sample Size Consideration for Cohort 1 
The following statistical considerations were applicable prior to the termination of 
enrollment on 18 September 2020 and subsequent unblinding of Cohort 1 on 
21 September 2020.  At that time, a total of 127 patients had been enrolled in Cohort 1. 
Approximately 525 patients will be enrolled and randomized in a 1:1:1 ratio to Arm A 
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placebo) and Arm C (paclitaxel plus placebo plus placebo).  The sample size is 
determined by the co-primary endpoints: PFS comparing Arm A versus Arm C, PFS 
comparing Arm B versus Arm C, and OS comparing Arm A versus Arm C. 
The primary analysis of PFS will be conducted when approximately 239 PFS events 
from all three arms (including approximately 171 PFS events for the comparison of Arm 
B vs. Arm C and approximately 166 PFS events for the comparison of Arm A vs. Arm C) 
are observed or when the last patient has been randomized, whichever occurs later.   
With 172 PFS events for the comparison of Arm B versus Arm C, this allows for 80% 
power to detect an improvement in median PFS from 5.6 months to approximately 9.4 
months (hazard ratio = 0.593) at the 1% level of significance (two sided).  The largest 
hazard ratio deemed to be statistically significant at the 1% level will be approximately 
0.675 (with median improvement in PFS from 5.6 to 8.3 months).  With 166 PFS events 
for the comparison of Arm A vs. C, this allows for 94% power to detect an improvement 
in median PFS from 5.6 months to approximately 10.6 months (hazard ratio = 0.528) at 
the 1% level of significance (two sided).  The largest hazard ratio deemed to be 
statistically significant at the 1% level will be approximately 0.670 (with median 
improvement in PFS from 5.6 to 8.4 months). 
If the 0.02 α assigned to PFS is recycled, the co-primary endpoint, OS, will be tested at 
the 5% level of significance (two sided).  The final OS analysis will be conducted when 
approximately 216 OS events for the comparison of Arm A vs. Arm C are observed.  
With α spending to the interim analyses of OS (see details in Section 6.9.2.1), at the OS 
final analysis, 216 OS events for the comparison of Arm A vs. C will allow for 80% power 
to detect an improvement in median OS from 18.4 to 27.1 months (hazard ratio = 0.680) 
at the 5% level of significance (two sided).  The largest OS hazard ratio deemed to be 
statistically significant will be approximately 0.759 (with median OS improvement from 
18.4 to 24.2 months). 
If the 0.02 α assigned to PFS is not recycled or only 0.01 α is recycled, the co-primary 
endpoint, OS, will be tested at the 3% or 4% level of significance (two sided), 
respectively.  The final OS analysis timing and the require number of OS events will be 
adjusted accordingly to allow 80% power to detect an improvement in median OS from 
18.4 to 27.1 months (hazard ratio = 0.680) at the 3% or 4% level of significance (two 
sided).  Further details will be provided in the Statistical Analysis Plan. 
The enrollment duration is projected to be approximately 22 months (from the first 
patient randomized).  For all three arms, an annual loss to follow-up rate of 5% and 2% 
are assumed for PFS and OS, respectively.  Based on these, it is projected that the 
primary PFS analysis will occur when the last patient is randomized, and the final OS 
analysis is projected to occur approximately 49 months after the first patient is enrolled, 
if the 0.02 α assigned to PFS is recycled for OS. 


 
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6.1.3 
Sample Size Consideration for Cohort 2 
The following statistical considerations were applicable prior to the termination of 
enrollment on 6 August 2020 and subsequent unblinding of Cohort 2 on 7 August 2020.  
At that time, a total of 115 patients had been enrolled in Cohort 2.  
Approximately 630 patients will be enrolled and randomized in a 1:1 ratio to Arm A 
(ipatasertib plus atezolizumab plus paclitaxel) and Arm B (atezolizumab plus paclitaxel 
plus placebo).  
The primary analysis of PFS will be conducted when approximately 228 PFS events are 
observed or when the last patient has been randomized, whichever occurs later.  Based 
on the enrollment assumption, it is most likely driven by the last patient’s randomization 
as described at the end of this section. 
With 228 PFS events, this allows for 80% power to detect an improvement in median 
PFS from 7.5 to approximately 11.8 months (hazard ratio = 0.636) at the 1% level of 
significance (two sided).  The largest hazard ratio deemed to be statistically significant at 
the 1% level will be approximately 0.711 (with median improvement in PFS from 7.5 to 
10.5 months). 
If the 0.01 α assigned to PFS is recycled, the co-primary endpoint, OS, will be tested at 
the 5% level of significance (two sided).  The final OS analysis will be conducted when 
approximately 417 OS events are observed.  With α spending to the interim analyses of 
OS (see details in Section 6.9.2.2), at the OS final analysis, it will allow for 80% power to 
detect a hazard ratio of 0.758 (median OS improvement from 25 to 33 months) at the 5% 
level of significance (two sided).  The largest OS hazard ratio deemed to be statistically 
significant will be approximately 0.820 (with median OS improvement from 25 to 
30.5 months). 
If the 0.01 α assigned to PFS is not recycled, the co-primary endpoint, OS, will be tested 
at the 4% level of significance (two sided).  The final OS analysis will be conducted when 
approximately 444 OS events are observed.  With α spending to the interim analyses of 
OS (see details in Section 6.9.2.2), at the OS final analysis, it will allow for 80% power to 
detect a hazard ratio of 0.758 (median OS improvement from 25 to 33 months) at the 4% 
level of significance (two sided).  The largest OS hazard ratio deemed to be statistically 
significant will be approximately 0.818 (with median OS improvement from 25 to 
30.6 months). 
The enrollment duration is projected to be approximately 36 months (from the first 
patient randomized).  For both arms, an annual loss to follow-up rate of 5% and 2% are 
assumed for PFS and OS, respectively.  Based on these, it is projected that the primary 
PFS analysis will occur when the last patient is randomized, and it is predicted that there 
will be approximately 372 PFS events.  With 372 PFS events, the largest hazard ratio 
deemed to be statistically significant at the 1% level will be approximately 0.766 (with 


 
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median PFS improvement from 7.5 to 9.8 months).  The final OS analysis is projected to 
occur approximately 70 months after the first patient is enrolled, if the 0.01 α assigned to 
PFS is recycled for OS. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment and duration, study drug discontinuation, study discontinuation, 
reasons for study drug discontinuation and study discontinuation will be summarized by 
treatment arm independently for each cohort.  Major protocol deviations, including major 
deviations of inclusion/exclusion criteria, will also be reported and summarized by 
treatment arms independently for each cohort. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
The independent evaluation of treatment group comparability between the treatment 
arms in each cohort will include demographics summaries, stratification factors, patient 
treatment history, and other baseline disease characteristics.  
Continuous data will be summarized with means, standard deviations, and medians and 
ranges.  Categorical data will be summarized by counts and proportions. 
6.4 
EFFICACY ANALYSES 
Efficacy analyses will be performed independently for each cohort.  All efficacy analyses 
will be based on the ITT population within each cohort according to the treatment arm to 
which patients are allocated.  The analysis of DOR will include all patients with an 
objective response. 
All primary and secondary endpoints based on tumor burden will be based on 
radiological (or photographic, if applicable) assessments by the local radiologist or 
investigator, unless otherwise specified. 
6.4.1 
Co-Primary Efficacy Endpoints 
The co-primary efficacy endpoints are investigator-assessed PFS and OS. 
Investigator-assessed PFS, defined as the time from randomization to the first 
occurrence of disease progression, as determined locally by the investigator using 
RECIST v1.1 (see Appendix 5) or death from any cause, whichever occurs first.  Data 
for patients without the occurrence of disease progression or death as of the clinical data 
cutoff date will be censored at the time of the last tumor assessment (or at the time of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit). 
OS is defined as the time from randomization to death from any cause.  Data for patients 
who have not died as of the clinical data cutoff date will be censored at the last date they 
are known to be alive.  Data for patients who do not have postbaseline information will 
be censored at the randomization plus 1 day. 


 
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Both PFS and OS 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.  For each treatment arm, Kaplan-Meier 
methodology will be used to estimate the median PFS and OS, and the 
Brookmeyer-Crowley method will be used to construct the 95% CI for the median PFS 
and OS (Brookmeyer and Crowley 1982).  Kaplan-Meier curves will be produced as well. 
6.4.2 
Exploratory Efficacy Endpoints 
6.4.2.1 
Objective Response Rate 
An objective response is defined as response (CR or PR) on two consecutive occasions 
≥ 4 weeks apart, as determined by the investigator using RECIST v1.1.  Patients not 
meeting these criteria, including patients without any postbaseline tumor assessment, 
will be considered non-responders.  ORR is defined as the proportion of patients who 
had an objective response.  The analysis population for ORR will be all randomized 
patients with measurable disease at baseline.  
An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson 
method for each treatment arm.  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 used 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. 
6.4.2.2 
Duration of Response 
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time from the first occurrence of 
a documented objective response (CR or PR, whichever status is recorded first) to the 
first occurrence of progressive disease, as determined by the investigator according to 
RECIST v1.1, or death, whichever occurs first.  Patients who have not progressed and 
who have not died at the time of analysis will be censored at the time of last tumor 
assessment date.   
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. 
6.4.2.3 
Clinical Benefit Rate 
CBR is defined as the proportion of patients who have a CR, PR, or stable disease for at 
least 24 weeks, as determined by the investigator using RECIST v1.1.  The CBR will be 
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6.4.2.4 
Patient Subgroup Analysis in Each Cohort 
The co-primary endpoints, PFS and OS, and key secondary endpoints ORR, DOR, and 
CBR will also be explored in two subgroups:  patients with PIK3CA/AKT1/PTEN-altered 
tumors and patients without PIK3CA/AKT1/PTEN -altered tumors. 
6.4.2.5 
Patient-Reported Outcomes of Role and Physical Function and 
GHS/QoL and EORTC Data  
The main PRO endpoints are the mean and the mean change from baseline scores in 
function (role, physical) and GHS/QoL.  Summary statistics (mean, standard deviation, 
median, and range) of linearly transformed absolute scores and the mean change from 
baseline will be calculated for the Functional (role [Questions 6 and 7], physical 
[Questions 1−5]) and the GHS/QoL (Questions 29 and 30) scales of the EORTC 
QLQ-C30 at each assessment timepoint for each arm.  The mean (and 95% CI) and 
median of the absolute scores and the change from baseline will be reported for interval 
and continuous variables.  Previously published minimally important differences will be 
used to identify clinically meaningful change from baseline within each treatment group 
on the Functional and GHS/QoL scales (Osoba et al. 1998; Cocks et al. 2011). 
The EORTC QLQ-C30 (Version 3) data will be scored according to the EORTC scoring 
manual (Fayers et al. 2001).  PRO completion, compliance rates, and reasons for 
missing data will be summarized at each timepoint by treatment arm.   
Missing data will be assessed and reported by cycle.  In the event of incomplete data, for 
all questionnaire subscales, if > 50% of the constituent items are completed, a pro-rated 
score will be computed consistent with the scoring manuals and validation papers.  For 
subscales with < 50% of the items completed, the subscale will be considered as 
missing.  
6.4.2.6 
Progression-Free Survival 2 (PFS2) 
PFS2 is defined as the time from randomization to second occurrence of objective 
disease progression, as determined by the investigator using RECIST v1.1, or death 
from any cause (whichever occurs first).  Data for patients alive and for whom a second 
objective disease progression has not been observed should be censored at the last 
time known to be alive and without second objective disease progression.  This analysis 
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6.4.2.7 
Patient-Reported Outcomes of Disease- and Treatment-Related 
Symptoms, and Cognitive, Emotional, and Social Function:  
EORTC Data 
Summary statistics (mean, standard deviation, median, and range) of linearly 
transformed absolute scores and mean change from baseline scores will be calculated 
for all disease/treatment-related symptom items and scales, and the Cognitive, 
Emotional, and Social Function scales of the EORTC QLQ-C30 (see Appendix 10) at 
each assessment timepoint for each arm.   
6.4.2.8 
Health Economic EQ-5D-5L Data 
Health utility data from the EQ-5D-5L (see Appendix 11) will be evaluated in 
pharmacoeconomic models.  The results from the health economic data analyses will be 
reported separately from the Clinical Study Report. 
6.5 
SAFETY ANALYSES 
6.5.1 
Analyses of Exposure, Adverse Events, Laboratory Data, and 
Vital Signs  
All safety analyses will be based on the safety-evaluable population (i.e., all patients who 
receive any study treatment) according to the treatment received.  
The frequency, nature, and severity of treatment-emergent adverse events, adverse 
events leading to death, adverse events leading to study drug discontinuation and dose 
modification, serious adverse events, and adverse events of special interest will be 
summarized by treatment arm.  All deaths will be summarized.  Laboratory 
measurements outside of the normal range will be identified.  Selected laboratory data 
will be summarized by treatment received and grade compared with baseline.  Relevant 
vital signs will be presented using summary statistics by treatment received and visit.  
Drug exposure will be summarized as well, including duration of treatment, cumulative 
dose, and dose intensity. 
Treatment-emergent adverse events are defined as adverse events that occur after the 
first dose of study treatment.  Adverse events will be summarized by mapped MedDRA 
preferred terms and appropriate MedDRA hierarchy.  Adverse event severity will be 
graded according to NCI CTCAE v5.0.  Multiple occurrences of the same event will be 
counted once at the maximum severity. 
6.5.2 
Exploratory Safety Analysis of Patient-Reported Symptomatic 
Adverse Events:  PRO-CTCAE Data 
PRO-CTCAE analyses will be primarily descriptive, with a focus on characterizing the 
pattern of symptomatic treatment toxicities during the study.  Results from these 
exploratory analyses will be presented separately from the safety analyses for each 
cohort.  PRO-CTCAE data will be analyzed at the item level consistent with current NCI 
recommendations for data handling (Basch et al. 2014).  


 
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PRO-CTCAE data will be summarized over time.  The proportion of missing data at each 
assessment timepoint will also be summarized to facilitate interpretation of data. 
The number and percentage of patients reporting each symptom, including overall side 
effect bother, and the change from baseline by category (frequency of occurrence, 
severity, interference) will be summarized at each assessment timepoint by treatment 
arm.  For items that are rated on a 5-point Likert scale, the maximum postbaseline score 
and change from baseline will be summarized by treatment arm.  
Graphical representation of PRO-CTCAE data over time will also be provided. 
6.6 
EXPLORATORY PHARMACOKINETIC ANALYSES 
For each cohort, atezolizumab, ipatasertib, and G-037720, a metabolite of ipatasertib, 
serum or plasma concentration versus time data, together with information on dosing 
and patient characteristics, will be analyzed using a population-PK analysis approach.  
Concentration−time data will be compared with existing models to determine if 
exposures are consistent with previously characterized pharmacokinetic.  Samples will 
also be used to characterize the immunogenicity of atezolizumab.  Nonlinear 
mixed-effect modeling will be used for the estimation of population-PK parameters for 
the relevant analytes.  Covariates, such as patient demographics (e.g., age, sex, body 
size), total protein, serum albumin, liver function tests (e.g., AST, ALT, and ALP), and 
serum creatinine will be tested for significance on PK parameters of interest, as needed. 
For each cohort, the PK data will be combined with the safety and efficacy (e.g., PFS) 
data for exposure−response modeling as data permit for one or both study drugs, as 
appropriate.  PK and PK/pharmacodynamic analyses may be reported in separate 
stand-alone reports.  Additional analyses may be explored as warranted by the data.  
Population-PK results may be reported separately. 
Additional analyses may be explored as warranted by the data. 
6.7 
EXPLORATORY IMMUNOGENICITY ANALYSES  
Immunogenicity will be independently evaluated for each cohort.  The immunogenicity 
analysis population will consist of all patients with at least one ADA assessment.  
Patients will be grouped according to treatment received or, if no treatment is received 
prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA-positive if they are ADA-negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
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baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA-negative if they are ADA-negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA-positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60-titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics. 
6.8 
EXPLORATORY BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and may also be explored in aggregate with 
data from other studies.  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.  Biomarker analyses may be reported in a separate report. 
6.9 
INTERIM ANALYSES 
6.9.1 
Planned Interim Safety Analyses 
An external iDMC will be formed to evaluate safety data in Cohorts 1 and 2 on a periodic 
basis, approximately every 6 months from the time of the first patient’s enrollment until 
the time of the primary analysis of PFS for both cohorts are complete.  All 
summaries/analyses by treatment arm for the iDMC's review will be prepared by an 
external iDCC for each cohort.  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. 
In the absence of extenuating circumstances, accrual will not be halted while the interim 
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.  The final decision will rest 
with the Sponsor.  In addition, the Sponsor may request ad-hoc meetings of the iDMC at 
any time during the study to review ongoing safety summary data. 
Due to the early termination of enrollment and unblinding of patients, the iDMC’s review 
of the ongoing safety summary data will be terminated after the unblinding.  The study 
team (see Safety Data Monitoring, Section 3.1.3 ) will be responsible for the ongoing 
monitoring of patient safety in the study. 


 
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6.9.2 
Planned Interim Analysis of OS at the Primary Analysis of PFS 
6.9.2.1 
Planned Interim OS Analysis for Cohort 1 
The following statistical considerations were applicable prior to the early termination of 
enrollment on 18 September 2020 and subsequent unblinding of Cohort 1 on 
21 September 2020, and they are not appliacable as of protocol V5. 
There are two planned OS interim analyses for the comparisons across the three 
treatment arms.  The first OS interim analysis will be performed at the time of PFS 
analysis.  The second OS interim analysis will be performed when around 80% of the 
OS events required for the final OS analysis for the comparison of Arm A versus Arm C 
is reached.  As shown in Figure 2 in Section 6.1.1, OS will be tested in a hierarchical 
sequence of Arm A versus Arm C followed by Arm B versus Arm C, and the Lan-DeMets 
α-spending function with an O’Brien-Fleming boundary will be used to control the type I 
error accounting for the interim and final analyses of OS.  The comparison of Arm A 
versus Arm B will be conducted for descriptive purposes only with no type I error control.  
If the 0.02 α assigned to PFS is recycled, the final OS will be analyzed when 216 OS 
events for the comparison of Arm A vs. Arm C occur at approximately 49 months after 
the first patient has been enrolled.  It is estimated that there will be approximately (76, 
176, 216) OS events at the first interim, the second interim, and the final OS analyses for 
the comparison of Arm A versus Arm C, with corresponding p-value boundaries of 
(0.0003, 0.0259, 0.0424) and hazard ratio boundaries of (0.438, 0.715, 0.759) at the first 
interim, the second interim, and the final OS analysis for the comparison of Arm A 
versus Arm C, respectively.  The actual boundaries will be adjusted according to the 
actual information fractions at the interim analyses using the Lan-DeMets α-spending 
function with an O’Brien-Fleming boundary.  
If the 0.02 α assigned to PFS is not recycled or only 0.01 α is recycled, the final OS 
analysis timing, the required number of OS events, the p-value and hazard ratio 
boundaries for the interim and final analyses will be adjusted accordingly.  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. 
At the time of each OS analysis, OS test comparing Arm B versus Arm C will be formally 
performed only if the OS test comparing Arm A versus Arm C is passed with statistical 
significance; otherwise, OS test for Arm B versus C will be descriptive only.  When 
comparison of Arm B versus Arm C is formally tested, the same p-value and hazard ratio 
boundaries used by Arm A versus Arm C comparison will be used, so that the overall 
type I error of 5% is controlled.  The OS test for Arm A versus Arm B will be performed 
descriptively only.  Further details will be provided in the Statistical Analysis Plan. 


 
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6.9.2.2 
Planned Interim OS Analysis for Cohort 2 
The following statistical considerations were applicable prior to the termination of 
enrollment on 6 August 2020 and subsequent unblinding of Cohort 2 on 7 August 2020, 
and they are not appliacable as of protocol V4. 
There are two planned OS interim analyses for the comparisons between the two 
treatment arms.  The first OS interim analysis will be performed at the time of PFS 
analysis.  The second OS interim analysis will be performed when 80% of the OS events 
required for the final OS analysis is reached.  The Lan-DeMets α-spending function with 
an O’Brien-Fleming boundary will be used to control the type I error accounting for the 
interim and final analyses of OS.  
If the 0.01 α assigned to PFS is recycled, the final OS will be analyzed when 417 OS 
events occur at approximately 70 months after the first patient has been enrolled.  It is 
estimated that there will be approximately (184, 334, 417) OS events at the first interim, 
the second interim and the final OS analyses, with corresponding p-value boundaries of 
(0.0015, 0.0204, 0.0427) and corresponding hazard ratio boundaries of (0.626, 0.781, 
0.820) at the first interim, the second interim, and the final OS analysis, respectively.  
The actual boundaries will be adjusted according to the actual information fractions at 
the interim analyses using the Lan-DeMets α-spending function with an O’Brien-Fleming 
boundary. 
If the 0.01 α assigned to PFS is not recycled, the final OS will be analyzed when 444 OS 
events occur at approximately 76 months after the last patient has been enrolled.  It is 
estimated that there will be approximately (184, 355, 444) OS events at the first interim, 
the second interim and the final OS analysis, with corresponding p-value boundaries of 
(0.0006, 0.0183, 0.0345) and corresponding hazard ratio boundaries of (0.603, 0.779, 
0.818) at the first interim, the second interim, and the final OS analysis, respectively.   
6.10 
CHINA SUBPOPULATION ANALYSES  
Due to the early termination of the enrollment, this section is no longer applicable. 
After the enrollment of patients in the global phase of this study is complete, additional 
Chinese patients may be recruited into the China extension cohort.  Data from the 
additional patients enrolled during the China extension phase will not be included in the 
analysis of the global study.  The analysis population for China subpopulation analyses 
includes Chinese patients recruited in the global study population and China extension 
cohort combined.  The total number of patients in China subpopulation is aimed to show 
treatment benefit consistency between global population and the China subpopulation.  
Similar to the global study, the enrollment of China extension in Cohort 1 and Cohort 2 
may be closed separately depending on when the required number of patients in the 
China subpopulation in each cohort is reached.  A prespecified clinical data cutoff for the 
China subgroup analysis will be planned before the PFS primary analysis. 


 
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China subpopulation analyses will be performed and summarized in a separate study 
report.  Further details will be provided in the Statistical Analysis Plan.  
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.  Data from these questionnaires will 
be entered into the EDC system by site staff on the eCRFs.  
Patient diaries to document specific home medication use, selected adverse events, and 
possibly home glucose values, will be collected in paper diaries.  Selected data from 
these and diaries 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 that must be kept with the study records.  Acknowledgement of receipt 
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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 on 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, 
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 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, medication inventory records, and images must be retained by the Principal 
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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 study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
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 
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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. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
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 
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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 


 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.  
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits areprovided in 
a Quality Tolerance Limit Management Plan. 


 
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9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Up to 350 sites globally will participate to randomize approximately 1155 patients.  
Screening and enrollment will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.9.  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 throughout the study.  
Tumor response and progression will be evaluated by an independent review committee. 
As of protocol Version 5, images for tumor assessments will no longer be collected for 
blinded independent central review. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following website: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
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 


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


 
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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. 
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. 
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. 
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. 
Zhou H, Mascelli MA. Mechanisms of monoclonal antibody−drug interactions. Annu Rev 
Pharmacol Toxicol 2011;51:359−72.


 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol CO41101, Version 6 
Appendix 1 Schedule of Activities  
Table 1 
Schedule of Activities: Applicable before unblinding 
 
Assessment/Procedure 
Screening 
(Days −28 
to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 
D15 
D1 D8 
D15 
D1 
D8 
D15 
Signed informed consent(s)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology d 
x d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical history, and 
prior cancer treatment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue sample submitted at 
screening e 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for WGS f 
 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for biomarkers g 
 
x g 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Complete physical examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination i 
 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
 
x 
 
Weight  
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance Status 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Cardiac function (ECHO or MUGA 
scan) 
x k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG l 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol CO41101, Version 6 
Assessment/Procedure 
Screening 
(Days −28 
to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 
D15 
D1 D8 
D15 
D1 
D8 
D15 
Hematology m 
x 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x 
 
INR and PTT (or aPTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Fasting serum chemistry o 
x 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x n 
x 
 
TSH, free T3 (or total T3), free T4 p 
x 
x 
 
 
 
 
 
x 
 
 
x p 
 
 
x 
 
Fasting lipid profile, and amylase 
and lipase q 
x 
 
 
 
x q 
 
 
 
 
 
x q 
 
 
x 
 
HbA1C 
x 
x 
 
 
x  
 
 
x 
 
 
x  
 
 
x 
 
C-reactive protein r 
 
x r 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis s 
x 
As clinically indicated 
x 
 
Pregnancy test t 
x 
x t 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Tumor assessments u 
x 
 
 
 
x v 
 
 
 
 
 
x v 
 
 
x w 
x w 
Bone scan 
x x,y 
See Footnotes "x” and “y." 
x x,y 
x x,y 
Head scan (CT or MRI scan) 
x x,z 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis with 10 mg of 
prednisone (or equivalent) for 3−5 
consecutive days aa, bb 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Daily antihistamine prophylaxis bb 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis antidiarrheal (2 mg of 
loperamide BID 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) bb 
 
If side effects are not tolerated, doses may be reduced.  After one 
cycle without any diarrhea, continuation is at physician's discretion.   
If diarrhea occurs, it should be managed per the guidelines in 
Appendix 13, Table 2; antidiarrheal treatment should also be resumed 
with loperamide prophylaxis as needed. 
 
 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol CO41101, Version 6 
Assessment/Procedure 
Screening 
(Days −28 to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 D15 
D1 D8 
D15 
D1 
D8 
D15 
Ipatasertib/placebo 
dispensing and accountability 
 
x cc 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
Atezolizumab/placebo 
administration 
 
x cc 
 
x  
x 
 
x 
x 
 
x 
x 
 
x 
 
 
Paclitaxel administration dd 
 
x cc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Record all historical 
cancer-related medications, 
radiotherapy, and surgical 
procedures 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Concomitant medications ee 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events ff 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x ff 
x gg 
EORTC QLQ-C30 hh, ii 
 
x 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x ii 
PRO-CTCAE hh 
 
x 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
EQ-5D-5L hh,ii 
 
x 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x ii 
PK and ADA samples  
 
Refer to Appendix 2 for the PK and ADA sample collection.  
 
Tumor tissue sample 
obtained at time of 
progression (optional) jj 
 
 
 
 
 
 
 
 
 
 
 
 
 
x jj 
 
Site personnel review of 
patient diary (medication, 
dosing log, and kit ID) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol CO41101, Version 6 
ADA = anti-drug antibody; BID = twice a day; CT = computed tomography; D = day; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic Case Report Form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire−Core 30; EQ-5D-5L = EuroQol 5-Dimension Questionnaire, 5-Level Version; FNA = fine-needle aspiration; HbA1C = glycosylated 
hemoglobin; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV−hepatitis B virus; HCV = hepatitis C virus; QoL = quality of 
life; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; NGS = next-generation sequencing; PK = pharmacokinetic; 
PRO = patient-reported outcome; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; 
RBR = Roche Biosample Repository; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SDDV = study drug discontinuation 
visit; T3 = triiodothyronine; T4 =  thyroxine; 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 4.1.1.1.  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.  Please note that with rare exception, the actual study visit and IV study treatment administration should only occur on Days 1, 
8, 15, or on Day 22 if any of the prior days must be skipped.  Visit windows may be utilized to accommodate holidays, vacations, and unforeseen 
delays; however, study cycle day count continues without breaks (a sample calendar is presented in Appendix 6. 
b The SDDV should occur approximately ≤ 28 days after the last administration of ipatasertib/placebo, atezolizumab/placebo, or paclitaxel, 
whichever is discontinued last, or prior to initiation of another anti-cancer treatment.  If it is anticipated that the patient will be unable to return for 
a visit, then it is acceptable to perform this visit on the date of last study drug discontinuation.   
c After treatment discontinuation, PROs and information on survival follow-up and new anti-cancer therapy (including targeted therapy and 
immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless 
the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be 
documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only.  As of protocol Version 6, these long-term follow-up 
assessments are no longer required. 
d Viral serology includes HIV, HBsAg, total HBcAb, and HCV antibody.  HIV serology will be performed as per local standard after any applicable 
local consenting requirement is met.  HBV serology includes HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) 
HBV DNA.  If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to 
determine if the patient has an HBV infection, prior to randomization.  HCV serology includes HCV antibody and (if HCV antibody test is positive) 
HCV RNA.  If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has 
an HCV infection, prior to randomization.  If HCV antibody is positive, then need to test HCV RNA to confirm that HCV RNA is undetectable. 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol CO41101, Version 6 
e Archival tissue (either formalin-fixed, paraffin-embedded tumor specimens or a minimum of 15 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 is preferred.  If less than 15 slides or only two 
cores are available, a patient may still be eligible for the study, after Sponsor approval has been obtained and if sample contains a minimum of 
50 viable tumor cells that preserve cellular context and tissue architecture regardless of needle gauge or retrieval method. 
f Not applicable for a site that has not been granted approval for WGS.  Samples will be collected on Day 1 of Cycle 1 only. 
g To be performed on Day 1 of Cycle 1, the first tumor assessment ± 7 days, and at the study drug discontinuation visit.  Blood should be drawn 
before the administration of any study drug, if applicable. 
h A complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
i Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated. 
j Vital signs include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature while the patient is sitting 
or supine in a comfortable position.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  
At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Vital signs should be measured 
within 60 minutes prior to each in-clinic ipatasertib/placebo administration, atezolizumab/placebo infusion (one set may be performed to cover 
predose vital signs for both drug administrations), and between atezolizumab/placebo and paclitaxel infusions (on days when both drugs are 
administered).  Refer to Section 4.5.5, Table 2, for the timing of vital sign measurements for the first and subsequent infusions.  On days when no 
atezolizumab/placebo is given, one set may be performed as predose vital signs for both ipatasertib/placebo and paclitaxel.  On paclitaxel 
dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  Vital signs may be repeated if clinically indicated, 
during the infusion.  
k Perform within 12 weeks prior to Day 1 of Cycle 1.  If the left ventricular ejection fraction 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 scan), if this is 
consistent with local standard practice. 
l A single 12-lead ECG measurement at screening and at the treatment discontinuation visit and may be obtained at unscheduled timepoints as 
clinically indicated (refer to Section 4.5.8).  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 
the ECG recording. 
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).  
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol CO41101, Version 6 
n Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic with at least 8-hour fasting for glucose 
measurement as indicated.  The chemistry and hematology results should be available to assess prior to dosing.  
o Fasting serum chemistry panel (following ≥8-hour fast) includes glucose (plasma glucose is also acceptable per local practice), bicarbonate or 
total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, magnesium, BUN or urea, creatinine, 
total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH.  At investigational sites in countries where bicarbonate may 
not be collected as part of the standard chemistry panel, bicarbonate will not be measured.  Chemistry evaluation to be conducted per local 
guidelines. 
p 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.). 
q Fasting lipid profile, which includes total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides performed following a ≥ 8-hour fast, as 
well as (fasting or non-fasting) amylase, and lipase will be assessed at screening, every 3 cycles starting on Day 1 of Cycle 3 and at treatment 
discontinuation visit. 
r C-reactive protein in serum collections will be assessed only on Day 1 of Cycle 1 prior to dosing. 
s Urinalysis consists of pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
t For women of childbearing potential, a negative serum pregnancy test must be confirmed either within 96 hours of Day 1, Cycle 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).  In addition, pregnancy tests (serum or urine) are to be performed within 96 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 before any 
further study treatment may be administered.  For all other women, documentation must be present in medical history confirming that patient is 
not of childbearing potential.   
u 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.  Please note that PET/CT imaging is not an acceptable 
alternative to CT or MRI, unless the CT portion of the PET/CT scan is of diagnostic quality; in such cases where the CT portion is of diagnostic 
quality, consult with the Medical Monitor prior to using PET/CT for study-related tumor assessments.  
v Tumor assessments should be calculated from Day 1 of Cycle 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 (refer to the sample calendar in Appendix 6. 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol CO41101, Version 6 
w At treatment discontinuation visit, tumor assessments should be performed only if not performed within the previous 6 weeks.  If a patient 
discontinues from study treatment 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 weeks until documented progressive disease per RECIST v1.1, elective 
withdrawal from the study, or study completion or termination. 
x Images for tumor assessments will be prospectively collected to enable retrospective blinded independent central review. 
y 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 on contrast-enhanced CT or MRI scan 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 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 weeks until documented progressive disease per RECIST v1.1.  Please note that positron emission tomography imaging is not an 
acceptable alternative to the bone scan.  
z Perform contrast-enhanced CT or MRI scan of head within 6 weeks prior to Day 1 of Cycle 1. 
aa For the first cycle (or the first 28 days of triplet combination dosing) only:  On days when patients will receive atezolizumab (typically, on 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 administration is 
to give at least 10 mg/day prednisone on the day of paclitaxel, then the additional 10 mg of 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 a 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. 
bb Following the unblinding of treatment assignments in Cohort 2, rash, and antidiarrheal prophylaxis is no longer applicable to patients in Arm B of 
Cohort 2.  
cc 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 on days when 
the patient will receive both atezolizumab and paclitaxel.  Please note that non-dosing of initial study drug on the day of enrollment may impact 
accurate data entry on the eCRFs, which are located in folders specifically labeled with the number of cycles and days.  Following the unblinding 
of treatment assignments in Cohort 2, placebo for ipatasertib will no longer be administered to patients in Arm B of Cohort 2. 
dd If the patient's weight changes by > 10% from baseline during the study, the body surface area and dose of paclitaxel should be recalculated.  
Recalculation based on a lesser change from baseline weight is left to the investigator’s discretion.  


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol CO41101, Version 6 
ee At screening and on 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 antidiarrheal and pain 
medications, antihistamines, steroids, and other premedications at each dosage change should be recorded by patients using the diary to record 
daily ipatasertib/placebo dosing and specifically any antidiarrheal, antihistamine, or analgesic medications used (prescribed or over the counter) 
taken during that cycle of treatment.  The intake of analgesic, antihistamine, and loperamide medications will be reported on the Analgesics 
Medication, Antihistamine, and Targeted Loperamide Concomitant Medications eCRF, respectively (see Section 4.5.2). 
ff After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the final dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  After this period, 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.  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.   
gg 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 final dose of study drug).  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.  
hh 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 in this order (EORTC QLQ-C30 
first, then PRO-CTCAE second, followed by the EQ-5D-5L last) on Day 1 of each cycle, on Day 15 of Cycles 1 and 2, and at the SDDV visit.  The 
PRO-CTCAE questionnaire will be completed when available in the local language of the investigational site. 
ii Selected scales of the EORTC QLQ-C30: the GHS/QoL (Questions 29 and 30), Physical Function (Questions 1−5), Role Function (Questions 6 
and 7), Pain (Questions 9 and 19), Fatigue (Questions 10, 12, and 18) and Dyspnea (Question 8), as well as the EQ-5D-5L will be administered 
during post-treatment follow-up calls (or visits) approximately every 3 (±1) months until death.  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 by 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.  
jj Tumor biopsy collection is optional for study participation.  For patients who sign an Informed Consent Form for Optional Tumor Tissue Biopsy 
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 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol CO41101, Version 6 
Table 2 
Schedule of Activities: Applicable after unblinding and thereafter 
Assessment/Procedure 
Screening 
(Days −28 
to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 
D15 
D1 D8 
D15 
D1 
D8 
D15 
Signed informed consent(s)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology d 
x d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical history, and 
prior cancer treatment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue sample submitted at 
screening e 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for WGS f 
 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for biomarkers g 
 
x g 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Complete physical examination h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination i 
 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
 
x 
 
Weight  
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance Status 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Cardiac function (ECHO or MUGA 
scan) 
x k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG l 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol CO41101, Version 6 
Assessment/Procedure 
Screening 
(Days −28 
to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 
D15 
D1 D8 
D15 
D1 
D8 
D15 
Hematology m 
x 
x n 
x n 
x n 
x n x n 
x n 
x n x n 
x n 
x n 
x n 
x n 
x 
 
INR and PTT (or aPTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Fasting serum chemistry o 
x 
x n 
x n 
x n 
x n x n 
x n 
x n x n 
x n 
x n 
x n 
x n 
x 
 
TSH, free T3 (or total T3), free T4 p 
x 
x 
 
 
 
 
 
x 
 
 
x p 
 
 
x 
 
Fasting lipid profile, and amylase and 
lipase q 
x 
 
 
 
x q 
 
 
 
 
 
x q 
 
 
x 
 
HbA1C 
x 
x 
 
 
x  
 
 
x 
 
 
x  
 
 
x 
 
C-reactive protein r 
 
x r 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis s 
x 
As clinically indicated 
x 
 
Pregnancy test t 
x 
x t 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Tumor assessments u 
x 
 
 
 
x v 
 
 
 
 
 
x v 
 
 
x w 
x w 
Bone scan 
x x,y 
See Footnotes "x” and “y." 
x x,y 
x x,y 
Head scan (CT or MRI scan) 
x x,z 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis with 10 mg of 
prednisone (or equivalent) for 3−5 
consecutive days aa, bb 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Daily antihistamine prophylaxis bb 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis antidiarrheal (2 mg of 
loperamide BID 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) bb 
 
If side effects are not tolerated, doses may be reduced.  After one 
cycle without any diarrhea, continuation is at physician's discretion.   
If diarrhea occurs, it should be managed per the guidelines in 
Appendix 13, Table 2; antidiarrheal treatment should also be resumed 
with loperamide prophylaxis as needed. 
 
 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol CO41101, Version 6 
Assessment/Procedure 
Screening 
(Days −28 to –1) 
Treatment Cycle (28-Day Cycles) a 
SDDV b 
Post-
Treat.  
Follow-  
Up c 
Cycles 1  
and 2 
Cycle 3 
Cycle 4 
Cycles 5 and 
Beyond 
D1 
D8 D15 D1 D8 D15 
D1 D8 
D15 
D1 
D8 
D15 
 
 
Ipatasertib dispensing and 
accountability 
 
x cc 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
Atezolizumab administration 
 
x cc 
 
x  
x 
 
x 
x 
 
x 
x 
 
x 
 
 
Paclitaxel administration dd 
 
x cc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Record all historical 
cancer-related medications, 
radiotherapy, and surgical 
procedures 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Concomitant medications ee 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events ff 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x ff 
x gg 
Tumor tissue sample 
obtained at time of 
progression (optional) hh 
 
 
 
 
 
 
 
 
 
 
 
 
 
x hh 
 
Site personnel review of 
patient diary (medication, 
dosing log, and kit ID) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol CO41101, Version 6 
ADA = anti-drug antibody; BID = twice a day; CT = computed tomography; D = day; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; eCRF = electronic Case Report Form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire−Core 30; EQ-5D-5L = EuroQol 5-Dimension Questionnaire, 5-Level Version; FNA = fine-needle aspiration; 
HbA1C = glycosylated hemoglobin; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV−hepatitis B virus; HCV = hepatitis 
C virus; QoL = quality of life; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; NGS = next-generation sequencing; 
PK = pharmacokinetic; PRO = patient-reported outcome; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology Criteria 
for Adverse Events; RBR = Roche Biosample Repository; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SDDV = study 
drug discontinuation visit; T3 = triiodothyronine; T4 =  thyroxine; 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 4.1.1.1.  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 should be performed within ±3 days of the scheduled date.  Please note that 
with rare exception, the actual study visit and IV study treatment administration should only occur on Days 1, 8, 15, or on Day 22 if any of the 
prior days must be skipped.  Visit windows may be utilized to accommodate holidays, vacations, and unforeseen delays; however, study cycle 
day count continues without breaks (a sample calendar is presented in Appendix 6. 
b The SDDV should occur approximately 28 (±3) days after the last administration of ipatasertib/placebo, atezolizumab/placebo, or paclitaxel, 
whichever is discontinued last, or prior to initiation of another anti-cancer treatment.  If it is anticipated that the patient will be unable to return for 
a visit, then it is acceptable to perform this visit on the date of last study drug discontinuation.   
c After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 ( ± 1) months until death (unless the 
patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be 
documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only.  As of protocol Version 6, these long-term follow-up 
assessments are no longer required. 
d Viral serology includes HIV, HBsAg, total HBcAb, and HCV antibody.  HIV serology will be performed as per local standard after any applicable 
local consenting requirement is met.   HBV serology includes HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) 
HBV DNA.  If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to 
determine if the patient has an HBV infection, prior to randomization.  HCV serology includes HCV antibody and (if HCV antibody test is positive) 
HCV RNA.  If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has 
an HCV infection, prior to randomization.  If HCV antibody is positive, then need to test HCV RNA to confirm that HCV RNA is undetectable. 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol CO41101, Version 6 
e Archival tissue (either formalin-fixed, paraffin-embedded tumor specimens or a minimum of 15 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 is preferred.  If less than 15 slides or only two 
cores are available, a patient may still be eligible for the study, after Sponsor approval has been obtained and if sample contains a minimum of 50 
viable tumor cells that preserve cellular context and tissue architecture regardless of needle gauge or retrieval method. 
f Not applicable for a site that has not been granted approval for WGS.  Samples will be collected on Day 1 of Cycle 1 only. 
g To be performed on Day 1 of Cycle 1, the first tumor assessment ± 7 days, and at the study drug discontinuation visit.  Blood should be drawn 
before the administration of any study drug, if applicable. 
h A complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
i Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated. 
j Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature while the patient is 
sitting or supine in a comfortable position.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Vital signs should be 
measured within 60 minutes prior to each in-clinic ipatasertib/placebo administration, atezolizumab/placebo infusion (one set may be performed 
to cover predose vital signs for both drug administrations), and between atezolizumab/placebo and paclitaxel infusions (on days when both drugs 
are administered).  Refer to Section 4.5.5, Table 2, for the timing of vital sign measurements for the first and subsequent infusions.  On days 
when no atezolizumab/placebo is given, one set may be performed as predose vital signs for both ipatasertib/placebo and paclitaxel.  On 
paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  Vital signs may be repeated if clinically 
indicated, during the infusion.  
k Perform within 12 weeks prior to Day 1 of Cycle 1.  If the left ventricular ejection fraction 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 scan), if this is 
consistent with local standard practice. 
l A single 12-lead ECG measurement at screening and at the treatment discontinuation visit and may be obtained at unscheduled timepoints as 
clinically indicated (refer to Section 4.5.8).  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 
the ECG recording. 
m Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).  
 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol CO41101, Version 6 
n Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic with at least 8-hour fasting for glucose 
measurement as indicated.  The chemistry and hematology results should be available to assess prior to dosing.  
o Fasting serum chemistry panel (following ≥8-hour fast) includes glucose (plasma glucose is also acceptable per local practice), bicarbonate or 
total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, magnesium, BUN or urea, creatinine, 
total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH.  At investigational sites in countries where bicarbonate may 
not be collected as part of the standard chemistry panel, bicarbonate will not be measured.  Chemistry evaluation to be conducted per local 
guidelines. 
p 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.). 
q Fasting lipid profile, which includes total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides performed following a  ≥ 8-hour fast, as 
well as (fasting or non-fasting) amylase, and lipase will be assessed at screening, every 3 cycles starting on Day 1 of Cycle 3 and at treatment 
discontinuation visit. 
r C-reactive protein in serum collections will be assessed only on Day 1 of Cycle 1 prior to dosing. 
s Urinalysis consists of pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
t For women of childbearing potential, a negative serum pregnancy test must be confirmed either within 96 hours of Day 1, Cycle 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).  In addition, pregnancy tests (serum or urine) are to be performed within 96 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 before any 
further study treatment may be administered.  For all other women, documentation must be present in medical history confirming that patient is 
not of childbearing potential.   
u 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.  Please note that PET/CT imaging is not an acceptable 
alternative to CT or MRI, unless the CT portion of the PET/CT scan is of diagnostic quality; in such cases where the CT portion is of diagnostic 
quality, consult with the Medical Monitor prior to using PET/CT for study-related tumor assessments.  As of protocol Version 5, images for tumor 
assessments will no longer be collected for blinded independent central review. 
v Tumor assessments should be calculated from Day 1 of Cycle 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 (refer to the sample calendar in Appendix 6). 


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol CO41101, Version 6 
w At treatment discontinuation visit, tumor assessments should be performed only if not performed within the previous 6 weeks.  If a patient 
discontinues from study treatment for any reason other than disease progression per RECIST v1.1, every effort should be made to obtain 
follow-up CT scans as per standard of care to assess disease response until documented progressive disease per RECIST v1.1, elective 
withdrawal from the study, or study completion or termination. 
x Images for tumor assessments will be prospectively collected to enable retrospective blinded independent central review.  As of protocol 
Version 5, images for tumor assessments will no longer be collected for blinded independent central review. 
y 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 on contrast-enhanced CT or MRI scan 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 every 16 weeks 
(window is 7 days of the given week) and at the study termination visit only if not performed within the previous 12 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 and bone scans as per standard of care to assess disease  until documented progressive disease per RECIST v1.1.  Please note that 
positron emission tomography imaging is not an acceptable alternative to the bone scan.  
z Perform contrast-enhanced CT or MRI scan of head within 6 weeks prior to Day 1 of Cycle 1. 
aa For the first cycle (or the first 28 days of triplet combination dosing) only:  On days when patients will receive atezolizumab (typically, on 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 administration is 
to give at least 10 mg/day prednisone on the day of paclitaxel, then the additional 10 mg of 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 a 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. 
bb As of protocol Version 5, rash and antidiarrheal prophylaxis is no longer applicable to patients in Arm C of Cohort 1 and Arm B of Cohort 2.  
cc 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 on days when 
the patient will receive both atezolizumab and paclitaxel.  Please note that non-dosing of initial study drug on the day of enrollment may impact 
accurate data entry on the eCRFs, which are located in folders specifically labeled with the number of cycles and days.  As of protocol Version 5, 
placebo for ipatasertib and placebo for atezolizumab will no longer be administered. 
dd If the patient's weight changes by > 10% from baseline during the study, the body surface area and dose of paclitaxel should be recalculated.  
Recalculation based on a lesser change from baseline weight is left to the investigator’s discretion.  


Appendix 1: Schedule of Activities 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol CO41101, Version 6 
ee At screening and on 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.  The intake of analgesic, antihistamine, and 
loperamide medications will be reported on the Concomitant Medications eCRF(see Section 4.5.2). 
ff After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the final dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  After this period, 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.  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.   
gg 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 final dose of study drug).  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.  
hh Tumor biopsy collection is optional for study participation.  For patients who sign an Informed Consent Form for Optional Tumor Tissue Biopsy 
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 and Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol CO41101, Version 6 
Appendix 2  
Schedule of Pharmacokinetic and Immunogenicity Samples 
As of protocol Version 5, blood samples for PK and ADA analyses will no longer be 
collected. 
Visit 
Timepoint(s) 
Sample Type(s) 
Day 1 of Cycle 1 
Prior to start of first 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
30 (± 10) minutes after end of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
1−3 hours after ipatasertib/placebo 
dose  
• Ipatasertib and G-037720 
(plasma) 
Day 15 of Cycle 1 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
Prior to ipatasertib/placebo dose a 
• Ipatasertib and G-037720 
(plasma) 
1−3 hours after ipatasertib/placebo 
dose  
• Ipatasertib and G-037720 
(plasma) 
Day 1 of Cycle 2 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
Day 1 of Cycle 3 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
Day 15 of Cycle 3 
Prior to ipatasertib/placebo dose a 
• Ipatasertib and G-037720 
(plasma) 
2−4 hours after ipatasertib/placebo 
dose  
• Ipatasertib and G-037720 
(plasma) 
Day 1 of Cycle 4 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
Day 1 of Cycle 8 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
Day 1 of Cycles 12 
and 16 
Prior to start of 
atezolizumab/placebo infusion 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
SDDV (≤ 28 days after 
final dose) 
At visit 
• Atezolizumab PK (serum) 
• Atezolizumab ADA (serum) 
ADA = anti-drug antibody; PK= pharmacokinetic; SDDV = study drug discontinuation visit. 
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 after ipatasertib administration should also be recorded for the day of PK sampling.  
PK sampling timepoint should be accurately reported.  With the exception of the Cycle 1, 
Day 1 visit, if 3 or more consecutive doses of ipatasertib/placebo are 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 performed any day after Day 12 of the relevant cycle corresponding 
with a planned ipatasertib/placebo dosing day.  Prior to start of atezolizumab/placebo and 
ipatasertib/placebo dose = 0 to 3 hours prior to dosing of the drug(s) on the day of the visit. 
 
 


 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol CO41101, Version 6 
Appendix 3  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about > 50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair > 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
 


 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol CO41101, Version 6 
Appendix 4  
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 
• Antiphospholipid 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 
• 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 and Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol CO41101, Version 6 
Appendix 5  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)  
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009), are presented below, with the addition of 
explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions and lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
• 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ≤ 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                              
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol CO41101, Version 6 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 mm 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 lungs, peritoneal spread, and abdominal 
mass/abdominal organomegaly- identified by physical examination that is not 
measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
• 
Technetium-99m bone scans, positron emission tomography (PET) scans, and 
plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered 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 malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
• 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.   
 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol CO41101, Version 6 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and not usually more than 4 weeks prior to the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter 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 because CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is ≤ 5 mm.  When CT scans 
have slice thickness of > 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 (with or without MRI 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 (with or without MRI IV contrast) will be performed should also be based on 
the tumor type and the anatomic location of the disease, and should be optimized to 
allow for comparison with the prior studies if possible.  Each case should be discussed 
with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward.  Care 
must be taken in measurement of target lesions and interpretation of non-target disease 


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or new lesions on a different modality because, the same lesion may appear to have 
a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, AND HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 × 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 


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but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to < 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, given that a normal lymph node is defined as 
having a short axis of < 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non−lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but is too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but is too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 


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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is < 5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce During Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
the maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to < 10 mm in the short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "unequivocal progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis < 10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the following criteria used to determine objective tumor response for target 
lesions are provided: 
• 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to < 10 mm. 
• 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
• 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥ 5 mm. 
• 
Stable disease (SD):  Neither sufficient shrinkage to qualify for a CR or a PR nor 
sufficient increase to qualify for PD 
 


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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
• 
CR:  Disappearance of all non-target lesions  
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions  
• 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.   
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as 
a "new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it truly represents new disease.  If repeat scans 
confirm there is definitely a new lesion, progression should be declared as of the date of 
the initial scan. 


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CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients.   
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.  
Table 1 
Criteria for Overall Response at a Single Timepoint 
Target Lesions 
Non-Target Lesions 
New Lesions 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD or 
NE 
No 
PR 
PR 
CR, non-CR/Non-PD, 
or NE 
No 
PR 
SD 
CR, non-CR/Non-PD, 
or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR 
NED b 
No 
CR 
PR 
NED b 
No 
PR 
SD 
NED b 
No 
SD 
NED a 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NED a 
CR 
No 
CR 
NED a 
NE 
No 
NE 
NED a 
NED b 
No 
NED 
CR = complete response; NE = not evaluable; NED = not evaluable disease; 
PD = progressive disease; PR = partial response; SD = stable disease. 
a No target lesions identified at baseline  
b No non-target lesions identified at baseline. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging or measurement is performed at all at a particular timepoint, the 
patient is not evaluable at that timepoint.  If measurements are made on only a subset of 
target lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 


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individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had 
a baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not 
a descriptor of an objective response; it is a reason for stopping study treatment.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1 and Table 2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Fluorodeoxyglucose (FDG)-PET is not yet validated for use in clinical trials to 
determine response but may complement CT/MRI in the assessment of progression. 
FDG-PET imaging to identify new lesions is described in the following table. 


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Baseline FDG-PET 
Post-Baseline FDG-PET  
Determination 
Negative FDG-PET 
Positive FDG-PET  
New lesion (PD) 
None 
Positive FDG-PET corresponds 
to a new site of disease 
confirmed by CT/MRI 
New lesion (PD) 
None 
Positive FDG-PET not 
confirmed as a new site of 
disease on CT/MRI 
Additional follow-up CT/MRI scans 
are needed to determine if there is 
truly progression occurring at that 
site. 
If so, new lesion (PD) with the date 
of PD being the date of the initial 
abnormal FDG-PET scan date 
If not, it is not a new lesion. 
None 
Positive FDG-PET that 
corresponds to a preexisting 
site of disease on CT/MRI that 
is not progressing on the basis 
of the anatomic images 
Not a new lesion 
CT = computed tomography; FDG = fluorodeoxyglucose; MRI = magnetic resonance imaging; 
PD = progressive disease; PET = positron emission tomography. 
Note:  A positive FDG-PET scan lesion indicates one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47.   
Schwartz LH., Litiére S, de Vries SE, et al. RECIST 1.1−update and clarification: from 
RECIST Committee. Eur J Cancer 2016; 62:132−7. 
 




 
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Appendix 7  
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous 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 as required by patient 
status and directed by the physician in charge. 
4. 
Continue to observe the patient and document observations. 
 


 
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Appendix 8  
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations 
 
REFERENCE 
Fitzgibbons PL, Murphy DA, Hammond ME, et al. Recommendations for validating 
estrogen and progesterone receptor immunohistochemistry assays. Arch Path Lab 
Med 20101;134;930−5.








 
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Appendix 10  
European Organisation for Research and Treatment of Cancer 
Quality of Life−Core 30 Questionnaire (EORTC QLQ-C30) 
Note:  Copies of the official version of the selected scales of the EORTC QLQ-C30 along 
with instructions for administration of the questionnaire during the follow-up period will be 
provided to sites. 
 
 


Appendix 10: European Organisation for Research and Treatment of Cancer Quality of 
 Life−Core 30 Questionnaire (EORTC QLQ-C30) 
  
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Appendix 11  
EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
Note:  Copies of the official version of the ED-5D-5L along with instructions for 
administration of the questionnaire during the follow-up period will be provided to sites. 
 


Appendix 11:  EuroQol 5-Dimension Questionnaire:  EQ-5D-5L 
  
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188/Protocol CO41101, Version 6 
 


Appendix 11:  EuroQol 5-Dimension Questionnaire:  EQ-5D-5L 
  
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Appendix 12  
Selected Items from the Patient-Reported Outcomes Version of 
the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) 
 


Appendix 12:  Selected Items from the Patient-Reported Outcomes Version of the  
Common Terminology Criteria for Adverse Events (PRO-CTCAE) (cont.) 
 
 
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Appendix 13  
Overall Guidelines for Management of Patients Who Experience 
Adverse Events  
DOSE MODIFICATIONS 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided below.  There will be no dose modifications for atezolizumab/placebo in this 
study. 
Note:  Reference to ipatasertib/placebo refers to the placebo for ipatasertib and 
atezolizumab/placebo refers to the placebo for atezolizumab in this appendix.   
Any dose interruption, dose modification, overdose or incorrect administration of 
ipatasertib/placebo (for ipatasertib), atezolizumab/placebo (for atezolizumab), or 
paclitaxel should be noted on the corresponding Study Drug Administration and Adverse 
Event (Special Situations) electronic Case Report Form (eCRF). 
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 (see 
Table 1 and Table 2).  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 on 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/µL 
• 
Platelet count ≥ 100,000/µL 
• 
(Maximum) 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 is exactly 28 days in length.  It is 
recommended that once the first date of study treatment administration is confirmed, 
that a calendar be laid out for the remainder of the study.  The first day of study 
treatment administration should be considered Day 1 of Cycle 1 (i.e., the first day of 
the first 28-day cycle) and should be considered Day 1 of Cycle 1 and used for the 
purposes of utilizing the appropriate eCRF folder and page.  (Note:  Each folder 
encompasses one 28-day cycle and is to be used to record anticipated study 
treatments and procedures falling within the 28-day calendar period.  The recording 
of actual treatment and procedure dates within each folder will account for 


Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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treatments and procedures that occur on study days other than those that were 
expected.)  
• 
Interruption or discontinuation of individual study drugs: 
– 
If ipatasertib/placebo treatment is interrupted, atezolizumab/placebo and/or 
paclitaxel treatment may continue if medically appropriate (per investigator 
discretion).  
– 
If atezolizumab/placebo treatment is interrupted, ipatasertib and/or paclitaxel 
treatment may continue if medically appropriate (per the investigator’s 
discretion).  
– 
If paclitaxel treatment is interrupted, ipatasertib/placebo and/or 
atezolizumab/placebo treatment may continue if medically appropriate (per 
investigator discretion).  If paclitaxel treatment is interrupted, consider delaying 
the ipatasertib/placebo treatment concurrently for up to 7 days (i.e., shifting the 
7 days off week for ipatasertib/placebo in order that 21 daily doses 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. 
– 
If both atezolizumab/placebo and paclitaxel have been permanently 
discontinued, a documented discussion should take place between the 
investigator and the patient regarding the possibility of receiving 
ipatasertib/placebo alone, and if medically appropriate the patient may continue 
ipatasertib/placebo alone.  The upcoming tumor assessment should be 
performed as scheduled.   
– 
If both ipatasertib/placebo and paclitaxel have been permanently discontinued, 
a documented discussion should take place between the investigator and the 
patient regarding the possibility of receiving atezolizumab/placebo alone, and if 
medically appropriate the patient may continue atezolizumab/placebo alone.  
The upcoming tumor assessment should be performed as scheduled.   
– 
Although there are prespecified windows allowed around dosing days, it is 
strongly suggested that paclitaxel administration occur only on Days 1, 8, and 
15 (or Day 22 as a day to compensate for missed paclitaxel on any of the 
3 previous days), and that atezolizumab/placebo be given only on Days 1 and 
15.  The Medical Monitor is available to advise as needed. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience
Adverse Events (cont.)
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
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, 15, or 22).  However, laboratory 
assessments and clinical visits should be scheduled as needed for follow-up of 
adverse events.  In addition, the tumor assessment during every 8th week 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 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.  Because this is broad 
guidance, please refer to specific adverse event management guidelines, as certain 
minimal safety guidance is to be followed regardless of attribution to study drugs.  

Dose reductions or interruptions may not be required for anemia (non-hemolytic) if 
satisfactorily managed by transfusions.

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, 15, or 22 
laboratory value).  

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.  A dose hold for longer than 4 weeks for 
a study treatmentrelated adverse event requires permanent discontinuation of 
the attributable treatment component and per specific adverse event 
management guidelines below.  
Atezolizumab/placebo may be held for up to 12 weeks.  For additional details, 
see below and Appendix 14.
DOSAGE MODIFICATION 
If the patient does not tolerate the once a day (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 200 mg/day of ipatasertib/placebo) will be allowed (see Table 1).  
Dose re-escalation is not permitted for ipatasertib/placebo.


Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Table 1 
Dose Reductions for Ipatasertib/Placebo  
Dose 
Dose of Ipatasertib/Placebo 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction a 
200 mg 
Third dose reduction 
Not permitted 
a If the patient continues to experience specified study 
drug−related adverse events after the second 
reduction, treatment should be discontinued. 
 
To manage paclitaxel-related toxicity, no more than one dose reduction for paclitaxel will 
be allowed (see Table 2).  Paclitaxel doses other than specified in Table 2 will not be 
allowed. 
Table 2 
Dose Reductions for Paclitaxel 
Dose a 
Dose of 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 study 
drug−related adverse events after dose reduction, 
treatment should be discontinued. 
 
TREATMENT INTERRUPTION 
Ipatasertib/placebo, atezolizumab/placebo, and/or paclitaxel treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures).  The acceptable 
length of treatment interruption 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.  Particular care should be taken to maintain the schedule of tumor 
assessments even when treatment is interrupted.  For both surgery and palliative 
radiotherapy, all study treatment should be suspended temporarily.  The length of 
paclitaxel suspension must be considered sufficient in the investigator’s judgment and 
be explained in the source documents.   No study treatment should be resumed before 
sufficient recovery from the procedure (i.e., no Grade > 1 procedure-related adverse 
events).   


Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Interruption of Ipatasertib/Placebo 
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.  If ipatasertib/placebo is held for >28 consecutive 
days for reasons other than toxicity, and 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 and there is no evidence of progression, study drug may be 
restarted.  
If daily systemic corticosteroids are initiated for treatment of any toxicity or other 
condition, they must be tapered to ≤10 mg/day of oral prednisone or equivalent before 
ipatasertib or ipatasertib/placebo can be resumed.  Steroids used as prophylaxis (i.e., as 
premedication prior to scans, as protocol-directed rash prophylaxis, or as standard 
premedication prior to paclitaxel or atezolizumab) do not require holding of 
ipatasertib/placebo.  Steroids used on a single day to manage infusion-related reactions 
(IRRs) or allergic reactions similarly do not require holding of ipatasertib/placebo. 
Interruption of Atezolizumab/Placebo 
Atezolizumab/placebo treatment may be temporarily suspended in patients experiencing 
toxicity considered to be related to atezolizumab/placebo.  If atezolizumab/placebo (is 
withheld for > 12 weeks owing to atezolizumab/placebo-related toxicity (as measured 
from the first day of interruption of scheduled atezolizumab/placebo dosing), the patient 
will be discontinued from atezolizumab/placebo.  
If daily corticosteroids are initiated for treatment of the toxicity, they must be tapered 
over ≥ 1 month to ≤10 mg/day of oral prednisone or equivalent before 
atezolizumab/placebo (for atezolizumab) can be resumed.  If atezolizumab/placebo (for 
atezolizumab) is withheld for > 12 weeks after event onset, the patient will be 
discontinued from atezolizumab/placebo.  Given that a slow taper of steroids, as directed 
above, is required by protocol, atezolizumab/placebo may be withheld for > 12 weeks to 
allow for patients to taper off corticosteroids prior to resuming treatment.  
Atezolizumab/placebo can then be resumed after being withheld for > 12 weeks if the 
patient is likely to derive clinical benefit.  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. 
The acceptable length of treatment interruption must be based on an assessment of 
benefit−risk by the investigator and in alignment with the protocol requirements for the 


Appendix 13: Overall Guidelines for Management of Patients Who Experience
Adverse Events (cont.)
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd
197/Protocol CO41101, Version 6
duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed.
MANAGEMENT GUIDELINES
Adverse Event Management Guidelines for Ipatasertib/Placebo Plus 
Atezolizumab/Placebo Plus Paclitaxel
Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 14 and Table 3, as outlined below:

Table 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 3.  For these potential 
overlapping toxicities, guidelines in Table 3 override any other instruction in this 
document.

Table 3 provides guidelines for the management of patients who experience 
adverse events associated with ipatasertib/placebo.  It is recommended that 
atezolizumab/placebo and/or ipatasertib/placebo be withheld or discontinued per the 
guidelines in Table 3.

Appendix 14 provides guidelines for the management of patients who experience 
atezolizumab/placebo-associated IRRs and immune-mediated adverse events.  It is 
recommended that atezolizumab/placebo be withheld or discontinued per the 
guidelines in Appendix 14 and that ipatasertib/placebo be withheld or discontinued 
per the guidelines in Table 3.
For cases in which management guidelines are not covered in Table 3 elsewhere in this 
appendix or in Appendix 14, patients should be managed and treatments should be 
withheld or discontinued as deemed appropriate by the investigator according to 
best medical judgment. See Appendix 14 for further management guidelines for events 
not described herein that are related to atezolizumab/placebo alone.


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol CO41101, Version 6
Table 3
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel
Event
Action to Be Taken
Infusion-related 
reactions and 
anaphylaxis
Follow guidelines for atezolizumab/placebo in Appendix 14.
Withhold ipatasertib/placebo.
For anaphylaxis precautions, see Appendix 14.
For severe hypersensitivity reactions, permanently discontinue atezolizumab/placebo 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 antidiarrheal 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 antidiarrheal 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, 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
199/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Gastrointestinal 
toxicity (cont.) 
 
General guidance 
(cont.) 
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. 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 1.  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/placebo 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.  Loperamide prophylaxis is to be taken throughout at least the first cycle. 
 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.)  
Event 
Action to Be Taken 
Gastrointestinal 
toxicity (cont.) 
 
Diarrhea, Grade 2 
• Withhold atezolizumab/placebo 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/placebo at a fixed dose.  If not, 
permanently discontinue atezolizumab/placebo. 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 1) 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/placebo (for 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo (for 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
201/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (for Ipatasertib) Plus 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.)  
Event 
Action to Be Taken 
Diarrhea, Grade 3 
• Withhold ipatasertib/placebo, atezolizumab/placebo, 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/placebo (for atezolizumab) at a fixed 
dose.  If not, permanently discontinue atezolizumab/placebo 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 1) 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 1).  Consider 
reducing paclitaxel by one dose level when treatment is restarted (see Table 2). 
• 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/placebo (for 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo (for 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
202/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.)  
Event 
Action to Be Taken 
Diarrhea, Grade 4  
• Permanently discontinue atezolizumab/placebo 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 2). 
GI = gastrointestinal; NSAID = non-steroidal anti-inflammatory drug. 
a Atezolizumab/placebo (for 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo (for 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
203/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Gastrointestinal 
toxicity (cont.) 
 
Colitis, Grade 1 
• Continue atezolizumab/placebo 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/placebo 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/placebo at a fixed dose.  If not, 
permanently discontinue atezolizumab/placebo 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/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
204/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Gastrointestinal 
toxicity (cont.) 
 
Colitis, Grade 3 
• Withhold atezolizumab/placebo 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/placebo at a fixed dose.  If not, permanently 
discontinue atezolizumab/placebo 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/placebo 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. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
205/Protocol CO41101, Version 6 
GI = gastrointestinal; NSAID = non-steroidal anti-inflammatory drug. 
a Atezolizumab/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
206/Protocol CO41101, Version 6 
Table 3 Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Endocrine disorders  
Asymptomatic 
hypothyroidism 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• Continue ipatasertib/placebo. 
Symptomatic 
hypothyroidism 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• Continue ipatasertib/placebo. 
Asymptomatic 
hyperthyroidism 
Thyroid-stimulating hormone ≥ 0.1 mU/L and < 0.5 mU/L: 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• Continue ipatasertib/placebo. 
Thyroid-stimulating hormone < 0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• 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 1).  If 
not, permanently discontinue ipatasertib/placebo. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
207/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Endocrine disorders (cont.) 
Symptomatic adrenal 
insufficiency, Grade 2, 
3, or 4 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• 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 an event of fasting glucose value  
250−500 mg/dL.   
• 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-GAD45 antibody. 
• Treat hyperglycemia per institutional guidelines with fluid replacement, insulin, and correction of electrolyte 
abnormalities.   
Hyperglycemia,  
fasting glucose value  
> ULN to 160 mg/dL 
(8.9 mmol/L) 
• Continue atezolizumab/placebo 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, fasting 
glucose value  
>160−250 mg/dL 
(> 8.9−13.9 mmol/L) 
• Withhold atezolizumab/placebo and ipatasertib/placebo dosing until fasting glucose value resolves to ≤160 mg/dL.  
(Investigate for diabetes.  If patient has Type 1 diabetes, treat as a fasting glucose value 250−500 mg/dL 
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 1). 
• 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
208/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Plus Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Endocrine disorders (cont.) 
Hyperglycemia, 
glucose value  
 > 250−500 mg/dL 
( > 13.9−27.8 mmol/L) 
• Withhold atezolizumab/placebo and ipatasertib/placebo dosing until fasting glucose value resolves to 
≤160 mg/dL 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 mo          nitoring. 
• 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 250−500 mg/dL recurs, the dose of ipatasertib/placebo should be reduced by one dose level 
(see Table 1) when treatment is restarted. 
• Resume atezolizumab/placebo when symptoms resolve and glucose levels are stable. 
Hyperglycemia,  
glucose value 
> 500 mg/dL  
(> 27.8 mmol/L);  
life-threatening 
consequences 
• Withhold atezolizumab/placebo and ipatasertib/placebo dosing until fasting glucose value resolves to 
≤ 160 mg/dL.  
• 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 ≤160 mg/dL, reduce ipatasertib/placebo by one dose level (see Table 1) 
when treatment is restarted. 
• Resume atezolizumab/placebo when symptoms resolve and glucose levels are stable. 
• If glucose value > 500 mg/dL recurs, permanently discontinue ipatasertib/placebo and atezolizumab/placebo 
and contact Medical Monitor. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
209/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for 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/placebo 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/placebo and ipatasertib/placebo. 
• Refer patient to pulmonary specialist 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/placebo at a fixed dose.  If not, 
permanently discontinue atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
210/Protocol CO41101, Version 6 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab/placebo 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
211/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Pulmonary events (cont.) 
Pulmonary event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab/placebo 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/placebo 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/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
212/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Hepatic events (cont.) 
AST/ALT > 3 × ULN 
to 5 × ULN with total 
bilirubin ≤ 2 × ULN 
• Continue atezolizumab/placebo 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/placebo is withheld and event resolves to AST/ALT ≤ 3 × ULN with total bilirubin ≤ 2 × ULN within 
12 weeks, resume atezolizumab/placebo at a fixed dose.  If not, permanently discontinue atezolizumab/placebo 
and ipatasertib/placebo and contact Medical Monitor. a, b, c 
LFT = liver function test; ULN = upper limit of normal. 
a Atezolizumab/placebo 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo 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 judgment should be used when determining appropriate frequency for 
monitoring LFTs (e.g., patients with documented liver or bone metastases may have baseline AST/ALT < 5x ULN); monitoring of LFTs for 
such patients may be as per clinical judgment until a threshold of ALT/AST 5x ULN. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
213/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for 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/placebo and ipatasertib/placebo. 
• Monitor LFTs d, f  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/placebo. 
• 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/placebo at a fixed 
dose.  If not, permanently discontinue atezolizumab/placebo and ipatasertib/placebo and contact Medical Monitor. a ,b, c 
LFT = liver function test; ULN = upper limit of normal. 
a Atezolizumab/placebo 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo 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 judgment 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 judgment until a threshold of ALT/AST 5 × ULN. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
214/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Hepatic events (cont.) 
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. 
AST/ALT > 3 × to  
< 10 × ULN with total 
bilirubin > 2× ULN 
• Withhold atezolizumab/placebo and ipatasertib/placebo. 
• Monitor LFTs d, f 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/placebo 
at a fixed dose.  If not, permanently discontinue atezolizumab/placebo 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 1).  If not, permanently discontinue ipatasertib/placebo. 
• Permanently discontinue atezolizumab/placebo and ipatasertib/placebo for life-threatening hepatic events and 
contact the Medical Monitor. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
215/Protocol CO41101, Version 6 
LFT = liver function test; ULN = upper limit of normal. 
a Atezolizumab/placebo 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo 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 judgment 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 judgment until a threshold of ALT/AST 5 × ULN. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
216/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Hepatic events 
(cont.) 
 
AST/ALT ≥ 10 × ULN 
• Permanently discontinue atezolizumab/placebo and ipatasertib/placebo and contact Medical Monitor. c 
• Monitor LFTs d, f 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/placebo 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/placebo (for atezolizumab) can be resumed. 
c Resumption of atezolizumab/placebo 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 judgment 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 judgment until a threshold of ALT/AST 5 × ULN. 
 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
217/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for 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/placebo (typically, Days 1 and 15), patients should receive at least 10 mg prednisone (or equivalent) 
as premedication prior to atezolizumab/placebo, 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.  
• 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.   
Dermatologic event, 
Grade 1 
• Consider referring patient to a dermatologist.  
• Continue atezolizumab/placebo and ipatasertib/placebo. 
• Initiate supportive care (e.g., topical corticosteroids and continue antihistamine administration).   
• Consider treatment with 10 mg/day oral prednisone or equivalent. 
 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
218/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Dermatologic toxicity (cont.) 
• 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 
• 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/placebo:  If steroid dose is ≤ 10 mg/day, atezolizumab/placebo should be continued. 
Dermatologic event, 
Grade 3 
• Withhold atezolizumab/placebo 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/placebo:  if event resolves to Grade 1 or better within 12 weeks, resume atezolizumab/placebo at a 
fixed dose.  If not, permanently discontinue atezolizumab/placebo and contact Medical Monitor.  Only restart 
atezolizumab/placebo (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/placebo and ipatasertib/placebo and contact Medical Monitor. 


Appendix 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
219/Protocol CO41101, Version 6 
a Atezolizumab/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
220/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
221/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for 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/placebo (for 
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/placebo. 
• 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 1 and Table 2. 
• 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 13: Overall Guidelines for Management of Patients Who Experience Adverse Events 
 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
222/Protocol CO41101, Version 6 
Table 3 
Management Guidelines for Selected Adverse Events for Ipatasertib/Placebo (Placebo for Ipatasertib) 
Atezolizumab/Placebo (for Atezolizumab) Plus Paclitaxel (cont.) 
Event 
Action to Be Taken 
Atezolizumab/placebo- 
related toxicities not  
described in  
Appendix 13 
 
Grade  ≥ 3 
• Follow guidelines for atezolizumab/placebo in Appendix 14. 
• 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 1. 
• 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 and Atezolizumab—F. Hoffmann-La Roche Ltd 
223/Protocol CO41101, Version 6 
Appendix 14  
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/placebo 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/placebo.  In patients who 
have met the criteria for permanent discontinuation, resumption of atezolizumab/placebo 
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.  Even in the absence of pulmonary 
events, patients will be assessed for pulmonary signs and symptoms throughout the 
study and will have imaging 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 13, Table 3. 


Appendix 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
224/Protocol CO41101, Version 6 
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 13, Table 3. 
GASTROINTESTINAL EVENTS 
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Appendix 13, Table 3. 
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 13, Table 3. 
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.  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 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
225/Protocol CO41101, Version 6 
Table 1 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
• Continue atezolizumab/placebo. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
Symptomatic 
hypothyroidism 
• Withhold atezolizumab/placebo. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab/placebo when symptoms are 
controlled and thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab/placebo. 
• 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/placebo. 
• Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab/placebo when symptoms are 
controlled and thyroid function is improving. 
• Permanently discontinue atezolizumab/placebo and contact 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
MRI = magnetic resonance imaging 
a Atezolizumab/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
226/Protocol CO41101, Version 6 
Table 1 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 2−4  
• Withhold atezolizumab/placebo for up to 12 weeks after 
event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate 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 event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab/placebo. b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
MRI = magnetic resonance imaging. 
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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
227/Protocol CO41101, Version 6 
Table 1 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(panhypopituitarism), 
Grade 2 or 3  
• Withhold atezolizumab/placebo for up to 12 weeks after 
event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate 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. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume 
atezolizumab/placebo. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab/placebo, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(panhypopituitarism), 
Grade 4  
• Permanently discontinue atezolizumab/placebo and contact 
Medical Monitor. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate 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. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging 
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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
228/Protocol CO41101, Version 6 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 2. 
Table 2 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• Continue atezolizumab/placebo. 
• 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/placebo 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab/placebo and contact 
Medical Monitor. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone.   
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
229/Protocol CO41101, Version 6 
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. 


Appendix 14
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd
230/Protocol CO41101, Version 6
Table 3
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated 
myocarditis, Grade 24

Permanently discontinue atezolizumab/placebo 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 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 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.
c Resumption of atezolizumab/placebo 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.
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
Although no premedication is normally indicated for the administration of Cycle 1 of 
atezolizumab, in this study premedication is given to prevent rash (see Section 4.3.3).  
Patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
antipyretics, 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 


Appendix 14
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd
231/Protocol CO41101, Version 6
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 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 14
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd
232/Protocol CO41101, Version 6
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, antipyretics, 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. e

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.

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, antipyretics, 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 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
233/Protocol CO41101, Version 6 
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. f 
• 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. f 
• 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. e  For patients who are refractory 
to anti-cytokine therapy, experimental treatments g may be 
considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
• Hospitalize patient until complete resolution of symptoms. 


Appendix 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
234/Protocol CO41101, Version 6 
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:  The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v5.0 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, antipyretics, 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 There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), 
but data are limited, and the role of such treatment in the setting of antibody-associated 
CRS has not been established. 
f 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.  For subsequent infusions, administer 
oral premedication with antihistamines, antipyretics, 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. 
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
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 workup 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 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
235/Protocol CO41101, Version 6 
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/placebo. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
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/placebo 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 corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume 
atezolizumab/placebo. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
• For recurrent events, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
GI = gastrointestinal; ULN = upper limit of normal. 
a Atezolizumab/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
236/Protocol CO41101, Version 6 
Table 5 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
• Withhold atezolizumab/placebo for up to 12 weeks after 
event onset. a 
• Refer patient to GI specialist. 
• Initiate 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 event resolves to Grade 1 or better, resume 
atezolizumab/placebo. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
• For recurrent events, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
• Permanently discontinue atezolizumab/placebo and contact 
Medical Monitor. c 
• Refer patient to GI specialist. 
• Initiate 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 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; ULN = upper limit of normal. 
a Atezolizumab/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 both the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed. 
 


Appendix 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
237/Protocol CO41101, Version 6 
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/placebo 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.


 
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Table 6 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
• Continue atezolizumab/placebo. 
• Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
• Continue atezolizumab/placebo. 
• 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/placebo for up to 12 weeks after event onset. a 
• Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
• Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
 
a Atezolizumab/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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. 


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Adverse Events Associated with Atezolizumab 
  
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Table 6 
Management Guidelines for Dermatologic Events (cont.)  
Dermatologic 
event, Grade 4 
• Permanently discontinue atezolizumab/placebo and contact Medical 
Monitor. c 
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/placebo 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/placebo can be resumed. 
c Resumption of atezolizumab/placebo 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 workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 7. 


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Table 7 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, 
Grade 1 
• Continue atezolizumab/placebo. 
• Investigate etiology. 
Immune-mediated 
neuropathy,  
Grade 2  
• Withhold atezolizumab/placebo 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab/placebo 
and contact Medical Monitor. c 
Immune-mediated 
neuropathy,  
Grade 3 or 4 
• Permanently discontinue atezolizumab/placebo 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/placebo and contact 
Medical Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 
mg/kg/day oral or IV prednisone. 
a Atezolizumab/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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 


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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.  
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/placebo and contact 
Medical Monitor. a 
• Refer patient to neurologist. 
• Initiate 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 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/placebo 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 


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Adverse Events Associated with Atezolizumab 
  
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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. 
Table 9 
Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab/placebo. 
• 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/placebo 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab/placebo 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/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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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 (increased serum creatine kinase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist 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. 
 
 


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Table 10 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue atezolizumab/placebo. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab/placebo 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, /placebo permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
a Atezolizumab/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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Table 10 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
• Withhold atezolizumab/placebo 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/placebo. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab/placebo, permanently discontinue 
atezolizumab/placebo and contact Medical Monitor. c 
• For recurrent events, treat as a Grade 4 event. 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab/placebo 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. 
a Atezolizumab/placebo 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/placebo can be 
resumed. 
c Resumption of atezolizumab/placebo 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. 
 


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Adverse Events Associated with Atezolizumab 
  
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION 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/µL) 
– 
ANC < 1.0 × 109/L (1000/µL) 
• 
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) 
• 
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) 
 


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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 Program 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. 
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. 


Appendix 14 Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
248/Protocol CO41101, Version 6 
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. 
 


 
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Appendix 15  
Drugs with Known Risk of TdP; https://www.crediblemeds.org 
 


 
Appendix 15: 
Drugs with Known Risk of TdP; https://www.crediblemeds.org 
 
Ipatasertib and Atezolizumab—F. Hoffmann-La Roche Ltd 
250/Protocol CO41101, Version 6 
 


 
Appendix 15: 
Drugs with Known Risk of TdP; https://www.crediblemeds.org 
 
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251/Protocol CO41101, Version 6 
 


 
Appendix 15: 
Drugs with Known Risk of TdP; https://www.crediblemeds.org 
 
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252/Protocol CO41101, Version 6