Conditions: Breast Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 139
Healthy volunteers: no

Brief summary:
This is a study consisting of four cohorts in this setting. In Cohort 1, the safety and efficacy of ipatasertib (ipat) in combination with atezolizumab (atezo) and paclitaxel (pac) or nab-paclitaxel will be evaluated for participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not previously received chemotherapy. In Cohort 2, ipatasertib and atezolizumab (with no chemotherapy), will be administered to participants with locally advanced or metastatic TNBC. In Cohort 3, the safety and efficacy of neoadjuvant ipatasertib, atezolizumab, doxorubicin and cyclophosphamide (AC) (Ipat + Atezo + AC) followed by Ipat + Atezo + Pac will be evaluated in participants with locally advanced Type 2-4 (T2-4) TNBC. In Cohort 4, the safety and efficacy of Ipat + Atezo + Pac will be evaluated in participants with PD-L1 (Programmed Death-Ligand-1) positive locally advanced or metastatic TNBC that is not amenable to resection and who have not previously received chemotherapy in the advanced setting.

Detailed description:

Arms:
arm 1: Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 2: Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 3: Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 4: Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 5: Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 6: Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 7: Expansion (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 8: Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 9: Expansion (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 10: Participants (Cohort 2) will receive Ipatasertib orally daily on Days 1-28 of Cycle 1 (35-day cycle) and on Days 1-21 of subsequent cycles (28-day cycles). Atezolizumab will be administered by IV infusion on Days 8 and 22 of Cycle 1 and on Days 1 and 15 of subsequent cycles. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. arm 11: Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first. arm 12: Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first. arm 13: Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first. arm 14: Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first. arm 15: Participants (Cohort 4) will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.

Interventions: intervention 1: Ipatasertib intervention 2: Paclitaxel intervention 3: Atezolizumab intervention 4: Nab-Paclitaxel intervention 5: AC
Intervention descriptions: intervention 1: Ipatasertib will be administered at a dose of 400 milligrams (mg) orally daily on Days 1-21 of each 28 day cycle for all arms except for arms F1/F2 where it will be administered at a dose of 300 milligrams (mg) orally daily for the first two cycles and 400 mg for the remaining three cycles. intervention 2: Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) as IV infusion on Days 1, 8, and 15 of each 28 day cycle for all arms, with the exceptions of Arms F1, F2, G1 and G2, where it will be also administered on Day 22 as well, of each 28 day cycle. intervention 3: Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28 day cycle for all arms, although in Arms C1/C2, it will be administered on Day 15 of Cycle 1 followed by Days 1 and 15 in subsequent cycles. intervention 4: Nab-paclitaxel will be administered by IV infusion at a dose of 100 mg/m\^2 on Days 1, 8, and 15 of each 28 day cycle. intervention 5: AC (Doxorubicin and Cyclophosphamide) will be administered by IV infusion at 60 mg/m\^2 and 600 mg/m\^2 respectively on Days 1 and 15 of Cycles 1 and 2 for Arms F1, F2, G1 and G2.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Ipatasertib—F. Hoffmann-La Roche Ltd
Protocol CO40151, Version 6
PROTOCOL
TITLE:
A PHASE Ib, OPEN-LABEL, MULTICENTER STUDY 
EVALUATING THE SAFETY AND EFFICACY OF 
IPATASERTIB IN COMBINATION WITH 
ATEZOLIZUMAB AND PACLITAXEL OR 
NAB-PACLITAXEL IN PATIENTS WITH LOCALLY
ADVANCED OR METASTATIC TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER:
CO40151
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001957-15
IND NUMBER:
133823
NCT NUMBER:
NCT03800836
TEST PRODUCTS:
Atezolizumab (RO5541267), Ipatasertib (RO5532961)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 10 June 2017
DATES AMENDED:
Version 2:  2 March 2018
Version 3:  27 July 2018
Version 4: 6 March 2019
Version 5: 25 October 2019
Version 5 (United Kingdom):  8 February 2020
Version 6: See electronic date stamp below.
 
26-Jan-2021 10:40:21
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Ipatasertib—F. Hoffmann-La Roche Ltd
2/Protocol CO40151, Version 6
PROTOCOL AMENDMENT, VERSION 6
RATIONALE
Protocol CO40151 has primarily been amended to align the protocol with the most 
recent Atezolizumab Investigator’s Brochure (Version 17).  Changes to the protocol, 
along with a rationale for each change, are summarized below:

Section 1.3 has been updated to indicate that Atezolizumab is also approved for the 
treatment of hepatocellular carcinoma, and melanoma.

It has been clarified that patients will not be allowed to make up missed doses of 
ipatasertib and atezolizumab study drugs and should resume dosing at their next 
scheduled dose. If clinically possible, patients should receive 4 doses of 
doxorubicin and cyclophosphamide and 12 doses of weekly paclitaxel prior to 
surgery, as per local standard of care (Section 3.1.7).

Two changes specifically for Cohort 3 in response to Medicines and Healthcare 
Products Regulatory Agency feedback in the Version 5 (United Kingdom) have also 
been added to the global study protocol.  These two changes are as follows: 
–
Text has been modified to state that live, attenuated vaccines are prohibited
with cyclophosphamide treatment:  Live, attenuated vaccines are prohibited 
within 4 weeks prior to initiation of study treatment, during treatment with 
atezolizumab or cyclophosphamide, and for 5 months after the last dose of 
atezolizumab or 3 months after the last dose of cyclophosphamide, whichever 
occurs later (Section 4.4.3).
–
An ECG will be assessed during screening, at each doxorubicin administration 
(Days 1 and 15 of Cycles 12), at the study completion/early terminiation visit,
and as clinically indicated.  Screening ECG assessments obtained48 hours 
before Day 1 of Cycle 1 do not have to be repeated on Day 1 of Cycle 1
(Section 4.5.8 and Appendix 3).

Section 4.5.7 has been updated to allow investigators to obtain NGS report from 
baseline and/or at the time of disease progression, after the patient has 
discontinued study treatment.

List of identified risks for atezolizumab has been revised to include severe 
cutaneous adverse reactions (Section 5.1.2).

Guidelines for management of atezolizumab-associated dermatologic adverse 
events have been revised to provide guidance on severe cutaneous adverse 
reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis 
(Section 5.1.9.4, Table 6, and Appendix 13).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), hemophagocytic lymphohistiocytosis (HLH) and 
macrophage activation syndrome (MAS) have replaced systemic inflammatory 
response syndrome on the list of atezolizumab-associated adverse events of special 
interest (Section 5.2.3).


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
Language has been added to clarify that if a patient experiences both a local and 
systemic reaction to a single administration of study treatment, each reaction should 
be recorded separately on the Adverse Event eCRF (Section 5.3.5).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12).

Language has been updated to indicate that 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 during the adverse event 
reporting period (Section 5.5.1).

The list of study records and documents to be retained by Prinicipal Investigator has 
been amended to include images (Section 7.5).

A new section has been added to describe the implementation of a system to 
manage the quality of the study (Section 9.3).

The name of a Roche policy on data sharing has been corrected (Section 9.6).

It has been clarified that hematology and fasting serum chemistry laboratory 
assessments are not required on Days 8 and 22 during Cycles 12 because 
no chemotherapy infusions are being given on these days.  Other assessments 
such as vital signs, weight, and assessment of adverse events, concomitant 
medications, and review of the patient diary are still required on Days 8 and 22 
during Cycles 12 as indicated in the protocol. It has also been clarified that 
screening local laboratory assessments obtained 48 hours before Day 1 of Cycle 1 
do not have to be repeated on Day 1 of Cycle 1 (Appendix 3).

Appendix 11 has been revised to indicate that 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 management guidelines for Grade 1 Immune-mediated myocarditis have been 
removed since it is considered standard of care for patients that are suspected of 
presenting signs or symptoms suggestive of myocarditis (Appendix 13).  The 
guidelines are also summarized in Section 6.7.6 of the IB.

To address a request by the French ANSM, the management guidelines for 
infusion-related reactions associated with atezolizumab have been updated to 
include guidelines for cytokine-release syndrome (CRS) to align with the definition, 
grading, and management of CRS reflected in a recent publication (Lee et al. 2019) 
(Appendix 13).

To address a request by the French ANSM, the management guidelines for HLH 
and MAS have been modified to indicate that HLH should be considered when CRS 
presentation is atypical or prolonged, to add anticytokine therapy as an option for 
treating HLH or MAS, and to suggest that published guidelines should be followed 
for HLH or MAS events that do not respond to treatment within 24 hours 
(Appendix 13).


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
Language has been added to clarify that hemophagocytic lymphohistiocytosis and 
macrophage activation syndrome are considered potential risks for atezolizumab 
(Appendix 13).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents 
cumulative changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15
PROTOCOL SYNOPSIS .................................................................................... 16
1.
BACKGROUND .......................................................................................... 35
1.1
Background on Triple-Negative Breast Cancer ..................... 35
1.2
Background on Ipatasertib..................................................... 37
1.3
Background on Atezolizumab................................................ 38
1.4
Study Rationale and BenefitRisk Assessment..................... 39
2.
OBJECTIVES AND ENDPOINTS ............................................................... 42
3.
STUDY DESIGN......................................................................................... 47
3.1
Description of the Study......................................................... 47
3.1.1
Overview of Study Design ..................................................... 47
3.1.2
Safety Run-In Stage with Safety Assessment 
Window (Cohort 1: Arms A1 and B1)..................................... 53
3.1.3
Expansion Stage (Cohort 1:  Arms A2, B2, and 
A3)......................................................................................... 54
3.1.4
Safety Run-In Stage with Safety Assessment 
Window (Cohort 1:  Arms C1 and D1) ................................... 54
3.1.5
Expansion Stage (Cohort 1:  Arms C2 and D2)..................... 55
3.1.6
Biopsy Cohort (Cohort 2)....................................................... 56
3.1.7
Safety Run-In Stage with Safety Assessment 
Window (Cohort 3:  Arms F1 and G1) ................................... 57
3.1.8
Expansion Stage (Cohort 3:  Arms F2 and G2) ..................... 58
3.1.9
PD-L1Positive Cohort (Cohort 4:  Arm H)............................ 58
3.1.10
Assessments and Monitoring................................................. 58
3.1.11
Internal Safety Monitoring...................................................... 59
3.2
End of Study and Length of Study......................................... 59
3.3
Rationale for Study Design.................................................... 59
3.3.1
Rationale for Patient Population ............................................ 59
3.3.2
Rationale for Ipatasertib in Combination with 
Atezolizumab and Paclitaxel or Nab-Paclitaxel...................... 60
3.3.2.1
Rationale for Targeting the PI3K/Akt Pathway....................... 60


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3.3.2.2
Rationale for Immunotherapy in Breast Cancer..................... 61
3.3.2.3
Rationale for Combining Ipatasertib with 
Atezolizumab......................................................................... 62
3.3.3
Rationale for Combination Treatment with 
Ipatasertib, Atezolizumab, Paclitaxel, 
Doxorubicin, and Cyclophosphamide .................................... 63
3.3.4
Rationale for Starting Dose and Schedule of 
Ipatasertib.............................................................................. 65
3.3.5
Rationale for Treatment with Paclitaxel and 
Choice of Paclitaxel Regimen................................................ 66
3.3.6
Rationale for Treatment with Nab-Paclitaxel and 
Choice of Nab-Paclitaxel Regimen........................................ 67
3.3.7
Rationale for Atezolizumab Dose and Schedule.................... 68
3.3.8
Rationale for Staggered Dose and Schedule......................... 68
3.3.9
Rationale for Atezolizumab Treatment beyond 
Initial Radiographic Progression............................................ 68
3.3.10
Rationale for Pathologic Complete Response as 
Primary Endpoint in Cohort 3................................................. 69
3.3.11
Rationale for Biomarker Assessments................................... 69
3.3.11.1
Rationale for Using Archival Tissue for 
Examining PIK3CA/AKT1/PTEN-Altered Tumor 
Status .................................................................................... 70
3.3.11.2
Rationale for Collection of Blood Samples for 
Non-Invasive Disease Monitoring.......................................... 70
3.3.11.3
Rationale for Collection of DNA (Blood) for 
Exploratory Whole Genome Sequencing............................... 71
3.3.11.4
Rationale for Optional Collection of New Tumor 
Biopsies at Disease Progression for 
Exploratory Purposes, Mandatory Collection of 
Serial Tumor Biopsies for Biopsy Cohort, and 
Mandatory Collection of Tumor Tissue from 
Surgical Resection in Cohort 3 .............................................. 72
3.3.12
Rationale for the Pharmacokinetic Evaluation 
Schedule................................................................................ 72
4.
MATERIALS AND METHODS .................................................................... 73
4.1
Patients.................................................................................. 73
4.1.1
Inclusion Criteria.................................................................... 73
4.1.2
Exclusion Criteria................................................................... 78


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4.2
Method of Treatment Assignment.......................................... 84
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 84
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 84
4.3.1.1
Ipatasertib.............................................................................. 84
4.3.1.2
Atezolizumab......................................................................... 84
4.3.1.3
Paclitaxel ............................................................................... 85
4.3.1.4
Nab-Paclitaxel ....................................................................... 85
4.3.1.5
Doxorubicin............................................................................ 85
4.3.1.6
Cyclophosphamide................................................................ 85
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 85
4.3.2.1
Ipatasertib.............................................................................. 85
4.3.2.2
Atezolizumab......................................................................... 86
4.3.2.3
Paclitaxel ............................................................................... 88
4.3.2.4
Nab-Paclitaxel ....................................................................... 88
4.3.2.5
Doxorubicin............................................................................ 88
4.3.2.6
Cyclophosphamide................................................................ 88
4.3.3
Other Treatments:  Premedications and 
Prophylactic Treatment.......................................................... 89
4.3.4
Investigational Medicinal Product Accountability ................... 90
4.3.5
Continued Access to Ipatasertib and 
Atezolizumab......................................................................... 91
4.4
Concomitant Therapy ............................................................ 92
4.4.1
Permitted Therapy................................................................. 92
4.4.2
Cautionary Therapy ............................................................... 94
4.4.2.1
Medications Given with Precaution due to Effects 
Related to CYP450 Enzymes ................................................ 94
4.4.2.2
Herbal Therapies................................................................... 95
4.4.3
Prohibited Therapy ................................................................ 95
4.4.4
Prohibited Food ..................................................................... 96
4.4.5
Additional Restrictions ........................................................... 96
4.5
Study Assessments ............................................................... 97
4.5.1
Informed Consent Forms and Screening Log........................ 97


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4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 97
4.5.3
Physical Examinations........................................................... 97
4.5.4
Vital Signs.............................................................................. 98
4.5.5
Tumor and Response Evaluations for Cohorts 1, 
2, and 4.................................................................................. 98
4.5.6
Disease Assessments and Management for 
Cohort 3................................................................................. 99
4.5.6.1
Disease Status Assessment.................................................. 99
4.5.6.2
Ultrasound of Breast and Axilla ........................................... 100
4.5.6.3
Mammograms...................................................................... 100
4.5.6.4
Other Radiographic Assessments ....................................... 100
4.5.6.5
Tumor Measurements.......................................................... 101
4.5.6.6
Lymph Node Assessments and Staging.............................. 101
4.5.6.7
Surgical Plan and Procedures ............................................. 101
4.5.6.8
Surgical Specimen Pathology.............................................. 102
4.5.6.9
Confirmation of Disease Progression or Second 
Primary Cancer.................................................................... 102
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples............................................................................... 102
4.5.8
Electrocardiograms and Cardiac Function 
Assessment......................................................................... 106
4.5.9
Mandatory Samples for Whole Genome 
Sequencing.......................................................................... 107
4.5.10
Post-Treatment Follow-Up for Cohorts 1, 2, and 4 .............. 108
4.5.11
Optional Samples for Research Biosample 
Repository ........................................................................... 108
4.5.11.1
Overview of the Research Biosample Repository................ 108
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 109
4.5.11.3
Sample Collection................................................................ 109
4.5.11.4
Confidentiality...................................................................... 110
4.5.11.5
Consent to Participate in the Research 
Biosample Repository.......................................................... 110
4.5.11.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 110


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4.5.11.7
Monitoring and Oversight..................................................... 111
4.6
Treatment, Patient, Study, and Site 
Discontinuation.................................................................... 111
4.6.1
Study Treatment Discontinuation......................................... 111
4.6.2
Patient Discontinuation from Study...................................... 112
4.6.3
Study Discontinuation.......................................................... 112
4.6.4
Site Discontinuation............................................................. 113
5.
ASSESSMENT OF SAFETY..................................................................... 113
5.1
Safety Plan .......................................................................... 113
5.1.1
Risks Associated with Ipatasertib ........................................ 114
5.1.2
Risks Associated with Atezolizumab ................................... 114
5.1.3
Risks Associated with Combination Use of 
Atezolizumab and Ipatasertib .............................................. 114
5.1.4
Risks Associated with Ipatasertib in Combination 
with Paclitaxel...................................................................... 114
5.1.5
Risks Associated with Paclitaxel.......................................... 115
5.1.6
Risks Associated with Nab-Paclitaxel.................................. 115
5.1.7
Risks Associated with Doxorubicin ...................................... 116
5.1.8
Risks Associated with Cyclophosphamide........................... 116
5.1.9
Management of Patients Who Experience 
Specific Adverse Events...................................................... 117
5.1.9.1
Treatment Interruption for Toxicities .................................... 119
5.1.9.2
General Guidelines.............................................................. 119
5.1.9.3
Infusion-Related Reactions to Paclitaxel ............................. 121
5.1.9.4
Management Guidelines for Adverse Events....................... 121
5.2
Safety Parameters and Definitions ...................................... 138
5.2.1
Adverse Events ................................................................... 138
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 138
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 139
5.2.4
Selected Adverse Events..................................................... 140
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 141
5.3.1
Adverse Event Reporting Period ......................................... 141


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5.3.2
Eliciting Adverse Event Information..................................... 141
5.3.3
Assessment of Severity of Adverse Events ......................... 142
5.3.4
Assessment of Causality of Adverse Events ....................... 142
5.3.5
Procedures for Recording Adverse Events.......................... 143
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 144
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................. 144
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 144
5.3.5.4
Abnormal Laboratory Values ............................................... 145
5.3.5.5
Abnormal Vital Sign Values ................................................. 146
5.3.5.6
Abnormal Liver Function Tests............................................ 146
5.3.5.7
Deaths ................................................................................. 146
5.3.5.8
Preexisting Medical Conditions............................................ 147
5.3.5.9
Lack of Efficacy or Worsening of Breast Cancer ................. 147
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 147
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 148
5.3.5.12
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ................... 149
5.3.5.13
Left Ventricular Systolic Dysfunction ................................... 151
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 151
5.4.1
Emergency Medical Contacts.............................................. 152
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 152
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 152
5.4.2.2
Events That Occur after Study Treatment 
Initiation ............................................................................... 152
5.4.3
Reporting Requirements for Pregnancies............................ 153
5.4.3.1
Pregnancies in Female Patients.......................................... 153
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 153
5.4.3.3
Abortions ............................................................................. 154
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 154
5.5
Follow-Up of Patients after Adverse Events ........................ 154


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5.5.1
Investigator Follow-Up......................................................... 154
5.5.2
Sponsor Follow-Up .............................................................. 155
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 155
5.6.1
Reporting for Cohorts 1, 2, and 4 ........................................ 155
5.6.2
Reporting for Cohort 3 ......................................................... 155
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 156
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 156
6.1
Determination of Sample Size ............................................. 157
6.1.1
Cohorts 1 and 3:  Safety Run-In Stage................................ 157
6.1.2
Cohort 1:  Expansion Stage................................................. 157
6.1.3
Cohort 2:  Biopsy................................................................. 159
6.1.4
Cohort 3:  Expansion Stage................................................. 159
6.1.5
Cohort 4............................................................................... 160
6.2
Summaries of Conduct of Study.......................................... 161
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 161
6.4
Efficacy Analyses for Cohort 1 and Cohort 4....................... 161
6.4.1
Primary Efficacy Endpoint.................................................... 162
6.4.1.1
Objective Response Rate.................................................... 162
6.4.1.2
Duration of Response.......................................................... 162
6.4.2
Secondary Efficacy Endpoints............................................. 162
6.4.2.1
Progression-Free Survival ................................................... 162
6.4.2.2
Clinical Benefit Rate ............................................................ 162
6.4.2.3
Overall Survival ................................................................... 162
6.4.3
Exploratory Efficacy Endpoints............................................ 163
6.5
Exploratory Efficacy Analyses for Cohort 2.......................... 163
6.6
Efficacy Analyses for Cohort 3............................................. 163
6.7
Safety Analyses................................................................... 163
6.8
Pharmacokinetic Analyses................................................... 164
6.9
Immunogenicity Analyses.................................................... 164
6.10
Biomarker Analyses............................................................. 165


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7.
DATA COLLECTION AND MANAGEMENT ............................................. 165
7.1
Data Quality Assurance....................................................... 165
7.2
Electronic Case Report Forms............................................. 166
7.3
Source Data Documentation................................................ 166
7.4
Use of Computerized Systems ............................................ 167
7.5
Retention of Records........................................................... 167
8.
ETHICAL CONSIDERATIONS.................................................................. 167
8.1
Compliance with Laws and Regulations .............................. 167
8.2
Informed Consent................................................................ 168
8.3
Institutional Review Board or Ethics Committee.................. 169
8.4
Confidentiality...................................................................... 169
8.5
Financial Disclosure ............................................................ 170
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 170
9.1
Study Documentation .......................................................... 170
9.2
Protocol Deviations.............................................................. 170
9.3
Management of Study Quality ............................................. 170
9.4
Site Inspections ................................................................... 171
9.5
Administrative Structure....................................................... 171
9.6
Publication of Data and Protection of Trade 
Secrets ................................................................................ 171
9.7
Protocol Amendments ......................................................... 172
10. REFERENCES ......................................................................................... 173
LIST OF TABLES
Table 1a
Objectives and Corresponding Endpoints for Cohorts 1 and 4 ... 43
Table 1b
Objectives and Corresponding Endpoints for Cohort 2 
(Biopsy)....................................................................................... 45
Table 1c
Objectives and Corresponding Endpoints for Cohort 3............... 46
Table 2
Administration of First and Subsequent Infusions of 
Atezolizumab .............................................................................. 87
Table 3
Suggested Dose Reductions for Ipatasertib:  Cohorts 1, 2, 
and 4 and Arms G1 and G2 of Cohort 3 ................................... 117


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Table 4
Suggested Dose Reductions for Ipatasertib:  Arms F1 and 
F2 of Cohort 3........................................................................... 118
Table 5
Suggested Dose Reductions for Paclitaxel and Nab-
Paclitaxel................................................................................... 118
Table 6
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Ipatasertib and Atezolizumab..... 123
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 142
Table 8
Causal Attribution Guidance ..................................................... 143
Table 9
Probabilities of Observing Adverse Events with Different 
Underlying Incidences:  Safety Run-In Stage for Cohorts 1 
and 3......................................................................................... 157
Table 10
Estimated Objective Response Rate and Its 95% CI for 
20 Patients in Arms A and B, Respectively............................... 158
Table 11
Estimated Objective Response Rate and Its 95% CI for 
12 Patients in Arms C and D, Respectively............................... 158
Table 12
Estimated Objective Response Rate and Its 95% CI for 
90 Patients in Arm A and B Combined...................................... 159
Table 13
Estimated Pathologic Complete Response Rate and Its 95% 
CI for 12 Patients in Arm F or Arm G ........................................ 160
Table 14
Estimated Pathologic Complete Response Rate and Its 95% 
CI for 18 Patients in Arm F or Arm G ........................................ 160
Table 15
Estimated Objective Response Rate and Its 95% CI for 
90 PD-L1Positive Patients in Cohorts 1 and 4 ........................ 161
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 50
Figure 2
Dosing Schedule......................................................................... 51
LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Cohorts 1 and 4 ................................... 180
Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) ................................. 188
Appendix 3
Schedule of Activities:  Cohort 3 ............................................... 195
Appendix 4
Schedule of Pharmacokinetic and Immunogenicity Samples:   
Cohorts 1 and 4 ........................................................................ 202
Appendix 5
Schedule of Pharmacokinetic and Immunogenicity Samples:  
Cohort 2 (Biopsy Cohort) .......................................................... 204
Appendix 6
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples:  Cohort 3.................................................. 205
Appendix 7
Eastern Cooperative Oncology Group Scale of Performance 
Status........................................................................................ 206


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Appendix 8
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations.................................................... 207
Appendix 9
ASCO/CAP HER2 Test Guideline Recommendations.............. 209
Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication ............................... 212
Appendix 11
Preexisting Autoimmune Diseases and Immune Deficiencies .. 223
Appendix 12
Anaphylaxis Precautions........................................................... 224
Appendix 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 225
Appendix 14
Axillary Lymph Node Staging and Management ....................... 250


Ipatasertib—F. Hoffmann-La Roche Ltd
15/Protocol CO40151, Version 6
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib, OPEN-LABEL, MULTICENTER STUDY 
EVALUATING THE SAFETY AND EFFICACY OF 
IPATASERTIB IN COMBINATION WITH 
ATEZOLIZUMAB AND PACLITAXEL OR 
NAB-PACLITAXEL IN PATIENTS WITH LOCALLY
ADVANCED OR METASTATIC TRIPLE-NEGATIVE 
BREAST CANCER
PROTOCOL NUMBER:
CO40151
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001957-15
IND NUMBER:
133823
NCT NUMBER:
NCT03800836
TEST PRODUCTS:
Atezolizumab (RO5541267), Ipatasertib (RO5532961)
MEDICAL MONITOR:
, M.D., Ph.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 to the Sponsor or their designee.


Ipatasertib—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib, OPEN-LABEL, MULTICENTER STUDY EVALUATING 
THE SAFETY AND EFFICACY OF IPATASERTIB IN 
COMBINATION WITH ATEZOLIZUMAB AND PACLITAXEL OR 
NAB-PACLITAXEL IN PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC TRIPLE-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
CO40151
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001957-15
IND NUMBER:
133823
NCT NUMBER:
NCT03800836
TEST PRODUCTS:
Atezolizumab (RO5541267), Ipatasertib (RO5532961)
PHASE:
Phase Ib
INDICATION:
Metastatic triple-negative breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Specific objectives and corresponding endpoints are outlined below (see Tables 1a1c) for the 
following cohorts:

Cohort 1:  patients with locally advanced or metastatic triple-negative breast cancer (TNBC) 
that is not amenable to resection who have not previously received chemotherapy in the 
advanced setting

Cohort 2:  patients with locally advanced or metastatic TNBC that is not amenable to 
resection who have received no more than two lines of prior systemic chemotherapy and 
are willing to undergo serial biopsies (biopsy cohort)

Cohort 3:  patients with locally advanced cT24 cN03 cM0 TNBC (hereafter referred to as 
T24 TNBC)

Cohort 4:  patients with PD-L1positive locally advanced or metastatic TNBC that is not 
amenable to resection who have not previously received chemotherapy in the advanced 
setting
Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive tumors to 
investigate treatment effect in patients with PD-L1positive TNBC.


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17/Protocol CO40151, Version 6
Table 1a
Objectives and Corresponding Endpoints for Cohorts 1 and 4
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only) in all patients regardless 
of PD-L1 status (Cohort 1 only) or in 
patients with PD-L1positive tumors only 
(Cohorts 1 and 4)
ORR, defined as the proportion of patients with 
a confirmed complete response or partial response on 
two consecutive occasions 4 weeks apart, as 
determined by the investigator according to 
RECIST v1.1 (primary endpoint)
DOR, defined as the time from the first occurrence of 
a documented confirmed complete response or partial 
response to the first date of recorded disease 
progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause 
(whichever occurs first) (secondary endpoint)
Primary Safety Objective
Corresponding Endpoints
To evaluate the safety of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only)) in all patients 
regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only)) in all patients regardless 
of PD-L1 status (Cohort 1 only) or in 
patients with PD-L1positive tumors only 
(Cohorts 1 and 4)
PFS, defined as the time from enrollment to the date 
of the first recorded occurrence of disease 
progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause 
(whichever occurs first)
CBR, defined as proportion of patients with stable 
disease for at least 24 weeks or with confirmed 
complete or partial response, as determined by the 
investigator according to RECIST v1.1
OS, defined as the time from enrollment to death from 
any cause 
Note:  Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive 
tumors to investigate treatment effect in patients with PD-L1positive TNBC. 
ADAanti-drug antibody; CBRclinical benefit rate; DORduration of response; 
nab-paclitaxelnanoparticle albumin-bound paclitaxel; NCI CTCAE v4.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRobjective response 
rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic; 
RECIST Response Evaluation Criteria in Solid Tumors.


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Table 1a
Objectives and Corresponding Endpoints for Cohorts 1 and 4 (cont.)
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics 
of ipatasertib and its metabolite 
(G-037720) and atezolizumab when 
administered in combination with 
paclitaxel (Cohorts 1 and 4) or 
nab-paclitaxel (Cohort 1 only)) in all 
patients regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Plasma concentration of ipatasertib, G-037720, and 
atezolizumab at specified timepoints for analysis 
using non-compartment methodology or population 
PK methodology
Exploratory Pharmacokinetic Objectives
Corresponding Endpoints
To evaluate potential relationships 
between ipatasertib exposure and 
safety and efficacy endpoints
Relationship between ipatasertib plasma 
concentration and safety and efficacy endpoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
IpatAtezo combined with either 
paclitaxel (Cohorts 1 and 4) or 
nab-paclitaxel (Cohort 1 only)) in all 
patients regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive biomarkers) 
or are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers) 
To assess the mechanisms of intrinsic 
and acquired resistances
Relationship between biomarkers in blood and tumor 
tissue and efficacy
Changes in molecular biomarkers in pretreatment 
and post-progression tumor tissues, plasma, and 
blood
Note:  Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive 
tumors to investigate treatment effect in patients with PD-L1positive TNBC. 
ADAanti-drug antibody; CBRclinical benefit rate; DORduration of response; 
nab-paclitaxelnanoparticle albumin-bound paclitaxel; NCI CTCAE v4.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRobjective response 
rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic; 
RECIST Response Evaluation Criteria in Solid Tumors.


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Table 1b
Objectives and Corresponding Endpoints for Cohort 2 (Biopsy)
Exploratory Biomarker Objectives
Corresponding Endpoints
To evaluate the pharmacodynamic 
effects of ipatasertib and IpatAtezo in 
tumor cells and on the tumor 
microenvironment
To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive biomarkers) 
or are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers) 
To assess the mechanisms of intrinsic 
and acquired resistances
Changes in markers of immune cell infiltration and 
activity as well as in pretreatment and on-treatment 
tumor tissues
Change in circulating immune cell repertoires
Changes in molecular biomarkers in pretreatment 
and on-treatment tumor tissues
Relationship between biomarkers in blood and 
tumor tissue and efficacy
Changes in molecular biomarkers in pretreatment 
and post-progression tumor tissues, plasma, and 
blood
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the anti-tumor activity of 
IpatAtezo as 2L/3L treatment in 
patients with TNBC and in patients with 
TNBC who have PIK3CA/AKT1/PTEN-
altered tumors
The following endpoints will be evaluated using 
RECIST v1.1:
ORR
DOR
CBR
PFS
OS
Safety Objective
Corresponding Endpoints
To evaluate the safety of IpatAtezo in 
patients in Cohort 2 (i.e., biopsy cohort)
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results
2Lsecond line; 3Lthird line; Atezoatezolizumab; CBRclinical benefit rate; DORduration 
of response; Ipatipatasertib; NCI CTCAE v4.0National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0; ORRobjective response rate; OSoverall survival; 
PFSprogression-free survival; RECIST Response Evaluation Criteria in Solid Tumors; 
TNBCtriple-negative breast cancer.
Table 1c
Objectives and Corresponding Endpoints for Cohort 3
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
neoadjuvant Ipat Atezo AC followed 
by Ipat Atezo Pac
pCR rate, defined as the proportion of patients who 
have no residual invasive disease in the breast and 
no residual disease in the lymph nodes (ypT0/Tis 
ypN0 in the current AJCC staging system)
Primary Safety Objective
Corresponding Endpoints
To evaluate the safety of neoadjuvant 
Ipat Atezo AC followed by 
Ipat Atezo Pac
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results


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Table 1c
Objectives and Corresponding Endpoints for Cohort 3 (cont.)
Exploratory Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
ipatasertib and its metabolite 
(G-037720) and atezolizumab when 
administered in combination with 
paclitaxel or AC
Plasma concentration of ipatasertib and G-037720 at 
specified timepoints
Serum concentration of atezolizumab at specified 
timepoints
Exploratory Immunogenicity Objectives
Corresponding Endpoints
To evaluate the immune response to 
atezolizumab
Incidence of ADAs to atezolizumab during the study 
and prevalence of ADAs to atezolizumab at baseline
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify and/or evaluate biomarkers 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are early surrogates of efficacy, are 
associated with progression to a more 
severe disease state (i.e., prognostic 
biomarkers), are associated with 
acquired resistance to study treatment, 
are associated with susceptibility to 
developing adverse events or can lead 
to improved adverse event monitoring 
or investigation (i.e., safety biomarkers), 
can provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology and drug safety
Relationship between biomarkers in blood, plasma, 
and tumor tissue and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
ACdoxorubicin plus cyclophosphamide; ADAanti-drug antibody; AJCCAmerican Joint 
Committee on Cancer; Atezoatezolizumab; EFSevent-free survival; Ipatipatasertib; 
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
Pac paclitaxel; pCRpathologic complete response; PKpharmacokinetic.
Study Design
Description of Study
This is a Phase Ib, open-label, multicenter study consisting of four cohorts.  In Cohort 1, the 
safety and efficacy of ipatasertib atezolizumab paclitaxel (Ipat Atezo Pac) and 
ipatasertib atezolizumab nab-paclitaxel (Ipat Atezo Nab-Pac) will be evaluated in patients 
with locally advanced or metastatic TNBC who have not previously received chemotherapy in 
the advanced setting.  In Cohort 2 (biopsy cohort), Ipat Atezo (with no chemotherapy) will be 
administered in the second-line and third-line setting to patients with locally advanced or 
metastatic TNBC for the main purpose of conducting exploratory biomarker assessments.  In 
Cohort 3, the safety and efficacy of neoadjuvant ipatasertib atezolizumab doxorubicin 
cyclophosphamide (Ipat Atezo AC) followed by Ipat Atezo Pac will be evaluated in patients 
with locally advanced T24 TNBC.  In Cohort 4, the safety and efficacy of Ipat Atezo Pac will 
be evaluated in patients with PD-L1positive locally advanced or metastatic TNBC who have 
not previously received chemotherapy in the advanced setting.
There is a known and acceptable safety profile of ipatasertib with paclitaxel and atezolizumab 
with paclitaxel or nab-paclitaxel.  If an unexpected safety signal is detected at any time, doublet 


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21/Protocol CO40151, Version 6
safety of ipatasertib with atezolizumab may be further evaluated.  The safety and efficacy of the 
combination of ipatasertib with atezolizumab is being assessed both in Cohort 2 of this trial and 
separately (i.e., in Study CO39611 for HR-positive/HER2-negative metastatic breast cancer and 
Study CO40115 for TNBC).  
Up to 25 sites in North America, Europe, and the Asia Pacific will enroll approximately 
202 patients (114 patients in Cohort 1, 14 patients in Cohort 2, 24 patients in Cohort 3, and 
50 patients in Cohort 4).
Number of Patients
Approximately 178 patients with locally advanced or metastatic TNBC that is not amenable to 
resection and approximately 24 patients with locally advanced T24 TNBC are expected to be 
enrolled in this study.
Target Population
Inclusion Criteria
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form(s)

Woman or man age  18 years at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group Performance Status of 0 or 1 

Adequate hematologic and organ function within 14 days before the first study treatment on 
Day 1 of Cycle 1, defined by the following:
–
Neutrophils (absolute neutrophil count [ANC] 1500/L) (Cohort 3 patients should meet 
this criterion without granulocyte colonystimulating factor support within the preceding 
2 weeks)
–
For Cohort 3:  lymphocyte count 500/L
–
Hemoglobin 9 g/dL (Cohort 3 patients should meet this criterion in the absence of any 
transfusion within the preceding 2 weeks)
–
Platelet count 100,000/L (Cohort 3 patients should meet this criterion in the absence 
of any transfusion within the preceding 2 weeks)
–
Serum albumin 3 g/dL
–
Total bilirubin 1.5the upper limit of normal (ULN) (Cohorts 1, 2, and 4) or total 
bilirubin 1.0ULN (Cohort 3), 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:
Cohort 1, 2, and 4 patients with documented liver or bone metastases may 
have AST and ALT 5ULN.
–
ALP 2 ULN, with the following exceptions: 
Cohort 1, 2, and 4 patients with known liver involvement may have ALP 
5ULN
Cohort 1, 2, and 4 patients with known bone involvement may have ALP 
7ULN
–
PTT (or aPTT) and INR 1.5ULN (except for patients receiving anticoagulation 
therapy)  
Patients receiving heparin treatment should have a PTT (or aPTT) between 
1.5 and 2.5 ULN (or patient value before starting heparin treatment).  Patients 
receiving coumarin derivatives should have an INR between 2.0 and 3.0 
assessed in two consecutive measurements 1 to 4 days apart.


Ipatasertib—F. Hoffmann-La Roche Ltd
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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 serum glucose 150 mg/dL and glycosylated hemoglobin 7.5%

For Cohorts 1, 2, and 4:  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 defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 1 month after the last dose of 
ipatasertib, 5 months after the last dose of atezolizumab, 6 months after the last dose of 
paclitaxel, nab-paclitaxel, or doxorubicin, and 12 months after the last dose of 
cyclophosphamide, whichever occurs later.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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; and sexual abstinence.
Hormonal contraceptive methods may be used in accordance with specific country and 
local requirements for patients with breast cancer. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.

For men:  consider conserving sperm before treatment because of possible irreversible 
infertility due to therapy with paclitaxel, agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure rate 
of 1% per year during the treatment period and for 1 month after the last dose of 
ipatasertib or 6 months after the last dose of paclitaxel, nab-paclitaxel, 
cyclophosphamide, or doxorubicin, 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 1 month after the last dose of ipatasertib or 6 months after the 
last dose of paclitaxel, nab-paclitaxel, cyclophosphamide, or doxorubicin, 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, and sexual abstinence.


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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.
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific criteria for study entry:

For Cohorts 1, 2, and 4:  histologically documented TNBC (negative HER2, ER, and PgR 
status) 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 (nonfine-needle aspiration [FNA] sample) as assessed locally (or centrally, 
if not available locally) according to the American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) guidelines 

For Cohort 2:  disease progression following one or two lines of systemic therapy for 
inoperable locally advanced or metastatic TNBC
–
Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or 
radiation treatment for early stage breast cancer, provided all chemotherapy was 
completed 12 months prior to Day 1 of Cycle 1.

For Cohorts 1, 2, and 4:  measurable disease according to RECIST v1.1

For Cohort 2:  Treated brain or spinal cord metastases are allowed if patients have stable 
disease and are not on steroid treatment.

For Cohort 3:  histologically documented TNBC (negative HER2, ER, and PgR status) that 
meets both of the following criteria:
–
Primary breast tumor size of 2 cm by at least one radiographic or clinical 
measurement 
–
Disease stage at presentation of cT24 cN03 cM0
Note:  Receptor status at study entry should correspond to the evaluation of the most 
recent biopsy (non-FNA sample) as assessed locally (or centrally, if not available 
locally) according to the ASCO/CAP guidelines.  Patients with multifocal tumors (more 
than one tumor confined to the same quadrant as the primary tumor) are eligible 
provided all discrete lesions have been biopsied and centrally confirmed as TNBC.

For Cohort 3:  patient agreement to undergo appropriate surgical management, including 
axillary lymph node surgery and partial or total mastectomy, after completion of neoadjuvant 
treatment

Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or a minimum 
of 20 (for Cohorts 1 and 2) or 15 (for Cohorts 3 and 4) freshly cut unstained, serial tumor 
slides from the most recently collected tumor tissue for central analysis of PD-L1 status to 
determine eligibility for Cohort 4 and for central molecular analysis (retrospective next 
generation sequencing [NGS] testing for PIK3CA/AKT1/PTEN-altered status and for other 
protocol-mandated secondary and exploratory assessments).  Cytologic or FNA samples 
are not acceptable.  Tumor tissue from bone metastases that is subject to decalcification is 
not acceptable.


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–
For Cohorts 1, 2, and 4:  If a more recent specimen is either insufficient or unavailable, 
the patient may still be eligible if the patient can provide a tissue block (preferred) or 
a minimum of 20 unstained serial slides from an older archival tumor tissue, or if the 
patient is willing to consent to and undergo an additional pretreatment core or 
excisional biopsy of a non-target lesion (a non-target lesion is preferred if it is 
assessable and the biopsy can be safely obtained).  In general, a minimum of three 
core biopsies for NGS testing are required.
–
For Cohort 3:  If the specimen is either insufficient or unavailable, the patient may still 
be eligible if the patient is willing to undergo an additional pretreatment core biopsy.  
In general, a minimum of three core biopsies for NGS testing are required.
–
For Cohort 4:  Patients must have a PD-L1positive tumor (defined as 1% expressing 
tumor-infiltrating immune cells [%ICs] evaluated as proportion of tumor area) as 
determined by central testing prior to enrollment.
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.  The PD-L1 score for each patient will be the maximum 
PD-L1 score among the samples.
If a patient already has results based on the commercial FoundationOneCDx 
assay by Foundation Medicine, 10 freshly cut unstained, serial tumor slides from 
the most recently collected tumor tissue are acceptable for central molecular 
analysis (as described above), upon confirmation by the Medical Monitor.
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general criteria will be excluded from study entry:

Inability to comply with study and follow-up procedures

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills 

Active infection requiring antibiotics 

History of or current evidence of HIV infection 

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] 
or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis
–
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive total hepatitis B core antibody test, 
accompanied by a negative HBV DNA test) are eligible.
–
Patients positive for HCV antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA. 

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
Day 1 of Cycle 1 or anticipation of need for a major surgical procedure (other than 
anticipated breast surgery for Cohort 3) during the course of the study 
–
Placement of a vascular access device is not considered major surgery. 

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
1 month after the last dose of ipatasertib, 5 months after the last dose of atezolizumab, 
6 months after the last dose of paclitaxel, nab-paclitaxel, or doxorubicin, or 12 months after 
the last dose of cyclophosphamide, 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 within 48 hours prior to initiation of study treatment.

New York Heart Association (NYHA) Class II, III, or IV heart failure; left ventricular ejection 
fraction 50%; or active ventricular arrhythmia requiring medication


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
Current unstable angina or history of myocardial infarction within 6 months prior to Day 1 of 
Cycle 1

Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
480 milliseconds 

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion, including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction

Treatment with approved or investigational cancer therapy within 14 days prior to Day 1 of 
Cycle 1 

Prior treatment with an Akt inhibitor
–
Note that prior PI3K or mechanistic target of rapamycin inhibitors are allowed

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease 
or condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment complications 
Disease-Specific Exclusion Criteria for Cohorts 1, 2, and 4
For Cohorts 1, 2, and 4, patients who meet any of the following disease-specific criteria will be 
excluded from study entry:

Patients with leptomeningeal carcinomatosis

For Cohorts 1 and 4 only:  history of or known presence of brain or spinal cord metastases

For Cohorts 1 and 4:  previous systemic therapy for inoperable locally advanced or 
metastatic TNBC, including chemotherapy, immune checkpoint inhibitors, or targeted 
agents
–
Patients in Cohorts 1 and 4 may have received prior neoadjuvant or adjuvant 
chemotherapy and/or radiation treatment for early stage breast cancer, provided all 
chemotherapy was completed 12 months prior to Day 1 of Cycle 1.

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 
peripheral neuropathy 

Patients who have received palliative radiation treatment to peripheral sites (e.g., bone 
metastases) for pain control and whose last treatment was completed 14 days prior to 
Day 1 of Cycle 1 may be enrolled in the study if they have recovered from all acute, 
reversible effects 

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 
(i.e., stable in the 14 days before Day 1 of Cycle 1). 
–
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to enrollment.  
Patients should be recovered from the effects of radiation (Grade 1 or better) prior to 
study enrollment.  There is no required minimum recovery period beyond the 14 days 
required for radiation therapy.
–
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., bone metastasis) should be considered for 
loco-regional therapy if appropriate prior to enrollment. 


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
Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy 
–
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events (e.g., bone metastasis, osteoporosis) and who do not have a history of clinically 
significant hypercalcemia are eligible. 

Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
Stage I uterine cancer
Exclusion Criteria for Cohort 3
For Cohort 3, patients who meet any of the following criteria will be excluded from study entry:

Prior history of invasive breast cancer

Prior systemic therapy for treatment and/or prevention of invasive breast cancer 

Previous therapy with anthracyclines or taxanes for any malignancy

Bilateral breast cancer 

Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes 
with one exception:
–
Patients who have undergone sentinel lymph node biopsy (SLNB) prior to initiation of 
neoadjuvant therapy (as per local practice) may be eligible if the SLNB is free of 
invasive carcinoma.  However, any patient with a positive SLNB result (involved with 
invasive carcinoma) is ineligible to participate in this study.

Undergone axillary lymph node dissection prior to initiation of neoadjuvant therapy 

History of other malignancy within 5 years prior to screening, with the exception of those 
with a negligible risk of metastasis or death (e.g., 5-year overall survival 90%), such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized 
prostate cancer, or Stage I uterine cancer

History of cerebrovascular accident within 12 months prior to initiation of study treatment

Cardiopulmonary dysfunction as defined by any of the following prior to initiation of study 
treatment:
–
History of Common Terminology Criteria for Adverse Events, Version 4.0, Grade 3 
symptomatic congestive heart failure, NYHA Class II, III, or IV heart failure, or left 
ventricular ejection fraction 53%
–
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease
–
High-risk uncontrolled arrhythmias (e.g., atrial tachycardia with a heart rate 100 beats 
per minute at rest, significant ventricular arrhythmia [ventricular tachycardia], or 
second- or third-degree atrioventricular block)
–
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia
–
Myocardial infarction within 12 months prior to initiation of study treatment
–
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)
–
Evidence of transmural infarction on ECG
–
Requirement for oxygen therapy

Known allergy or hypersensitivity to the components of cyclophosphamide or doxorubicin 
formulations

Known allergy or hypersensitivity to filgrastim or pegfilgrastim formulations


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
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

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

Prior treatment with CD137 agonists or immune checkpointblockade therapies, including 
anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following ipatasertib-specific criteria will be excluded from study 
entry:

History of Type I or Type II diabetes mellitus requiring insulin 
–
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment.

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis)

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment
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’s syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of the following conditions are met:
o
Rash must cover 10% of body surface area.
o
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.
o
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within 
the previous 12 months.


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
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with atezolizumab or 
within 5 months after the last dose of atezolizumab

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or recombinant human 
antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to 
initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during the course of the 
study, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant medication or 
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study.
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.
Paclitaxel-Specific Exclusion Criteria
Patients who meet any of the following paclitaxel-specific criteria will be excluded from study 
entry:

Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate 

Grade 2 peripheral neuropathy
End of Study
The study will end when the last data point required for statistical analysis is collected and 
safety follow-up is completed, or the Sponsor decides to end the trial, whichever occurs first.
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 35 years.
Investigational Medicinal Products
Test Product (Investigational Drugs)
The investigational medicinal products for this study are ipatasertib, atezolizumab, paclitaxel, 
nab-paclitaxel, doxorubicin, and cyclophosphamide.  Ipatasertib is to be administered before 
atezolizumab and chemotherapy.  Atezolizumab is to be administered before chemotherapy.
Ipatasertib
In Cohort 1, ipatasertib will be administered at the starting dose of 400 mg orally once a day 
(QD), beginning on Cycle 1, on Days 121 of each 28-day cycle (in Arms A, B, and C), until the 
patient experiences disease progression, intolerable toxicity, or withdraws consent.  In Arm D, 
ipatasertib will be administered at the starting dose of 400 mg orally QD on Days 1521 of the 
first cycle.  In all subsequent treatment cycles (Cycles 2), ipatasertib 400 mg will be 


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administered orally QD on Days 121 until the patient experiences disease progression, 
intolerable toxicity, or withdraws consent.  
In Cohort 2, ipatasertib 400 mg will be administered orally QD on Days 128 of Cycle 1 (35-day 
cycle) and on Days 121 of subsequent cycles (28-day cycles).
In Arm F of Cohort 3, ipatasertib will be administered orally QD at a dose of 300 mg on 
Days 121 of Cycles 1 and 2 and at a dose of 400 mg on Days 121 of Cycles 35.  In Arm G 
of Cohort 3, ipatasertib will be administered orally QD at a dose of 400 mg on Days 121 of 
Cycles 15.
In Cohort 4, ipatasertib 400 mg will be administered orally QD on Days 121 of each 28-day 
cycle.
Atezolizumab
In Cohort 1, patients will receive atezolizumab 840 mg administered by IV infusion every 
2 weeks (on Days 1 and 15) of each 28-day cycle (in Arms A, B, and D).  In Arm C, 
atezolizumab 840 mg will be administered by IV infusion on Day 15 of the first cycle.  In all 
subsequent treatment cycles (Cycles 2) atezolizumab will be administered by IV infusion at 
a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.
In Cohort 2, atezolizumab 840 mg will be administered by IV infusion on Days 8 and 22 of 
Cycle 1 (35-day cycle) and on Days 1 and 15 of subsequent cycles (28-day cycles).  
In Cohort 3, atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of 
Cycles 15 (28-day cycles).  
In Cohort 4, atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 
28-day cycle.
Chemotherapy
In Cohorts 1 and 4, the dose of paclitaxel is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle.  Nab-paclitaxel will be administered by IV infusion at a starting 
dose of 100 mg/m2 on Days 1, 8, and 15 of every 28-day cycle.
In Cohort 3, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 will be administered by IV 
infusion on Days 1 and 15 of Cycles 1 and 2.  Paclitaxel 80 mg/m2 will be administered by IV 
infusion on Days 1, 8, 15, and 22 of Cycles 35.  
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. H2-receptor 
antagonists, such as cimetidine, which are known to inhibit cytochrome P450, are excluded.
In general, chemotherapy supportive care should be administered per ASCO, European 
Organisation for Research and Treatment of Cancer, or European Society for Medical Oncology 
guidelines or institutional practice.  In Cohort 3, filgrastim or pegfilgrastim must be used in 
conjunction with each AC administration.  Chemotherapy-induced nausea and vomiting 
prophylaxis and treatment should be administered as clinically indicated.  It is highly 
recommended that aprepitant be included as premedication for AC to prevent nausea and/or 
vomiting.  Because systemic corticosteroids may attenuate the potential beneficial immunologic 
effects of treatment with atezolizumab, alternative agents should be considered when clinically 
feasible.
To improve diarrhea management and patient experiences, loperamide (2 mg twice a day) will 
be administered daily as prophylaxis for diarrhea in the first cycle.  If side effects are not 
tolerated, doses may be reduced.  Investigators are encouraged to continue this dosing for the 
remainder of the study using their discretion based on clinical judgments.
Because of the risk of rash, patients should receive the following prophylactic treatment, unless 
contraindicated, during the first cycle in which all three study treatments (ipatasertib, 
atezolizumab, and taxane) are to be given in Cohorts 1 and 4 or during the first 28 days (i.e., 
Weeks 14) in which all four study treatments (ipatasertib, atezolizumab, and AC) are to be 
given in Cohort 3:  On days when patients will receive atezolizumab, patients should receive at 
least 10 mg/day prednisone (or equivalent) as premedication, followed by a fixed dose of 


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10 mg/day prednisone (or equivalent) for 24 consecutive days thereafter.  The timing of 
corticosteroid administration on days when patients will receive atezolizumab and paclitaxel will 
be determined by the investigator according to best medical judgment.  In addition, patients 
should receive daily oral antihistamine for at least the first cycle in which all three treatments 
(four treatments for Cohort 3) are to be given.  It is suggested that a non-sedating oral 
antihistamine (such as loratadine, cetirizine, or fexofenadine) and a longer-acting formulation be 
used.  Protocol-required premedication should be omitted on the day of paclitaxel infusion if 
already administered as taxane premedication per institutional practice.
Statistical Methods
Primary Analysis
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
complete response or partial response on two consecutive occasions 4 weeks apart, as 
determined by the investigator according to RECIST v1.1.  Patients without a postbaseline 
tumor assessment will be considered as non-responders.  ORR is defined as the proportion of 
patients who have an objective response; an estimate of ORR will be calculated for each 
treatment arm, and its 95% CI will be calculated using the ClopperPearson method. 
Duration of Response
Duration of response (DOR) will be analyzed to support ORR.  DOR is defined as the time from 
the first occurrence of a documented objective response to disease progression, as determined 
by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first.  
Patients who have not progressed or died at the time of analysis will be censored at the last 
disease assessment date.
Determination of Sample Size
There is no formal hypothesis testing planned. The determination of sample size for each 
cohort is described below.
Cohorts 1 and 3:  Safety Run-In Stage
In Cohorts 1 and 3, the number of patients enrolled during the safety run-in stage (n 6) in each 
arm (i.e., A1, B1, C1, D1, F1, and G1) allows for a reasonable likelihood of observing a given 
adverse event in at least 1 patient even when the incidence of the specific adverse event is low 
Cohort 1:  Expansion Stage
No formal statistical hypothesis testing is planned in this study.  Instead, the analysis here is for 
hypothesis generation, and the emphasis is on estimations.  To evaluate the primary endpoint 
of overall response rate for Cohort 1, for each arm, the analyses will be based on combining 
patients enrolled in the safety run-in and expansion stages, which is approximately 20 patients 
(Cohort 1, Arms A and B) or 12 patients (Cohort 1, Arms C and D).  Twenty patients provide 
reasonably reliable estimates for hypothesis generation in the expansion stage in Arms A and 
B. Twelve patients will provide reasonably reliable estimates for hypothesis generation in the 
expansion stage in Arms C and D.
Cohort 2:  Biopsy
If there is sufficient evidence of meaningful benefit from the combination of ipatasertib and 
atezolizumab with taxane in Cohort 1, (e.g., ORR 50%), the Sponsor may decide to open 
enrollment of a separate mandatory on-treatment biopsy cohort to evaluate biomarker endpoints 
of patients treated with ipatasertib combined with atezolizumab to further understand the 
molecular basis of treatment benefit.  To provide a reliable estimate of the effects of ipatasertib 
and ipatasertib atezolizumab on immune cell infiltration and activation, as well as molecular 
tumor biomarkers and circulating immune cell repertoires, a total of up to 14 patients will be 
enrolled in this cohort for exploratory analyses.
Cohort 3:  Expansion Stage
No formal statistical hypothesis testing is planned in this study.  Instead, the analysis here is for 
hypothesis generation, and the emphasis is on estimations.  To evaluate the primary efficacy 
endpoint of pCR for Cohort 3, for each arm, the analyses will be based on combining patients 
enrolled in the safety run-in stage (n 6) and expansion stage (n 6 or 12, as determined by the 
Sponsor) for a total of either 12 patients or 18 patients.  The minimum sample size, 12 patients, 
will provide reasonably reliable estimates for hypothesis generation in the expansion stage in 
Arms F and G.  Any additional patients will strengthen the evidence by reducing estimate 
uncertainty.


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Cohort 4
No formal statistical hypothesis testing is planned in this study.  Patients from Cohort 4 
(approximately 50 patients with PD-L1positive tumors) will be pooled with approximately 
40 patients with PD-L1positive tumors in Cohort 1.  The total sample size for this pooled 
analysis is expected to be approximately 90 patients, which will provide a reasonably reliable 
estimate for the ORR in the PD-L1positive population compared with historical data in this 
population.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
Akt
protein kinase B
ALND
axillary lymph node dissection
ASCO
American Society of Clinical Oncology
CAP
College of American Pathologists
CBR
clinical benefit rate
CIT
cancer immunotherapy
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DOR
duration of response
EBC
early breast cancer
EC
Ethics Committee
ECHO
echocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
EORTC
European Organisation for Research and Treatment of 
Cancer
ER
estrogen receptor
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded tumor
FMI
Foundation Medicine, Inc.
FNA
fine-needle aspiration
G-CSF
granulocyte colonystimulating factor
HbA1c
glycosylated hemoglobin
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HLH
hemophagocytic lymphohistiocytosis
HR
hormone receptor
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation


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Abbreviation
Definition
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRR
infusion-related reaction
IRB
Institutional Review Board
ITT
intent-to-treat (population)
LVEF
left ventricular ejection fraction
MAS
macrophage activation syndrome
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition (scan)
nab-paclitaxel
nanoparticle albumin-boundpaclitaxel
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
pCR
pathologic complete response
PFS
progression-free survival
PI3K
phosphoinositide 3-kinase
PI3K/Akt
phosphoinositide 3-kinase/protein kinase B
PIK3CA
phosphatidylinositol-4, 5bisphosphate 3-kinase, 
catalytic subunit, alpha
PgR
progesterone receptor
PK
pharmacokinetic
popPK
population PK
PRO
patient-reported outcome
PTEN
phosphatase and tensin homolog
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once a day
QTcF
QT interval corrected using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RBR
Research Biosample Repository
sb-paclitaxel
solvent based
SLNB
sentinel lymph node biopsy
T3
triiodothyronine


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Abbreviation
Definition
TNBC
triple-negative breast cancer
TNF-
tumor necrosis factor
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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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 for estrogen receptor (ER), 
progesterone receptor (PgR), and non-amplified HER2 expression (per American 
Society of Clinical Oncology [ASCO] /College of American Pathologists [CAP] guidelines 
[ASCO-CAP 2010; 2013]).  Patients with metastatic TNBC exhibit a particularly poor 
clinical outcome, generally with rapid progression and a median overall survival (OS) 
rate of approximately 16 months (Rodler et al. 2010; Miles et al. 2013).  Although TNBC 
may respond to chemotherapy, including taxanes, there are no approved first-line 
regimens or targeted therapies for patients with this specific subtype of breast cancer.  
Because of an increase in toxicity and little survival benefit with combination 
chemotherapy, treatment with sequential single agents is generally preferred 
(Cardoso et al. 2017; NCCN 2017).  There is a pressing need for clinically active agents 
for the triple-negative subtype of metastatic breast cancer (MBC).
Both National Comprehensive Cancer Network (NCCN; 2017) and the European Society 
for Medical Oncology (ESMO; 2016) (clinical practice guidelines cite paclitaxel as an 
appropriate first-line regimen, with a median progression-free survival (PFS) of 
approximately 6 months in patients with TNBC (Miles et al. 2013; Miles et al. 2017).  The 
response rates for paclitaxel administered as a single agent to patients with MBC are 
approximately 25% in first-line treatment (Wilson et al. 1994; Seidman et al. 1995;
Nabholtz et al. 1996; Gradishar et al. 2005).
Nanoparticle albumin-bound (nab)-paclitaxel is an albumin-bound formulation of 
paclitaxel that was developed to avoid the toxicities associated with the vehicles that are 
necessary for parenteral administration of solvent-based (sb)-paclitaxel (polyethylated 
castor oil and polysorbate 80). Nab-paclitaxel can be administered without steroid or 
antihistamine premedication. Based on the results of the randomized Phase III study in 
which patients received either nab-paclitaxel or sb-paclitaxel (control) administered 
every 3 weeks (Q3W) (n 460; Gradishar et al. 2005), nab-paclitaxel was approved for 
the treatment of MBC after failure of front-line combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy. Although it is not labeled 
for use in the front-line metastatic setting, NCCN and ESMO clinical practice guidelines 
include nab-paclitaxel as a standard of care that may be administered as a single agent 
to patients with recurrent or metastatic breast cancer (Cardoso et al. 2017; NCCN 2017). 


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Early-stage TNBC accounts for 10%20% of all new diagnoses of early breast cancer 
(EBC), defined as Stages IIII (Lehmann et al. 2011; Howlader et al. 2016).  Three-year 
event-free survival (EFS) rates of 74%76% have been reported for patients with TNBC 
who have received neoadjuvant anthracycline- and taxane-containing therapy 
(Sikov et al. 2016).  Upon relapse, patients with metastatic TNBC have poor outcomes, 
with rapid progression and decreased OS (Kassam et al. 2009).
Multi-agent chemotherapy regimens have proven benefit as neoadjuvant or adjuvant 
therapy for early-stage TNBC, improving both disease-specific and OS outcomes 
(Berry et al. 2006; Senkus et al. 2015; NCCN 2016).  It is currently recommended that 
chemotherapy be given preoperatively (neoadjuvant) or postoperatively (adjuvant) to 
reduce the risk of relapse in patients with early-stage TNBC.
The most effective chemotherapy combinations used for early-stage TNBC include 
anthracyclines, topoisomerase II inhibitors, platinum agents, cyclophosphamide, and/or 
taxanes (Early Breast Cancer Trialists’ Collaborative Group 2005; Peto et al. 2012).  
Studies looking at optimizing the dose and schedule of EBC chemotherapy regimens 
(Citron et al. 2003; Sparano et al. 2008; Budd et al. 2015) have established one of the 
optimal regimens with respect to maximizing efficacy as doxorubicin 60 mg/m2 and 
cyclophosphamide 600 mg/m2 administered every 2 weeks (Q2W) for four cycles, 
followed by paclitaxel 80 mg/m2 administered once a week for 12 weeks.  This regimen 
is included as a preferred option in international guidelines (Senkus et al. 2015; 
NCCN 2016).
However, despite having received standard anthracycline- or taxane-based therapy, 
approximately 30%40% of patients with clinically localized TNBC at diagnosis develop 
metastatic disease and die of the cancer (Haffty et al. 2006; Tan et al. 2008; Budd et al. 
2015).  Thus, there is a substantial need to improve long-term treatment outcomes for 
patients with early-stage TNBC.
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 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 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 (Cancer Genome Atlas Network 2012).  
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 adenosine triphosphate 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).
Up-regulation of Akt signaling (whether intrinsic or induced following chemotherapy) 
represents a potentially important survival pathway in response to genotoxic/mitotic 
stress (Xu et al. 2012).  Activation of Akt signaling following chemotherapy (including 
taxanes) may promote cell survival and chemoresistance across several cancer models, 
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 (Cancer Genome Atlas 
Network 2012), clinical trials evaluating the preliminary safety and efficacy of the 
combination of ipatasertib and paclitaxel in patients with breast cancer have been 
conducted.  These trials include a Phase Ib study with an expansion cohort of patients 
with HER2-negative breast cancer (Study PAM4983g, Arm C), a randomized Phase II 
study (Study GO29227, LOTUS) comparing ipatasertibpaclitaxel versus 
placebopaclitaxel as first-line treatment for patients with inoperable locally advanced 
or metastatic TNBC, and a randomized Phase II study (FAIRLANE) comparing 
neoadjuvant ipatasertibpaclitaxel versus placebopaclitaxel in patients with early 
TNBC (defined as T1.5 cm, N02). 


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In the Phase Ib study PAM4983g, 3 of the 15 patients (20%) with breast cancer 
remained progression free for 6 months (hormone receptor
[HR]-positive/HER2-negative: n2; TNBC: n1), and 4 partial responses included 
patients who had prior exposure to paclitaxel or investigational PI3K inhibitors 
(HR-positive/HER2-negative: n2; TNBC: n2).
In the randomized Phase II study GO29227, one of the objectives was to investigate the 
added benefit of ipatasertib to paclitaxel in the subgroup of patients with 
PIK3CA/AKT1/PTEN-altered tumors. Results from this study showed improvement in 
median PFS in the intent-to-treat (ITT) population (hazard ratio0.60; 6.2 months in the 
ipatasertib arm compared with 4.9 months in the control arm); and more pronouncedly in 
the pre-specified patient population with PIK3CA/AKT1/PTEN-altered tumors (hazard 
ratio0.44; 9 months vs. 4.9 months).
In the Phase II FAIRLANE study, pathologic complete response (pCR) rate, defined as 
ypT0/Tis ypN0, following administration of ipatasertibpaclitaxel versus 
placebopaclitaxel was 17% versus 13%, respectively, in the ITT population (n151)
and 18% versus 12%, respectively, in the PIK3CA/AKT1/PTEN-altered population 
(n62). Complete response rate following administration of ipatasertibpaclitaxel 
versus placebopaclitaxel was 28% versus 13%, respectively, in the ITT population and 
39% versus 9%, respectively, in the PIK3CA/AKT1/PTEN-altered population.
Common adverse events associated with ipatasertib include nausea, vomiting, diarrhea, 
stomatitis/mucosal inflammation, asthenia, hyperglycemia, and rash.  No new safety 
findings were identified with the combination with paclitaxel.  For benefitrisk 
assessments of study treatments, refer to Section 1.4.
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and clinical 
studies, including single-agent activities in the Phase I study (PAM4743g).
1.3
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab is a humanized 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 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 patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 


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therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy (CIT).
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, TNBC, hepatocellular carcinoma, and melanoma.
In metastatic TNBC, combination treatment with nab-paclitaxel showed promising 
activity in the Phase 1b study GP28328. Arm F (atezolizumab 800 mg IV 
Q2W nab-paclitaxel 125 mg/m2 21-day on/7-day off dosing schedule) of the six 
treatment arms in this Phase Ib study evaluated preliminary anti-tumor activity of 
patients with metastatic TNBC. As of the clinical cut-off date of 14 January 2016, 
32 patients with metastatic TNBC across various lines of therapy were evaluable for 
efficacy:  first line13 patients; second line9 patients, third line10 patients.  
Overall, the investigator-assessed objective response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) was 37.5% (confirmed 
responses). Clinical benefit was observed across all lines of therapy, with first-line and 
third-linepatients having ORRs that were comparable (46.2% and 40.0%, respectively).  
The one complete response of the 12 responders was in first-line therapy.
Atezolizumab in combination with chemotherapeutic regimens, including anthracyclines 
and cyclophosphamide, is currently being investigated in various indications in
Studies GP28328, BO29563, and GO29831. Thus far, reported adverse events for 
combination regimens have been similar to those experienced with each individual agent
and have generally been manageable. According to data available from the metastatic 
TNBC cohort in Study GP28328 (atezolizumab in combination with nab-paclitaxel), the 
most commonly occurring adverse events (30% incidence) have been fatigue, 
diarrhea, nausea, constipation, alopecia, peripheral sensory neuropathy, pyrexia, cough, 
decreased neutrophil count, peripheral neuropathy, and neutropenia.
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.  Overall, treatment with atezolizumab is well 
tolerated, with a manageable adverse event profile.  Currently, no maximum tolerated 
dose, no dose-limiting toxicities, and no clear dose-related trends in the incidence of 
adverse events have been determined.  Across all studies and tumor types, the most 
commonly reported adverse events with single-agent atezolizumab include fatigue, 
nausea, decreased appetite, diarrhea, constipation, and cough.  
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
TNBC remains a challenging disease. Outcomes for patients with high-risk primary 
TNBC remain relatively poor compared with those of other breast cancer subtypes. 


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Chemotherapy remains the mainstay of treatment, but benefits are frequently short-lived 
with rapid development of resistance. Approximately 40% of patients receiving 
neoadjuvant anthracycline- and taxane-based chemotherapy achieve a pCR (ypT0 ypN0 
or ypT0/is ypN0). The literature supports the existence of a correlation between pCR 
and long-term clinical benefit with regard to EFS hazard ratio for patients achieving pCR 
vs. patients not achieving pCR: 0.24 [95% CI: 0.18 to 0.33]) and OS (hazard ratio for 
patients achieving pCR vs. patients not achieving pCR: 0.16 [95% CI: 0.11 to 0.25])
(Cortazar et al. 2014). While several randomized trials and a meta-analysis of 
neoadjuvant chemotherapy have demonstrated that TNBC is more chemo-sensitive than
other breast cancer subtypes, as demonstrated by substantially increased pCR rates 
and clinical response rates, patients with TNBC still have a poorer prognosis overall, as 
demonstrated by significantly higher disease recurrence and lower survival rates. The 
poor long-term outcome in TNBC has been found to be driven by patients who did not 
achieve a pCR after neoadjuvant chemotherapy, making it a clinical priority to develop 
new treatment strategies that can improve pCR rates in TNBC. 
For patients with metastatic TNBC, clinical outcome is particularly poor, generally with 
rapid progression and a median OS of approximately 16 months (Rodler et al. 2010; 
Miles et al. 2013). Although chemotherapy is a mainstay treatment, resistance inevitably 
develops and benefit is often short-lived.
Results of the Phase II randomized study GO29227 demonstrated that adding 
ipatasertib to paclitaxel as first-line therapy for inoperable locally advanced or metastatic 
TNBC improves PFS in the ITT and in PTEN-low populations; the PFS improvement was 
more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors identified with the 
FoundationOnenext-generation sequencing (NGS) assay (representing approximately 
40% of the randomized patients in this setting).   
CIT has demonstrated extraordinary success, with significant survival benefits observed 
across multiple advanced malignancies.  Currently, the prevailing CIT approach is to 
circumvent immune evasion mechanisms and reinvigorate anti-tumor responses by 
identifying and targeting T-cell co-inhibitory surface receptors such as cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) and PD-L1/PD-1.  While these targets have 
resulted in remarkable clinical therapeutic success for various cancer indications, 
ongoing research indicates a series of stepwise events necessary for the generation of 
a continuous anti-tumor immune response (Chen and Mellman 2013).  Each event is 
critical for an effective response, and each is also susceptible to several tumor immune 
evasion mechanisms.  Thus, the need to identify and circumvent the various factors 
involved in tumor immune evasion will be critical for propagating the anti-tumor immune 
response and advancing the field of CIT, most likely through combined targeted therapy 
regimens.
Recently, nonclinical and clinical data have indicated a correlation between PTEN loss 
and impaired anti-tumor immune responses, including reduced CD8 T-cell infiltration and 


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reduced efficacy of anti-PD1 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 tolerable safety profiles of 
atezolizumab and ipatasertib, combination treatment with these two agents appears to 
have promising therapeutic potential in solid tumors such as TNBC.  
This Phase Ib study is designed to evaluate safety, tolerability, and efficacy of ipatasertib 
in combination with atezolizumab and chemotherapy. 
The clinical safety profile of ipatasertib as a single agent in the Phase Ia 
study (PAM4743g), in combination with paclitaxel in the Phase Ib (PAM4983g) and 
Phase II (GO29227) studies, supports continued development of ipatasertib in MBC.  As 
a single agent, ipatasertib has reasonable pharmacokinetic (PK) profile with a half-life of 
approximately 48 hours and significantly down-regulates the PI3K/Akt pathway at doses 
200 mg.  In Study GO29227, the adverse effects of ipatasertib plus paclitaxel in 
metastatic TNBC were consistent with previous experiences of ipatasertib and of 
paclitaxel, most notably ipatasertib-related gastrointestinal toxicities that are manageable 
and reversible.  No new safety signals were identified. 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 with a 3% higher incidence in the ipatasertib arm than in the placebo arm 
included diarrhea, neutropenia, 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. Please refer to the Ipatasertib 
Investigator’s Brochure for detailed safety information.
In Study GO29227, diarrhea was more common in the ipatasertib arm compared with 
the placebo arm (93% vs. 19%); however, the majority of cases were low grade.  The 
onset of diarrhea was most common within the first cycle and frequency of patients with 
new onset of diarrhea decreased with increased treatment duration; and, no cases of 
colitis were reported.  Diarrhea generally responded to loperamide treatment, ipatasertib 
dose holds and dose reductions when resuming treatment; limited (only 3%) 
discontinuation of ipatasertib treatment due to diarrhea was reported. Despite the high 
frequency of diarrhea in the ipatasertib arm, the median relative dose intensity of both 
ipatasertib and paclitaxel approached 100% and was comparable in the ipatasertib and 
placebo arms.


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In this current study, to improve diarrhea management and patient experiences, 
anti-diarrhea prophylaxis (loperamide) will be mandated for the first cycle for all patients 
and implemented subsequently as clinically indicated.  Patients will be provided with 
educational materials and monitored for early signs of diarrhea symptoms, and 
investigators are provided with comprehensive management guidelines (Section 5.1.9.4
and Table 6) for study treatmentrelated symptoms or potential risks.
The adverse events observed with atezolizumab in combination with chemotherapy 
and/or targeted therapies are consistent with the known risks of each study treatment.  
The most commonly reported adverse events with single-agent atezolizumab include 
fatigue, nausea, decreased appetite, diarrhea, constipation, and cough.  
Immune-mediated adverse events are consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance.  Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-mediated adverse 
events will be closely monitored in this study.  Immune-mediated adverse events 
associated with atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré 
syndrome, myasthenic syndrome/myasthenia gravis, hypophysitis, myocarditis, and 
meningoencephalitis.  Guidance regarding the management of immune-mediated
adverse events is provided in Section 5.1.9.4 and Appendix 13 of the protocol.
Adverse events of special interest, in addition to overall safety, will be monitored as 
outlined in this protocol.
2.
OBJECTIVES AND ENDPOINTS
Specific objectives and corresponding endpoints are outlined below (see Tables 1a1c) 
for the following cohorts:

Cohort 1:  patients with locally advanced or metastatic TNBC that is not amenable to 
resection who have not previously received chemotherapy in the advanced setting

Cohort 2:  patients with locally advanced or metastatic TNBC that is not amenable to 
resection who have received no more than two lines of prior systemic chemotherapy
and are willing to undergo serial biopsies (biopsy cohort)

Cohort 3:  patients with locally advanced cT24 cN03 cM0 TNBC (hereafter 
referred to as T24 TNBC)

Cohort 4:  patients with PD-L1positive locally advanced or metastatic TNBC that is 
not amenable to resection who have not previously received chemotherapy in the 
advanced setting
Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive 
tumors to investigate treatment effect in patients with PD-L1positive TNBC.


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In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., ipatasertib, atezolizumab, paclitaxel, nab-paclitaxel, 
doxorubicin, and/or cyclophosphamide).
Table 1a Objectives and Corresponding Endpoints for Cohorts 1 and 4
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only) in all patients regardless 
of PD-L1 status (Cohort 1 only) or in 
patients with PD-L1positive tumors only 
(Cohorts 1 and 4)
ORR, defined as the proportion of patients 
with a confirmed complete response or partial 
response on two consecutive occasions 4 weeks 
apart, as determined by the investigator according to 
RECIST v1.1 (primary endpoint)
DOR, defined as the time from the first occurrence of 
a documented confirmed complete response or partial 
response to the first date of recorded disease 
progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause 
(whichever occurs first) (secondary endpoint)
Primary Safety Objective
Corresponding Endpoints
To evaluate the safety of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only)) in all patients 
regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of IpatAtezo 
combined with either paclitaxel 
(Cohorts 1 and 4) or nab-paclitaxel
(Cohort 1 only)) in all patients regardless 
of PD-L1 status (Cohort 1 only) or in 
patients with PD-L1positive tumors only 
(Cohorts 1 and 4)
PFS, defined as the time from enrollment to the date 
of the first recorded occurrence of disease 
progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause 
(whichever occurs first)
CBR, defined as proportion of patients with stable 
disease for at least 24 weeks or with confirmed 
complete or partial response, as determined by the 
investigator according to RECIST v1.1
OS, defined as the time from enrollment to death from 
any cause 
Note:  Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive 
tumors to investigate treatment effect in patients with PD-L1positive TNBC. 
ADAanti-drug antibody; CBRclinical benefit rate; DORduration of response; 
nab-paclitaxelnanoparticle albumin-bound paclitaxel; NCI CTCAE v4.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRobjective response 
rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic; 
RECIST Response Evaluation Criteria in Solid Tumors.


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Table 1a Objectives and Corresponding Endpoints for Cohorts 1 and 4
(cont.)
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics 
of ipatasertib and its metabolite 
(G-037720) and atezolizumab when 
administered in combination with 
paclitaxel (Cohorts 1 and 4) or 
nab-paclitaxel (Cohort 1 only)) in all 
patients regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Plasma concentration of ipatasertib, G-037720, and 
atezolizumab at specified timepoints for analysis 
using non-compartment methodology or population 
PK methodology
Exploratory Pharmacokinetic Objectives
Corresponding Endpoints
To evaluate potential relationships 
between ipatasertib exposure and 
safety and efficacy endpoints
Relationship between ipatasertib plasma 
concentration and safety and efficacy endpoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
IpatAtezo combined with either 
paclitaxel (Cohorts 1 and 4) or 
nab-paclitaxel (Cohort 1 only)) in all 
patients regardless of PD-L1 status 
(Cohort 1 only) or in patients with 
PD-L1positive tumors only 
(Cohorts 1 and 4)
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive biomarkers) 
or are associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers)
To assess the mechanisms of intrinsic 
and acquired resistances
Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy
Changes in molecular biomarkers in pretreatment 
and post-progression tumor tissues, plasma, and 
blood
Note:  Patients from Cohort 4 will be pooled with patients from Cohort 1 with PD-L1positive 
tumors to investigate treatment effect in patients with PD-L1positive TNBC. 
ADAanti-drug antibody; CBRclinical benefit rate; DORduration of response; 
nab-paclitaxelnanoparticle albumin-bound paclitaxel; NCI CTCAE v4.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0; ORRobjective response 
rate; OSoverall survival; PFSprogression-free survival; PKpharmacokinetic; 
RECIST Response Evaluation Criteria in Solid Tumors.


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Table 1b Objectives and Corresponding Endpoints for Cohort 2 (Biopsy)
Exploratory Biomarker Objectives
Corresponding Endpoints
To evaluate the pharmacodynamic 
effects of ipatasertib and IpatAtezo in 
tumor cells and on the tumor 
microenvironment
To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive biomarkers) 
or are associated with progression to 
a more severe disease state 
(i.e., prognostic biomarkers) 
To assess the mechanisms of intrinsic 
and acquired resistances
Changes in markers of immune cell infiltration and 
activity as well as in pretreatment and on-treatment 
tumor tissues
Change in circulating immune cell repertoires
Changes in molecular biomarkers in pretreatment 
and on-treatment tumor tissues
Relationship between biomarkers in blood and 
tumor tissue (listed in Section 4.5.7) and efficacy
Changes in molecular biomarkers in pretreatment 
and post-progression tumor tissues, plasma, and 
blood
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the anti-tumor activity of 
IpatAtezo as 2L/3L treatment in 
patients with TNBC and in patients with 
TNBC who have PIK3CA/AKT1/PTEN-
altered tumors
The following endpoints will be evaluated using 
RECIST 1.1:
ORR
DOR
CBR
PFS
OS
Safety Objective
Corresponding Endpoints
To evaluate the safety of IpatAtezo in 
patients in Cohort 2 (i.e., biopsy cohort)
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results
2Lsecond line; 3Lthird line; Atezoatezolizumab; CBRclinical benefit rate; DORduration 
of response; Ipatipatasertib; NCI CTCAE v4.0National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0; ORRobjective response rate; OSoverall survival; 
PFSprogression-free survival; RECIST Response Evaluation Criteria in Solid Tumors; 
TNBCtriple-negative breast cancer.


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Table 1c Objectives and Corresponding Endpoints for Cohort 3
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
neoadjuvant Ipat Atezo AC followed 
by Ipat Atezo Pac
pCR rate, defined as the proportion of patients who 
have no residual invasive disease in the breast and 
no residual disease in the lymph nodes (ypT0/Tis 
ypN0 in the current AJCC staging system)
Primary Safety Objective
Corresponding Endpoints
To evaluate the safety of neoadjuvant 
Ipat Atezo AC followed by 
Ipat Atezo Pac
Incidence, nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v4.0
Change from baseline in targeted clinical laboratory 
test results
Exploratory Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
ipatasertib and its metabolite 
(G-037720) and atezolizumab when 
administered in combination with 
paclitaxel or AC
Plasma concentration of ipatasertib and G-037720 at 
specified timepoints
Serum concentration of atezolizumab at specified 
timepoints
Exploratory Immunogenicity Objectives
Corresponding Endpoints
To evaluate the immune response to 
atezolizumab
Incidence of ADAs to atezolizumab during the study 
and prevalence of ADAs to atezolizumab at baseline
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify and/or evaluate biomarkers 
that are predictive of response to study 
treatment (i.e., predictive biomarkers), 
are early surrogates of efficacy, are 
associated with progression to a more 
severe disease state (i.e., prognostic 
biomarkers), are associated with 
acquired resistance to study treatment, 
are associated with susceptibility to
developing adverse events or can lead 
to improved adverse event monitoring 
or investigation (i.e., safety biomarkers), 
can provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology and drug safety
Relationship between biomarkers in blood, plasma, 
and tumor tissue (listed in Section 4.5.7) and 
efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints
ACdoxorubicin plus cyclophosphamide; ADAanti-drug antibody; AJCCAmerican Joint 
Committee on Cancer; Atezoatezolizumab; EFSevent-free survival; Ipatipatasertib; 
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
Pac paclitaxel; pCRpathologic complete response; PKpharmacokinetic.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase Ib, open-label, multicenter study consisting of four cohorts.  In Cohort 1, 
the safety and efficacy of ipatasertibatezolizumabpaclitaxel (IpatAtezoPac) and 
ipatasertibatezolizumabnab-paclitaxel (IpatAtezoNab-Pac) will be evaluated in
patients with locally advanced or metastatic TNBC who have not previously received 
chemotherapy in the advanced setting.  In Cohort 2 (biopsy cohort), IpatAtezo
(with no chemotherapy) will be administered in the second-line and third-line setting to 
patients with locally advanced or metastatic TNBC for the main purpose of conducting 
exploratory biomarker assessments.  In Cohort 3, the safety and efficacy of neoadjuvant 
ipatasertibatezolizumabdoxorubicincyclophosphamide (IpatAtezoAC) followed 
by IpatAtezoPac will be evaluated in patients with locally advanced T24 TNBC.
In Cohort 4, the safety and efficacy of IpatAtezoPac will be evaluated in patients with 
PD-L1positive locally advanced or metastatic TNBC who have not previously received 
chemotherapy in the advanced setting.
There is a known and acceptable safety profile of ipatasertib with paclitaxel and 
atezolizumab with paclitaxel or nab-paclitaxel (Sections 1.2 and 1.3). If an unexpected 
safety signal is detected at any time, doublet safety of ipatasertib with atezolizumab may 
be further evaluated.  The safety and efficacy of the combination of ipatasertib with 
atezolizumab is being assessed both in Cohort 2 of this trial and separately (i.e., in 
Study CO39611 for HR-positive/HER2-negative MBC and Study CO40115 for TNBC).
Up to 25 sites in North America, Europe, and the Asia Pacific will enroll approximately 
202 patients (114 patients in Cohort 1, 14 patients in Cohort 2, 24 patients in Cohort 3, 
and 50 patients in Cohort 4).
3.1.1
Overview of Study Design
Two triplets (Arm A and Arm B) are being evaluated as first-line treatment for patients 
with locally advanced or metastatic TNBC in Cohort 1 (see Figure 1).  Both arms have 
a safety run-in cohort of 6 patients (Stage 1 within each arm [A1 and B1]) who will be 
evaluated for safety and tolerability before the expansion stage of 14 patients (Stage 2 
within each arm [A2 and B2]). Two additional arms (Arms C and D) will explore 
staggered dosing schedules of the triplet combination to obtain additional safety and 
tolerability data (see Figure 1). Both of these additional arms have a safety run-in cohort 
of 6 patients (Stage 1 within each arm [C1 and D1]) who will be evaluated for safety and 
tolerability of the staggered dosing schedule before the expansion stage of 6 patients
(Stage 2 within each arm [C2 and D2]). 
Based on a confirmed ORR of 70% being reached in the first 26 patients enrolled,
Arm A in Cohort 1 will be extended to include up to approximately 50 additional patients 
(Arm A3) in the expansion phase (Stage 3 for Arm A [A3]) to further investigate the 
tolerability and efficacy of the triplet combination in first-line locally advanced or 


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metastatic TNBC. Arm A3 will open after Arms C2 and D2 have been filled.  If 
a differential efficacy signal is detected, the Sponsor may elect to restrict enrollment to 
patients with a particular tumor biomarker status.
A biopsy cohort (Cohort 2) evaluating biomarker assessments of the doublet of 
ipatasertib plus atezolizumab (Arm E) in 14 patients in the second-line and third-line 
setting was opened for enrollment after preliminary encouraging efficacy and acceptable 
tolerability from Cohort 1 (see Figure 1).
A locally advanced T24 TNBC cohort (Cohort 3) of approximately 24 patients was 
added to enable evaluation of neoadjuvant IpatAtezoAC for two cycles followed by 
IpatAtezoPac for three cycles (duration of each cycle, 28 days).  In Arm F, the 
ipatasertib dose will be 300 mg for the first two cycles and 400 mg for the remaining 
three cycles.  In Arm G, the ipatasertib dose will be 400 mg for all five cycles.  Both arms 
have a safety run-in cohort of 6 patients (Stage 1 within each arm [F1 and G1]) who will 
be evaluated for safety and tolerability before the expansion stage (Stage 2), in which 
a total of 12 patients may be enrolled, with the Sponsor determining allocation to 
Arm F2, Arm G2, or both (see Figure 1).  Patients should undergo breast surgery 
between 2 and 6 weeks after the final dose of neoadjuvant treatment.  Efficacy will be 
evaluated in relation to tumor biomarker status (e.g., PD-L1 expression or alteration in 
PIK3CA, AKT1, or PTEN).
Because of lower prevalence of PD-L1positive tumors relative to PD-L1negative 
tumors and the availability of data in patients with PD-L1positive tumors 
(Study WO29522 [IMpassion130]), Cohort 4 will further evaluate the triplet combination 
of IpatAtezoPac as first-line treatment in approximately 50 additional patients with 
PD-L1positive tumors (see Figure 1).  
Patients in Cohorts 1, 2, and 4 will continue to be treated until unacceptable toxicity or 
loss of clinical benefit as determined by the investigator after an integrated assessment 
of radiographic and biochemical data, local biopsy results (if available), and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease).  Because of 
the possibility of an initial increase in tumor burden caused by immune-cell infiltration in 
the setting of a T-cell response (termed pseudoprogression) with atezolizumab 
treatment, radiographic progression per RECIST v1.1 may not be indicative of true 
disease progression.  In the absence of unacceptable toxicity, patients who meet criteria 
for disease progression per RECIST v1.1 while receiving atezolizumab will be permitted 
to continue atezolizumab if they meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator following a review of 
all available data

Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease


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
Absence of decline in ECOG Performance Status (see Appendix 7) that can be 
attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
Patients in Cohort 3 will continue to be treated for five cycles (28-day cycles; 20 weeks) 
or until disease progression or unacceptable toxicity, whichever occurs first.
A schedule of activities is provided for Cohorts 1, 2, 3, and 4 in Appendix 1, Appendix 2,
Appendix 3, and Appendix 1, respectively, and the dosing schedule for each arm is 
provided in Figure 2.




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Figure 2
Dosing Schedule
Arms A, B, and H:  ipatasertibtaxane aatezolizumab
a Paclitaxel or nab-paclitaxel for Arms A and B; paclitaxel for Arm H.
Arm C:  ipatasertibpaclitaxel alone for 2 weeks, thenatezolizumab
Arm D:  atezolizumabpaclitaxel alone for 2 weeks, then ipatasertib


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Figure 2
Dosing Schedule (cont.)
Arm E (biopsy cohort):  ipatasertibatezolizumab
21/721-days on/7-days off dosing schedule; C2Cycle 2; PO by mouth; Q2W every 
2 weeks.
Arm F:
ipatasertibatezolizumabAC (ipatasertib dose of 300 mg) followed by 
ipatasertibatezolizumabpaclitaxel (ipatasertib dose of 400 mg)
ACdoxorubicincyclophosphamide; QDonce a day.
Note:  Each cycle is 28 days.
Cycles 1 and 2
Day
1
8
15
22
28
*********************
Ipatasertib
300 mg QD, Days 121
400 mg QD, Days 121
*********************
Cycles 35
1
8
15
22
28
Atezolizumab
AC
Neoadjuvant Treatment
Paclitaxel


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Figure 2
Dosing Schedule (cont.)
Arm G:
ipatasertibatezolizumabAC (ipatasertib dose of 400 mg) followed by 
ipatasertibatezolizumabpaclitaxel (ipatasertib dose of 400 mg)
ACdoxorubicincyclophosphamide; QDonce a day.
Note:  Each cycle is 28 days.
3.1.2
Safety Run-In Stage with Safety Assessment Window (Cohort 
1: Arms A1 and B1)
Up to 6 patients were enrolled in Arm A to evaluate the safety and tolerability of 
ipatasertib in combination with atezolizumab and paclitaxel in an initial 28-day (1 cycle) 
period (Cohort 1, hereafter referred to as A1; see Figure 1 in Section 3.1.1). Ipatasertib 
400 mg was administered orally once a day (QD) on Days 121, and atezolizumab was
administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day
cycle. Paclitaxel 80 mg/m2 was administered by IV infusion on Days 1, 8, and 15 of 
each 28-day cycle.  Tolerability was assessed during the safety assessment window 
following the first dose of ipatasertib for 28 days. Patients who withdraw from the study 
prior to completing the safety assessment for any reason other than a treatment-related 
adverse event will be replaced.  In addition, patients who miss more than 7 total days of 
dosing of ipatasertib during the safety assessment window for reasons other than 
a treatment-related toxicity will be replaced.  Patients will not be allowed to make up 
missed doses of study drugs (refer to Section 4.3.2.1 on study treatment administration); 
patients will resume dosing at their next scheduled dose.  All patients who do not receive
three doses of chemotherapy or two doses of atezolizumab during the safety
assessment window for any reason other than a treatment-related toxicity will be 
replaced. The totality of safety information from patients in A1 were assessed by all 
participating investigators together with the Sponsor.
After enrollment was completed for Arm A Cohort 1 (i.e., A1), up to 6 patients were
enrolled into Arm B to evaluate safety of ipatasertib in combination with atezolizumab 
Cycles 1 and 2
Day
1
8
15
22
28
*********************
Ipatasertib
400 mg QD, Days 121
400 mg QD, Days 121
*********************
Cycles 35
1
8
15
22
28
Atezolizumab
AC
Neoadjuvant Treatment
Paclitaxel


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and nab-paclitaxel (Cohort 1, hereafter referred to as B1). Ipatasertib 400 mg was
administered orally QD on Days 121, with atezolizumab 840 mg administered by IV 
infusion on Days 1 and 15.  Nab-paclitaxel 100 mg/m2 was administered by IV infusion 
on Days 1, 8, and 15 of each 28-day cycle.  Tolerability was assessed similarly to A1. 
Beyond the safety assessment period, patients will continue to be treated until loss of 
clinical benefit, unacceptable toxicity, withdrawal of consent, or end of the study. The
pharmacokinetics of ipatasertib and its metabolite G-037720, and atezolizumab will be 
assessed in all patients receiving the study drugs. Any patient who does not receive any 
study treatment will be replaced.
3.1.3
Expansion Stage (Cohort 1: Arms A2, B2, and A3)
The Sponsor opened enrollment into the expansion arms with input from all participating 
investigators, after an integrated assessment of safety data from Arms A1 and B1 had 
been reviewed. Up to 14 patients were enrolled into the expansion stage of each 
corresponding arm (hereafter referred to as A2 or B2, correspondingly).
Based on a confirmed overall response rate of 70% being reached in the first 
26 patients enrolled, Arm A will be further extended (after completion of Arms A1, B1, 
A2, B2, C1, D1, C2, and D2 enrollment) to include up to approximately 50 additional 
patients (Arm A3) into the expansion phase (Stage 3 of Arm A) to further investigate the 
tolerability and efficacy of the triplet combination in first-line metastatic TNBC.
Up to approximately 114 patients would be enrolled in Cohort 1 (i.e., ipatasertib-
atezolizumab-taxane arms) of the study.  Patients’ PIK3CA/AKT1/PTEN-altered tumor 
status would be evaluated on an ongoing basis.  Based on the observed prevalence, 
enrollment may be restricted to patients with PIK3CA/AKT1/PTEN-altered tumors.
3.1.4
Safety Run-In Stage with Safety Assessment Window 
(Cohort 1:  Arms C1 and D1)
To further explore tolerability of the triplet combination, an additional two arms (Arms C 
and D) evaluating staggered dosing have been added to the study to obtain additional 
safety and tolerability data.  Enrolment into these arms will supersede enrollment into 
Arm B2. 
Up to 6 patients will be enrolled in a safety run-in cohort of Arm C to evaluate the safety 
and tolerability of a 2-week lead-in with ipatasertib in combination with paclitaxel, 
followed by the addition of atezolizumab, in an initial 28-day (1 cycle) period (hereafter 
referred to as Arm C1; see Figure 1 in Section 3.1.1).  Ipatasertib 400 mg will be 
administered orally QD on Days 121, with paclitaxel 80 mg/m2 administered by IV 
infusion on Days 1, 8, and 15. Atezolizumab 840 mg will be administered by IV infusion 
on Day 15 of the first cycle (see Figure 2).  In all subsequent treatment cycles 
(Cycles 2), ipatasertib 400 mg will be administered orally QD on Days 121, paclitaxel 
80 mg/m2 will be administered by IV infusion on Days 1, 8, and 15, and atezolizumab will 


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be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 
28-day cycle (see Figure 2).  Tolerability will be assessed within the initial 28 days of the 
triplet regimen (safety assessment window).  Patients who withdraw from the study prior 
to completing the safety assessment for any reason other than a treatment-related 
adverse event will be replaced.  In addition, patients who miss more than 7 total days of 
dosing of ipatasertib during the safety assessment window for reasons other than a 
treatment-related toxicity will be replaced.  Patients will not be allowed to make up 
missed doses of study drugs (refer to Section 4.3.2.1 on study treatment administration); 
patients will resume dosing at their next scheduled dose.  All patients who do not receive 
three doses of chemotherapy or one dose of atezolizumab during the safety assessment 
window for any reason other than a treatment-related toxicity will be replaced.  The 
totality of safety information from patients in Arm C1 will be shared with all participating 
investigator.
After enrollment is completed for Arm C1, up to 6 patients will be enrolled into a safety 
run-in cohort of Arm D to evaluate the safety and tolerability of a 2-week lead-in with 
atezolizumab in combination with paclitaxel, followed by the addition of ipatasertib in an 
initial 28-day (1 cycle) period (hereafter referred to as Arm D1).  Atezolizumab 840 mg 
will be administered by IV infusion on Days 1 and 15, with paclitaxel 80 mg/m2
administered by IV infusion on Days 1, 8, and 15.  Ipatasertib 400 mg will be 
administered orally QD on Days 1521 of the first cycle (see Figure 2).  In all 
subsequent treatment cycles (Cycles 2), ipatasertib 400 mg will be administered orally 
QD on Days 121, paclitaxel 80 mg/m2 will be administered by IV infusion on Days 1, 8, 
and 15, and atezolizumab will be administered by IV infusion at a fixed dose of 840 mg 
on Days 1 and 15 of each 28-day cycle (see Figure 2). Tolerability will be assessed 
within the initial 28 days of the triple regimen (safety assessment window), similar to 
Arm C1. 
Beyond the safety assessment period, patients will continue to be treated until loss of 
clinical benefit, unacceptable toxicity, withdrawal of consent, or end of the study.  The 
pharmacokinetics of ipatasertib and its metabolite G-037720, and atezolizumab will be 
assessed in all patients receiving the study drugs.  Any patient who does not receive any 
study treatment will be replaced.
3.1.5
Expansion Stage (Cohort 1:  Arms C2 and D2)
After either Arms C1 or D1 is assessed and the safety is found to be acceptable, up to 
6 patients may be enrolled into the expansion stage of each corresponding arm 
(hereafter referred to as C2 or D2, correspondingly).  Initiation of Arm D2 enrollment will
follow completion of Arm C2 enrollment when applicable.  Patients’ 
PIK3CA/AKT1/PTEN-altered tumor status will be evaluated on an ongoing basis.  Based 
on the observed prevalence, enrollment may be restricted to patients with 
PIK3CA/AKT1/PTEN-altered tumors.


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Arms C1, C2, D1, and D2 may not need to be opened or be fully accrued if safety 
management and toxicity profile is deemed jointly by Sponsor and investigators to be 
well understood any time during the study.
3.1.6
Biopsy Cohort (Cohort 2)
Since the combination of ipatasertib and atezolizumab with taxane in Cohort 1 
demonstrated meaningful clinical activity (i.e., ORR at least 50%), the Sponsor opened 
enrollment of a separate mandatory on-treatment biopsy cohort (to be called Cohort 2) to 
evaluate biomarker endpoints in patients treated with ipatasertib combined with 
atezolizumab to further understand the molecular basis of treatment benefit. The 
opening of the biopsy cohort was enabled with input from all participating investigators, 
along with the Sponsor, after an integrated assessment of radiographic and biochemical 
data, local biopsy results (if available), safety data, and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease) from Cohort 1 (safety run-in and 
expansion stages) had been reviewed.
Up to 14 patients with TNBC who have progressed after at least one line of 
chemotherapy in the advanced setting and who have a safely accessible tumor will 
undergo serial biopsies.  Any patient who does not undergo at least two evaluable 
biopsies will be replaced.
Prior to Day 1 of Cycle 1, a tumor tissue sample will be collected from all patients, 
preferably by means of a biopsy performed at study entry if it is safely accessible, 
according to the treating physician.  If a biopsy is not deemed feasible by the 
investigator, archival tumor tissue may be submitted, provided that the tissue was 
obtained from a biopsy performed within 6 months prior to enrollment and that the 
patient has not received any anti-cancer therapy since the time of the biopsy. The 
archival biopsy must be from the same lesion from which subsequent biopsies will be 
collected. In other words, if serial biopsy is not possible at the site where the archival 
biopsy is from, a new biopsy from another site appropriate for serial biopsies should be 
performed. Tumor locations more appropriate for serial biopsies (such as cutaneous 
lesions or superficial lymph node metastases) should be prioritized over visceral sites 
(such as lung or liver metastasis).  Furthermore, the Sponsor will clarify that all tumor 
biopsies (i.e., initial and subsequent serial biopsies) should come from the same site to 
help isolate tumor response to treatment from inter-tumoral heterogeneity.
Patients in the biopsy expansion cohort will start treatment with ipatasertib alone on 
Day 1 of Cycle 1 and will receive the first dose of atezolizumab on Day 8 of Cycle 1.
The first on-treatment biopsy will be collected either Day 7 or 8 of Cycle 1, prior to the 
patient receiving atezolizumab. An additional biopsy will be collected on Day 15 of 
Cycle 2, prior to receiving the scheduled dose of atezolizumab.  For patients in the 
biopsy expansion cohort, the first treatment cycle will be 35 days, and all following 
treatment cycles will be 28 days in duration (see Figure 2). Ipatasertib 400 mg will be 
administered orally QD on Days 128 of Cycle 1 (35-day cycle) and on Days 121 of 


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subsequent cycles (28-day cycles).  Atezolizumab will be administered by IV infusion at 
a fixed dose of 840 mg on Days 8 and 22 of Cycle 1 and on Days 1 and 15 of 
subsequent cycles.  See Appendix 2 and Appendix 5 for a schedule of safety and PK 
assessments, respectively.
3.1.7
Safety Run-In Stage with Safety Assessment Window 
(Cohort 3: Arms F1 and G1)
Up to 6 patients will be enrolled in Arm F1 to evaluate the safety and tolerability of 
IpatAtezoAC (ipatasertib dose of 300 mg) followed by IpatAtezoPac (ipatasertib 
dose of 400 mg) before surgery (see Figure 1 in Section 3.1.1).  Patients will be treated 
for five cycles of 28 days each.  Ipatasertib will be administered orally QD at a dose of 
300 mg on Days 121 of Cycles 1 and 2 and at a dose of 400 mg on Days 121 of 
Cycles 35.  Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg 
on Days 1 and 15 of Cycles 15.  Doxorubicin 60 mg/m2 and cyclophosphamide 
600 mg/m2 will be administered by IV infusion (with filgrastim or pegfilgrastim support) on 
Days 1 and 15 of Cycles 1 and 2.  Paclitaxel 80 mg/m2 will be administered by 
IV infusion on Days 1, 8, 15, and 22 of Cycles 35 (see Figure 2).  Tolerability will be 
assessed when at least 6 patients have completed at least 4 weeks of study treatment 
(safety assessment window).  Patients who receive non-protocol therapy prior to surgery 
will be discontinued from study treatment.  Patients who discontinue all study treatment 
prior to completing the safety assessment window for any reason other than 
treatment-related toxicity will be replaced.  Patients who miss more than 7 total days of 
dosing of ipatasertib during the treatment period for any reason other than 
treatment-related toxicity will be replaced.  In addition, patients who do not receive at 
least three doses of chemotherapy and at least two doses of atezolizumab during the 
treatment period for any reason other than treatment-related toxicity will be replaced.  
Patients will not be allowed to make up missed doses of ipatsertib and atezolizumab
study drugs; patients will resume dosing at their next scheduled dose (refer to 
Section 4.3.2.1 for details on study treatment administration).  If clinically possible, 
patients should receive 4 doses of doxorubicin and cyclophosphamide and 12 doses of 
weekly paclitaxel prior to surgery, as per local standard of care.  The totality of safety 
information from patients in Arm F1 will be assessed by all participating investigators 
together with the Sponsor, with the Sponsor retaining the ultimate decision about 
whether to move forward to Arm G1.
If the treatment regimen for Arm F1 is found to be acceptable, up to 6 patients will be 
enrolled in Arm G1 to evaluate the safety and tolerability of IpatAtezoAC (ipatasertib 
dose of 400 mg) followed by IpatAtezoPac (ipatasertib dose of 400 mg) before 
surgery (see Figure 1 in Section 3.1.1).  Patients will be treated for five cycles of 28 days 
each.  Ipatasertib 400 mg will be administered orally QD on Days 121 of Cycles 15.  
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of Cycles 15.  Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 will be 
administered by IV infusion (with filgrastim or pegfilgrastim support) on Days 1 and 15 of 


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Cycles 1 and 2 (see Figure 2).  Paclitaxel 80 mg/m2 will be administered by IV infusion 
on Days 1, 8, 15, and 22 of Cycles 35.  Tolerability for Arm G1 will be assessed in the 
same manner as for Arm F1. 
3.1.8
Expansion Stage (Cohort 3:  Arms F2 and G2)
If the treatment regimens for Arms F1 and G1 are found to be acceptable, a total of up to 
12 patients may be enrolled during the expansion stage, with the Sponsor determining 
allocation to Arm F2, Arm G2, or both.
3.1.9
PD-L1Positive Cohort (Cohort 4:  Arm H)
Approximately 50 patients with PD-L1positive tumors will be enrolled in Cohort 4 to 
further investigate the tolerability and efficacy of the IpatAtezoPac as first-line 
treatment in patients with locally advanced or metastatic TNBC.  Ipatasertib 400 mg will 
be administered orally QD on Days 121, atezolizumab will be administered by IV 
infusion at a fixed dose of 840 mg on Days 1 and 15, and paclitaxel 80 mg/m2 will be 
administered by IV infusion on Days 1, 8, and 15 of each 28-day cycle.  
3.1.10
Assessments and Monitoring
All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory 
safety assessments will include the regular monitoring of hematology and blood 
chemistry.
Blood samples will be taken at various timepoints before and during study treatment 
administration to enable PK and immunogenicity analyses.  On the basis of a review of 
real-time safety data and available PK data, treatment regimens may be modified by the 
Sponsor as deemed appropriate.  The schedule of activities for PK samples is presented 
in Appendix 4, Appendix 5, and Appendix 6.
Patients in Cohorts 1, 2, and 4 will undergo tumor assessments every 8 weeks (from 
Day 1 of Cycle 1).  Response will be assessed by the investigator using RECIST v1.1 
(see Appendix 10).
Patients in Cohort 3 will undergo radiographic and other disease assessments as 
outlined in Section 4.5.6.  Evaluation of the primary efficacy endpoint, pCR rate 
(ypT0/Tis ypN0), will be based on local review following completion of neoadjuvant 
therapy and surgery.  Details on disease staging are provided in Section 4.5.6.
Baseline tumor tissue samples will be collected from all patients, preferably by means of 
a biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted, provided that the tissue was obtained from 
a biopsy performed within 6 months prior to enrollment and that the patient has not 
received any anti-cancer therapy since the time of the biopsy.  If deemed clinically 


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feasible by the investigator, tumor tissue will also be collected for patients who 
discontinue because of unacceptable toxicity, disease progression per RECIST v1.1, or 
loss of clinical benefit as determined by the investigator.  For patients enrolled in 
Cohort 2 (i.e., mandatory on-treatment biopsy cohort), two additional tumor tissue 
samples will be collected during treatment (if clinically feasible).  These samples, as well 
as blood samples collected during the study, will be utilized for biomarker research (see 
rationale for biomarker assessments in Section 3.3.10 and details on tissue sample 
collection in Section 4.5.7).
3.1.11
Internal Safety Monitoring
The Study Team, including the Study Medical Monitor and Safety Scientist, will monitor 
patient safety throughout the study.  In addition to the ongoing assessment of the 
incidence, nature and severity of adverse events, serious adverse events, deaths, and 
laboratory abnormalities performed by the investigators and the Medical Monitor, the 
Study Team will review all necessary cumulative data at regular intervals (i.e.,
approximately three times a year) during the study.  Assessment of safety for the 
safety-run-in cohorts (i.e., Arms A1, B1, C1, D1, F1, and G1) will be performed by the 
Study Team prior to opening enrollment for the expansion cohorts.
3.2
END OF STUDY AND LENGTH OF STUDY
The study will end when the last data point required for statistical analysis is collected 
and safety follow-up is completed, or the Sponsor decides to end the trial, whichever 
occurs first.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 35 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
Despite multiple treatment options, TNBC remains a challenging disease.  Although 
chemotherapy is a mainstay treatment for TNBC, resistance inevitably develops and 
benefit is often short lived.  Ipatasertib with paclitaxel has shown encouraging clinical 
benefit for advanced TNBC in the randomized Phase II study (GO29227 or LOTUS).  
In addition, CIT has shown promising preliminary clinical data in the treatment of TNBC
(Nanda et al. 2016; Schmid et al. 2017), and it has changed the standard of care for 
other cancers.
Taxanes, particularly 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, which causes concern about 
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 


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taxane exposure, guidelines support the re-use of a taxane in the metastatic setting, 
particularly if there has been at least 1 year of disease-free survival since its use in the 
adjuvant setting (Cardoso et al. 2017).  In this study, for Cohorts 1, 2, and 4, patients 
must have a minimum 12-month window between completion of any 
neoadjuvant/adjuvant chemotherapy treatment (including taxane) and initiation of study 
treatment, thus selecting for patients who are likely to retain sensitivity to taxane 
chemotherapy in the metastatic setting.  
Recently, the TNT study demonstrated superiority of carboplatin over docetaxel for the 
treatment of patients with breast and ovarian cancer susceptibility gene (BRCA) 
mutation-positive breast cancer (Tutt et al. 2015).  Thus, in patients with 
BRCA-associated TNBC or endocrine-resistant MBC, a platinum regimen may be 
a preferred option, if not previously administered (Cardoso et al. 2017).  The efficacy of 
ipatasertib or atezolizumab for patients with homologous recombination repair deficiency 
(e.g., patients with BRCA1/2 germline mutationpositive disease) is unknown.
Cohort 1 evaluates the benefit/risk of ipatasertib with atezolizumab and a taxane in 
locally advanced or metastatic TNBC with no previous systemic treatment in the 
advanced setting. 
Cohort 3 evaluates the combination of ipatasertib, atezolizumab, AC, and paclitaxel as 
neoadjuvant treatment in patients with locally advanced T24 TNBC. This cohort will 
enroll patients with T24 TNBC (see Section 4.1.1) because increased primary tumor 
size has been identified as a poor prognostic variable and has been associated with 
decreased disease-free survival and increased likelihood of early metastatic disease in 
patients with TNBC (Pistelli et al. 2013; Rosa Mendoza et al. 2013).
Cohort 4 evaluates the benefit versus risk of ipatasertib, atezolizumab, and paclitaxel in 
patients with PD-L1positive locally advanced or metastatic TNBC who have not 
previously received chemotherapy in the advanced setting.
3.3.2
Rationale for Ipatasertib in Combination with Atezolizumab and 
Paclitaxel or Nab-Paclitaxel
3.3.2.1
Rationale for Targeting the PI3K/Akt Pathway
Large-scale comprehensive genomic analyses (Cancer Genome Atlas Network 2012;
Lehmann and Pietenpol 2014; Pereira et al. 2016) have characterized the 
heterogeneous nature of breast cancer and its diverse gene-expression patterns and 
underlying genomic changes.  In breast cancer, Akt is an important node along the 
PI3K/Akt pathway that controls apoptosis and cell growth (Yap et al. 2008), and this 
pathway is known to be highly activated in breast cancers (Cancer Genome Atlas 
Network 2012). 
Up-regulation of Akt signaling (whether intrinsic or induced following chemotherapy) 
represents a potentially important survival pathway in response to genotoxic or mitotic 


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stress (Xu et al. 2012).  Data from nonclinical models of ipatasertib plus microtubule
inhibitors or DNA-damaging chemotherapy agents showed a clear advantage of the 
combination over respective single-agent treatment (refer to the Ipatasertib Investigator’s 
Brochure for further information).  
Based on the scientific rationale that PI3K/Akt blockade attenuates survival signals 
associated with mitotic stress from treatment with microtubule inhibitors and the high 
prevalence of PI3K/Akt pathway activation signatures in breast cancers (Cancer 
Genome Atlas Network 2012), clinical trials evaluating the preliminary safety and 
efficacy of the combination of ipatasertib and paclitaxel in patients with breast cancer 
have been conducted. 
In the randomized, placebo-controlled Phase II study (GO29227) in patients with locally 
advanced or metastatic TNBC, ipatasertib 400 mg was administered QD on Days 121
of each 28-day cycle, and paclitaxel 80 mg/m2 was administered weekly on Days 1, 8, 
and 15 of each 28-day cycle.  Patients in the ipatasertibpaclitaxel arm showed a more 
pronounced improvement in PFS in the pre-specified patient population with 
PIK3CA/AKT1/PTEN-altered tumors (hazard ratio0.44, 9.0 months with 
ipatasertibpaclitaxel vs. 4.9 months with paclitaxel alone) compared with patients with 
PIK3CA/AKT1/PTEN non-altered tumors (hazard ratio0.76, 5.3 months with 
ipatasertibpaclitaxel vs. 3.7 months with paclitaxel alone) or unselected ITT patients 
(hazard ratio0.60, 6.2 months with ipatasertibpaclitaxel vs. 4.9 months with paclitaxel 
alone).  The combination of ipatasertib and paclitaxel has been generally well tolerated.  
The most common adverse events in the ipatasertibpaclitaxel arm (incidence of 10% 
higher than in the placebopaclitaxel arm) were diarrhea, nausea, asthenia, and 
peripheral sensory neuropathy.  When grouping the adverse event preferred terms with 
similar medical concepts for basket term analysis, asthenia/fatigue and peripheral 
neuropathy were not significantly different between the two arms. 
Overall, efficacy results from Study GO29227 support the hypothesis that inhibition of 
Akt signaling may improve the effectiveness of taxane treatment and that patients with 
PI3K/Akt-activated tumors are more sensitive to ipatasertib.  
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and clinical 
studies.
3.3.2.2
Rationale for Immunotherapy in Breast Cancer
CIT has demonstrated extraordinary success, with significant survival benefits observed 
across multiple advanced malignancies.  Currently, the prevailing CIT approach is to 
circumvent immune evasion mechanisms and reinvigorate anti-tumor responses by 
identifying and targeting T-cell co-inhibitory surface receptors such as CTLA-4 and 
PD-L1/PD-1.  While these targets have resulted in remarkable clinical therapeutic 
success for various cancer indications, ongoing research indicates a series of stepwise 
events necessary for the generation of a continuous anti-tumor immune response 


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(Chen and Mellman 2013).  Each event is critical for an effective response, and each is 
also susceptible to several tumor immune evasion mechanisms.  Thus, the need to 
identify and circumvent the various factors involved in tumor immune evasion will be 
critical for propagating the anti-tumor immune response and advancing the field of CIT, 
most likely through combined targeted therapy regimens.
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that down-regulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, gastric cancer, breast cancer, and sarcoma.  The combination of 
atezolizumab and nab-paclitaxel has shown encouraging efficacy (Adams et al. 2016)
(see Atezolizumab Investigator's Brochure for detailed efficacy results).  
3.3.2.3
Rationale for Combining Ipatasertib with Atezolizumab
Recently, the loss of PTEN, a direct antagonist of Akt, has emerged as a potential 
mechanism for resistance to checkpoint inhibitor therapy, and inhibition of the PI3K/Akt 
pathway has shown reversal of Tcell-mediated immunotherapy resistance (Peng et al. 
2016; George et al. 2017).  Potential impacts of Akt inhibition on immune response 
include the following: 1) improving recognition of cancer cells by host immune system 
and rekindling suppressed immune response (Xue et al. 2015); 2) restoring and 
enhancing physiological functionalities of T cells in the tumor microenvironment, in 
addition to enhancing expansion of tumor-specific lymphocytes with memory cell 
phenotype (Crompton et al. 2015); and 3) promoting the generation of superior, 
stem-like tumor-reactive T cells for adoptive immunotherapy (van der Waart et al. 2014).


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Due to encouraging data for TNBC seen in both combinations of ipatasertib with 
paclitaxel and atezolizumab with nab-paclitaxel, this study tests the hypothesis of 
improved efficacy with the combination of ipatasertib with atezolizumab and paclitaxel or 
nab-paclitaxel.  
3.3.3
Rationale for Combination Treatment with Ipatasertib,
Atezolizumab, Paclitaxel, Doxorubicin, and Cyclophosphamide
Multi-agent chemotherapy regimens have proven beneficial as neoadjuvant or adjuvant 
therapy for EBC, improving both disease-specific and OS outcomes (Berry et al. 2006; 
NCCN 2016).  The most effective combination regimens include anthracyclines, 
topoisomerase II inhibitors, cyclophosphamide, and taxanes (Early Breast Cancer 
Trialists’ Collaborative Group 2005; Peto et al. 2012).  In the neoadjuvant setting, 
anthracycline- and taxane-based regimens have routinely been used in patients with 
TNBC, resulting in reported pCR rates of 41%48% (Sparano et al. 2008; Sikov et al. 
2015; Untch et al. 2016).  Three-year EFS rates of 74%76% have been reported for 
patients with TNBC who have received neoadjuvant anthracycline- and 
taxane-containing therapy (von Minckwitz et al. 2014; Sikov et al. 2015), leaving room 
for improvement in outcomes. 
A commonly used regimen for TNBC is weekly paclitaxel for 12 weeks followed by AC
every 23 weeks for four cycles (14-day cycles). A recent meta-analysis by the Early 
Breast Cancer Trialists Collaborative Group including individual patient data from seven
randomized trials with 10,004 women demonstrated that patients who received 
chemotherapy every 2 weeks were 17% and 15% less likely to have disease recurrence 
and die from breast cancer within 10 years, respectively, compared with those who 
received treatment every 3 weeks. The 15% risk reduction was similar in ER-positive 
and ER-negative disease, and did not differ significantly with respect to any other patient 
or tumor characteristics, including age, HER2 status, nodal status, tumor size, and tumor 
grade (Gray et al. SABCS 2017). The chemotherapy regimen included in this study is 
built upon the aforementioned regimen.
Treatment with CIT has demonstrated significant survival benefits 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 PD-L1 or PD-1. Emerging clinical trial data 
have shown that the addition of immune checkpoint inhibitors to chemotherapy 
enhances efficacy as determined by pCR.  In TNBC, early results from combination trials 
of antiPD-1/PD-L1 checkpoint inhibitors and anthracycline- and taxane-based 
neoadjuvant chemotherapy have demonstrated high pCR rates of around 60% 
(Nanda et al. 2014; Schmid et al. 2017). Phase III studies are underway to confirm 
these results. 
As stated in Section 1.3, the safety of atezolizumab in combination with 
chemotherapeutic regimens, including anthracyclines and cyclophosphamide, is 


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currently being investigated in various indications in Studies GP28328, BO29563, and 
GO29831.  Thus far, reported adverse events for combination regimens have been 
similar to those experienced with each individual agent and have generally been 
manageable.
While PD-1/PD-L1targeting agents have resulted in remarkable clinical therapeutic 
success for various cancer indications, ongoing research indicates that a series of 
stepwise events is 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 
(which is common in TNBC) and impaired anti-tumor immune responses, including 
reduced CD8 T-cell infiltration and 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-1/PD-L1 axis blockade (Peng et al. 
2016). In addition, Akt inhibitors may restore and enhance physiologic 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). 
Results of the randomized LOTUS study (GO29227) demonstrate that adding ipatasertib 
to paclitaxel as first-line therapy for metastatic TNBC improves PFS in the ITT 
population; the PFS improvement was more pronounced in patients with
PIK3CA/AKT1/PTEN-altered tumors identified by NGS (representing approximately 40% 
of the randomized patients in this setting). On the basis of these results as well as the 
tolerable safety profiles of atezolizumab and ipatasertib, combination treatment with 
these two agents appears to have promising therapeutic potential in TNBC.
The value of ipatasertib and atezolizumab added to a standard neoadjuvant 
chemotherapy approach has not yet been determined, and the net impact on immune
response is unknown. However, the current experience with ipatasertib in combination 
with atezolizumab and taxanes in this study (Cohort 1) suggests that the study 
treatments can be given with an acceptable toxicity profile along with promising 
confirmed response rates. All patients enrolled in the Cohort 3 will be closely monitored 
for safety and tolerability.


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3.3.4
Rationale for Starting Dose and Schedule of Ipatasertib
For ipatasertib, the starting dose of 400 mg QD on Days 121 of each 28-day cycle was 
selected on the basis of safety and PK data from Arm C of Study PAM4983g (Phase Ib 
trial of ipatasertib combined with paclitaxel; refer to the Ipatasertib Investigator's 
Brochure for details).  The pharmacokinetics of paclitaxel and ipatasertib following 
co-administration showed no evidence of drugdrug interaction (See Section 3.3.12), 
and 400 mg ipatasertib was better tolerated than 600 mg ipatasertib in this combination. 
In the randomized, placebo-controlled Phase II study (GO29227) in patients with locally 
advanced or metastatic TNBC, the combination of ipatasertib 400 mg administered QD 
on Days 121 of each 28-day cycle and paclitaxel 80 mg/m2 administered weekly on 
Days 1, 8, and 15 of each 28-day cycle was generally well tolerated and showed an 
improvement in PFS (refer to Section 1.2 and Section 1.3); the sparse sampling 
exposure results in this study were also consistent with the known PK profiles of 
ipatasertib (and its metabolite G-037720).
Doxorubicin is not a substrate of CYP3A and is not reported to be a CYP3A4 inhibitor or 
inducer in vivo. As such, no drugdrug interaction is expected between doxorubicin and 
ipatasertib. CYP3A4 does not play a major role in metabolism of cyclophosphamide,
and cyclophosphamide is not reported to be a CYP3A4 inhibitor or inducer in vivo. As 
such, no drugdrug interaction is expected between cyclophosphamide and ipatasertib.  
Atezolizumab is a monoclonal antibody, is not metabolized by CYP450 enzymes, and 
does not inhibit or induce CYP450 enzymes in vivo. As such, no drugdrug interaction 
is expected between atezolizumab and ipatasertib.
In addition, the totality of pharmacodynamics data from Phase I (PAM4743g, 
PK/pharmacodynamic analysis) and safety and efficacy data from randomized Phase II 
studies of ipatasertib (Study GO29227 and Study GO27983, which evaluated two dose 
levels of 200 mg and 400 mg of ipatasertib in patients with metastatic castration-
resistant prostate cancer) and exploratory exposure-response analyses for both safety 
and efficacy endpoints (data on file) support the selected starting dose of 400 mg 
ipatasertib for sufficient pathway inhibition and efficacy with a generally acceptable 
safety profile (refer to the Ipatasertib Investigator's Brochure for details).  In the 
ipatasertib paclitaxel arm of the GO29227 study, despite dose reduction of ipatasertib 
that occurred in 21.3% of patients due to adverse events, discontinuation of 
ipatasertib/placebo due to any adverse event occurred in 4 patients (6.6%) in the 
ipatasertib arm compared with 1 patient (1.6%) in the control arm.  The median 
cumulative dose intensity of both ipatasertib and paclitaxel in the ipatasertib arm was 
maintained at 99.0% (ipatasertib) and 100% (paclitaxel). Discontinuation of paclitaxel 
due to any adverse event was 6.6% in the ipatasertib arm and 8.1% in the control arm. 
A relative bioavailability and food-effect study (GO29868) was conducted in healthy 
subjects.  This study confirmed that the Phase III tablet formulation of ipatasertib to be 
used in this study will provide exposures similar to the exposures observed following 


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administration of powder-in-capsule formulation and Phase II tablet formulation of 
ipatasertib used in the Phase I (PAM4743g, PAM4983g) and Phase II (GO29227) 
studies, respectively.
3.3.5
Rationale for Treatment with Paclitaxel and Choice of 
Paclitaxel Regimen
Chemotherapy is the primary systemic treatment for patients without amplified HER2 
expression and for whom endocrine therapy is not an option.  A variety of chemotherapy 
choices exist including anthracyclines (doxorubicin, epirubicin, and pegylated liposomal 
doxorubicin), taxanes (paclitaxel, docetaxel, and albumin-bound paclitaxel), 
anti-metabolites (capecitabine and gemcitabine), platinums (cisplatin and carboplatin), 
and non-taxane microtubule inhibitors (eribulin and vinorelbine).  Generally, combination 
chemotherapy is associated with higher ORRs than single-agent chemotherapy;
however, because of an increase in toxicity and little survival benefit, sequential use of 
single agents is usually preferred (Cardoso et al. 2017; NCCN 2017).
Currently, there is no defined standard regimen for paclitaxel in the metastatic setting, as 
paclitaxel can be administered weekly (8090 mg/m2) or Q3W (175 mg/m2) 
(Swanton 2006; Cardoso et al. 2017; NCCN 2017).  Meta-analysis showed no difference 
in PFS (6 studies, 1610 patients, hazard ratio 1.02, 95% CI: 1.081.32), while OS was 
statistically higher among patients receiving weekly paclitaxel (5 studies, 1471 patients, 
hazard ratio 0.78, 95% CI: 0.670.89).  Furthermore, the incidence of serious adverse 
events, neutropenia, neutropenic fever, and peripheral neuropathy were significantly 
lower in weekly taxane schedules (Mauri et al. 2010).  Neurotoxicity, however, is 
a treatment-limiting toxicity for weekly continuous paclitaxel treatment (Seidman et al. 
2008).  Among weekly paclitaxel regimens that have been studied, continuous weekly 
dosing may be associated with more neurotoxicity than dosing on Days 1, 8, and 15 of 
each 28 day-cycle (Swanton 2006; Seidman et al. 2008; Miller et al. 2007).
In several recent randomized studies of paclitaxel in combination with targeted agents 
versus paclitaxel control, the median PFS seen in patients with HR-positive and
HER2-negative disease receiving weekly paclitaxel (90 mg/m2 on Days 1, 8, and 15 of 
each 28-day cycle) in the control arm was approximately 78 months (E2100, Miller et 
al. 2007; RIBBON-1, Robert et al. 2011; PEGGY, Vuylsteke et al. 2016) in the first-line 
chemotherapy setting.
In Study GO29227 (LOTUS), paclitaxel was administered in a weekly regimen of 
80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle, which maintains the cumulative 
dose intensity of paclitaxel when administered Q3W (175 mg/m2, as recommended by 
the current prescribing information for paclitaxel IV injection [TaxolUS PI; Paclitaxel UK 
PC]).  The control arm (paclitaxelplacebo) demonstrated a median PFS of 4.93 months 
(90% CI: 3.585.36 months), which is similar to the efficacy seen in the TNBC 
subgroups of several clinical trials using weekly paclitaxel (90 mg/m2 on Days 1, 8, and 
15 of each 28-day cycle) as the control arm (Miller et al. 2007; Miles et al. 2013; Miles et 


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al. 2017). In LOTUS, the ipatasertib arm showed an ORR 40% compared to control arm 
of 32% in the ITT population.
Cohorts 1 and 4 of the current study will use the same paclitaxel dose and schedule as 
in Study GO29227.  Paclitaxel (80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle) is 
considered an appropriate regimen for studying the added effect of ipatasertib in the 
TNBC populations as specified.  
3.3.6
Rationale for Treatment with Nab-Paclitaxel and Choice of 
Nab-Paclitaxel Regimen
Nab-paclitaxel is an albumin-bound formulation of paclitaxel that was developed to 
mitigate the significant toxicities associated with the vehicles that are necessary for 
parenteral administration of sb-paclitaxel (polyethylated castor oil and polysorbate 80). 
In addition, it has an advantageous PK profile compared with sb-paclitaxel and achieves 
a 33% higher tumor uptake in preclinical models (Yardley 2013). Steroids are routinely 
administered with sb-paclitaxel to lower the risk of hypersensitivity allergic reactions, but 
steroid premedication is not required with the use of nab-paclitaxel.
Nab-paclitaxel received a label from the U.S. Food and Drug Administration (FDA) for 
the treatment of MBC after failure of front-line combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy, based on the pivotal 
Phase III study performed by Gradishar et al. (2005). However, in real-world practice,
nab-paclitaxel is used throughout the continuum of care for patients with MBC. Both the
NCCN and ESMO clinical practice guidelines include nab-paclitaxel as a standard of 
care that may be administered as a single agent to patients with newly diagnosed 
recurrent or metastatic breast cancer (Cardoso et al. 2017; NCCN 2017).
The Q3W dose of nab-paclitaxel (260 mg/m2) in the FDA label established from the 
Phase III study comparing sb-paclitaxel with nab-paclitaxel (Gradishar et al. 2005) is not
generally used in current clinical practice. Instead, weekly dosing of nab-paclitaxel is the
most commonly utilized schedule given the better tolerability and suggestions of
increased efficacy of weekly dosing compared to Q3W dosing.
The superiority of the weekly regimen of nab-paclitaxel was first demonstrated in 
a randomized Phase II study conducted in patients with previously untreated MBC 
(Gradishar et al. 2009). In the four arms of this study, the ORRs were 37% with Q3W
nab-paclitaxel, 45% with weekly nab-paclitaxel 100 mg/m2 (3-weeks-on/1-week-off
schedule), 49% with weekly nab-paclitaxel 150 mg/m2 (3-weeks-on/1-week-off 
schedule), and 35% with Q3W docetaxel 100 mg/m2 (independent radiologist 
assessment), illustrating the anti-tumor advantages of the weekly dosing schedule. PFS 
was 11.0 months, 12.8 months, 12.9 months, and 7.5 months (independent radiologist 
assessment) for each of the four arms, respectively. The difference in PFS and ORR 
between the 100- and 150-mg/m2 weekly dose levels of nab-paclitaxel was not 
statistically significant, but patients receiving the higher dose experienced a greater 


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incidence of Grade 3 or 4 neutropenia (44% vs. 25%) and Grade 3 sensory neuropathy 
(14% vs. 8%).
Subsequent clinical studies have not clearly demonstrated that weekly doses of
nab-paclitaxel greater than 100 mg/m2 are more efficacious. Furthermore, higher doses 
of nab-paclitaxel are associated with greater toxicities. The CALGB 40502 Phase III trial 
randomized patients with chemotherapy-naïve, HER2-negative MBC to receive weekly 
paclitaxel, weekly nab-paclitaxel at a higher dose of 150 mg/m2, or ixabepilone, with all 
agents given in combination with bevacizumab, and on a 3-weeks-on/1-week-off 
schedule (Rugo et al. 2012). Nab-paclitaxel was not tolerable at this higher weekly dose
and did not improve PFS in any subtype over standard dose paclitaxel, leading to the
conclusion that 150 mg/m2 should not be utilized.
To date, 100 mg/m2 of nab-paclitaxel weekly on a 3-weeks-on/1-week-off schedule is the 
best-studied and tolerated dose, with suggestions of improved efficacy and decreased 
toxicities in MBC compared with both higher weekly doses and the Q3W dosing 
schedule of the same drug. As a result, subjects on this study will receive nab-paclitaxel 
100 mg/m2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle. 
3.3.7
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg Q2W, which 
is an approved dosage for atezolizumab (TecentriqU.S. Package Insert).
3.3.8
Rationale for Staggered Dose and Schedule
The development of combination treatments, while desirable, poses unique challenges.  
These include the selection of agents for combination therapy that may lead to improved 
efficacy while maintaining acceptable toxicity.  To date, most combinations have added
one or more investigational agents to a standard backbone already in clinical practice 
(Hurwitz et al. 2004; Pirker et al. 2009; Bang et al. 2010; Flaherty et al. 2012; Scagliotti 
et al. 2012).  One challenge is the need to distinguish the incremental toxicity of the 
combination.  Hamberg et al. (2010) proposes some solutions, including an intra-patient 
control (e.g., by introducing the novel agent after the standard backbone has been 
started).
To explore the effect of stepwise introduction of the treatment drugs in the first cycle on 
tolerability, a staggered dosing schedule has been proposed for Cohort 1, Arms C and D
(see Section 3 for detailed description of the schedule).  This approach will enable 
a better understanding of the contribution of individual agents with the goal of refining 
adverse event management guidance.  
3.3.9
Rationale for Atezolizumab Treatment beyond Initial 
Radiographic Progression
In studies of immunotherapeutic agents, complete response, partial response, and 
stable disease have each been shown to occur after radiographic evidence of an 


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apparent increase in tumor burden.  This initial increase in tumor burden caused by
immune cell infiltration in the setting of a T-cell response has been termed 
“pseudoprogression” (Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types.  In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells.  Because of the potential for a response after pseudoprogression, this study will 
allow patients in Cohorts 1, 2, and 4 to continue combination treatment after apparent 
radiographic progression per RECIST v1.1, provided the benefitrisk ratio is judged to 
be favorable by the investigator (see criteria in Section 4.6.1).  Patients should be 
discontinued for unacceptable toxicity or loss of clinical benefit as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, local 
biopsy results (if available), and clinical status. 
3.3.10
Rationale for Pathologic Complete Response as Primary 
Endpoint in Cohort 3
The primary objective for Cohort 3 is to evaluate the efficacy of neoadjuvant treatment 
with IpatAtezoPac followed by AtezoAC (Arm F) or IpatAtezoPac followed by 
IpatAtezoAC (Arm G) in patients with locally advanced T24 TNBC.  pCR was 
selected as the primary efficacy endpoint for Cohort 3.  It is a validated, meaningful 
measure of response to therapy.  Data from several analyses and clinical trials and 
meta-analyses indicate there is a correlation between pCR and long-term clinical benefit
(Liedtke et al. 2008; von Minckwitz et al. 2012; Cortazar et al. 2014).  This correlation 
was especially strong in patients with TNBC (EFS hazard ratio for patients achieving 
pCR vs. patients not achieving pCR: 0.24 [95% CI: 0.18 to 0.33]; OS hazard ratio for 
patients achieving pCR vs. patients not achieving pCR: 0.16 [95% CI: 0.11 to 0.25]) 
(Cortazar et al. 2014).
pCR will be defined as the absence of residual invasive cancer in the breast and 
absence of residual disease in the lymph nodes (ypT0/Tis ypN0 in the current American 
Joint Committee on Cancer staging system), based on hematoxylin and eosin evaluation 
of the complete resected breast specimen and all sampled regional lymph nodes 
following completion of neoadjuvant therapy, which is in line with the U.S. FDA and 
European Medicines Agency guidance for industry on pCR endpoints. 
3.3.11
Rationale for Biomarker Assessments
Breast cancer is a heterogeneous disease with many distinct subtypes as defined by 
molecular signatures and a diverse array of mutational profiles.  In addition to 
PIK3CA/AKT1/PTENalteration status, samples will be assessed for additional 
biomarkers in an effort to identify factors that may correlate with the safety and efficacy 
of the study treatments.
Through the use of NGS, whole genome sequencing (WGS), and/or other methods, the 
collected DNA from blood samples and tumor tissue from this study will be analyzed to 


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identify germline (e.g., BRCA1/2) and somatic alterations that are predictive of response
to study drug, are associated with progression to a more severe disease state, are 
associated with acquired resistance to study drug, or can increase the knowledge and 
understanding of disease biology.  
3.3.11.1
Rationale for Using Archival Tissue for Examining 
PIK3CA/AKT1/PTEN-Altered Tumor Status
Activation of PI3K/Akt signaling frequently occurs in breast cancer through activating 
mutations in PIK3CA or AKT1 as well as through alterations in PTEN.  These alterations 
occur in approximately 35% of TNBCs (Pereira et al. 2016).  In the Phase II study 
GO29227, a pre-specified patient population with PIK3CA/AKT1/PTEN-altered tumors 
as identified using archival or newly obtained biopsy tissue demonstrated a substantial 
benefit from ipatasertib treatment (hazard ratio0.44, 9 months vs. 4.9 months). 
These considerations support the use of archival tissue (i.e., sample from primary breast 
tumor) or a newly obtained biopsy to determine the PIK3CA/AKT1/PTEN-altered status 
of the disease to evaluate for a patient population with a higher probability of having 
a clinically meaningful response to ipatasertib combined with paclitaxel.  In the current 
study, PIK3CA/AKT1/PTEN-altered tumor status will be determined using an NGS assay 
(e.g., Foundation Medicine, Inc. [FMI]), and the results will be used for secondary and 
exploratory analyses.  Review of PIK3CA/AKT1/PTEN-altered status in archival tissue 
and response measures will be performed on an ongoing basis, and in the dose-
expansion cohorts, enrollment may be restricted to patients with tumors demonstrating 
PI3K/Akt pathway activation.
To obtain the most accurate reflection of the patient’s current disease while minimizing 
burden, a specimen from the most recently obtained tumor tissue is requested.
3.3.11.2
Rationale for Collection of Blood Samples for Non-Invasive 
Disease Monitoring
Circulating tumor DNA (ctDNA) can be detected in the blood of patients with epithelial 
cancers and may have diagnostic and therapeutic significance (Schwarzenbach et al. 
2011).  For example, the mutational status of tumor cells may be obtained through the 
isolation of ctDNA (Maheswaran et al. 2008), and ctDNA has been used to monitor 
treatment effectiveness in melanoma (Shinozaki et al. 2007).  In the current study, blood 
samples will be collected to enable evaluation of oncogenic genetic alterations at 
baseline and to assess for the possible emergence of new alteration after treatment with 
ipatasertib, atezolizumab, and taxane.  Genetic alterations will be evaluated in relevant 
genes in the PI3K/Akt pathway (including, but not limited to, PIK3CA and AKT1) and
other cancer-related genes.  Identifying potential discordances in the PIK3CA/AKT1
status between tumor samples and ctDNA may help clarify the prognostic and predictive 
significance of PIK3CA/AKT1 mutations in patients with breast cancer treated with 
ipatasertib, atezolizumab, and paclitaxel or nab-paclitaxel.  


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3.3.11.3
Rationale for Collection of DNA (Blood) for Exploratory Whole 
Genome Sequencing 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For example, genetic variants of drug-metabolizing enzymes and transporters can alter 
the pharmacokinetics of drugs, affecting their safety and efficacy.  For example, patients 
who carry defective alleles of the gene encoding 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 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.  The 
decision to analyze the samples will be based on a review of the PK data.  For example, 
if a patient in a given cohort has substantially higher ipatasertib plasma levels than other 
patients in that cohort, he or she may carry a defective allele of a gene important in the 
metabolism or transport of ipatasertib.  The genotyping efforts would be guided by 
results from in vitro metabolism studies and by results from ongoing clinical studies with 
ipatasertib.
The pharmacogenetic analysis, if needed, will be performed on identifiable (referring to 
the blinded clinical trial number assigned to the patient at the time of enrollment and not 
to the actual name or other protected health information of the patient) DNA samples, 
because it is necessary to link a patient’s PK data with genotype.  This analysis will be 
restricted to the evaluation of genes that may be involved in the pharmacokinetics of 
ipatasertib (e.g., drug metabolism, disposition, or elimination genes, or genes influencing 
these processes). 
In addition, tumor DNA can contain both reported and unreported chromosomal 
alterations resulting from the tumorigenesis process.  To help control for sequencing 
calls in previously unreported genomic alterations, the WGS blood sample will help 
determine whether an observed alteration identified in the tumor tissue is somatic 
throughout the evaluation of the DNA isolated in peripheral blood.
This sample for WGS will be collected if approved locally.


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3.3.11.4
Rationale for Optional Collection of New Tumor Biopsies at 
Disease Progression for Exploratory Purposes, Mandatory 
Collection of Serial Tumor Biopsies for Biopsy Cohort, and 
Mandatory Collection of Tumor Tissue from Surgical Resection 
in Cohort 3
Tumor tissue may be collected at the time of disease progression for DNA and/or RNA 
extraction for exploratory NGS or other research on non-inherited biomarkers (including,
but not limited to, cancer-related genes and biomarkers associated with common 
molecular and biological pathways). For patients who sign an Optional Research 
Biosample Repository Informed Consent Form, and if tumor biopsies can be obtained 
with minimal risk and discomfort to the patient, a tumor biopsy would be 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.
Understanding the mechanisms of resistance to the combination of ipatasertib, 
atezolizumab, and paclitaxel or nab-paclitaxel is critical for the development of agents in 
the PI3K/Akt pathway and may provide an opportunity to develop next-generation 
inhibitors to prevent resistance.
Pharmacodynamic biomarkers will be assessed to demonstrate evidence of biologic 
activity of ipatasertib in combination with atezolizumab in patients and will be assessed 
in on-treatment biopsies, which will be collected from patients who consent to this 
procedure.  Tumor immunobiology, stromal markers, and critical signaling targets of the 
PI3K/Akt signaling cascade may also be analyzed.
Progression biopsy tissue samples will aid in determining a resistance mechanism for 
the combination of ipatasertib, atezolizumab, and paclitaxel or nab-paclitaxel; may 
potentially influence future therapies for patients who progress on a PI3K/Akt inhibitor;
and may be part of a potential substudy.  NGS will be performed by a clinical cancer 
genomic profiling laboratory (e.g., FMI).
Evaluation of tumor tissue samples from surgical resection will aid in determining 
a resistance mechanism for the combination of ipatasertib, atezolizumab, AC, and 
paclitaxel, and may potentially influence future therapies for patients who progress on 
a PI3K/Akt inhibitor.  NGS may be performed by a clinical cancer genomic profiling 
laboratory (e.g., FMI).
3.3.12
Rationale for the Pharmacokinetic Evaluation Schedule
Serum and plasma samples for PK characterization of atezolizumab and ipatasertib
(parent and its metabolite G-037720), respectively, will be collected as outlined in 
Appendix 4, Appendix 5, and Appendix 6.  The sampling schedule is designed to enable 
characterization of ipatasertib using population PK (popPK) methodology. In addition, 
the PK data will allow comparison with single-agent ipatasertib data from the Phase I 
clinical trial (Study PAM4743g) and with ipatasertib data from other trials to evaluate 


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whether ipatasertib exposures are altered in combination with atezolizumab and 
paclitaxel/nab-paclitaxel.
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.  Data from Study 
PAM4983g showed that paclitaxel and ipatasertib pharmacokinetics, when administered 
in combination, 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 the biopsy cohort, samples will also be collected to measure coproporphyrin I and III, 
which are putatively transported into the liver by uptake transporters OATP1B1 and 
OATP1B3. The levels of these endogenous substrates of OATP transporters will be 
measured in an exploratory way to understand the impact of ipatasertib on OATP 
functionality.
Doxorubicin is not a substrate of CYP3A and is not reported to be a CYP3A4 inhibitor or 
inducer in vivo.  As such, no drugdrug interaction is expected between doxorubicin and 
ipatasertib.  Therefore, doxorubicin pharmacokinetics will not be evaluated in this study.
CYP3A4 does not play a major role in metabolism of cyclophosphamide, and 
cyclophosphamide is not reported to be a CYP3A4 inhibitor or inducer in vivo. As such, 
no drugdrug interaction is expected between cyclophosphamide and ipatasertib. 
Therefore, cyclophosphamide pharmacokinetics will not be evaluated in this study.
Any remaining PK samples after evaluation of atezolizumab, ipatasertib, and its 
metabolite may be used for exploratory evaluation of other analytes related to the 
administered drugs or biomarkers, enzymes, and transporters affecting their disposition.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 178 patients with locally advanced or metastatic TNBC that is not 
amenable to resection and approximately 24 patients with locally advanced T24 TNBC
are expected to be enrolled in this study.
4.1.1
Inclusion Criteria
Women or men with locally advanced or metastatic TNBC who have not received prior 
systemic chemotherapy in this setting and who are candidates for taxane therapy may 
be eligible for Cohort 1 of this study. Women or men with locally advanced or metastatic 


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TNBC who have received no more than two lines of prior systemic chemotherapy may 
be eligible for Cohort 2 of this study. Women or men with locally advanced T24 TNBC
may be eligible for Cohort 3 of this study. In patients with BRCA-associated tumors, 
PARP inhibitors in addition to platinum chemotherapy as potentially the preferred 
treatment option (Cardoso et al. 2017) should be taken into consideration when 
determining if this study may be appropriate for these patients.  For Cohorts 1, 2, and 4, 
patients may have received prior chemotherapy in the neoadjuvant/adjuvant setting, and 
locally advanced disease must not be amenable to resection with curative intent.  
Patients must have sufficient tumor tissues for central molecular assessment of 
PIK3CA/AKT1/PTEN-altered status and must comply with all eligibility criteria to be 
enrolled.  Inclusion criteria for Cohort 4 are identical to Cohort 1, with the addition of the 
requirement for PD-L1positive tumors (as defined below) as determined by central 
testing prior to enrollment.
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent Form(s) 

Woman or man age 18 years at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group Performance Status of 0 or 1 

Adequate hematologic and organ function within 14 days before the first study 
treatment on Day 1 of Cycle 1, defined by the following:
–
Neutrophils (absolute neutrophil count [ANC] 1500/L) (Cohort 3 patients 
should meet this criterion without granulocyte colonystimulating factor 
[G-CSF] support within the preceding 2 weeks)
–
For Cohort 3:  lymphocyte count 500/L
–
Hemoglobin 9 g/dL (Cohort 3 patients should meet this criterion in the 
absence of any transfusion within the preceding 2 weeks)
Platelet count 100,000/L (Cohort 3 patients should meet this criterion in the 
absence of any transfusion within the preceding 2 weeks)
–
Serum albumin 3 g/dL
–
Total bilirubin 1.5the upper limit of normal (ULN) (Cohorts 1, 2, and 4) or 
total bilirubin 1.0ULN (Cohort 3), 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:
Cohort 1, 2, and 4 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:
Cohort 1, 2, and 4 patients with known liver involvement may have 
ALP 5ULN.
Cohort 1, 2, and 4 patients with known bone involvement may have 
ALP 7ULN.
–
PTT (or aPTT) and INR 1.5ULN (except for patients receiving 
anticoagulation therapy)  
Patients receiving heparin treatment should have a PTT (or aPTT) 
between 1.5 and 2.5ULN (or patient value before starting heparin 
treatment).  Patients receiving coumarin derivatives should have an INR 
between 2.0 and 3.0 assessed in two consecutive measurements 1 to 
4 days apart.
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min based on 
CockcroftGault glomerular filtration rate estimation:
(140 age) (weight in kg) 0.85 (if female)
72 (serum creatinine in mg/dL)
–
Fasting total serum glucose 150 mg/dL and glycosylated hemoglobin (HbA1c)
7.5%

For Cohorts 1, 2, and 4: 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 defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 1 month after the last dose 
of ipatasertib, 5 months after the last dose of atezolizumab, 6 months after the 
last dose of paclitaxel, nab-paclitaxel, or doxorubicin, and 12 months after the 
last dose of cyclophosphamide, whichever occurs later.  Women must refrain 
from donating eggs during this same period.3
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
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; and sexual abstinence.
Hormonal contraceptive methods may be used in accordance with specific 
country and local requirements for patients with breast cancer. 


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  consider conserving sperm before treatment because of possible 
irreversible infertility due to therapy with paclitaxel, agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraceptive measures, and 
agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for 1 month after 
the last dose of ipatasertib or 6 months after the last dose of paclitaxel, 
nab-paclitaxel, cyclophosphamide, or doxorubicin, 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 1 month after the last dose of ipatasertib or 
6 months after the last dose of paclitaxel, nab-paclitaxel, cyclophosphamide, or 
doxorubicin, 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, 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.
Disease-Specific Inclusion Criteria
Patients must meet the following disease-specific criteria for study entry:

For Cohorts 1, 2, and 4: histologically documented TNBC (negative HER2, ER, and 
PgR status) 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 (nonfine-needle aspiration [FNA] sample) as assessed locally 
(or centrally, if not available locally) according to the ASCO/CAP guidelines 
(see Appendix 8 and Appendix 9)

For Cohort 2:  disease progression following one or two lines of systemic therapy for 
inoperable locally advanced or metastatic TNBC
–
Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or 
radiation treatment for early stage breast cancer, provided all chemotherapy 
was completed 12 months prior to Day 1 of Cycle 1.


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
For Cohorts 1, 2, and 4:  measurable disease according to RECIST v1.1 (see 
Appendix 10)

For Cohort 2:  Treated brain or spinal cord metastases are allowed if patients have 
stable disease and are not on steroid treatment.

For Cohort 3: histologically documented TNBC (negative HER2, ER, and PgR 
status) that meets both of the following criteria:
–
Primary breast tumor size of 2 cm by at least one radiographic or clinical 
measurement
–
Disease stage at presentation of cT24 cN03 cM0
Note:  Receptor status at study entry should correspond to the evaluation of the 
most recent biopsy (non-FNA sample) as assessed locally (or centrally, if not 
available locally) according to the ASCO/CAP guidelines (see Appendix 8 and 
Appendix 9).  Patients with multifocal tumors (more than one tumor confined to 
the same quadrant as the primary tumor) are eligible provided all discrete 
lesions have been biopsied and centrally confirmed as TNBC.

For Cohort 3:  patient agreement to undergo appropriate surgical management, 
including axillary lymph node surgery and partial or total mastectomy, after 
completion of neoadjuvant treatment 

Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or 
a minimum of 20 (for Cohorts 1 and 2) or 15 (for Cohorts 3 and 4) freshly 
cut unstained, serial tumor slides from the most recently collected tumor tissue for 
central analysis of PD-L1 status to determine eligibility for Cohort 4 and for central 
molecular analysis (retrospective NGS testing for PIK3CA/AKT1/PTEN-altered 
status and for other protocol-mandated secondary and exploratory assessments).  
Cytologic or FNA samples are not acceptable.  Tumor tissue from bone metastases 
that is subject to decalcification is not acceptable.
–
For Cohorts 1, 2, and 4:  If a more recent specimen is either insufficient or 
unavailable, the patient may still be eligible if the patient can provide a tissue 
block (preferred) or a minimum of 20 unstained serial slides from an older 
archival tumor tissue, or if the patient is willing to consent to and undergo an 
additional pretreatment core or excisional biopsy of a non-target lesion (a 
non-target lesion is preferred if it is assessable and the biopsy can be safely 
obtained).  In general, a minimum of three core biopsies for NGS testing are 
required.
–
For Cohort 3:  If the specimen is either insufficient or unavailable, the patient 
may still be eligible if the patient is willing to undergo an additional pretreatment 
core biopsy.  In general, a minimum of three core biopsies for NGS testing are 
required.


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–
For Cohort 4:  Patients must have a PD-L1positive tumor (defined as 1%
expressing tumor-infiltrating immune cells [%ICs] evaluated as proportion of 
tumor area) as determined by central testing prior to enrollment.
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.  The PD-L1 score for each patient will be 
the maximum PD-L1 score among the samples.
If a patient already has results based on the commercial FoundationOne
CDx assay by Foundation Medicine, 10 freshly cut unstained, serial tumor 
slides from the most recently collected tumor tissue are acceptable for 
central molecular analysis (as described above), upon confirmation by the 
Medical Monitor.
4.1.2
Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following general criteria will be excluded from study entry:

Inability to comply with study and follow-up procedures

History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills 

Active infection requiring antibiotics 

History of or current evidence of HIV infection 

Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B 
surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current 
drug or alcohol abuse, or cirrhosis 
–
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive total 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 
is negative for HCV RNA. 

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure (other 
than anticipated breast surgery for Cohort 3) during the course of the study 
–
Placement of a vascular access device is not considered major surgery. 

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 1 month after the last dose of ipatasertib, 5 months after the last dose of 
atezolizumab, 6 months after the last dose of paclitaxel, nab-paclitaxel, or 
doxorubicin, or 12 months after the last dose of cyclophosphamide, whichever 
occurs later 


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–
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 within 48 hours prior to initiation of 
study treatment.

New York Heart Association (NYHA) Class II, III, or IV heart failure; left ventricular 
ejection fraction 50%; or active ventricular arrhythmia requiring medication

Current unstable angina or history of myocardial infarction within 6 months prior to 
Day 1 of Cycle 1

Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF) 480 milliseconds 

History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction

Treatment with approved or investigational cancer therapy within 14 days prior to 
Day 1 of Cycle 1 

Prior treatment with an Akt inhibitor
–
Note that prior PI3K or mechanistic target of rapamycin inhibitors are allowed

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of 
a disease or condition that contraindicates the use of an investigational drug or that 
may affect the interpretation of the results or render the patient at high risk from 
treatment complications 
Disease-Specific Exclusion Criteria for Cohorts 1, 2, and 4
For Cohorts 1, 2, and 4, patients who meet any of the following disease-specific criteria 
will be excluded from study entry:

Patients with leptomeningeal carcinomatosis 

For Cohorts 1 and 4 only: history of or known presence of brain or spinal cord 
metastases

For Cohorts 1 and 4:  previous systemic therapy for inoperable locally advanced or 
metastatic TNBC, including chemotherapy, immune checkpoint inhibitors, or 
targeted agents
–
Patients in Cohorts 1 and 4 may have received prior neoadjuvant or adjuvant 
chemotherapy and/or radiation treatment for early stage breast cancer, 
provided all chemotherapy was completed 12 months prior to Day 1 of 
Cycle 1.

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and 
Grade 1 peripheral neuropathy 


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
Patients who have received palliative radiation treatment to peripheral sites 
(e.g., bone metastases) for pain control and whose last treatment was completed 
14 days prior to Day 1 of Cycle 1 may be enrolled in the study if they have 
recovered from all acute, reversible effects 

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 (i.e., stable in the 14 days before Day 1 of Cycle 1). 
–
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation (Grade 1 
or better) prior to study enrollment.  There is no required minimum recovery 
period beyond the 14 days required for radiation therapy.
–
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., bone metastasis) should be 
considered for loco-regional therapy if appropriate prior to enrollment. 

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy 
–
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events (e.g., bone metastasis, osteoporosis) and who do not have 
a history of clinically significant hypercalcemia are eligible. 

Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, 
except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, or Stage I uterine cancer
Exclusion Criteria for Cohort 3
For Cohort 3, patients who meet any of the following criteria will be excluded from study 
entry:

Prior history of invasive breast cancer

Prior systemic therapy for treatment and/or prevention of invasive breast cancer 

Previous therapy with anthracyclines or taxanes for any malignancy

Bilateral breast cancer 

Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph 
nodes with one exception:
–
Patients who have undergone sentinel lymph node biopsy (SLNB) prior to 
initiation of neoadjuvant therapy (as per local practice) may be eligible if the 
SLNB is free of invasive carcinoma.  However, any patient with a positive 
SLNB result (involved with invasive carcinoma) is ineligible to participate in this 
study.


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
Undergone axillary lymph node dissection (ALND) prior to initiation of neoadjuvant 
therapy 

History of other malignancy within 5 years prior to screening, with the exception of 
those with a negligible risk of metastasis or death (e.g., 5-year OS of 90%), such 
as adequately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, localized prostate cancer, or Stage I uterine cancer

History of cerebrovascular accident within 12 months prior to initiation of study 
treatment

Cardiopulmonary dysfunction as defined by any of the following prior to initiation of 
study treatment:
–
History of NCI CTCAE v4.0 Grade 3 symptomatic congestive heart failure,
NYHA Class II, III, or IV heart failure, or left ventricular ejection fraction (LVEF)
53%
–
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia 
not controlled by adequate medication, severe conduction abnormality, or 
clinically significant valvular disease
–
High-risk uncontrolled arrhythmias (e.g., atrial tachycardia with a heart 
rate 100 beats per minute at rest, significant ventricular arrhythmia 
[ventricular tachycardia], or second- or third-degree atrioventricular block)
–
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia
–
Myocardial infarction within 12 months prior to initiation of study treatment
–
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic 
blood pressure 100 mmHg)
–
Evidence of transmural infarction on ECG
–
Requirement for oxygen therapy

Known allergy or hypersensitivity to the components of cyclophosphamide or 
doxorubicin formulations

Known allergy or hypersensitivity to filgrastim or pegfilgrastim formulations

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

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study.

Prior treatment with CD137 agonists or immune checkpointblockade therapies, 
including anti-CD40, antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic 
antibodies


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
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following ipatasertib-specific criteria will be excluded from 
study entry:

History of Type I or Type II diabetes mellitus requiring insulin 

Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment.

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

History of or active inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment
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’s syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 11 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of the following conditions 
are met:
o
Rash must cover 10% of body surface area.
o
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.


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o
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with 
atezolizumab or within 5 months after the last dose of atezolizumab

History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication 
during the course of the study, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study.
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.
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


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4.2
METHOD OF TREATMENT ASSIGNMENT 
This Phase Ib study is open label. In Cohort 1, enrollment will be opened sequentially in 
the following order: A1 B1 A2 B2 (see Figure 1). The Sponsor may open 
enrollment for more than one arm at a time.  However, Arm A2 may be opened only after 
determination of safety from Arm A1, and Arm B2 may be opened only after 
determination of safety from Arm B1. To further explore tolerability of the combination 
treatment, additional arms with stepwise introduction of the treatment drugs will be 
opened.  Enrollment order in Cohort 1 will then be as follows:  A1 B1 A2 B2/C1 
D1 C2 D2.  Both Arm B2 and Arms C or D can be open simultaneously, but 
priority for filling of arms will go to Arms C and D. Arm A will be extended to include an
expansion phase (Stage 3 Arm A3) to further investigate the tolerability and efficacy of 
the triplet combination in first-line metastatic TNBC. Arm A3 will open after Arms C2 and 
D2 have been filled. In Cohort 3, enrollment will be opened sequentially in the following 
order:  F1 G1 F2 and/or G2 (see Figure 1).  Arm F2 may be opened only after 
determination of safety from Arm F1, and Arm G2 may be opened only after 
determination of safety from Arm G1.  During the expansion stage for Cohort 3, the 
Sponsor will determine the allocation of 12 total patients to Arm F2, Arm G2, or both.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are ipatasertib, 
atezolizumab, paclitaxel, nab-paclitaxel, doxorubicin, and cyclophosphamide.
Loperamide (or racecadotril, which may more commonly be used in Europe) and other 
prophylactic medications (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 
Ipatasertib drug product is intended for oral administration and will be supplied as 
100- and 200-mg tablets.  For information on the formulation and handling of ipatasertib, 
see the pharmacy manual and the Ipatasertib Investigator’s Brochure.
The period between re-dispensing and last tablet consumed should not exceed 1 month.  
The investigational product is for investigational use only and is to be used only within 
the context of this study.  The study drug supplied for this study must be maintained 
under adequate security and stored under the conditions specified on the label until 
dispensed for patient use or returned to the Sponsor.   
4.3.1.2
Atezolizumab
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in 
a single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation, handling, storage, and preparation 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.
Paclitaxel may be locally supplied or may be supplied by the Sponsor.
4.3.1.4
Nab-Paclitaxel
Refer to the nab-paclitaxel (Abraxane®) Package Insert for details on formulation and
storage.
Nab-paclitaxel may be locally supplied or may be supplied by the Sponsor.
4.3.1.5
Doxorubicin
For information on the formulation, packaging, and handling of doxorubicin, see the local 
prescribing information for doxorubicin.
Doxorubicin may be locally supplied or may be supplied by the Sponsor. 
4.3.1.6
Cyclophosphamide
For information on the formulation, packaging, and handling of cyclophosphamide, see 
the local prescribing information for cyclophosphamide.
Cyclophosphamide may be locally supplied or may be supplied by the Sponsor. 
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.  Patients in Cohorts 1, 2, and 4
will continue to be treated until loss of clinical benefit, unacceptable toxicity, or 
withdrawal of consent, whichever occurs first.  Patients in Cohort 3 will continue to be 
treated for five cycles (28-day cycles; 20 weeks) or until loss of clinical benefit, 
unacceptable toxicity, or withdrawal of consent, whichever occurs first.
Ipatasertib is to be administered before atezolizumab and chemotherapy.  Atezolizumab 
is to be administered before chemotherapy. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.9 and Appendix 13.
4.3.2.1
Ipatasertib 
In Cohort 1, ipatasertib will be administered at the starting dose of 400 mg orally QD, 
beginning on Cycle 1, on Days 121 of each 28-day cycle (in Arms A, B, and C) until the 


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patient experiences disease progression, intolerable toxicity, or withdraws consent.  In 
Arm D, ipatasertib will be administered at the starting dose of 400 mg orally QD on 
Days 1521 of the first cycle.  In all subsequent treatment cycles (Cycles 2), ipatasertib 
400 mg will be administered orally QD on Days 121 until the patient experiences 
disease progression, intolerable toxicity, or withdraws consent.
In Cohort 2, ipatasertib 400 mg will be administered orally QD on Days 128 of Cycle 1 
(35-day cycle) and on Days 121 of subsequent cycles (28-day cycles).
In Arm F of Cohort 3, ipatasertib will be administered orally QD at a dose of 300 mg on 
Days 121 of Cycles 1 and 2 and at a dose of 400 mg on Days 121 of Cycles 35.  In 
Arm G of Cohort 3, ipatasertib will be administered orally QD at a dose of 400 mg on 
Days 121 of Cycles 15.
In Cohort 4, ipatasertib 400 mg will be administered orally QD on Days 121 of each 
28-day cycle.  
Each dose of ipatasertib should be taken with a minimum of 3 ounces (90 mL) of fluid.  
Ipatasertib may be taken with or without food.  If a dose is missed (not taken within 
8 hours after the scheduled dosing time), the patient should resume dosing with the next 
scheduled dose.  Missed or vomited doses will not be made up.
On study days requiring a predose blood draw for PK sampling, patients will be 
instructed to take their daily oral dose of ipatasertib in the clinic after completion of the 
pretreatment assessments (see Appendix 1, Appendix 2, and Appendix 3).  Ipatasertib 
should be taken at approximately the same time each day.  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.  Any incidence of vomiting within 3 hours post drug 
administration should also be recorded for the day of PK sampling.
A sufficient amount of ipatasertib should be provided to the patient to last one treatment 
cycle.  Patients will be instructed to bring their bottles of ipatasertib and their medication 
diaries to each study visit.
4.3.2.2
Atezolizumab
In Cohort 1, patients will receive atezolizumab 840 mg administered by IV infusion Q2W
(on Days 1 and 15 [3] days) of each 28-day cycle (in Arms A, B, and D). In Arm C, 
atezolizumab 840 mg will be administered by IV infusion on Day 15 of the first cycle.  In 
all subsequent treatment cycles (Cycles 2), atezolizumab will be administered by 
IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle. 
In Cohort 2, atezolizumab 840 mg will be administered by IV infusion on Days 8 and 22 
of Cycle 1 (35-day cycle) and on Days 1 and 15 of subsequent cycles (28-day cycles).  


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In Cohort 3, atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 
of Cycles 15 (28-day cycles).  
In Cohort 4, atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 
of each 28-day cycle.  
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 12.
Atezolizumab infusions will be administered per the instructions outlined in Table 2.
Table 2
Administration of First and Subsequent Infusions of 
Atezolizumab
First Infusion
Subsequent Infusions

Premedication should be limited to 
prophylaxis as outlined in Section 4.3.3
for the purpose of preventing rash.

Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion.

Atezolizumab should be infused over 
60 (15) minutes.

If clinically indicated, vital signs should be 
measured every 15 (5) minutes during 
the infusion and at 30 (10) minutes after 
the infusion.  

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

On Day 15 of Cycle 1, premedication may 
be given as prophylaxis as outlined in 
Section 4.3.3 for the purpose of preventing 
rash.

If the patient experienced an infusion-
related reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital signs 
should be recorded during the infusion and 
at 30 (5) minutes after the infusion.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 13.
No dose modification for atezolizumab is allowed.


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4.3.2.3
Paclitaxel
In Cohorts 1 and 4, the dose of paclitaxel is 80 mg/m2 administered by IV infusion on 
Days 1, 8, and 15 of each 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can 
be given on Day 22. In Cohort 3, paclitaxel 80 mg/m2 will be administered by IV infusion 
on Days 1, 8, 15, and 22 of Cycles 35.  Calculation of body surface area for the 
purposes of dosing of paclitaxel should be made according to the prescribing 
information.  If the patient's weight changes by 10% during the study, the body surface 
area and drug doses should be recalculated.  
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per 
institutional guidelines and administered after the oral dose of ipatasertib.  
Patients should be monitored during paclitaxel administration per institutional policies.  
Patients may receive anti-emetic and other prophylactic treatments, according to 
institutional practice.
4.3.2.4
Nab-Paclitaxel
Nab-paclitaxel will be administered according to the local prescribing information.  The 
starting dose level of nab-paclitaxel in this study will be 100 mg/m2 administered 
intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle (21-days 
on/7-days off schedule). Dose modifications should be performed according to 
Section 5.1.9.
Sites should follow their institutional standard of care for determining the nab-paclitaxel 
dose for patients who are obese and for dose adjustments in the event of patient weight 
changes. The infusion site should be closely monitored for possible infiltration during 
drug administration. 
4.3.2.5
Doxorubicin
In Cohort 3, doxorubicin 60 mg/m2 will be administered by IV infusion on Days 1 and 
15 of Cycles 1 and 2.  Doxorubicin should be given as an IV bolus over 35 minutes or 
as an IV infusion over 1530 minutes, in accordance with institutional practice.  Dose 
delays and dose reductions for toxicity are permitted in accordance with the local 
prescribing information.  Doxorubicin and cyclophosphamide should be administered 
after atezolizumab.
Refer to the local prescribing information for details regarding the preparation and 
administration of doxorubicin.  
4.3.2.6
Cyclophosphamide
In Cohort 3, cyclophosphamide 600 mg/m2 will be administered by IV infusion on Days 1 
and 15 of Cycles 1 and 2.  The dose should be capped at 1200 mg.  Note that oral 
cyclophosphamide is not permitted.  Cyclophosphamide should be given as an IV bolus 
over 35 minutes or as an IV infusion over 12 hours, in accordance with institutional 


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practice.  Dose delays and dose reductions for toxicity are permitted in accordance with 
the local prescribing information.  Doxorubicin and cyclophosphamide should be 
administered after atezolizumab.
Refer to the local prescribing information for details regarding the preparation and 
administration of cyclophosphamide.
4.3.3
Other Treatments: Premedications and Prophylactic Treatment
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophorvehicle, precautions must be taken to decrease the risk of anaphylaxis.  
Patients must be premedicated prior to paclitaxel with dexamethasone, 
diphenhydramine, and an H2-receptor blocker (i.e., ranitidine or famotidine) or per 
institutional practice. H2-receptor antagonists, such as cimetidine, which are known to 
inhibit cytochrome P450, are excluded.
In general, chemotherapy supportive care should be administered per ASCO, European 
Organisation for Research and Treatment of Cancer (EORTC), or European Society for 
Medical Oncology (ESMO) guidelines or institutional practice.  In Cohort 3, filgrastim or 
pegfilgrastim must be used in conjunction with each AC administration.  
Chemotherapy-induced nausea and vomiting prophylaxis and treatment should be 
administered as clinically indicated.  It is highly recommended that aprepitant be 
included as premedication for AC to prevent nausea and vomiting.  Because systemic 
corticosteroids may attenuate the potential beneficial immunologic effects of treatment 
with atezolizumab, alternative agents should be considered when clinically feasible 
(see Section 4.4.2 for further guidance).
Diarrhea is a common adverse event associated with ipatasertib and atezolizumab, and 
sometimes with chemotherapy treatment. In this current study, to improve diarrhea 
management and patient experiences, loperamide (2 mg twice a day) will be 
administered daily as prophylaxis for diarrhea in the first cycle.  If side effects are not 
tolerated, doses may be reduced.  Investigators are encouraged to continue this dosing 
for the remainder of the study using their discretion based on clinical judgments.
Treatment modifications for diarrhea (any grade), when it occurs, should be instituted as 
early as possible.  Guidelines for treatment of diarrhea following the prophylactic dose of 
loperamide indicate use of loperamide 2 mg every 4 hours or after each loose, watery 
stool, up to the maximum total dose of 16 mg/day or per institutional guidelines and 
standard of care. If diarrhea control is inadequate despite use of maximum dose of 
loperamide or due to intolerance of loperamide, additional anti-diarrheal agents may be 
used per institutional standards of care such as Lomotil(diphenoxylate and atropine), 
codeine, or octreotide.  Duration of diarrhea may be minimized by taking ipatasertib with 
food, avoiding lactose-containing foods, and hydrating with 810 glasses per day 
(~12 oz/glass) of electrolyte-containing clear liquid, such as broth or low-calorie drinks.  


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For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal 
agent(s) and/or withholding dosing of ipatasertib, gastroenterologists should be 
consulted to rule out the risk of colitis and infection (e.g., obtaining CT images or a stool 
culture for infectious workup [Clostridium difficile, enteric bacteria, cytomegalovirus]).  
Patients should be educated on the symptoms and importance of early reporting of 
diarrhea to receive instructions of treatment and prevention of dehydration so that 
patients can be promptly and appropriately managed. Educational materials will be 
provided to investigators and patients outlining these guidelines. 
If diarrhea occurs, it should be managed per guidelines in Section 5.1.9.4; upon 
resolution or when study treatment is restarted, loperamide prophylaxis should be 
considered to resume and continue based on clinical judgments.
Additionally, patients who experience diarrhea may have fecal samples collected to test 
fecal calprotectin, at the investigator's discretion, to provide additional information for 
aiding the Sponsor in understanding how to better guide future diarrhea management.
Because of the risk of rash, patients should receive the following prophylactic treatment, 
unless contraindicated, during the first cycle in which all three study treatments 
(ipatasertib, atezolizumab, and taxane) are to be given in Cohorts 1 and 4 or during the 
first 28 days (i.e., Weeks 14) in which all four study treatments (ipatasertib, 
atezolizumab, and AC) are to be given in Cohort 3: On days when patients will receive 
atezolizumab, patients should receive at least 10 mg/day prednisone (or equivalent) as 
premedication, followed by a fixed dose of 10 mg/day prednisone (or equivalent) for 
24 consecutive days thereafter.  The timing of corticosteroid administration on days 
when patients will receive atezolizumab and paclitaxel will be determined by the 
investigator according to best medical judgment.  In addition, patients should receive 
daily oral antihistamine for at least the first cycle in which all three treatments (four 
treatments for Cohort 3) are to be given.  It is suggested that a non-sedating oral 
antihistamine (such as loratadine, cetirizine, or fexofenadine) and a longer-acting 
formulation be used.  Protocol-required premedication should be omitted on the day of 
paclitaxel infusion if already administered as taxane premedication per institutional 
practice.
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local practices.  The study site will acknowledge receipt of IMPs supplied by 
the Sponsor using the interactive voice or Web-based response system to confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  


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The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.5
Continued Access to Ipatasertib and Atezolizumab
The Sponsor will evaluate the appropriateness of continuing to provide ipatasertib and/or 
atezolizumab to patients assigned to this treatment after evaluating the primary and 
secondary efficacy outcome measures and safety data gathered in the study. These 
analyses may be conducted prior to completion of the study.
The Sponsor will offer continued access to Sponsor study drug (ipatasertib and/or 
atezolizumab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Sponsor study drugs (ipatasertib 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 or atezolizumab) 
after completing the study if any of the following conditions are met:

The Sponsor study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the drug or data suggest that the 
drug is not effective for breast cancer

The Sponsor has reasonable safety concerns regarding the drug as treatment for 
breast cancer

Provision of the drug is not permitted under the laws and regulations of the patient's 
country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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4.4
CONCOMITANT THERAPY 
Concomitant therapy includes 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 study treatment from 14 days prior to initiation 
of study treatment to the treatment discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives, as allowed per local guidelines

For Cohorts 1, 2, and 4: palliative radiotherapy (e.g., treatment of known bony 
metastases or symptomatic relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
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).  The 
patient may continue ipatasertib treatment after treatment holding has been 
completed and the patient has sufficiently recovered.

For Cohort 2 only: radiotherapy to the brain as outlined below:
History of radiotherapy (either stereotactic radiosurgery or whole-brain radiation 
therapy) to the brain is allowed provided that all of the following criteria are met:
–
The patient has no evidence of progression or hemorrhage after 
completion of CNS-directed therapy.
–
The most recent radiotherapy to the brain is completed more than 14 days 
prior to study treatment initiation.
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy may receive study treatment following 
Medical Monitor approval.
–
Anti-convulsant therapy, if required, is administered at a stable dose

Premedication with antihistamines, antipyretics, and/or analgesics prior to 
atezolizumab or paclitaxel administration

Prophylaxis use of loperamide (or racecadotril, which may more commonly be used
in Europe) 
Treatment with loperamide is mandated in the first cycle and as clinically 
indicated in subsequent cycles to prevent diarrhea.  Patients who experience 
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guidelines provided in Section 5.1.9.4; please refer to that section for additional 
details.  Patients are asked to be cognizant of the onset, duration, severity, and 
frequency of symptoms and the medications administered.  

For patients receiving paclitaxel, treatment with granulocyte colony-stimulating 
factor
The primary prophylaxis should be administered per the ASCO, European 
Organisation for Research and Treatment of Cancer, and ESMO guidelines; 
namely, in patients who are 60 years of age and/or with comorbidities 
(Smith et al. 2006; Aapro et al. 2011).

For patients receiving bisphosphonates or denosumab prior to enrollment, 
maintenance on bisphosphonate or denosumab therapy during screening and while 
actively treated with study drug
Both types of agents have potential immunomodulatory properties, but may be 
used as clinically indicated.

Luteinizing hormone-releasing hormone agonists for ovarian function preservation 

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment

Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

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) 

For Cohort 3:  G-CSF (i.e., filgrastim or pegfilgrastim)
G-CSF is permitted for patients receiving chemotherapy and is required when 
patients are receiving AC.  G-CSF should be administered as primary 
prophylaxis per the ASCO, EORTC, or ESMO guidelines (Smith et al. 2006; 
Crawford et al. 2009; Aapro et al. 2011) or institutional practice. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine), or 
equivalent medications per local standard practice.  Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 


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oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists).
4.4.2
Cautionary Therapy
For Cohorts 1, 2, and 4, patients who require radiation or surgery as part of medical 
treatment in the absence of radiographic disease progression must exercise caution, 
and all study treatment should be temporarily held for at least 7 days before and after 
the procedure (at least 14 days after radiation is recommended).  After the temporary 
treatment hold is complete, study treatment may be re-initiated with Medical Monitor 
approval when the patient has sufficiently recovered.
Systemic corticosteroids and tumor necrosis factor(TNF-) inhibitors may attenuate 
potential beneficial immunologic effects of treatment with atezolizumab.  Therefore, in 
situations in which systemic corticosteroids or TNF-inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific immune-mediated adverse events when associated with 
atezolizumab (refer to Appendix 13 for details).
4.4.2.1
Medications Given with Precaution due to Effects Related to 
CYP450 Enzymes
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a 
time-dependent inhibitor of CYP3A4.  A clinical drugdrug interaction study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  Therefore, 
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  Given 
that ipatasertib is primarily metabolized by CYP3A, there is a high potential for 
drugdrug interactions of ipatasertib with any medication that strongly inhibits or induces 
CYP3A.  Data from a clinical study showed that ipatasertib exposures were reduced by 
approximately 50% when co-administered with enzalutamide, a strong CYP3A inducer.  
Itraconazole, a strong CYP3A4 inhibitor, increased ipatasertib AUC and Cmax by 
approximately 5-fold and 2-fold, respectively (Study GP30057).  As such, other strong 
CYP3A inhibitors are expected to increase ipatasertib exposures.  Therefore, the 
following drugs should be avoided or used with caution. 

Strong CYP3A4/5 inhibitors, such as, but not limited to, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, voriconazole, and/or grapefruit juice 

Strong CYP3A4/5 inducers, such as, but not limited to, rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin

CYP3A4/5 substrates with a narrow therapeutic index


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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. 
Caution should be exercised when nab-paclitaxel is concomitantly administered with 
known inhibitors of CYP3A4 (e.g., atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) and 
inducers of CYP3A4 (e.g., rifampin, phenobarbital, phenytoin, St. John’s Wort, and 
carbamazepine).  Caution should also be exercised when nab-paclitaxel is concomitantly 
administered with known inhibitors of CYP2C8 (e.g., gemfibrozil) and inducers of 
CYP2C8 (e.g., rifampin).
Patients who require short-term use of a strong CYP3A4/5 inhibitor or use of sensitive 
CYP3A substrates with a narrow therapeutic window for medical treatment (i.e., an 
alternative treatment cannot be used) must exercise caution and all study treatment 
should be temporarily held until at least 7 days after the last dose of these drugs.
Patients are permitted to take moderate inhibitors of CYP3A4/5 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. FDA):  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(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) is prohibited 
within 14 days prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 


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therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details).

Quinidine or other anti-arrhythmic agents with narrow therapeutic index
Stable doses of calcium-channel blockers are permitted.
Stable doses of -blockers, if an alternative treatment cannot be used, are 
permitted with caution.

Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section 4.4.2)

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab or 
cyclophosphamide, and for 5 months after the last dose of atezolizumab or 3 months 
after the last dose of cyclophosphamide, whichever occurs later.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin 2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab.

Systemic 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, is prohibited 
during the study treatment period and for 10 days after the last dose of study 
treatment.

Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period.
4.4.5
Additional Restrictions
No food or fluids other than water will be allowed for 8 hours prior to each Day 1 study 
visit until after study laboratory samples for fasting glucose and fasting lipid profile, as 
applicable, are obtained (see Appendix 1, Appendix 2, and Appendix 3).


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4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1,
Appendix 2, and Appendix 3.  All activities must be performed and documented for each 
patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Voluntary, written, dated, and signed informed consent for participation in the study must 
be obtained before performing any study-related procedures (including screening 
evaluations or submission of archival tissues).  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 by the Medical Monitor to 
confirm that patients meet all eligibility criteria before enrollment.  The investigator will 
maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status, will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 14 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Further, to assess compliance with specific medications and incidence of certain 
adverse events, patients will complete a diary each day. Patients will receive the diary 
on the first day of each cycle and complete their portion at home, with site staff 
completing other information during clinic visits.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 


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genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
Limited, targeted, symptom-directed physical examinations should be performed at 
specified 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.
4.5.4
Vital Signs
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure 
while the patient is in a seated position after resting for at least 5 minutes, respiratory 
rate and body temperature (oral, axillary, temporal, or tympanic).
On chemotherapy dosing days, vital signs should be recorded prior to dosing and at the 
end of the infusion.  
4.5.5
Tumor and Response Evaluations for Cohorts 1, 2, and 4
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, 
magnetic resonance imaging [MRI], and bone scans) through use of RECIST v1.1 (see 
Appendix 10).  Images for tumor assessments will be collected to enable retrospective 
blinded independent central review when needed. 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). To be suitable for RECIST assessments, CT and 
MRI scans should have a maximum thickness of 5 mm and no gaps. Assessments 
should be performed by the same evaluator to ensure internal consistency across visits. 
An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation.  At the investigator’s discretion, and if clinically indicated, CT scans may 
be repeated at any time if progressive disease is suspected, and other methods of 
assessment of measurable disease may be used (e.g., brain scans using CT or MRI) in 
addition to those listed above.  For symptomatic deterioration attributed to disease 
progression, every effort should be made to document progression through use of 
objective criteria per RECIST v1.1.  
Baseline tumor assessments should be performed 28 days before Day 1, Cycle 1.  
Contrast-enhanced (IV and oral) CT or (IV) MRI scans should include chest, abdomen, 
and pelvic scans; CT scans of the neck should be included if clinically indicated.  
Screening (or documented standard-of-care) bone scans (technetium bone scan) and 
head scans (CT or MRI) should be performed within 6 weeks before Day 1, Cycle 1.  
Tumor assessments should be performed based on a schedule calculated from Cycle 1, 
Day 1 (study Day 1) with the first assessment during Week 8 and every 8 weeks 
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assessments. Therefore, the window for each scan will be the 7 days of the given week.  
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).  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.  An 
assessment must be done at the treatment completion visit, unless the most recent 
tumor assessment was completed 6 weeks before the treatment completion visit.  
Patients who discontinue study treatment for any reason other than disease progression 
will continue to undergo tumor response evaluations at disease follow-up visits 
approximately every 812 weeks and undergo bone scans (if indicated) approximately 
every 16 weeks until documented progressive disease per RECIST v1.1.
A documented standard-of-care tumor assessment performed within 28 days before 
Cycle 1, Day 1 (bone or head scans within 6 weeks prior to Cycle 1, Day 1) may be used 
for the screening assessment, provided it meets the following requirements:

CT scans are the preferred imaging modality for tumor assessments.  Tumor 
assessments should include a diagnostic quality, contrast-enhanced CT scan of the 
chest, abdomen, and pelvis at baseline.  CT scans of the neck should be included if 
clinically indicated.  To be suitable for RECIST assessments, CT scans should have 
a maximum thickness of 5 mm and no gaps. Subsequent tumor assessments 
should include CT scans of the chest, abdomen, and pelvis and other known sites of 
disease.  

In patients for whom a CT scan is contraindicated because of an allergy to 
IV radiographic contrast, both a CT scan of the chest without contrast and a MRI 
scan of the abdomen and pelvis with contrast are recommended.

MRI scans may be performed in lieu of CT scans.  However, an MRI scan of the 
chest may be performed only with the approval of the Sponsor.  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. 
4.5.6
Disease Assessments and Management for Cohort 3
4.5.6.1
Disease Status Assessment
Assessments of primary tumor and regional lymph nodes must be done by physical 
examination during screening, within 3 days prior to each treatment cycle, within 14 days 
prior to surgery, and at the study completion or early termination visit.  Clinical 
assessments of the breast and lymph nodes should be conducted in a consistent 
manner at each evaluation.  Assessments should include measurement of tumors in the 
breast, preferably through use of calipers or a ruler or tape measure.  The main purpose 
of performing physical examinations prior to each cycle is for patient safety and to rule 
out progressive disease that would lead to study treatment discontinuation. 


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Additional disease assessments (e.g., liver function tests, radiographs) may be 
performed when clinically indicated to exclude metastatic disease, as per current 
institutional practice.  Whenever possible, disease recurrence should be confirmed 
pathologically.
4.5.6.2
Ultrasound of Breast and Axilla 
Ultrasound of the breast and axilla is mandated during screening and within 14 days 
prior to surgery. It is strongly recommended that abnormal lymph nodes be marked by 
metallic indicator or other standard approach prior to neoadjuvant therapy.
4.5.6.3
Mammograms
A baseline bilateral mammogram is required.  The unaffected breast should be imaged 
within 60 days prior to initiation of study treatment.  The affected breast should be 
imaged within 28 days prior to initiation of study treatment.  Mammograms are optional
during neoadjuvant treatment (i.e., may be performed at the investigator’s discretion).  
Results from optional mammograms are not required to be entered into the eCRF.  
A bilateral mammogram is required within 14 days prior to surgery. 
4.5.6.4
Other Radiographic Assessments
Additional Breast Imaging
Additional breast imaging such as MRI is not mandated by the protocol but may be 
performed at the investigator's discretion per local practice.  If MRI is conducted, 
suggested timelines for MRI are within 28 days prior to treatment initiation, after 
completion of Cycle 2, and 14 days prior to surgery.  Results from optional MRIs or other 
breast imaging (other than mammograms) should be entered into the eCRF.  
Baseline Distant-Site Tumor Assessments
Baseline distant-site tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to initiation of treatment. 
Per NCCN guidelines, baseline staging procedures are based on clinical stage as 
outlined below: 

Stage II and Stage IIIA:  A bone scan should be performed in the presence of bone 
pain and/or elevated alkaline phosphatase.  A CT scan of the abdomen and pelvis 
should be performed in case of elevated alkaline phosphatase, abnormal liver 
function tests, abdominal symptoms, or abnormal physical examination.  A chest 
CT scan should be performed for all patients. 

Stage IIIB and Stage IIIC:  A bone scan and a CT scan of the chest, abdomen, and 
pelvis should be performed for all patients.
Additional radiographic modalities may be considered when clinically indicated to 
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4.5.6.5
Tumor Measurements
The tumor site must be marked with a radiopaque marker via radiographic guidance 
(e.g., ultrasound) prior to initiation of neoadjuvant therapy.  Tumors should be measured 
at screening and within 14 days prior to surgery.  Tumors should be accurately 
measured in at least one dimension (longest diameter to be recorded) through use of
conventional techniques (most commonly mammogram, but may be supplemented as 
clinically indicated with positron emission tomography [PET] scan, CT scan, magnetic 
resonance imaging (MRI), ultrasound, or X-ray).  If possible, these measurements 
should be conducted by the same assessor at screening and throughout the study.  
4.5.6.6
Lymph Node Assessments and Staging
Patients who have clinically negative axillary nodes by physical examination or by any 
radiographic imaging (e.g., ultrasound) at screening should be staged as node negative.  
Patients with clinically negative axillary nodes may undergo sentinel lymph node biopsy 
(SLNB) prior to neoadjuvant therapy if consistent with institutional guidelines. If SLNB is 
conducted, it is strongly recommended that more than one lymph node (two to three
minimum) be removed.  Patients with a positive SLNB result (involved with invasive 
carcinoma) are ineligible to participate in the study.
Patients who have enlarged or suspicious axillary nodes by physical examination or by 
any radiographic imaging (e.g., cortical thickness 2 mm) at screening should undergo 
fine-needle aspiration (FNA) or core-needle biopsy prior to enrollment.  Patients with 
a positive biopsy result (pN1N3c) should be staged as node positive, and patients with 
a negative (pN0) or equivocal (pNX) biopsy result should be staged as node negative 
regardless of any other clinical measurements (see Appendix 14).
Patients who have clinically negative axillary nodes but have clinically positive internal 
mammary, subpectoral infraclavicular, or supraclavicular lymph nodes are not required 
to undergo FNA or core-needle biopsy.
4.5.6.7
Surgical Plan and Procedures
Patients should be evaluated at screening by a surgeon with experience in breast cancer 
surgery.  The surgeon will propose a surgical treatment plan, which should be 
documented in the eCRF.  Patients should be reassessed after completion of 
neoadjuvant therapy (prior to surgery), and the surgeon will determine whether to 
proceed with the proposed plan or a modified plan.  The final surgical treatment plan
should be documented in the eCRF. 
Patients should undergo breast surgery between 2 and 6 weeks after the final dose of 
neoadjuvant therapy.  Pre-operative laboratory tests should be performed as per
institutional practice.  
All patients with T4 tumors should undergo axillary lymph node dissection (ALND) at the 
time of surgery, unless not aligned with institutional guidelines.  Patients without 


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T4 tumors who are node positive (pN1N3c) as determined by FNA or core-needle 
biopsy should undergo ALND at the time of surgery.  Patients without T4 tumors who are 
node negative as determined by physical examination or radiographic imaging, or by 
FNA or core-needle biopsy (pN0 or pNX), should undergo ALND or SLNB at the time of 
surgery (see Appendix 14).
For patients who undergo SLNB, it is strongly recommended that more than one lymph 
node (two to three minimum) be removed and that all patients with positive 
macrometastases in sentinel nodes undergo ALND regardless of the number of positive 
nodes.
4.5.6.8
Surgical Specimen Pathology
The primary efficacy endpoint (pCR) will be established via local review following 
completion of neoadjuvant therapy and surgery.  Guidelines regarding pathology 
specimen preparation, labeling, and review are outlined in the Pathology Manual.  The 
Sponsor will prospectively collect local pathology reports.
4.5.6.9
Confirmation of Disease Progression or Second Primary 
Cancer
During neoadjuvant treatment, diagnosis of disease progression or second primary 
cancer should be supported by clinical, laboratory, radiologic, and/or (preferably) 
histologic findings.  The designation of disease progression, whether local, regional, or 
distant, or a diagnosis of a second primary cancer can be made only when clinical, 
laboratory, radiologic, and/or histologic findings support the diagnosis.  
Disease follow-up will end at the study completion or early termination visit, scheduled to 
occur not more than 60 days after the final dose of study treatment (refer to schedule of 
activities in Appendix 3 for details)
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples should be drawn according to the schedule of activities (see
Appendix 1, Appendix 2, and Appendix 3) and within 48 hours prior to study drug 
administration at the clinic; results of hematology, chemistry, and pregnancy tests should 
be available to assess dosing decision. Screening local laboratory assessments 
obtained 48 hours before Cycle 1, Day 1 do not have to be repeated for Cycle 1, 
Day 1. 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: hemoglobin, hematocrit, WBC count with differential (i.e., must be 
sufficient for the determination of ANCs, lymphocytes), and platelet count


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
Fasting serum chemistry: glucose, plus the chemistry panel including BUN or urea, 
bicarbonate, creatinine, sodium, potassium, magnesium, calcium, phosphorus, 
albumin, total bilirubin, ALP (total ALP), AST, ALT, and LDH following 8-hour fast
For investigational sites in countries where bicarbonate may not be collected as 
part of the standard chemistry panel, bicarbonate will not be measured.

Fasting lipid profile:  total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, performed following 8-hour fast

HbA1c

Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4)

Amylase and lipase

Coagulation: PTT (or aPTT) and INR

Urinalysis (dipstick allowed): pH, specific gravity, glucose, protein, ketones, and 
blood; microscopic examination if clinically indicated

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening (must be performed within 48 hours prior to Cycle 1, Day 1).  
Urine/serum pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).

Screening viral serology:  HIV, HBsAg, total HBcAb, HCV antibody; additional tests 
for HBV DNA or HCV RNA will be required to confirm eligibility in patients with 
a positive antibody result.
The following samples will be sent to the Sponsor or a designee for analysis:

Fecal sample for calprotectin test (optional)

Plasma or serum samples for PK analysis through use of a validated assay

Serum samples for assessment of ADAs to atezolizumab through use of a validated 
assay

Blood samples for WGS (if approved locally) 

Most recently collected tumor tissue for determination of PD-L1 expression to 
determine eligibility for Cohort 4 (prior to enrollment) and for determination of 


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PIK3CA/AKT1/PTEN-altered tumor status (using the FMI NGS assay) and for 
exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 (for Cohorts 1 and 2) or 15 (for Cohorts 3 and 4) slides containing unstained, 
freshly cut, serial sections should be submitted prior to planned study 
enrollment date. 
Tumor tissue should be of good quality based on total and viable tumor content. 
Samples collected via resection, core-needle biopsy (at least three cores, 
embedded in a single paraffin block), or excisional, incisional, punch, or forceps 
biopsy are acceptable.  FNA (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, cell pellets 
from pleural effusion, and lavage samples are not acceptable.  Tumor tissue 
from bone metastases that are subject to decalcification is not acceptable.
For Cohorts 1, 2, and 4:  If a more recent submitted tissue specimen is 
determined to be unsuitable for required testing, a pretreatment tumor biopsy 
from a non-target lesion can be performed (minimum of three core biopsies is 
required for NGS evaluation), or older archival tissue may be submitted to 
obtain a valid result.
For Cohort 3:  If the submitted tissue is determined to be unsuitable for required 
testing, a pretreatment tumor biopsy can be performed (minimum of three core 
biopsies is required for NGS evaluation).

For Cohort 3: FFPE tumor tissue block with at least three core biopsies obtained 
during scheduled surgical resection for exploratory biomarker research

For patients in Cohorts 1, 2, and 4 who experience diarrhea:  stool sample for fecal 
calprotectin assay
Optional stool sample should be collected at each clinic visit where patient 
reports diarrhea.

Biomarker samples (blood, plasma, and tissue) for mandatory exploratory biomarker 
research may include, but are not limited to, the following assays and assay 
platforms:
Mutations and copy-number variations by NGS in tumor tissue and ctDNA
Expression analysis (e.g., RNASeq) of genes related to PI3K/Akt pathway 
activity, immune infiltration/activation, apoptosis, and breast cancer biology 
(i.e., intrinsic subtypes)
Immunohistochemistry-based analysis or quantitative digital 
immunohistochemistry of tumor suppressors, such as PTEN, and markers of 
immune infiltration and activation, such as CD8 and PD-L1
T, B, NK cells enumeration
Circulating cytokines


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NGS of tissue samples collected at baseline and at the time of disease progression 
(optional biopsy for Cohorts 1, 2, and 4; see Section 4.5.11.3) or surgery (Cohort 3) may 
be performed by Foundation Medicine.  If performed by Foundation Medicine, the 
investigator can obtain results from these analyses in the form of an NGS report, which 
is available upon request directly from Foundation Medicine at the time of study 
treatment discontinuation.  If allowed by local laws, the investigator may share and 
discuss the results with the patient, unless the patient chooses otherwise.  The 
Foundation Medicine NGS assay has not been cleared or approved by health 
authorities.  The NGS report is generated for research purposes and is not provided for 
the purpose of guiding future treatment decisions.  Results may not be available for 
samples that do not meet testing criteria.
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:

Plasma samples collected for PK or immunogenicity analysis may be needed for 
additional or immunogenicity characterization, PK and immunogenicity assay 
development and validation, and evaluation of ipatasertib metabolites or its 
disposition related markers; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Blood samples collected for WGS (if approved locally) will be stored until they are 
no longer needed or until they are exhausted.  However, the storage period will be 
in accordance with the Institutional Review Board/Ethics Committee 
(IRB/EC)-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).

Tumor tissue and plasma samples collected for biomarker research will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after final closure of the study database, whichever 
occurs first.  For patients who are not enrolled, the remaining archival tissue blocks 
(if applicable) will be returned to the site no later than 6 weeks after eligibility 
determination.  The submitted tissues may still be analyzed using FMI NGS assays 
and may be used for future development of diagnostic tests related to 
PIK3CA/AKT1/PTEN-altered status.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.


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Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of the analyses, data derived from WGS 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms and Cardiac Function Assessment
A cardiac function assessment by echocardiogram (ECHO) or multiple-gated acquisition
(MUGA) scan (ECHO preferred for Cohort 3) should be performed within 12 weeks of 
Day 1 of Cycle 1, with additional assessments performed for Cohort 3 on Day 1 of 
Cycle 3 and at the study completion or early termination visit.  If the LVEF result as 
assessed by either of these imaging modalities is felt to be inconsistent with the clinical 
picture, the investigator may choose an alternative modality (i.e., cardiac MRI), if this is 
consistent with local standard practice.  The same technique used for baseline cardiac 
evaluation should be used throughout the study.
Single 12-lead ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1, Appendix 2, and Appendix 3) and may be 
obtained at unscheduled timepoints as indicated. In Cohort 3, a 12-lead ECG will be 
obtained during screening, at each doxorubicin administration (Days 1 and 15 of 
Cycles 12), at study completion/early termination visit, and as clinically indicated.  
Screening ECG assessments obtained 48 hours before Day 1 of Cycle 1 do not have to 
be repeated on Day 1 of Cycle 1.  All ECG recordings must be performed using a 
standard high-quality, high-fidelity digital electrocardiograph machine equipped with 
computer-based interval measurements.  Lead placement should be as consistent as 
possible.  ECG recordings must be performed after the patient has been resting in a 
supine position for at least 10 minutes.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 


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for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made, as described in Sections 5.2.1 and 4.6.1.  The 
investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia).
4.5.9
Mandatory Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
to identify germline mutations and somatic mutations that are predictive of response to 
study drug, are associated with progression to a more severe disease state, are 
associated with acquired resistance to study drug, are associated with susceptibility to 
developing adverse events, or can increase the knowledge and understanding of 
disease biology.  The blood samples may be sent to one or more laboratories for 
analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's IRB/EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS sampling, this section 
of the protocol (Section 4.5.9) will not be applicable at that site.
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.


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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
4.5.10
Post-Treatment Follow-Up for Cohorts 1, 2, and 4
At post-treatment follow-up visit, survival follow-up information, subsequent treatment 
and outcome, and patient-reported outcomes (PROs) will be collected via telephone 
calls, patient’s medical records, and/or clinic visits approximately every 3 months until
death, loss to follow-up, or study termination by Sponsor.  All patients will be followed for 
survival information unless the patient requests to be withdrawn from study survival 
follow-up; this request must be documented in the source file and signed by the 
investigator. 
For patients who discontinue treatment without evidence of disease progression per 
RECIST v1.1, in addition to survival follow-up, patients will be followed every 
812 weeks for tumor assessments (disease follow-up clinic visits; see Appendix 1 and
Appendix 2) until documented progression per RECIST v1.1, elective withdrawal from 
the study, or study completion or termination.  Images for tumor assessments will be 
collected to enable retrospective blinded independent central review when needed.
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to PI3K/Akt pathway activity, 
immune infiltration/activation, apoptosis, and breast cancer biology:

Leftover blood, serum, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides)

For Cohorts 1, 2, and 4:  Optional tumor biopsy tissues obtained at the time of 
progression (e.g., at the study treatment discontinuation visit), if deemed clinically 
feasible 
If performed, these biopsies should be performed within 6 weeks after 
progression or prior to the next anti-cancer therapy, whichever is sooner.  
Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy of the growing 
lesion(s) are preferred.
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, whole exome sequencing (WES), NGS, or other genomic 
analysis methods.  
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS, WES, and NGS provide a comprehensive characterization of the genome and 
exome, and, along with clinical data collected in this study, may increase the opportunity 
for developing new therapeutic approaches.  Data will be analyzed in the context of this 
study but will also be explored in aggregate with data from other studies.  The availability 
of a larger dataset will assist in identification of important pathways, guiding the 
development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.5.11.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
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 specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her specimens, the investigator must inform the Medical Monitor in 


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writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study CO40151 does not, by itself, constitute withdrawal of specimens from the 
RBR.  Likewise, a patient's withdrawal from the RBR does not constitute withdrawal from 
Study CO40151.
If a patient wishes to withdraw consent to the testing of his or her specimens 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
4.5.11.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment for any of the following:

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 the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Withdrawal of consent from the study treatment

Pregnancy

Use of an anti-cancer therapy not required per protocol

Loss of clinical benefit per Investigator’s assessment according to RECIST v1.1,
unless a patient has consented to treatment beyond progression

Confirmation of disease progression or disease recurrence


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients will return to the clinic for a treatment discontinuation visit 28 (3) days after the 
last dose of study treatment or prior to initiation of new anti-cancer therapy, whichever is 
sooner (see Appendix 1, Appendix 2, and Appendix 3 for additional details).
After treatment discontinuation, patients will return to the clinic for disease follow-up 
(if patient did not discontinue due to disease progression per RECIST v1.1), and 
information on survival follow-up will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months until approximately 2 years 
after enrollment (unless the patient withdraws consent from the study or the Sponsor 
terminates the study).  
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  Patients should be asked to return to the clinic for a study treatment 
discontinuation visit (if applicable). The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.  If a patient requests to be withdrawn 
from the study, this request must be documented in the source documents and signed 
by the investigator.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Ipatasertib is not currently approved for any indication, and clinical development is 
ongoing.  The safety plan for patients in this study is based on clinical experience with 
ipatasertib in completed and ongoing studies.
Measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including investigator’s 
assessment of the nature, frequency, and severity of adverse events, as well as 
expedited reporting of protocol-defined adverse events of special interest regardless of 
seriousness.  Vital signs and relevant laboratory values will be monitored at baseline and 
during the study. Administration of atezolizumab 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 
prophylaxis (for diarrhea), and criteria for dose modification (interruption, dose reduction 
or discontinuation) for the management of specific adverse events attributable to 
ipatasertib, atezolizumab, and paclitaxel or nab-paclitaxel, are summarized in
Section 5.1.9.4).  The instructions provided are intended to serve as a guideline to 
improve safety and tolerability for patients to continue receiving ongoing treatment.  
Suggested dose reductions for ipatasertib and for paclitaxel or nab-paclitaxel are listed 
in Table 3, Table 4, and Table 5. There is no dose reduction for atezolizumab allowed.  
Dose reductions for doxorubicin and/or cyclophosphamide are permitted at the
investigator's discretion.  Management guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section 5.1.9.4 and Appendix 13.
The Study Team (see Internal Safety Monitoring, Section 3.1.11) will be responsible for 
the ongoing monitoring of patient safety in the study. 


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5.1.1
Risks Associated with Ipatasertib 
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash. Ipatasertib's potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.
Refer to Section 6 of the Ipatasertib Investigator's Brochure for a detailed description of 
anticipated safety risks for Ipatasertib. 
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs,
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
hypophysitis, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, myositis, nephritis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome
(MAS) (considered to be potential risks for atezolizumab).  Refer to Appendix 13 of the 
protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.
5.1.3
Risks Associated with Combination Use of Atezolizumab and 
Ipatasertib
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and ipatasertib: gastrointestinal, dermatologic, 
hepatic, pulmonary, and hyperglycemia events.
5.1.4
Risks Associated with Ipatasertib in Combination with 
Paclitaxel
Ipatasertib in combination with paclitaxel has been administered to 61 patients with 
cancer in Study GO29227 (LOTUS).  Adverse events related to ipatasertib/placebo 
whose incidences were higher by 10% in patients receiving ipatasertibpaclitaxel 
versus placebopaclitaxel were diarrhea (93.4% vs. 19.4%) and nausea (41.0% vs. 
19.4%).  The most frequent Grade3 adverse events (reported in 5% of patients in 
either treatment arm) in patients in the ipatasertibpaclitaxel arm versus
placebopaclitaxel arm were diarrhea (14 patients [23.0%], all Grade 3, vs. 0 patients), 
neutropenia (6 patients [9.8%] vs. 1 patient [1.6%]), decreased neutrophil count 
(5 patients [8.2%] vs. 4 patients [6.5%]), and fatigue (2 patients [3.3 %] vs. 4 
patients [6.5%]), respectively.
The incidence of overall neutropenia in the LOTUS Study was similar in both arms 
(34% in the ipatasertibpaclitaxel arm vs. 39% in the placebopaclitaxel arm), but 


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Grade 3 neutropenia, analyzed by grouped terms of similar medical concept, was 
higher in the ipatasertibpaclitaxel arm (18% vs. 8%).  Thus, for recurrent Grade 3
neutropenia, ipatasertib should be reduced by one dose level when treatment is 
restarted (refer to the management guidelines in Section 5.1.9.4. 
Refer to the Ipatasertib Investigator’s Brochure for further information regarding the 
nonclinical and clinical safety evaluation of ipatasertib as a single agent and in 
combination with chemotherapy.
5.1.5
Risks Associated with Paclitaxel
In prior clinical trials of paclitaxel, the following safety signals associated with paclitaxel 
were identified:  nausea, vomiting, diarrhea, stomatitis, peripheral neuropathy, 
hypersensitivity reactions, and hematologic toxicity.  
To be eligible for the current study, patients must have adequate hematologic function, 
as manifested by measurements of complete blood cell counts.  Furthermore, blood cells 
will be assessed prior to each treatment cycle. 
Adverse events related to paclitaxel in the LOTUS study (GO29227) whose incidences 
were higher by 10% in patients receiving ipatasertibpaclitaxel versus 
placebopaclitaxel were diarrhea (78.7% vs. 12.9%), nausea (41.0% vs. 24.2%), and 
peripheral sensory neuropathy (26.2% vs. 16.1%).  Refer to the management guidelines 
in Section 5.1.9.4 for these adverse events.
Patients will be monitored for other paclitaxel-associated adverse events as outlined in 
this section.  For more details regarding the safety profile of paclitaxel, see the paclitaxel 
prescribing information.
5.1.6
Risks Associated with Nab-Paclitaxel
In clinical studies and post-marketing experience, nab-paclitaxel has been associated 
with alopecia, myelosuppression (primarily neutropenia, anemia, thrombocytopenia), 
peripheral neuropathy, cranial nerve palsies, hypersensitivity reactions, pneumonitis, 
gastrointestinal events (i.e., nausea, vomiting, diarrhea), myalgia, arthralgia, 
cardiotoxicity (myocardial disorders, cardiac failure, angina, tachycardia, ventricular 
arrhythmia), cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal 
necrolysis, sepsis, infusion site reactions/extravasation, hepatic toxicity (drug-induced 
liver injury), acute renal failure, hemolytic-uremic syndrome, and drug-induced lupus 
erythematous.
Patients will be monitored for nab-paclitaxel−related adverse events, including 
hematologic, gastrointestinal, hepatic toxicities, and peripheral neuropathy.
For more details regarding the safety profile of nab-paclitaxel, refer to the local 
prescribing information.


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5.1.7
Risks Associated with Doxorubicin
Doxorubicin is known to cause serious cardiomyopathy; arrhythmias, including 
life-threatening arrhythmias; increased incidence of secondary acute myelogenous 
leukemia and myelodysplastic syndrome; extravasation and tissue necrosis; severe 
myelosuppression resulting in serious infection, septic shock, need for transfusions, 
hospitalization, and death; tumor lysis syndrome; radiation sensitization and radiation 
recall; embryofetal toxicity; alopecia; and vomiting, nausea, and other gastrointestinal 
effects.
Patients treated with doxorubicin are at risk of developing cumulative dose-related 
myocardial damage.  Significant cardiac events, including acute heart failure and LVEF 
of 40%, have been observed in clinical trials of doxorubicin.  Cardiomyopathy may 
develop during treatment or up to several years after completion of treatment.  There is 
an additive or potentially synergistic increase in the risk of cardiomyopathy in patients 
who have received radiotherapy to the mediastinum or concomitant therapy with other 
known cardiotoxic agents such as cyclophosphamide.  Patients must meet specified 
LVEF requirements to be included in this study (see Section 4.1.2).  Left ventricular 
function will be monitored by measurement of ejection fraction through use of ECHO or 
MUGA scans as described in Section 4.5.8 and the schedule of activities (see
Appendix 3).
Refer to the doxorubicin local prescribing information for more details regarding the full 
safety profile of doxorubicin, including boxed warnings and contraindications.
5.1.8
Risks Associated with Cyclophosphamide
Cyclophosphamide has been associated with myelosuppression sometimes leading to 
severe immunosuppression and infections that can be serious and sometimes fatal; 
hemorrhagic cystitis, pyelitis, ureteritis, and hematuria; myocarditis, myopericarditis, 
pericardial effusion, arrhythmias, and congestive heart failure; pulmonary toxicity 
including pneumonitis, pulmonary fibrosis, and pulmonary veno-occlusive disease 
leading to respiratory failure; secondary malignancies; veno-occlusive liver disease; 
embryofetal toxicity; alopecia; and nausea, vomiting, and diarrhea.  
Refer to the cyclophosphamide local prescribing information for more details regarding 
the full safety profile of cyclophosphamide, including boxed warnings and 
contraindications.


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5.1.9
Management of Patients Who Experience Specific Adverse 
Events 
There will be no dose modifications for atezolizumab in this study.  
Patients may hold ipatasertib for up to 4 consecutive weeks (approximately 
28 consecutive days) in order to recover from toxicity or an adverse event related to the 
study drug.  If any of the three study treatments are discontinued, the other study 
treatments may be continued independent of each other (i.e., if the ipatasertib is 
discontinued at any time during the study, patients may have the option of continuing on 
study with atezolizumab and chemotherapy or atezolizumab alone or chemotherapy 
alone).
If the patient does not tolerate the QD dosing of ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
For Cohorts 1, 2, and 4 and for Arms G1 and G2 of Cohort 3, the dose of ipatasertib can 
be reduced by 100 mg once a day (one dose level) decrements up to two times for 
management of drug-related toxicities (i.e., from 400 to 300 mg and then from 300 to 
200 mg) as outlined in Table 3.  If further dose reduction is indicated after two dose 
reductions for a specified drug-related adverse event, the patient must discontinue 
ipatasertib but may continue treatment with atezolizumab and chemotherapy or 
atezolizumab alone or chemotherapy alone at the investigator’s discretion.
Table 3
Suggested Dose Reductions for Ipatasertib:  Cohorts 1, 2, and 4 
and Arms G1 and G2 of Cohort 3
Dose Level
Ipatasertib
Starting dose
400 mg
First dose reduction
300 mg
Second dose reduction
200 mg
Third dose reduction
Discontinue a
a If the patient continues to experience 
specified drug-related adverse events 
after the second reduction, the 
treatment should be discontinued.
For Arms F1 and F2 of Cohort 3, the dose of ipatasertib can be reduced by 100 mg once 
a day (one dose level) decrements up to one time (i.e., from 300 to 200 mg) during 
Cycles 1 and 2 and up to two times (i.e., from 400 to 300 mg and then from 300 to 
200 mg) during Cycles 35 for management of drug-related toxicities as outlined in
Table 4.  If further dose reduction is indicated after one dose reduction during Cycles 1 
and 2 or after two dose reductions during Cycles 35 for a specified drug-related 
adverse event, the patient must discontinue ipatasertib but may continue treatment with 


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atezolizumab and chemotherapy or atezolizumab alone or chemotherapy alone at the 
investigator’s discretion.  If a patient in Arm F1 or F2 is experiencing a drug-related 
toxicity at the start of Cycle 3, the ipatasertib dose can be maintained at 300 mg rather 
than escalating to 400 mg.
Table 4
Suggested Dose Reductions for Ipatasertib:  Arms F1 and F2 of 
Cohort 3
Cycles
Dose Level
Ipatasertib
Cycles 1 and 2
Starting dose
300 mg
First dose reduction
200 mg
Second dose reduction
Discontinue a
Cycles 35
Starting dose
400 mg
First dose reduction
300 mg
Second dose reduction
200 mg
Third dose reduction
Discontinue b
a If the patient continues to experience specified drug-related 
adverse events after the first reduction in Cycles 1 and 2, the 
treatment should be discontinued.
b If the patient continues to experience specified drug-related 
adverse events after the second reduction in Cycles 35, the 
treatment should be discontinued.
Dose modifications for paclitaxel or nab-paclitaxel will be performed as clinically 
appropriate based on the investigator’s medical judgment; details in this section can be 
used as guidance, however, only the specific dose levels shown should be used 
(Table 5).  Reasons for dose modifications (interruption or reduction) and 
discontinuation, the supportive measures taken, and the outcome will be documented in 
the patient's chart and recorded in the eCRF. Reasons for not adhering to the following 
guidance should also be documented in the patient’s chart. Suggested dose reductions 
for paclitaxel and nab-paclitaxel are provided in Table 5. 
Table 5
Suggested Dose Reductions for Paclitaxel and Nab-Paclitaxel
Dose Level 
Paclitaxel a
Nab-paclitaxel
Starting dose
80 mg/m2
100 mg/m2
First dose reduction
65 mg/m2
75 mg/m2
Second dose reduction
Discontinue
50 mg/m2
Third dose reduction
Not Applicable
Discontinue
a If the patient continues to experience specified drug-related adverse events 
after the first dose reduction of paclitaxel, the treatment should be 
discontinued.


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For guidelines regarding dose modifications for doxorubicin- or 
cyclophosphamide-associated toxicities, refer to the local prescribing information for 
each agent. 
5.1.9.1
Treatment Interruption for Toxicities
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks, the patient will be discontinued from atezolizumab.  However, atezolizumab 
may be withheld for 12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for 12 weeks if 
the Medical Monitor agrees that the patient is likely to derive clinical benefit.  
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) with Medical Monitor’s approval.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption. Following discussion with 
the Medical Monitor, the investigator may determine the acceptable length of treatment 
interruption based on sound medical and clinical judgment, and taking into consideration 
the overall benefitrisk for the patient.
Ipatasertib treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered to 10 mg/day oral prednisone or equivalent before 
ipatasertib can be resumed, if clinically appropriate.  If ipatasertib is withheld for 
28 days, the patient will be discontinued from ipatasertib.  If the investigator believes 
the patient is likely to derive clinical benefit and the Medical Monitor is in agreement, 
ipatasertib treatment can be resumed after being withheld for 28 days. Steroids used 
as prophylaxis (i.e., prior to scans, as protocol-directed rash prophylaxis, or prior to 
taxane or atezolizumab) do not require holding of ipatasertib.  Steroids used on a single 
day to manage IRRs or allergic reactions similarly do not require holding of ipatasertib.
If either atezolizumab or ipatasertib is discontinued, the other drug along with 
chemotherapy can be continued if the patient is likely to derive clinical benefit, as 
determined by the investigator and following discussion with the Medical Monitor.
For guidelines regarding treatment interruption rules for doxorubicin- or 
cyclophosphamide-associated toxicities, refer to the local prescribing information for 
each agent. 
5.1.9.2
General Guidelines
General guidelines for dosage/schedule modification are summarized as follows:

If any treatment component is interrupted (dose hold), the study cycle day count 
continues and does not shift (i.e., every cycle contains exactly 28 days).


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
If ipatasertib treatment is interrupted, atezolizumab and chemotherapy treatment 
should continue as applicable.

If chemotherapy treatment is interrupted, consider delaying the ipatasertib and 
atezolizumab treatment concurrently for up to 7 days (i.e., shifting the 7 days-off 
week for ipatasertib so that 21 daily doses in every 28 days is maintained), at the 
discretion of the investigator. The interrupted dose of chemotherapy may be 
administered later in the same cycle, ideally on Day 22, taking into consideration the 
chemotherapy dosing starting on Day 1 of the next cycle.

Given the complexity of this triple drug combination’s schedule, although there are 
pre-specified windows allowed around dosing days, it is strongly suggested that 
taxane chemotherapy administration only be on Day 1, Day 8, Day 15, (or Day 22 
as a day to compensate for missed chemotherapy on any of the 3 prior days), and 
that atezolizumab be given on Day 1 or Day 15.  If dosing is not feasible on those 
days, it is acceptable and encouraged to dose on the next suggested day using 
above guidance.  Sites are encouraged to reach out to the Medical Monitor for any 
guidance on this matter.  

If toxicity causes chemotherapy treatment to be omitted, clinic visits (and study 
procedures) associated with the administration of chemotherapy in that cycle may 
also be omitted.  However, laboratory assessments and clinical visits should be 
scheduled as needed for follow-up of adverse events.  In addition, tumor 
assessments, as outlined in the schedule of activities, 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 (other than Cycle 1 in Cohort 2, which contains 35 days).

For any concomitant conditions at baseline, dose modifications may apply according 
to the shift in toxicity grade, if the investigator deems it appropriate.  For example, if 
a patient has Grade 1 asthenia at baseline that increases to Grade 2 during 
treatment, this change may be considered a shift of one grade and may be treated 
as Grade 1 toxicity for dose-modification purposes, if medically appropriate.

For toxicities assessed by the investigator to be unrelated to study treatment and 
unlikely to develop into serious or life-threatening events, treatment may be 
continued at the same dose without reduction or interruption.

Dose reductions or interruptions may not be required for anemia (non-hemolytic) if 
satisfactorily managed by transfusions.

If any observed toxicity is attributable to only one drug as assessed by the 
investigator, the dose of the other drug(s) may not require modification.

Dose modifications for isolated abnormal hematologic laboratory values will be 
based on hematologic parameters at the start of a treatment cycle.

Patients who require chemotherapy dose reductions and tolerate the reduced dose 
for more than 28 days may be allowed to increase back to a 100% dose at the 
treating physician's discretion (no specific guidance is provided for ipatasertib 
re-escalation, as it is not permitted).


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
Chemotherapy may be interrupted to manage toxicity.  A dosing gap of up to 
4 consecutive weeks (approximately 28 days) is permitted.  
Any dose hold for longer than 4 weeks for a treatment-related adverse event will require 
permanent discontinuation of the attributable treatment component and per specific 
adverse event management guidelines in Section 5.1.9.4.  As applicable, patients should 
continue treatment with remaining study drugs (after discussion with the Medical 
Monitor).
5.1.9.3
Infusion-Related Reactions to Paclitaxel 
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 per institutional 
guidelines.  
Patients should be monitored during paclitaxel administration per institutional policies.  
Patients may receive anti-emetic and other prophylactic treatments (e.g., IV infusions of 
calcium and magnesium to try to decrease any potential peripheral neuropathy) 
according to institutional and/or local standards and per manufacturer’s instructions.
5.1.9.4
Management Guidelines for Adverse Events
Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 13, Table 6, and prescribing information, as outlined below:

Appendix 13 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated adverse events.  It is 
recommended that atezolizumab be withheld or discontinued per the guidelines in
Appendix 13 and that ipatasertib be withheld or discontinued per the guidelines in 
Table 6.

Table 6 provides guidelines for the management of patients who experience the 
following potential overlapping toxicities for atezolizumab and ipatasertib:  
gastrointestinal, dermatologic, hepatic, pulmonary, and hyperglycemia events.  It is 
recommended that study treatments be withheld or discontinued per the guidelines 
in Table 6.  For these potential overlapping toxicities, guidelines in Table 6 should 
be followed instead of guidelines in Appendix 13.

Table 6 provides guidelines for the management of patients who experience 
adverse events associated with ipatasertib.  It is recommended that atezolizumab 
and/or ipatasertib be withheld or discontinued per the guidelines in Table 6.

Guidelines for the management of patients who experience chemotherapy-related 
adverse events are found in the local prescribing information for each agent.
For cases in which management guidelines are not covered in Table 6 or Appendix 13, 
patients should be managed and treatments should be withheld or discontinued as 
deemed appropriate by the investigator according to best medical judgment.


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On the planned day of treatment, chemotherapy may be administered only if all of the 
following criteria are met:

ANC 1500/L

Platelet count 100,000/L

Grade 2 clinically significant chemotherapy-related gastrointestinal toxicity


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab
Event
Action to Be Taken
IRRs and 
anaphylaxis
Follow guidelines for atezolizumab in Appendix 13.
Withhold ipatasertib.
For anaphylaxis precautions, see Appendix 12.
For severe hypersensitivity reactions, permanently discontinue atezolizumab and ipatasertib.
Gastrointestinal 
toxicity
General guidance
For all patients, dispense loperamide 2 mg BID as prophylaxis for diarrhea in the first cycle.
After the first cycle, continue this dosing for the remainder of the study as clinically indicated.
Thoroughly evaluate all events of diarrhea or colitis for more common etiologies other than drug-induced 
effects.
For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal agent(s) and/or with dose 
hold of ipatasertib, 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 CRP, platelet count, or bandemia), perform sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.
Administer anti-diarrheal agents and other supportive care per institutional guidelines or per suggested 
supportive care outlined below:
Medication
As early as possible, institute treatment modifications for diarrhea (any grade) when it occurs.  Guidelines for 
treatment of diarrhea, following the prophylactic dose of loperamide 4 mg initial daily dose, include use of 
loperamide 2 mg after each loose watery stool, up to the maximum total dose of 16 mg/day or per institutional 
guidelines and standard of care, including, but not limited to, additional therapy with Lomotil(diphenoxylate 
and atropine), codeine, or octreotide.  Please note that loperamide prophylaxis alone is not sufficient if diarrhea 
occurs despite prophylaxis; if diarrhea occurs while on loperamide prophylaxis, loperamide use should be 
increased as noted above, or additional medications added.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
General guidance
(cont.)
Medication (cont.)
-
To minimize duration of diarrhea, encourage taking ipatasertib 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 by one level at a time (i.e., 400 to 300 mg; 300 to 200 mg) as outlined in
Table 3 and Table 4.  If Grade 2 diarrhea persists following dose reductions of ipatasertib to 200 mg daily 
and with maximum treatment for diarrhea, discontinue ipatasertib.
Oral Supplementation
-
Initiate potassium and/or magnesium if serum levels are less than the lower limit of normal.
-
Consider rehydration therapy with oral electrolyte solution for Grade 1 diarrhea or vomiting.
Dietary Modifications
-
Instruct patient to eat small meals and eliminate lactose-containing products from diet.
-
Suggest diet of bananas, rice, apples, and toast, while avoiding fiber from vegetables and other fruits.
-
Encourage adequate hydration with salt-containing liquids (e.g., broth, sports drinks such as Gatorade).
Diarrhea, Grade 1 
Continue atezolizumab and ipatasertib.
Initiate supportive care and monitor patient closely.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis if appropriate.
Upon resolution, loperamide prophylaxis can be considered and continued as clinically indicated, if allowed by 
local guidance.  Please note, loperamide prophylaxis is to be taken throughout at least the first cycle.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Diarrhea, Grade 2 
Withhold atezolizumab and ipatasertib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDS) while investigating etiology.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis, including biopsy if 
appropriate.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and contact Medical Monitor. a, b, c
Interrupt ipatasertib until diarrhea improves to Grade 1 or better.  Ipatasertib can be resumed at the same dose 
or one dose lower per investigator's evaluation upon improvement to Grade 1 or better.
Reduce ipatasertib by one (or one additional) dose level (see Table 3 and Table 4) for recurrent Grade 2 
diarrhea.
When study treatment is resumed, loperamide prophylaxis should also be resumed and continued as clinically 
indicated, if allowed by local guidance.  Please note, loperamide prophylaxis is to be taken throughout at least 
the first cycle.
Diarrhea, Grade 3
Withhold ipatasertib, atezolizumab, and taxanes.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while investigating etiology.
Investigate etiology, referring patient to GI specialist for evaluation of possible colitis, including biopsy if 
appropriate.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at a fixed dose.  If not, 
permanently discontinue atezolizumab and contact Medical Monitor. a, b, c
Interrupt ipatasertib and taxanes until diarrhea improves to Grade 1 or better.  Ipatasertib should be reduced by 
one dose level (see Table 3 and Table 4) when treatment is restarted.  Consider resuming taxanes at the same 
dose.
For recurrent Grade 3 diarrhea, reduce ipatasertib dose by one additional dose level (see Table 3 and Table 4).  
Consider reducing taxanes by one dose level when treatment is restarted (see Table 5).
When study treatment is resumed, loperamide prophylaxis should also be resumed and continues as clinically 
indicated, if allowed by local guidance.  Please note, loperamide prophylaxis is to be taken throughout at least 
the first cycle.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Diarrhea, Grade 4 
Permanently discontinue atezolizumab and ipatasertib 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 taxanes until diarrhea improves to Grade 1 or better.  Consider resuming taxanes by one dose level 
lower (see Table 5) or discontinuing taxanes per investigator's discretion.
Colitis, Grade 1
Continue atezolizumab and ipatasertib.
Initiate supportive care and monitor patient closely. 
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy if symptoms persist for 5 days.
Colitis, Grade 2
Withhold atezolizumab and ipatasertib.
Initiate supportive care and monitor patient closely.
Discontinue medications that may exacerbate colitis (e.g., NSAIDs).
Refer patient to GI specialist for evaluation and confirmatory biopsy.
For recurrent events or events that persist 5 days, initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and ipatasertib and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib with dose reduced by one level.  If not, 
permanently discontinue ipatasertib.
Colitis, Grade 3
Withhold atezolizumab and ipatasertib.
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.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Colitis, Grade 3
(cont.)
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and ipatasertib and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib with dose reduced by one level.  If not, 
permanently discontinue ipatasertib.
Colitis, Grade 4
Permanently discontinue atezolizumab and ipatasertib 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.
Endocrine disorders
Asymptomatic 
hypothyroidism
Follow guidelines for atezolizumab in Appendix 13.
Continue ipatasertib.
Symptomatic 
hypothyroidism
Follow guidelines for atezolizumab in Appendix 13.
Continue ipatasertib.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:
Follow guidelines for atezolizumab in Appendix 13.
Continue ipatasertib.
TSH 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism
Follow guidelines for atezolizumab in Appendix 13.
Continue ipatasertib.
For life-threatening immune-mediated hyperthyroidism, withhold ipatasertib.  If event becomes clinically 
manageable within 28 days, resume ipatasertib with dose reduced by one level (see Table 3 and Table 4).  If 
not, permanently discontinue ipatasertib.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Symptomatic adrenal 
insufficiency, 
Grade 2, 3, or 4
Follow guidelines for atezolizumab in Appendix 13.
Continue ipatasertib.
Hyperglycemia, 
Any Grade
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, HbA1c, C-peptide levels, anti-islet antibodies, and anti-GADD45 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 and ipatasertib.
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 and ipatasertib 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 should be reduced by one dose 
level (refer to Table 3 and Table 4).
If the patient previously has not been receiving any oral anti-diabetic medication, ipatasertib may be resumed at 
the previous dose level with initiation of oral anti-diabetic medication.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Hyperglycemia,
glucose value 
250500 mg/dL 
(13.927.8 mmol/L)
Withhold atezolizumab and ipatasertib 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 monitoring.
If the patient is already on an oral anti-diabetic medication, ipatasertib 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 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 should be reduced by one dose level (see 
Table 3 and Table 4) when treatment is restarted.
Resume atezolizumab when symptoms resolve and glucose levels are stable.
Hyperglycemia, 
glucose value 
500 mg/dL 
(27.8 mmol/L); 
life-threatening 
consequences
Withhold atezolizumab and ipatasertib 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 by one dose level (see Table 3 and Table 4)
when treatment is restarted.
Resume atezolizumab when symptoms resolve and glucose levels are stable.
If glucose value 500 mg/dL recurs, permanently discontinue ipatasertib and atezolizumab and contact Medical 
Monitor.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (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.
Pulmonary event, 
Grade 1
Continue atezolizumab and ipatasertib.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
Pulmonary event, 
Grade 2
Withhold atezolizumab and ipatasertib.
Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy or BAL. 
If bronchoscopy is consistent with immune-mediated etiology, initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and ipatasertib and contact Medical Monitor. a, b, c
If event resolves to Grade 1 or better within 28 days, resume ipatasertib at current dose.
For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary event, 
Grade 3 or 4
Permanently discontinue atezolizumab and ipatasertib 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 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.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Hepatic events
General guidance
When the cause of the hepatic event is unclear, suggested workup may include a reviewing of symptoms, 
concomitant drug use (including non-prescription medications and herbal and dietary supplement preparations), 
alcohol use, recreational drug use, and special diets; ruling out autoimmune or alcoholic hepatitis, non-alcoholic 
steatohepatitis, hypoxic/ischemic hepatopathy, biliary tract disease, and acute viral hepatitis types A, B, C, D, 
and E; reviewing exposure to environmental chemical agents; and conducting additional tests to evaluate liver 
function (e.g., INR, direct bilirubin).
AST/ALT ULN to 
3ULN with total 
bilirubin 2ULN
Continue atezolizumab and ipatasertib.
Monitor LFTs d until values resolve to within normal limits or to baseline values.
AST/ALT 3ULN 
to5ULN with total 
bilirubin 2ULN
Continue atezolizumab and ipatasertib.
Monitor LFTs d every 4872 hours until decreasing and then weekly until return to baseline.  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 elevations of up to 5ULN); monitoring of LFTs for such patients may be as per clinical judgment until 
a threshold of ALT/AST 5ULN.
Consider patient referral to a hepatologist and liver biopsy.
Suspected immune-mediated events of 5 days' duration:
Consider withholding atezolizumab.
Consider initiation of treatment with 12 mg/kg/day oral prednisone or equivalent.
If atezolizumab is withheld and event resolves to AST/ALT 3ULN with total bilirubin 2ULN within 
12 weeks, resume atezolizumab at fixed dose.  If not, permanently discontinue atezolizumab and ipatasertib and 
contact Medical Monitor. a, b, c
AST/ALT 5ULN to 
10ULN with total 
bilirubin ULN to 
2ULN
Continue atezolizumab and ipatasertib.
Monitor LFTs d every 4872 hours until decreasing and then weekly until return to baseline.
Consider patient referral to hepatologist and liver biopsy.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
AST/ALT 5ULN to 
10ULN with total 
bilirubin ULN to 
2ULN
(cont.)
Suspected immune-mediated events:
Withhold atezolizumab.
Consider initiation of treatment with 12 mg/kg/day oral prednisone or equivalent.
If corticosteroids are initiated and event does not improve within 48 hours, consider adding an 
immunosuppressive agent.
If event resolves to AST/ALT 3ULN with total bilirubin 2ULN within 12 weeks, resume atezolizumab at fixed 
dose.  If not, permanently discontinue atezolizumab and ipatasertib and contact Medical Monitor. a ,b, c
AST/ALT ULN to 
3ULN with total 
bilirubin 2ULN
Investigate causes for elevated bilirubin and initiate treatment as indicated per institutional guidelines.
Use best medical judgment when determining whether to continue study treatment.
AST/ALT 3ULN to 
10ULN with total 
bilirubin 2 ULN
Withhold atezolizumab and ipatasertib.
Monitor LFTs d every 4872 hours until decreasing and then monitor weekly.
Refer patient to hepatologist and consider liver biopsy.
Consider initiation of treatment with 12 mg/kg/day oral prednisone or equivalent.
If corticosteroids are initiated and event does not improve within 48 hours, consider adding an 
immunosuppressive agent.
If event resolves to AST/ALT 3ULN with total bilirubin 2ULN within 12 weeks, resume atezolizumab at fixed 
dose.  If not, permanently discontinue atezolizumab and contact Medical Monitor. a, b, c
If event resolves to AST/ALT 3ULN with total bilirubin 2ULN within 28 days, resume ipatasertib with dose 
reduced by one level (see Table 3 and Table 4).  If not, permanently discontinue ipatasertib.
Permanently discontinue atezolizumab and ipatasertib for life-threatening hepatic events and contact the Medical 
Monitor.
AST/ALT 10ULN
Permanently discontinue atezolizumab and ipatasertib and contact Medical Monitor. c
Monitor LFTs d every 4872 hours until decreasing and then monitor weekly.
Refer patient to hepatologist 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.
If event resolves to AST/ALT 3ULN with total bilirubin 2ULN, taper corticosteroids over 1 month.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Dermatologic toxicity
General guidance
Ipatasertib 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 are 
shown below
Consider having a dermatologist evaluate persistent and/or severe rash or pruritus.
Antihistamine prophylaxis is strongly recommended for 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 taxane infusion if the taxane premedication 
already includes an antihistamine.
First 28-day cycle of triplet study drug combination: On days when patients will receive atezolizumab (typically 
Day 1 and Day 15), patients should receive at least 10 mg prednisone (or equivalent) as premedication prior to 
atezolizumab, followed by 10 mg/day prednisone (or equivalent) for 24 consecutive days thereafter, unless 
contraindicated.  If institutional practice prior to taxane is to give at least 10 mg/day prednisone on the day of 
taxane, then the additional 10 mg prophylactic prednisone should not be given on that day to prevent rash.
Although uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis have been reported with atezolizumab. Atezolizumab should be permanently discontinued 
for confirmed cases (see Appendix 13).
Dermatologic event, 
Grade 1
Consider referring patient to a dermatologist. 
Continue atezolizumab and ipatasertib.
Initiate supportive care (e.g., topical corticosteroids and continue antihistamine administration).  
Consider treatment with 10 mg/day oral prednisone or equivalent.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
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 higher steroid dose may be 
necessary as clinically indicated.
Ipatasertib:  interrupt ipatasertib treatment until resolution to Grade 1 or the toxicity is no longer clinically 
significant.  If steroid dose is 10 mg/day, ipatasertib may be resumed if clinically appropriate.
Atezolizumab:  If steroid dose is 10 mg/day, atezolizumab should be continued.
Dermatologic event, 
Grade 3
Withhold atezolizumab and ipatasertib.
Refer patient to dermatologist.  Perform a biopsy if appropriate.
If no prior steroid treatment has been initiated, consider treatment with 10 mg/day oral prednisone or equivalent.
If prior oral steroid treatment or no improvement within 48 hours, consider increasing prednisone or equivalent dose 
to 12 mg/kg/day.
Atezolizumab:  if event resolves to Grade 1 within 12 weeks, resume atezolizumab at fixed dose.  If not, 
permanently discontinue atezolizumab and contact Medical Monitor.  Only restart atezolizumab if steroid dose is 
10 mg/day. a, b, c
Ipatasertib:  if event resolves to Grade 1 or the toxicity is no longer clinically significant, resume ipatasertib at the 
same dose or dose reduced by one level after discussion with Medical Monitor.  Only restart ipatasertib if steroid 
dose is 10 mg/day.  If not, permanently discontinue ipatasertib.
Dermatologic event, 
Grade 4
Permanently discontinue atezolizumab and ipatasertib and contact Medical Monitor. c


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Neutropenia 
Grade 2
Ipatasertib 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 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 and taxane should be reduced by one dose level when treatment is restarted. 
If patient has had more than three Grade 3 neutropenia episodes on study, despite the maximum dose 
reduction to 65 mg/m2 for paclitaxel and 50 mg/m2 for nab-paclitaxel, the taxane should be permanently 
discontinued, but the patient may continue to receive ipatasertib 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 following discussion with the Medical 
Monitor.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
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 and taxane should be reduced by one dose level when treatment is restarted. 
- Recurrent episode: Ipatasertib and taxane should be discontinued. Atezolizumab maybe continued after 
discussion with the Medical Monitor
Following a treatment hold of up to 4 weeks, if recovery to Grade 2 or better neutropenia does not occur, the 
patient will permanently discontinue all treatment.
Ipatasertibrelated toxicities not described above
Grade >3
Withhold ipatasertib.  Continue atezolizumab.
If the toxicity resolves to Grade 1 or better within 2 weeks, treatment may resume with ipatasertib at the prior 
dose level.
If the toxicity resolves to Grade 1 or better within 24 weeks, the dose of the ipatasertib should be reduced by 
one level per the suggested guidelines in Table 3 and Table 4.
Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or better takes 4 weeks, 
treatment may resume with the ipatasertib with dose reduction, or the ipatasertib may be permanently 
discontinued, at the discretion of the investigator.


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Table 6
Guidelines for Management of Patients Who Experience Specific Adverse Events with Ipatasertib
and Atezolizumab (cont.)
Event
Action to Be Taken
Atezolizumab- related toxicities not described above
Grade 3
Follow guidelines for atezolizumab in Appendix 13.
Withhold ipatasertib until resolution to Grade 1.
If the toxicity resolves to Grade 1 or better within 2 weeks, treatment with ipatasertib may resume at the prior 
dose level.
If the toxicity resolves to Grade 1 or better within 24 weeks, the dose of ipatasertib should be reduced by one 
level per the suggested guidelines in Table 3 and Table 4.
Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or better takes 4 weeks, 
treatment may resume with ipatasertib with dose reduction, or ipatasertib may be permanently discontinued, at 
the discretion of the investigator.
ANC= absolute neutrophil count; BALbronchoscopic alveolar lavage ; BIDtwice a day; CRPC-reactive protein; 
G-CSFgranulocyte-colony stimulating factor; GIgastrointestinal; HbA1cglycosylated hemoglobin; IRRinfusion-related reaction; 
LFTliver function test; NSAIDnon-steroidal anti-inflammatory drug; TSHthyroid-stimulating hormone; ULNupper limit of normal.
a If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed.
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the investigator and the
Medical Monitor.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.
d The LFT panel should include AST, ALT, alkaline phosphatase, and total bilirubin.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and 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 5.3.5.13.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 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 5.3.5.10)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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.
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) even if they are not serious.  Adverse events of 
special interest for the study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.6) and based on the following observations:
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

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


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
Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, HLH, and MAS

Nephritis

Ocular toxicities (e.g., uveitis, retinitis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Grade 3 rash

Grade 3 diarrhea or Grade 2 diarrhea that persists for longer than 5 days despite 
optimal medical management.

Grade 3 hyperglycemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis, erythema multiforme)
5.2.4
Selected Adverse Events
Additional data may be analyzed for the following selected adverse events:

Diarrhea

Asthenia (fatigue)

Nausea

Peripheral neuropathy (peripheral sensory neuropathy, neuropathy peripheral, 
peripheral motor neuropathy)

Neutropenia (neutrophil count decreased, febrile neutropenia)

Rash (maculopapular, erythema, urticarial, dermatitis, rash papular, skin exfoliation, 
toxic skin eruption)

Erythema multiforme

Vomiting

Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration)


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
Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased)

Hepatotoxicity (ALT, AST increased)

Hyperglycemia (blood glucose increased)

Pneumonia (lower respiratory tract infection)

Pneumonitis (interstitial lung diseases)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.3.5.135.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events identified by the investigator will be recorded in the patient’s medical 
record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study 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 last 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 last dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 7
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 8):

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 the study treatment or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 8
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study 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 the study treatment; 
and/or the adverse event abates or resolves upon discontinuation of the 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 the 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 the 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.
There is one eCRF page for recording adverse events or serious adverse events.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
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 separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF.


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5.3.5.1
Diagnosis versus Signs and Symptoms
If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity of selected adverse 
events (e.g., diarrhea, Section 5.2.4) will be captured on the Adverse Event Intensity or 
Grade Changes eCRF.  If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from "non-serious" to "serious," providing the date 


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that the event became serious, and completing all data fields related to serious adverse 
events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).


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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
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
Deaths
Deaths that occur during the protocol-specified adverse event reporting period (see
Section 5.3.1) that are attributed by the investigator solely to progression of underlying 
breast cancer should be recorded on the Study Discontinuation eCRF.  All other deaths 
that occur during the adverse event reporting period, regardless of relationship to study 


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drug, must be recorded on the Adverse Event eCRF and immediately reported to the 
Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During survival follow-up, deaths attributed to progression of underlying breast cancer
should be recorded only on the Study Discontinuation eCRF.  Deaths that occur after the 
adverse event reporting period should be reported as described in Section 5.6).
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression due to breast cancer, 
it should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., 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 drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of progression of the 
underlying disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event but, should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF, as described in Section 5.3.5.12.  If the 
associated adverse event fulfills seriousness criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.4.2).
No safety data related to overdosing of ipatasertib or atezolizumab are available.
Paclitaxel overdosage does not have a known antidote.  Bone marrow suppression, 
peripheral neurotoxicity, and mucositis are the primary anticipated complications of 
overdosage of paclitaxel.
All doses must be documented in the patient diary and on the dosing administration 
eCRF for each study drug.  Any study drug overdose or incorrect administration of study 
drug should be noted on the Study Drug Administration eCRF and reported as a protocol 
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5.3.5.12
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For ipatasertib, atezolizumab, paclitaxel/nab-paclitaxel, 
doxorubicin, and cyclophosphamide, 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.


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


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5.3.5.13
Left Ventricular Systolic Dysfunction
Symptomatic left ventricular systolic dysfunction should be reported as a serious 
adverse event.  If the diagnosis is heart failure, it should be reported as such and not in 
terms of the individual signs and symptoms thereof.  Heart failure should be graded 
according to the NCI CTCAE v4.0 and also according to the NYHA classification.  Heart 
failure occurring during the study and after the study (see Section 5.6) must be reported, 
irrespective of causal relationship, and followed 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.
Asymptomatic declines in LVEF should generally not be reported as adverse events 
because LVEF data are collected separately in the eCRF.  Exceptions to this rule are as 
follows:

An asymptomatic decline in LVEF of 10 percentage points from baseline to an 
LVEF of 50% must be reported as an adverse event with the term "ejection 
fraction decreased" as per NCI CTCAE v4.0.

An asymptomatic decline in LVEF requiring treatment delay or leading to 
discontinuation of ipatasertib, atezolizumab, nab-paclitaxel, doxorubicin, or 
cyclophosphamide must be reported as an adverse event with the term "ejection 
fraction decreased," and, in addition, a comment in the adverse event comments 
field should confirm that this event was asymptomatic.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information


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
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., Ph.D.
(Primary)
Mobile Telephone No.:
Medical Monitor/Roche Medical Responsible:
, M.D. (Secondary)
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 Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or
email address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study drug, serious adverse events will be reported until 30 days after 
the last 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 last 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 


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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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur28 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 1 month after the last 
dose of ipatasertib or nab-paclitaxel, 5 months after the last dose of atezolizumab, 
6 months after the last dose of paclitaxel or doxorubicin, or 12 months after the last dose 
of cyclophosphamide, 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 drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
1 month after the last dose of ipatasertib or 6 months after the last dose of paclitaxel,
nab-paclitaxel, cyclophosphamide, or doxorubicin, 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.  Attempts should be made to collect and 
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patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study treatment or 
trial-related procedures until a final outcome can be reported.


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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
5.6.1
Reporting for Cohorts 1, 2, and 4
After the end of the adverse event reporting period for serious adverse events and 
adverse events of special interest (defined as 90 days after the last 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 and in the Study Discontinuation eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study 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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.6.2
Reporting for Cohort 3
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study treatment or until initiation of new systemic 
anti-cancer therapy, whichever occurs first), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Ipatasertib Investigator's Brochure

Atezolizumab Investigator’s Brochure

E.U. Summary of Product Characteristics for paclitaxel

E.U. Summary of Product Characteristics for nab-paclitaxel

E.U. Summary of Product Characteristics for doxorubicin

E.U. Summary of Product Characteristics for cyclophosphamide
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 study is designed to obtain preliminary safety, tolerability, efficacy, PK, or biomarker 
information for the following:

Cohort 1
–
Arm A: IpatAtezoPac
–
Arm B:  IpatAtezoNab-Pac
–
Arm C:  IpatPac alone for 2 weeks, thenAtezo
–
Arm D:  AtezoPac alone for 2 weeks, thenIpat

Cohort 2 (biopsy cohort)
–
Arm E: IpatAtezo


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
Cohort 3
–
Arm F: IpatAtezoAC (ipatasertib dose of 300 mg) followed by 
IpatAtezoPac (ipatasertib dose of 400 mg)
–
Arm G: IpatAtezoAC (ipatasertib dose of 400 mg) followed by 
IpatAtezoPac (ipatasertib dose of 400 mg)

Cohort 4
–
Arm H: IpatAtezoPac
There is no formal hypothesis testing planned. Cohort 1, Cohort 2, Cohort 3, and 
Cohort 4 may be analyzed separately. Patients with PD-L1positive tumors receiving 
IpatAtezoPac in Cohort 1 will be pooled with patients in Cohort 4 for analyses.
6.1
DETERMINATION OF SAMPLE SIZE
There is no formal hypothesis testing planned. The determination of sample size for 
each cohort is described below.
6.1.1
Cohorts 1 and 3: Safety Run-In Stage
In Cohorts 1 and 3, the number of patients enrolled during the safety run-in stage (n6) 
in each arm (i.e., A1, B1, C1, D1, F1, and G1) allows for a reasonable likelihood of 
observing a given adverse event in at least 1 patient even when the incidence of the 
specific adverse event is low (see Table 9).
Table 9
Probabilities of Observing Adverse Events with Different 
Underlying Incidences: Safety Run-In Stage for Cohorts 1 and 3
Underlying AE Incidence
Probability of Observing the AE in 1 of 6 Patients
0.02
0.11
0.04
0.22
0.06
0.31
0.08
0.39
0.10
0.47
AE adverse event.
6.1.2
Cohort 1: Expansion Stage
No formal statistical hypothesis testing is planned in this study. Instead, the analysis 
here is for hypothesis generation, and the emphasis is on estimations. To evaluate the 
primary endpoint of overall response rate for Cohort 1, for each arm, the analyses will be 
based on combining patients enrolled in the safety run-in and expansion stages, which is 
approximately 20 patients (Cohort 1, Arms A and B) or 12 patients (Cohort 1, Arms C 
and D). Table 10 shows estimated ORR and its 95% CI based on the ClopperPearson 
method given various observed numbers of responders among the 20 patients in Arms A 
and B, respectively. Twenty patients provide reasonably reliable estimates for 


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hypothesis generation in the expansion stage in Arms A and B. Table 11 shows 
estimated ORR and its 95% CI based on the ClopperPearson method given various 
observed numbers of responders among the 12 patients in Arms C and D.  Twelve 
patients will provide reasonably reliable estimates for hypothesis generation in the 
expansion stage in Arms C and D. With enrolling additional up to 50 patients into 
Arm A3, Table 12 shows the estimated ORR and its 95% CI under different response 
rate scenarios when pooling all patients in Arm A (A1, A2, A3) and Arm B (B1, B2).
Table 10 Estimated Objective Response Rate and Its 95% CI for 
20 Patients in Arms A and B, Respectively
Number of Responders
ORR (%)
95% CI (%)
4
20
5.73, 43.66
6
30
11.89, 54.28
8
40
19.12, 63.95
10
50
27.20, 72.80
12
60
36.05, 80.88
14
70
45.72, 88.11
16
80
56.34, 94.27
ORR objective response rate.
Table 11 Estimated Objective Response Rate and Its 95% CI for 
12 Patients in Arms C and D, Respectively
Number of Responders
ORR (%)
95% CI (%)
2
16.67
2.09, 48.41
4
33.33
9.92, 65.11
6
50
21.09, 78.91
8
66.67
34.89, 90.08
10
83.33
51.59, 97.91
ORR objective response rate.


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Table 12 Estimated Objective Response Rate and Its 95% CI for 
90 Patients in Arm A and B Combined 
Number of Responders
ORR (%)
95% CI (%)
60
66.67
55.95 76.26
63
70
59.43 79.21
66
73.33
62.97 82.11
69
76.67
66.57 84.94
ORR objective response rate.
6.1.3
Cohort 2: Biopsy
If there is sufficient evidence of meaningful benefit from the combination of ipatasertib 
and atezolizumab with taxane in Cohort 1, (e.g., ORR 50%), the Sponsor may decide 
to open enrollment of a separate mandatory on-treatment biopsy cohort to evaluate 
biomarker endpoints of patients treated with ipatasertib combined with atezolizumab to 
further understand the molecular basis of treatment benefit. To provide a reliable 
estimate of the effects of ipatasertib and ipatasertib atezolizumab on immune cell 
infiltration and activation, as well as molecular tumor biomarkers and circulating immune 
cell repertoires, a total of up to 14 patients will be enrolled in this cohort for exploratory 
analyses.
6.1.4
Cohort 3:  Expansion Stage
No formal statistical hypothesis testing is planned in this study.  Instead, the analysis 
here is for hypothesis generation, and the emphasis is on estimations.  To evaluate the 
primary efficacy endpoint of pCR for Cohort 3, for each arm, the analyses will be based 
on combining patients enrolled in the safety run-in stage (n6) and expansion stage
(n6 or 12, as determined by the Sponsor) for a total of either 12 patients or 18 patients.  
Table 13 and Table 14 show estimated pCR rate and its 95% CI based on the 
ClopperPearson method given various observed numbers of responders among 
12 patients or 18 patients, respectively, in Arm F or Arm G.  The minimum sample size, 
12 patients, will provide reasonably reliable estimates for hypothesis generation in the 
expansion stage in Arms F and G.  Any additional patients will strengthen the evidence 
by reducing estimate uncertainty. 


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Table 13 Estimated Pathologic Complete Response Rate and Its 95% CI for 
12 Patients in Arm F or Arm G
Number of Responders
pCR Rate (%)
(n12)
95% CI (%)
7
58.33
27.67, 84.83
8
66.67
34.89, 90.08
9
75.00
42.81, 94.51
10
83.33
51.59, 97.91
11
91.67
61.52, 99.79
pCRpathologic complete response.
Table 14 Estimated Pathologic Complete Response Rate and Its 95% CI for 
18 Patients in Arm F or Arm G
Number of Responders
pCR Rate (%)
(n18)
95% CI (%)
12
66.67
40.99, 86.66
13
72.22
46.52, 90.31
14
77.78
52.36, 93.59
15
83.33
58.58, 96.42
16
88.89
65.29, 98.62
pCRpathologic complete response.
6.1.5
Cohort 4
No formal statistical hypothesis testing is planned in this study. Patients from Cohort 4
(approximately 50 patients with PD-L1positive tumors) will be pooled with 
approximately 40 patients with PD-L1positive tumors in Cohort 1. The total sample 
size for this pooled analysis is expected to be approximately 90 patients, which will 
provide a reasonably reliable estimate for the ORR in the PD-L1positive population
compared with historical data in this population.  Table 15 shows the estimated ORR 
and its 95% CI given various observed numbers of responders among patients with 
PD-L1positive tumors in Cohorts 1 and 4.


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Table 15 Estimated Objective Response Rate and Its 95% CI for 
90 PD-L1Positive Patients in Cohorts 1 and 4
Number of Responders
ORR (%)
(n90)
95% CI (%)
64
71.11%
[60.60, 80.18]
65
72.22%
[61.78, 81.15]
66
73.33%
[62.97, 82.11]
67
74.44%
[64.16, 83.06]
68
75.56%
[65.36, 84.00]
ORRobjective response rate.
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, study discontinuation, and discontinuation reasons will be 
summarized by treatment arm and by cohorts when applicable.  In addition, major 
protocol violations, including violations of inclusion and/or exclusion criteria, will be 
summarized as well.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographics summaries, patient treatment history, and other baseline disease 
characteristics will be summarized by treatment arms and by cohorts when applicable.
Descriptive summaries of continuous data will present the group mean, standard 
deviation, median, minimum, and maximum.  Descriptive summaries of discrete data will 
present the category counts as frequencies and percentages.
6.4
EFFICACY ANALYSES FOR COHORT 1 AND COHORT 4
All efficacy analyses, except for duration of response (DOR), will be based on efficacy 
evaluable patient population, which is defined as all enrolled patients who received at 
least one dose of study treatment, regardless of treatment allocation. DOR analysis will 
include all patients with an objective response (i.e., a confirmed complete response or 
partial response). Patients will be analyzed according to the treatment they receive. 
The treatment arms for Cohort 1 efficacy analyses are as follows:

Arm A:  IpatAtezoPac

Arm B:  IpatAtezoNab-Pac

Arm C:  IpatPac alone for 2 weeks, thenAtezo

Arm D:  AtezoPac alone for 2 weeks, thenIpat

Arm A and B combined: IpatAtezotaxane


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For Cohort 4, efficacy analyses will be carried out on the pooled data from 
PD-L1positive patients in Arms A, B, and H (ipatasertibatezolizumabpaclitaxel).
All primary and secondary endpoints based on tumor burden will be based on 
radiological (or photographical, if applicable) assessments by the local radiologist or 
investigator.
6.4.1
Primary Efficacy Endpoint
6.4.1.1
Objective Response Rate
ORR is defined as the proportion of patients with a confirmed complete response or 
partial response on two consecutive occasions 4 weeks apart, as determined by the 
investigator according to RECIST v1.1 (see Appendix 10).  Patients without a 
postbaseline tumor assessment will be considered as non-responders.  ORR is defined 
as the proportion of patients who have an objective response; an estimate of ORR will 
be calculated for each treatment arm, and its 95% CI will be calculated using the 
ClopperPearson method. 
6.4.1.2
Duration of Response
DOR will be analyzed to support ORR. DOR is defined as the time from the first 
occurrence of a documented objective response to disease progression, as determined 
by the investigator according to RECIST v1.1, or death from any cause, whichever 
occurs first.  Patients who have not progressed or died at the time of analysis will be 
censored at the last disease assessment date.
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Progression-Free Survival 
PFS is defined as the time from enrollment to the date of the first recorded occurrence of 
disease progression, as determined by the investigator using RECIST v1.1 (see 
Appendix 10), or death from any cause, whichever occurs first.  Data for patients who do 
not experience disease progression or death will be censored at the last date of 
evaluable tumor assessment.  For patients who do not have an evaluable tumor 
assessment after receiving first treatment, the data will be censored at the date of first 
treatment plus 1 day.
6.4.2.2
Clinical Benefit Rate
Clinical benefit rate (CBR) is defined as the proportion of patients who have an objective 
response (complete or partial), or stable disease for at least 24 weeks, as determined by 
the investigator according to RECIST v1.1.  For each arm, clinical benefit rate will be 
analyzed using methods similar to those used for ORR.
6.4.2.3
Overall Survival
OS is defined as the time from enrollment to death from any cause.  Data for patients 
who are not reported as having died at the time of analysis will be censored at the date 


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when they were last known to be alive.  Data for patients who do not have postbaseline 
information will be censored at the first treatment date plus 1 day.  
6.4.3
Exploratory Efficacy Endpoints
The potential relationship between the presence of PIK3CA/AKT1/PTEN genetic 
alterations in tumors and anti-tumor activity (including ORR, DOR, PFS, CBR, and OS) 
of ipatasertib in combination with atezolizumab and paclitaxel or nab-paclitaxel in Cohort 
1 and of ipatasertib in combination with atezolizumab in Cohort 2 will be explored as 
data allow.
6.5
EXPLORATORY EFFICACY ANALYSES FOR COHORT 2
Efficacy analyses for Cohort 2 will be performed on endpoints ORR, DOR, CBR, PFS, 
and OS using the methods described in Section 6.4.
6.6
EFFICACY ANALYSES FOR COHORT 3
The efficacy analyses will be based on the efficacy evaluable patient population, which is 
defined as all enrolled patients who received at least one dose study treatment, 
regardless of treatment allocation.
The primary efficacy objective for Cohort 3 is to evaluate the efficacy of neoadjuvant 
IpatAtezoAC (ipatasertib dose of 300 mg) followed by IpatAtezoPac (ipatasertib 
dose of 400 mg) (Arm F) or neoadjuvant IpatAtezoAC (ipatasertib dose of 400 mg) 
followed by IpatAtezoPac (ipatasertib dose of 400 mg) (Arm G) in patients with 
locally advanced T24 TNBC, as measured by pCR rate, defined as the proportion of 
patients who have no residual invasive cancer in the breast and no residual disease in 
the lymph nodes (ypT0/Tis ypN0).  The primary efficacy endpoint will be established 
following completion of neoadjuvant therapy and surgery.
In the primary analysis, patients whose pCR assessment is missing will be counted as 
not achieving a pCR.  An estimate of the pCR rate and its 95% CI will be calculated for 
each treatment arm through use of the ClopperPearson method (Clopper and Pearson 
1934).  
6.7
SAFETY ANALYSES
All safety analyses will be based on the safety-evaluable population for each cohort 
(i.e., all patients who received any study treatment) according to the treatment received.
Safety analyses will be conducted by treatment arms and include incidence, nature, and 
severity of treatment-emergent adverse events, including adverse events leading to 
death, serious adverse events, and adverse events of special interest.  All deaths will be 
summarized.  In addition, adverse events leading to study treatment discontinuation and 
dose modification will be summarized.  Laboratory measurements outside of the normal 
range will be identified.  Selected laboratory data will be summarized by treatment arm 


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and grade compared with baseline.  Relevant vital signs will be presented using 
summary statistics by treatment arm and visit.  Drug exposure will be summarized as 
well, including duration of treatment, cumulative dose, and dose intensity. 
Treatment-emergent adverse events are defined as adverse events that occur after the 
first dose of study treatment.  Adverse events will be summarized by mapped MedDRA 
preferred terms and appropriate MedDRA hierarchy.  Adverse event severity will be 
graded according to NCI CTCAE v4.0.  Multiple occurrences of the same event will be 
counted once at the maximum severity.
6.8
PHARMACOKINETIC ANALYSES
Sparse or intensive samples will be collected for PK analyses of atezolizumab (patients 
who receive at least one dose of atezolizumab) and ipatasertib and its metabolite 
G-037720 (patients who receive at least one dose of the respective drug) as described 
in Appendix 4, Appendix 5, and Appendix 6.  Serum or plasma concentrations of the 
various study drugs and PK markers (coproporphyrin I and III) will be summarized 
(mean, standard deviation, coefficient of variation) by treatment arm, and by cycle and 
day when appropriate and as data allow.  Individual and median serum or plasma 
concentrations of the various study drugs will be plotted by treatment arm and cycle and 
day.  Non-compartmental analysis will be conducted when the data allow for it (e.g.,
during the intensive sampling). Analyte concentration data for ipatasertib (and its 
metabolite, G-037220) and atezolizumab may be pooled with data from other studies 
using an established popPK model to derive PK parameters such as clearance, volume 
of distribution, and area under the curve as appropriate to assist in comparison with 
historical data. Covariates such as patient demographics (e.g., age, sex, body size), 
total protein, serum albumin, liver function tests (e.g., AST, ALT, alkaline phosphatase), 
and serum creatinine may be tested for significance on PK parameters of interest, if data 
allow.
The PK data will be analyzed with the safety and/or efficacy (e.g., PFS) data for 
exposureresponse modeling as data permit.  PK and pharmacodynamic analyses may 
be reported in separate standalone reports.  
Additional PK analyses will be conducted as appropriate.
6.9
IMMUNOGENICITY ANALYSES
Immunogenicity will be assessed for atezolizumab.  The immunogenicity analyses will 
include all patients with at least one anti-drug antibody (ADA) assessment.  Patients will 
be grouped according to treatment received or, if no treatment is received prior to study 
discontinuation, according to treatment assigned.
For atezolizumab, the numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after baseline 
(postbaseline incidence) will be summarized by treatment group. When determining 


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postbaseline incidence, patients are considered to be ADA positive if they are ADA 
negative or are 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 of one or more postbaseline samples is at least 0.60 titer unit 
greater than the titer of the 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.
6.10
BIOMARKER ANALYSES
In Cohorts 1, 2, and 4, the exploratory biomarker endpoints, including the effects of 
breast intrinsic subtypes, genetic alterations, and expression of tumor suppressors, will 
be evaluated for their association with drug response.
Additionally, for patients in Cohorts 2 and 3, tumor, plasma, and blood samples will be 
evaluated for changes in immune cell infiltration and activation as well as molecular 
tumor biomarkers and circulating immune cell repertoires, from ipatasertib and 
ipatasertib atezolizumab treatment.  These analyses will be done using appropriate 
statistical methods.
For Cohort 3, pCR analyses similar to that described in Section 6.6 will be run in the 
subgroup of patients with PIK3CA/AKT1/PTEN genetic alterations and/or subgroups of 
patients by PD-L1 status.
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.


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eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff on the eCRFs. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
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.


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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, Informed Consent Forms, laboratory test results, medication 
inventory records, and images must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
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.


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in 
a certified translation of the local language.  The Sponsor or its designee must review 
and approve any proposed deviations from the Sponsor's sample Informed Consent 
Forms or any alternate consent forms proposed by the site (collectively, the "Consent 
Forms") before IRB/EC submission.  The final IRB/ECapproved Consent Forms must 
be provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to 
a significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes 


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


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
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.  


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Details on the establishment and monitoring of quality tolerance limits areprovided in 
a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Up to 25 sites in the United States, Spain, France, the United Kingdom, and Australia
will participate to enroll approximately 202 patients.  Sequential enrollment into Arms A1, 
B1, A2, and B2 will be employed.  To further explore tolerability of the triplet 
combination, additional arms (Arms C and D), with stepwise introduction of the treatment 
drugs, will be opened.  Sequential enrollment order in Cohort 1 will then be as follows:  
A1 B1 A2 B2/C1 D1 C2 D2.  Both Arms B2 and Arms C or D can be 
open simultaneously, but priority for filling of arms will go to Arms C and D.  To further 
investigate the tolerability and efficacy of the triplet combination regime used in Arm A in 
first-line metastatic TNBC, Arm A will be further extended to include another expansion 
phase (Stage 3, Arm A3). Arm A3 will open after Arms C2 and D2 have been filled.
Enrollment into the biopsy cohort (Cohort 2) will be gated by encouraging efficacy as 
described in Section 3.1.6. To explore tolerability of the triplet combination in the locally 
advanced TNBC setting, Cohort 3, with two additional arms (Arms F and G), will be 
opened.  Enrollment order in Cohort 3 will be as follows:  F1 G1 F2 and/or G2.
Cohort 4 will further evaluate the triplet combination of IpatAtezoPac in patients with 
PD-L1positive tumors.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
The Study Medical Monitor and the Study Team (see Internal Safety Monitoring, 
Section 3.1.11) will monitor and evaluate patient safety throughout the study.  
9.6
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. Study data may be 
shared with others who are not participating in this study (see Section 8.4 for details), 


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and redacted Clinical Study Reports and other summary reports will be made available 
upon request. For more information, refer to the Roche Global Policy on Sharing of 
Clinical Study Information at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities:  Cohorts 1 and 4
Screening
(Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
Treatment 
Discon. b
Disease 
Follow-
Up
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1 D8
D15
D1
D8
D15
D1
D8
D15
Signed informed 
consent(s) c
x
Viral serology d
x
Demographics, medical 
history, prior cancer 
treatment
x
Tumor tissue sample 
submission at screening
x e
Plasma sample for 
biomarkers f
x g
x
Blood sample for WGS h
x
Complete physical 
examination i
x
x
Limited physical 
examination
x
x
x
x
x
x
x
x
Weight 
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
ECHO or MUGA scan
x k
12-Lead ECG l
x
x
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


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
181/Protocol CO40151, Version 6
Screening
(Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
Treatment 
Discon. b
Disease 
Follow-
Up
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1 D8
D15
D1
D8
D15
D1
D8
D15
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, 
amylase, lipase
x
x q
x q
x
HbA1c
x
x q
x q
x
Urinalysis
x
As clinically indicated
x
Pregnancy test r
x
x r
x
x
x
x
x r
Tumor assessments s
x
x t
x t
x u
x u
Bone scan
x v
See footnote "v"
x t
x u
Head scan (CT or MRI 
scan)
x w
Prophylaxis anti-diarrheal 
(2 mg BID loperamide or 
equivalent, as allowed per 
local guidelines, 2 mg after 
each loose watery stool, 
and up to 16 mg per day, or 
per local guidelines)
If side effects are not tolerated, doses may be reduced. After 
1 cycle without any diarrhea, continuation is at physician's 
discretion. If diarrhea occurs, it should be managed per guidelines 
in Section 5.1.9.4; anti-diarrheal treatment should also be resumed 
with loperamide prophylaxis as needed.


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
182/Protocol CO40151, Version 6
Screening
(Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
Treatment 
Discon. b
Disease 
Follow-
Up
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1 D8
D15
D1
D8
D15
D1
D8
D15
Stool sample (optional)
Samples will be used for fecal calprotectin assay when patients 
experience any diarrhea.  Test diarrhea sample at nearest Cycle 
and day clinic visit associated with diarrhea onset. This test 
should only be done on patients reporting diarrhea; do not request 
stool sample if patient has no complaints of diarrhea. Take 
voluntary stool sample at each clinic visit where patient continues 
to report event of diarrhea.
Ipatasertib distribution/
accountability
x x
x
x
x
Atezolizumab 
administration
x x
x 
x 
x
x
x
x
x
Paclitaxel or nab-paclitaxel 
administration y
x x
x
x
x
x
x
x
x
x
x
x
x
Record cancer-related 
medications and surgical 
procedures
x
x
Concomitant medications z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x bb
x bb
x bb
PK and ADA samples cc
x 
x dd
x
x
x
x ee
Tumor tissue sample 
obtained at time of 
progression (optional) ff
x ff


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
183/Protocol CO40151, Version 6
Screening
(Day 28 to 
Day –1)
Treatment Cycles (28-Day Cycles) a
Treatment 
Discon. b
Disease 
Follow-
Up
Post-
Treat. 
Follow-
Up
Cycles 
1 and 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D1 D8
D15
D1
D8
D15
D1
D8
D15
Patient diary (medication, 
dosing log, Kit ID)
x
x
x
x
x
x
x
x
x
x
x
x
x
Survival follow-up and anti-
cancer treatment
x gg
ADAanti-drug antibody; BIDtwice a day; CT computed tomography; Dday; Discon.discontinuation; ECHO echocardiogram; 
ECOGEastern Cooperative Oncology Group; FNAfine-needle aspiration; HbA1c glycosylated hemoglobin; HBcAb hepatitis B core antibody;
HBsAghepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition; NGSnext-
generation sequencing; PKpharmacokinetic; RECIST Response Evaluation Criteria in Solid Tumors; T3triiodothyronine; T4thyroxine; 
Treat.treatment; TSHthyroid-stimulating hormone; WGSwhole genome sequencing. 
Notes:  Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within the screening window 
(Days 28 to 1) may be used for the study.  Screening assessments are to be performed within 28 days preceding Day 1 of Cycle 1 unless 
otherwise noted, and patients must have adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of 
Cycle 1, as defined in Section 4.1.1.  All assessments or procedures are to be performed predose unless otherwise specified.
a Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period should be performed within 3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays; however, study cycle day count continues without breaks.  
b The study drug discontinuation visit should occur approximately 28 days after the last administration of ipatasertib, atezolizumab, paclitaxel or 
nab-paclitaxel, whichever is discontinued last, or prior to initiation of another therapeutic regimen.
c The Informed Consent Form needs to be re-signed if patient is treated beyond progression.
d HIV, HBsAg, total HBcAb, and HCV antibody. Additional tests for HBV DNA or HCV RNA will be required to confirm eligibility in patients with 
a positive antibody result.


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
184/Protocol CO40151, Version 6
e Archival tissue (either formalin-fixed, paraffin-embedded tumor specimens or a minimum of 20 unstained serial paraffin slides [or 15 slides for 
Cohort 4]) and an associated pathology report must be confirmed to be available prior to entry into the study.  In the absence of archival tissue, 
newly obtained tissue biopsy samples of non-target lesions (excluding cytology, FNA specimens and bone metastasis requiring decalcification) 
are acceptable (if it is assessable and the biopsy can be safely obtained).  In general, a minimum of three core biopsies for NGS testing are 
required.
f
Plasma sample collection for cytokine analysis; applies only to Arms C and D.  Plasma from one 6-mL blood draw collected prior to receiving 
study treatment on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 15.
g Plasma sample does not need to be collected on Cycle 2 Day 1.
h Samples will be collected on Cycle 1 Day 1 only and only at sites with local regulatory authority approval.
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  
j
Includes pulse rate, respiratory rate, systolic and diastolic blood pressure while patient is in a seated position after resting for 5 minutes, and 
temperature (oral, axillary, or tympanic).  On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion.  
From Cycle 5 onward, if paclitaxel treatment has been discontinued, the patient is not required to return to the clinic for Day 8 and Day 15 vital 
sign assessments.  However, if atezolizumab administration continues on these days then patient continue to have vital signs monitored when 
they present for atezolizumab infusions. A telephone call for adverse events and concomitant medication assessment may be performed as 
clinically indicated.
k Performed within 12 weeks prior to Day 1, Cycle 1. If the left ventricular ejection fraction (LVEF) result as assessed by either of these imaging 
modalities is felt to be inconsistent with the clinical picture, then the investigator may choose an alternative modality (i.e., cardiac MRI), if this is 
consistent with local standard practice.
l
A single 12-lead ECG measurement at screening and at the treatment discontinuation visit, and as clinically indicated (refer to Section 4.5.8).
m Includes WBC count, WBC differential count (including ANCs, lymphocytes), hemoglobin, hematocrit, and platelet count. Hematology 
assessments to be conducted per local guidelines prior to each chemotherapy dosing.
n Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated.
o Includes sodium, potassium, bicarbonate, glucose, BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, LDH, ALT, 
AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured.  Grade 3 non-hematologic toxicity should be monitored at least weekly. Chemistry evaluation to be 
conducted per local guidelines.


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
185/Protocol CO40151, Version 6
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, amylase, lipase, and HbA1c will be assessed at screening, every three cycles starting on Day 1 of Cycle 3, and at treatment 
discontinuation visit.
r
For women of childbearing potential.  A serum pregnancy test is to be performed at screening (must be performed within 48 hours prior to Cycle 
1, Day 1).  In addition, pregnancy tests (serum or urine) are to be performed within 48 hours of Day 1 of each treatment cycle, and a pregnancy 
test should be performed when clinically indicated.  During follow-up, urine pregnancy tests will be performed at 3 and 6 months after the final 
dose of study treatment.  If urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  For all other women, 
documentation must be present in medical history confirming that patient is not of childbearing potential.
s Tumor assessments performed according to RECIST v1.1.  The method used for a patient (CT or MRI scan or photographic measurements) 
must be the same throughout the study.  An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation. A missed tumor assessment should be rescheduled as soon as possible.  Images for tumor assessments will be collected to 
enable retrospective blinded independent central review when needed.
t
Tumor assessments performed every 8 weeks starting on Days 21–28 of Cycle 2 and every 8 weeks thereafter until documented disease 
progression per RECIST v1.1 or until loss of clinical benefit.  Tumor assessments should be performed and reviewed 7 days prior to 
continuation of study treatment on Day 1 of the subsequent cycle.  Images for tumor assessments will be collected to enable retrospective 
blinded independent central review when needed.
u At treatment discontinuation visit, tumor assessments should be performed only if not performed within the previous 6 weeks and bone scans (if 
applicable) should be performed 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 to assess disease response approximately 
every 812 weeks and obtain bone scans (if applicable) approximately every 16 weeks until documented progressive disease per RECIST v1.1.  
Images for tumor assessments and bone scans will be collected to enable retrospective blinded independent central review when needed.
v An initial technetium bone scan should be performed within 6 weeks prior to Day 1 of Cycle 1.  In addition, bone disease identified on bone 
imaging should be evaluated radiographically by CT scan, MRI or X-ray to ascertain the presence of bone destruction versus a healing reaction.  
For patients with known or suspected bone metastasis, follow-up bone scans should be performed during Days 16–28 of every fourth cycle 
(every 16 weeks) and at the treatment discontinuation visit.
w Performed within 6 weeks prior to Day 1 of Cycle 1.


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
186/Protocol CO40151, Version 6
x 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. If patient is in Arms C1 or C2, atezolizumab dose on Day 1 of Cycle 1 should not be administered (refer to 
Section 3 and Figure 2).  If patient is in Arms D1 or D2, ipatasertib 400 mg will be administered orally QD on Days 1521 of the first cycle.  In all 
subsequent treatment cycles (Cycles 2), ipatasertib 400 mg will be administered orally once a day (QD) on Days 121 (refer to Section 3 and 
Figure 2). 
y If the patient's weight changes by 10% from baseline during the study, the body surface area and drug doses of paclitaxel or nab-paclitaxel 
should be recalculated.
z At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent timepoints, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or premedications at each dosage change should be recorded. 
aa After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of 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 last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
bb Patients with an unresolved adverse event or serious adverse event will be followed until the event is resolved or stabilized, the patient is lost to 
follow-up, or it has been determined that the study treatment or participation is not the cause of the event.  Refer to Section 5.6 for adverse 
events that occur after the adverse event reporting period (defined as 30 days after the last dose of study drug).  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.
cc See Appendix 4 for a schedule of PK assessments.
dd Cycle 2 is applicable to Arms C and D only.
ee Discontinuation sample of PK and ADA must be within 30 days of the last dose.
ff Tumor biopsy collection is optional for study participation.  For patients who sign an Optional Research Biosample Repository Informed Consent 
Form and if tumor biopsies can be obtained with minimal risk and discomfort to the patient, a tumor biopsy would be collected at the time of 
progression within 6 weeks of the progression assessment and prior to initiation of a new anti-cancer therapy; tumor biopsy of the growing lesion 
is preferred.


Appendix 1
Schedule of Activities:  Cohort 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
187/Protocol CO40151, Version 6
gg 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 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.


Ipatasertib—F. Hoffmann-La Roche Ltd
188/Protocol CO40151, Version 6
Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy)
Screening
(Day 28 
to 
Day –1)
Treatment Cycle 
(35-Day Cycle) a
Treatment Cycle 
(28-Day Cycle) a
Treatment 
Discon. b
Disease 
FU
Post-
Treat. 
FU
Cycle 1
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D22
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Signed informed 
consent(s)
x
Viral serology c
x
Demographics, medical 
history, prior cancer 
treatment
x
Tumor biopsy d
x d
x d
x d
Plasma sample for 
biomarkers e
x e
x e
x e
x e
x e
Blood sample for 
biomarkers f
x f
x f
x f
x f
x f
Blood sample for WGS g
x
Complete physical 
examination h
x
x
Limited physical 
examination
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
Height
x
Vital signs i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance 
Status
x
x
x
x
x
x
ECHO or MUGA scan
x j


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
189/Protocol CO40151, Version 6
Screening
(Day 28 
to 
Day –1)
Treatment Cycle 
(35-Day Cycle) a
Treatment Cycle 
(28-Day Cycle) a
Treatment 
Discon. b
Disease 
FU
Post-
Treat. 
FU
Cycle 1
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D22
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
12-Lead ECG k
x
x
Hematology l
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
INR and PTT (or aPTT)
x
x
Fasting serum 
chemistry n
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
TSH, free T3 (or total 
T3), free T4 o
x
x
x
x o
x
Fasting lipid profile, 
amylase, lipase
x
x p
x p
x
HbA1c
x
x p
x p
x
Urinalysis
x
As clinically indicated
x
Pregnancy test q
x
x q
x
x
x
x
x
x q
Tumor assessments r
x
x s
x s
x t
x s
Bone scan
x u
See footnote "u"
x u
x s
Head scan (CT or MRI 
scan)
x v


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
190/Protocol CO40151, Version 6
Screening
(Day 28 
to 
Day –1)
Treatment Cycle 
(35-Day Cycle) a
Treatment Cycle 
(28-Day Cycle) a
Treatment 
Discon. b
Disease 
FU
Post-
Treat. 
FU
Cycle 1
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D22
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
Prophylaxis anti-
diarrheal (2 mg BID 
loperamide or 
equivalent, as allowed 
per local guidelines, 
2 mg after each loose 
watery stool, and up to 
16 mg per day, or per 
local guidelines)
If side effects are not tolerated, doses may be reduced. After 1 cycle without any 
diarrhea, continuation is at physician's discretion. If diarrhea occurs, it should be 
managed per guidelines in Section 5.1.9.4; anti-diarrheal treatment should also be 
resumed with loperamide prophylaxis as needed.
Stool sample (optional)
Samples will be used for fecal calprotectin assay when patients experience any 
diarrhea.  Test diarrhea sample at nearest Cycle and day clinic visit associated with 
diarrhea onset.  This test should only be done on patients reporting diarrhea; do not 
request stool sample if patient has no complaints of diarrhea.  Take voluntary stool 
sample at each clinic visit where patient continues to report event of diarrhea.
Ipatasertib distribution/
accountability
x w
x
x
x
x
Atezolizumab 
administration
x
x
x
x
x
x
x
x
x
x
Record cancer-related 
medications and 
surgical procedures
x
x
Concomitant 
medications y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x aa
x aa
x aa


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
191/Protocol CO40151, Version 6
Screening
(Day 28 
to 
Day –1)
Treatment Cycle 
(35-Day Cycle) a
Treatment Cycle 
(28-Day Cycle) a
Treatment 
Discon. b
Disease 
FU
Post-
Treat. 
FU
Cycle 1
Cycle 2
Cycle 3 
Cycle 4
Cycles 5
D1
D8
D15
D22
D1
D8
D15
D1
D8
D15
D1
D8
D15
D1
D8
D15
PK and ADA samples bb
x cc
x
x
x
x
xdd
Tumor tissue sample 
obtained at time of 
progression (optional)ee
xee
Patient diary 
(medication, dosing log, 
Kit ID)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Survival follow-up and 
anti-cancer treatment
x ff
ADAanti-drug antibody; BIDtwice a day; CT computed tomography; ctDNAcirculating tumor DNA; Dday; Discon. discontinuation; 
ECHOechocardiogram; ECOG Eastern Cooperative Oncology Group; FUfollow up; HbA1c glycosylated hemoglobin; HBcAb hepatitis B 
core antibody; HBsAghepatitis B surface antigen; HCVhepatitis C virus; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition; 
PKpharmacokinetic; RECIST Response Evaluation Criteria in Solid Tumors; T3triiodothyronine; T4thyroxine; Treat. treatment; 
TSHthyroid-stimulating hormone; WGSwhole genome sequencing. 
Notes:  Results of standard-of-care tests or examinations performed prior to obtaining informed consent but within the screening window 
(Days 28 to 1) may be used for the study.  Screening assessments are to be performed within 28 days preceding Day 1 of Cycle 1 unless 
otherwise noted, and patients must have adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of 
Cycle 1, as defined in Section 4.1.1.  All assessments or procedures are to be performed predose unless otherwise specified.
a Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period should be performed within 3 days of the 
scheduled date.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays; however, study cycle day count continues without breaks.  
b The study drug discontinuation visit should occur approximately 28 days after the last administration of ipatasertib, atezolizumab, whichever is 
discontinued last, or prior to initiation of another therapeutic regimen.
c HIV, HBsAg, total HBcAb, and HCV antibody.  Additional tests for HBV DNA or HCV RNA will be required to confirm eligibility in patients with 
a positive antibody result.


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
192/Protocol CO40151, Version 6
d The predose specimen will be obtained after eligibility criteria have been fulfilled and prior to Day 1 of Cycle 1. A subsequent biopsy will be 
performed on either Day 7 or 8 of Cycle 1, prior to the administration of atezolizumab. An additional biopsy will be collected on Day 15 of 
Cycle 2. See the laboratory manual for details. 
e Plasma will be collected for ctDNA and cytokine analysis at screening, on either Day 7 or 8 of Cycle 1, prior to the administration of 
atezolizumab, on Day 15 of Cycle 2, Day 1 of Cycle 3, and at the study drug discontinuation visit.
f
Blood will be collected for assessment of circulation biomarkers at screening, either Day 7 or 8 of Cycle 1, prior to the administration of 
atezolizumab, on Day 15 of Cycle 2, Day 1 of Cycle 3, and at the study drug discontinuation visit.
g Samples will be collected only at sites with local regulatory authority approval.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.
i
Includes pulse rate, respiratory rate, systolic and diastolic blood pressure while patient is in a seated position after resting for 5 minutes, and 
temperature (oral, axillary, or tympanic). A telephone call for adverse events and concomitant medication assessment may be performed as 
clinically indicated.
j
Performed within 12 weeks prior to Day 1, Cycle 1. If the left ventricular ejection fraction (LVEF) result as assessed by either of these imaging 
modalities is felt to be inconsistent with the clinical picture, then the investigator may choose an alternative modality (i.e., cardiac MRI), if this is 
consistent with local standard practice.
k A single 12-lead ECG measurement at screening and at the treatment discontinuation visit, and as clinically indicated (refer to Section 4.5.8).
l
Includes WBC count, WBC differential count (including ANCs, lymphocytes), hemoglobin, hematocrit, and platelet count.
m Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated.
n Includes sodium, potassium, bicarbonate, glucose, BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, LDH, ALT, 
AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured.  Grade 3 non-hematologic toxicity should be monitored at least weekly.
o 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.).
p Fasting lipid profile, amylase, lipase, and HbA1c will be assessed at screening, every three cycles starting on Day 1 of Cycle 3, and at the 
treatment discontinuation visit.


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
193/Protocol CO40151, Version 6
q For women of childbearing potential.  A serum pregnancy test is to be performed at screening (must be performed within 48 hours prior to 
Cycle 1, Day 1).  In addition, pregnancy tests (serum or urine) are to be performed within 48 hours of Day 1 of each treatment cycle, and 
a pregnancy test should be performed when clinically indicated.  During follow-up, urine pregnancy tests will be performed at 3 and 6 months 
after the final dose of study treatment.  If urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  For all other women, 
documentation must be present in medical history confirming that patient is not of childbearing potential.
r
Tumor assessments performed according to RECIST v1.1.  The method used for a patient (CT or MRI scan or photographic measurements) 
must be the same throughout the study.  An objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation. A missed tumor assessment should be rescheduled as soon as possible.  Images for tumor assessments will be collected to 
enable retrospective blinded independent central review when needed.
s Tumor assessments performed every 8 weeks starting on Days 21–28 of Cycle 2 and every 8 weeks thereafter until documented disease 
progression per RECIST v1.1 or until loss of clinical benefit.  Tumor assessments should be performed and reviewed 7 days prior to 
continuation of study treatment on Day 1 of the subsequent cycle.  Images for tumor assessments will be collected to enable retrospective 
blinded independent central review when needed.
t
At the treatment discontinuation visit, tumor assessments should be performed only if not performed within the previous 6 weeks and bone scans 
(if applicable) should be performed 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 to assess disease response 
approximately every 812 weeks and obtain bone scans (if applicable) approximately every 16 weeks until documented progressive disease per 
RECIST v1.1.  Images for tumor assessments and bone scans will be collected to enable retrospective blinded independent central review when 
needed.
u An initial technetium bone scan should be performed within 6 weeks prior to Day 1 of Cycle 1.  In addition, bone disease identified on bone 
imaging should be evaluated radiographically by CT scan, MRI or X-ray to ascertain the presence of bone destruction versus a healing reaction.  
For patients with known or suspected bone metastasis, follow-up bone scans should be performed during Days 16–28 of every fourth cycle 
(every 16 weeks) and at the treatment discontinuation visit.
v Performed within 6 weeks prior to Day 1 of Cycle 1.  
w 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.
x If the patient's weight changes by 10% from baseline during the study, the body surface area and drug doses of paclitaxel or nab-paclitaxel 
should be recalculated.  
y At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent timepoints, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or premedications at each dosage change should be recorded. 


Appendix 2
Schedule of Activities:  Cohort 2 (Biopsy) (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
194/Protocol CO40151, Version 6
z After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of 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 last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
aa Patients with an unresolved adverse event or serious adverse event will be followed until the event is resolved or stabilized, the patient is lost to 
follow-up, or it has been determined that the study treatment or participation is not the cause of the event.  Refer to Section 5.6 for adverse 
events that occur after the adverse event reporting period (defined as 30 days after the last dose of study drug).  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.
bb See Appendix 5 for schedule of PK assessments.
cc Plasma sample collection to measure coproporphyrin I and III concentrations only.
dd Discontinuation sample of PK and ADA must be within 30 days of the last dose.
ee Tumor biopsy collection is optional for study participation.  For patients who sign an Optional Research Biosample Repository Informed Consent 
Form, and if tumor biopsies can be obtained with minimal risk and discomfort to the patient, a tumor biopsy would be 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.
ff 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 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.




Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
196/Protocol CO40151, Version 6
Screening a
Neoadjuvant Treatment
(28-Day Cycles)
(Cycles 15; Weeks 120)
Pre-Surgery 
Visit b
Study Completion 
Visit c or 
Early Termination 
Visit d
Follow-Up
Days 28 
to 1
Day 1
(3 days)
Day 8
(3 days)
Day 15
(3 days)
Day 22
(3 days)
Fasting serum chemistry r
x q
x q
x q
x q
x q
x
x
Pregnancy test s
x q
x s
  x s
x s
INR and PTT (or aPTT)
x q
x
x
TSH, free T3 (or total T3),
and free T4 t
x q
Cycles 1 and 4 
only t
x
Fasting lipid profile, amylase, 
lipase
x
Cycle 1 only u
x
HbA1c
x
Cycle 1 only u
x
Viral serology v
x q
Urinalysis w
x q
As clinically indicated
x
Serum PK sample for 
ipatasertib and atezolizumab
See Appendix 6 for detailed schedule
Serum ADA sample for 
atezolizumab
See Appendix 6 for detailed schedule
Blood and plasma samples 
for biomarkers
See Appendix 6 for detailed schedule
Blood sample for RBR 
(optional) x
Cycle 1 only x
Tumor tissue from surgical 
resection
x y


Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
197/Protocol CO40151, Version 6
Screening a
Neoadjuvant Treatment
(28-Day Cycles)
(Cycles 15; Weeks 120)
Pre-Surgery 
Visit b
Study Completion 
Visit c or 
Early Termination 
Visit d
Follow-Up
Days 28 
to 1
Day 1
(3 days)
Day 8
(3 days)
Day 15
(3 days)
Day 22
(3 days)
Bilateral mammogram
x z, aa
As clinically indicated
x aa
Other radiographic 
assessments (e.g., CT scan, 
MRI, PET scan)
x l, aa, bb, cc
As clinically indicated l, aa, bb
Ultrasound of breast and 
axilla
x aa
x aa
Concomitant medications
x dd
x
x
x
x
x
x
x
Adverse events ee
x ee
x
x
x
x
x
x ee
x ee
Dispense ipatasertib
x
Review diary and collect 
unused medication
x
x
x
x
x
Prophylactic treatment 
administration
x ff
Study treatment 
administration hh
x
x gg
x
x gg


Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
198/Protocol CO40151, Version 6
ACdoxorubicincyclophosphamide; ADAanti-drug antibody; CT computed tomography; 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, 5-Level; ERestrogen receptor; FACT-GFunctional 
Assessment of Cancer Therapy-General; FVC = forced vital capacity; FEV1 = forced expiratory volume 1; FEF2575 = forced expiratory flow 
25%75%;  FFPEformalin-fixed, paraffin-embedded; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface antibody; HBsAg hepatitis B 
surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition; 
PD-L1programmed deathligand-1; PET positron emission tomography; PgRprogesterone receptor; PK pharmacokinetic; PRO patient-
reported outcome; QDonce daily; RBRResearch Biosample Repository; T3triiodothyronine; T4thyroxine; Term.termination; 
TSHthyroid-stimulating hormone.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Except for Day 1 of Cycle 1, all other 
study visits and assessments during the treatment period should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen delays; however, study cycle day count continues 
without breaks.  
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event).
a 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 prior to Day 1 of Cycle 1 unless 
otherwise noted.  Patients must have adequate hematologic and organ function within 14 days prior to Day 1 of Cycle 1, as defined in 
Section 4.1.1.
b The pre-surgery visit and associated assessments should occur within 14 days prior to surgery.  Surgery should be conducted between 2 and 
6 weeks after the final dose of neoadjuvant therapy.  Pre-operative laboratory tests should be performed as per institutional practice.
c The study completion visit should occur after all surgical pathology reports are available and not more than 60 days after the final dose of study 
treatment.  
d Patients who discontinue the study prematurely will return to the clinic for an early termination visit not more than 60 days after the final dose of 
study treatment.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.


Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
199/Protocol CO40151, Version 6
f
The most recently collected tumor tissue sample will be submitted for HER2, ER, and PgR determination and exploratory biomarker research.  
Retrieval and submission of tissue sample can occur more than 28 days prior to initiation of study treatment, provided it occurs after signing of 
the Informed Consent Form.  Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality 
of the submitted specimen is inadequate).  An FFPE block of at least 15 unstained slides and an associated pathology report must be confirmed 
to be available prior to entry into the study.  Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for evaluation.  Refer to Section 4.5.7 for details on 
tumor tissue samples.
g Includes respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first atezolizumab infusion, vital signs should be measured 
within 60 minutes prior to the infusion and, if clinically indicated, every 15 (5) minutes during and 30 (10) minutes after the infusion.  For 
subsequent atezolizumab infusions, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if 
symptoms occurred during the previous infusion, during and 30 (10) minutes after the infusion.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.
i
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.
j
See Appendix 7.
k Assessment of primary tumor and regional lymph nodes should be done by physical examination during screening, within 3 days prior to each 
treatment cycle, within 14 days prior to surgery, and at the study completion or early termination visit.  Assessments should include 
measurement of tumors in the breast, preferably through use of calipers or a ruler or tape measure.
l
Additional disease assessments (e.g., liver function tests, radiographs) may be performed when clinically indicated to exclude metastatic 
disease, as per current institutional practice.  Whenever possible, disease recurrence should be confirmed pathologically.
m Patients who have enlarged or suspicious axillary nodes by physical examination or by any radiographic imaging (e.g., cortical thickness 2 mm) 
at screening should undergo fine-needle aspiration or core-needle biopsy prior to enrollment.  Lymph nodes will be staged as described in 
Section 4.5.6.6.
n ECG recordings will be obtained during screening, at each doxorubicin administration (Days 1 and 15 of Cycles 12), at study 
completion/early termination visit, and as clinically indicated.  Screening ECG assessments obtained 48 hours before Day 1 of Cycle 1 do not 
have to be repeated on Day 1 of Cycle 1.  Patients should be resting in a supine position for at least 10 minutes prior to ECG recording.
o ECHO or MUGA scans will be performed on all patients enrolled in the study.  ECHO is the preferred method.  The same method used for 
a given patient at screening should be used throughout the study.  ECHO or MUGA scans should be performed at screening, at Day 1 of 
Cycle 3, and at the study completion or early termination visit if not performed within the previous 6 weeks.


Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
200/Protocol CO40151, Version 6
p Includes WBC count, WBC differential count (including ANCs, lymphocytes), hemoglobin, hematocrit, and platelet count.  
q Laboratory samples should be drawn within 48 hours prior to study drug administration at the clinic; results should be available to assess dosing; 
with at least 8-hour fasting for glucose measurement as indicated. Screening local laboratory assessments obtained 48 hours before Day 1 of 
Cycle 11 do not have to be repeated on Day 1 of Cycle 1. Note that hematology and fasting serum chemistry laboratories are not required on 
Days 8 and 22 during Cycles 12 because no chemotherapy infusions are being given on these days.
r
Includes sodium, potassium, bicarbonate, glucose, BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, albumin, LDH, ALT, 
AST, and ALP.  For investigational sites in countries where bicarbonate may not be collected as part of the standard chemistry panel, 
bicarbonate will not be measured. 
s All women of childbearing potential will have a serum pregnancy test at screening (must be performed within 48 hours prior to initiation of study 
treatment). Urine or serum pregnancy tests will be performed at specified subsequent visits.  During follow-up, urine pregnancy tests will be 
performed at 3, 6, 9, and 10 months after the final dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
t
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycles 1 and 4.
u Fasting lipid profile, amylase, lipase, and HbA1c will be assessed at screening, on Day 1 of Cycle 1, and within 14 days prior to surgery.
v Includes HIV, HBsAg, total HBcAb, and HCV antibody.  Additional tests for HBV DNA or HCV RNA will be required to confirm eligibility in 
patients with a positive antibody result.
w Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted, with microscopic examination performed is clinically 
indicated.
x Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  Blood sample will be collected on Day 1 of Cycle 1.
y An FFPE tumor tissue block with at least three core biopsies should be obtained during scheduled surgical resection.
z The unaffected breast should be imaged within 60 days prior to initiation of study treatment.  The affected breast should be imaged within 
28 days prior to initiation of study treatment. 
aa Tumors should be measured at screening and within 14 days prior to surgery.  Tumors should be accurately measured in at least one dimension 
(longest diameter to be recorded) through use of conventional techniques (most commonly mammogram, but may be supplemented as clinically 
indicated with other radiologic assessments such as PET scan, CT scan, MRI, ultrasound, or X-ray).
bb Additional breast imaging such as MRI is not mandated but may be performed at the investigator's discretion per local practice.  If MRI is 
conducted, suggested timelines for MRI are within 28 days prior to treatment initiation, after completion of Cycle 2, and 14 days prior to surgery.  
Results from optional MRIs or other breast imaging (other than mammograms) should be entered into the eCRF.


Appendix 3
Schedule of Activities:  Cohort 3 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
201/Protocol CO40151, Version 6
cc Baseline distant-site tumor staging procedures should be performed as clinically indicated in alignment with National Comprehensive Cancer 
Network (NCCN) or national guidelines (see Section 4.5.6.4).
dd At screening and Day 1 of Cycle 1, record all concomitant medications taken between 14 days prior to screening and Day 1 of Cycle 1; at 
subsequent timepoints, record new concomitant medications and any changes to the daily dosing.  Actual intake of anti-diarrheal, pain 
medication, or premedications at each dosage change should be recorded. 
ee After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new 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 last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs 
first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  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 treatment or trial-related procedures until a final outcome can be reported.
ff Prophylactic treatment should be administered as described in Section 4.3.3.
gg Patients will be treated for five cycles of 28 days each.  Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 
and 15 of Cycles 15.  Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 will be administered by IV infusion on Days 1 and 15 of 
Cycles 1 and 2.  Paclitaxel 80 mg/m2 will be administered by IV infusion on Days 1, 8, 15, and 22 of Cycles 35.  In Arm F, ipatasertib will be 
administered orally QD at a dose of 300 mg on Days 121 of Cycles 1 and 2 and at a dose of 400 mg on Days 121 of Cycles 35.  In Arm G, 
ipatasertib will be administered orally QD at a dose of 400 mg on Days 121 of Cycles 15.


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Appendix 4
Schedule of Pharmacokinetic and Immunogenicity Samples:  
Cohorts 1 and 4
Table 1
Schedule of Pharmacokinetic and Immunogenicity Samples for 
Cohort 1 (Arms A and B) and Cohort 4 (Arm H)
Visit
Time
Sample
Day 1 of Cycle 1
Prior to start of first 
atezolizumab infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
30 (10) minutes after end of 
atezolizumab infusion
Atezolizumab PK (serum)
Day 15 of Cycle 1
Prior to ipatasertib dose
Ipatasertib PK (plasma)
1 hour after ipatasertib dose
Ipatasertib PK (plasma)
2 hours after ipatasertib dose
Ipatasertib PK (plasma)
4 hours after ipatasertib dose
Ipatasertib PK (plasma)
6 hours after ipatasertib dose
Ipatasertib PK (plasma)
Day 15 of Cycle 1
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 2
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 3
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 15 of Cycle 3
13 hours after ipatasertib 
dose
Ipatasertib PK (plasma)
Day 1 of Cycle 4
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 8
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycles 12 and 16
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Treatment discontinuation visit 
(30 days after last dose)
At visit
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
ADAanti-drug antibody; PKpharmacokinetic.


Appendix 4
Schedule of Pharmacokinetic and Immunogenicity Samples:  
Cohorts 1 and 4 (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
203/Protocol CO40151, Version 6
Table 2
Schedule of Pharmacokinetic and Immunogenicity Samples for 
Cohort 1 (Arms C and D)
Visit
Time
Sample
Day 1 of Cycle 1 
Prior to start of first 
atezolizumab infusion (Arm D 
only)
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
30 (10) minutes after end of 
atezolizumab infusion (Arm D 
only)
Atezolizumab PK (serum)
Day 15 of Cycle 1 
Prior to start of atezolizumab 
infusion
Prior to start of ipatasertib 
dose (Arm C only)
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Ipatasertib PK (plasma)
30 (10) minutes after end of 
atezolizumab infusion (Arm C 
only)
Atezolizumab PK (serum)
2 hours (30) after ipatasertib 
dose (Arm D only)
Ipatasertib PK (plasma)
Day 1 of Cycle 2
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 15 of Cycle  2
Prior to ipatasertib dose
Ipatasertib PK (plasma)
1 hour after ipatasertib dose
Ipatasertib PK (plasma)
2 hours after ipatasertib dose
Ipatasertib PK (plasma)
4 hours after ipatasertib dose
Ipatasertib PK (plasma)
6 hours after ipatasertib dose
Ipatasertib PK (plasma)
Day 15 of Cycle 2
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 3
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 15 of Cycle 3
13 hours after ipatasertib 
dose
Ipatasertib PK (plasma)
Day 1 of Cycle 4
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 8
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycles 12 and 16
Prior to start of atezolizumab 
infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Treatment discontinuation visit 
(30 days after last dose)
At visit
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
ADAanti-drug antibody; PKpharmacokinetic.


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Appendix 5
Schedule of Pharmacokinetic and Immunogenicity Samples:  
Cohort 2 (Biopsy Cohort)
Visit
Time
Sample
Day 1 of Cycle 1
Prior to ipatasertib dose a
Coproporphyrin I and III
sample (plasma)
Day 8 of Cycle 1
Prior to ipatasertib dose
Ipatasertib PK (plasma)
Coproporphyrin I and III
sample (plasma)
1 hour after ipatasertib dose
Ipatasertib PK (plasma)
Coproporphyrin I and III
sample (plasma)
2 hours after ipatasertib dose
Ipatasertib PK (plasma)
Coproporphyrin I and III
sample (plasma)
Prior to start of first 
atezolizumab infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
30 (10) minutes after end of 
atezolizumab infusion
Atezolizumab PK (serum)
Day 1 of Cycle 2
Prior to atezolizumab infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 3
Prior to atezolizumab infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Day 1 of Cycle 4
Prior to atezolizumab infusion
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Treatment discontinuation visit 
(30 days after last dose)
At visit
Atezolizumab PK (serum)
Atezolizumab ADA (serum)
ADAanti-drug antibody; AtezoIpatatezolizumab plus ipatasertib; PKpharmacokinetic.
Notes:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment 
period should be performed within3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.
PK sampling should be conducted on the day of dosing and adapted based on actual date of 
dosing.
Dose time on the day before and day of PK sampling should be accurately reported. Ipatasertib 
dosing on the day of PK sampling should be taken in the clinic.
Any incidence of vomiting within 3 hours post ipatasertib administration should also be recorded 
for the day of PK sampling. 
PK sampling timepoint should be accurately reported.
a Predose0 to 3 hours prior to dosing with ipatasertib on the day of the visit.


Ipatasertib—F. Hoffmann-La Roche Ltd
205/Protocol CO40151, Version 6
Appendix 6
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples:  Cohort 3
Visit
Time
Sample
Day 1 of Cycle 1
Prior to the first dose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarker (blood and plasma)
30 (10) minutes after 
completion of atezolizumab 
infusion

Atezolizumab PK (serum)
Day 15 of Cycles 1 and 4 a
Prior to dose

Ipatasertib and G-037720 PK
(plasma)
2 to 4 hours after dose

Ipatasertib and G-037720 PK
(plasma)
Day 1 of Cycles 2, 3, 4, and 5
Prior to dose

Atezolizumab PK (serum)

Atezolizumab ADA (serum)
Surgical intervention
Prior to surgery

Biomarkers (blood and plasma)
Study completion visit or early 
termination visit (60 days after 
final dose of study treatment)
NA

Atezolizumab PK (serum)

Atezolizumab ADA (serum)

Biomarkers (plasma)
At disease recurrence
NA

Biomarkers (blood and plasma)
ADAanti-drug antibody; NAnot applicable; PKpharmacokinetic; RBRResearch Biosample 
Repository; WGS whole genome sequencing.
Notes:  Except for Day 1 of Cycle 1, all other study visits and assessments during the treatment period 
should be performed within 3 days of the scheduled date.  Study assessments may be delayed or 
moved ahead of the window to accommodate holidays, vacations, and unforeseen delays.
If treatment is withheld (e.g., due to adverse events), the pharmacokinetic, immunogenicity, and 
biomarker samples during the neoadjuvant phase should be taken during the same cycle as shown in 
the table above (e.g., if the dose on Day 1 of Cycle 2 is delayed, the atezolizumab PK [serum] sample 
and atezolizumab ADA [serum] sample scheduled for predose should still be taken on Day 1 of 
Cycle 2).  The only exception is on Day 1 of Cycle 1 when the sample should only be taken on the day 
of the patient’s first dose of the study. 
Biomarker (blood) sample may include whole blood WGS (i.e., at sites with local regulatory authority 
approval).  Please see lab manual for detailed collection instructions.
a Day 15 of Cycle 1 for Arm F; Day 15 of Cycles 1 and 4 for Arm G.


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Appendix 7
Eastern Cooperative Oncology Group
Scale of Performance Status
Grade
Performance Status
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 house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
Oken MM, Creech RH, Tormey DC, et al:  Toxicity and response criteria of the eastern 
cooperative oncology group. Am J Clin Oncol 1982;5:64955.


Ipatasertib—F. Hoffmann-La Roche Ltd
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Appendix 8
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations


Appendix 8
ASCO/CAP Estrogen Receptor and Progesterone Receptor 
Guideline Recommendations (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
208/Protocol CO40151, Version 6
The complete guideline recommendations can be downloaded from 
http://www.cap.org/web/home/resources/cap-guidelines/current-cap-guidelines/er-pgr-
guideline.








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


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
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mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
c. Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of 
bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
Target Lesions:  Specifications by Methods of Measurements 
a. Measurement of Lesions
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
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b. Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on a chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thicknesses greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (without IV contrast) will be used to evaluate the patient at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed should also be based on the 
tumor type and the anatomic location of the disease and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine whether substitution of these other approaches is possible and, 
if not, the patient should be considered not evaluable from that point forward.  Care must 
be taken in measurement of target lesions on a different modality and interpretation of 
non-target disease or new lesions since the same lesion may appear to have a different 
size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.


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


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


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


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
218/Protocol CO40151, Version 6
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
–
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
–
The appearance of one or more new lesions is also considered progression.
d. Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden on the basis of the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease; that is, an increase in tumor burden representing an 
additional 73% increase in volume (which is equivalent to a 20% increase in diameter in 
a measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large” or an increase in lymphangitic disease from localized to widespread or may be 
described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Although it would be ideal to have objective criteria apply to non-measurable 


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
219/Protocol CO40151, Version 6
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
e. New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocalthat is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
Evaluation of Response
a. Time Point Response (Overall Response)
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
220/Protocol CO40151, Version 6
Table 1 Time Point Response:  Patients with Target Lesions 
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
Table 2 Time Point Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.
b. Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered not evaluable at that time point unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm
with three measured lesions, and during the study, only two lesions were assessed but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
221/Protocol CO40151, Version 6
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, 
the response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess,” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that time point.
Table 3 Best Overall Response When Confirmation Is Required
Overall Response 
at First Time Point
Overall Response at 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
PR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first time point, any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first time point.  Under these circumstances, the original CR should be changed to PR and 
the best response is PR.


Appendix 10
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
222/Protocol CO40151, Version 6
c. Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


Ipatasertib—F. Hoffmann-La Roche Ltd
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Appendix 11
Preexisting Autoimmune Diseases and Immune Deficiencies
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Subjects 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 subjects 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.  
Contact the Medical Monitor regarding 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 cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 12
Anaphylaxis Precautions
EQUIPMENT NEEDED

Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications 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 13
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 6 in 
Section 5.1.9.4.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
226/Protocol CO40151, 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 Table 6 in Section 5.1.9.4.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 6 of Section 5.1.9.4.
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 below.  For events of hyperglycemia, see 
Table 6 of Section 5.1.9.4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
227/Protocol CO40151, Version 6
Table 1
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
Continue atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH weekly.
Symptomatic 
hypothyroidism
Withhold atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH weekly.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:
Continue atezolizumab.
Monitor TSH every 4 weeks.
TSH 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism
Withhold atezolizumab.
Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated
hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
228/Protocol CO40151, Version 6
Table 1
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
Initiate hormone replacement if clinically indicated.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent hypophysitis, treat as a Grade 4 event.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
229/Protocol CO40151, Version 6
Table 1
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 2 below.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
230/Protocol CO40151, Version 6
Table 2
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 
Continue atezolizumab.
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to ophthalmologist.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
231/Protocol CO40151, 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.  
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 below.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
232/Protocol CO40151, Version 6
Table 3
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.
Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
myocarditis, Grade 34
Permanently discontinue atezolizumab and contact Medical Monitor. c
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
233/Protocol CO40151, Version 6
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T-cells
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 4.
Severe COVID-19 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 COVID-19, 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 COVID-19 is confirmed, the disease should 
be managed as per local or institutional guidelines.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 4
below.  For subsequent cycles, IRRs should be managed according to institutional 
guidelines.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
234/Protocol CO40151, 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, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS.
Grade 2 a
Fever b with 
hypotension 
not requiring 
vasopressors
and/or
Hypoxia 
requiring 
low-flow 
oxygen d by 
nasal cannula 
or blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. 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. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
235/Protocol CO40151, 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 treatmentsg may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
236/Protocol CO40151, 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:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading 
for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or 
organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  In this 
case, the grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
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 event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after consulting the Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
237/Protocol CO40151, Version 6
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab.  The differential diagnosis of acute abdominal pain should include 
pancreatitis.  Appropriate work-up should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 5 below.
Table 5
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Continue atezolizumab.
Monitor amylase and lipase weekly.
For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Monitor amylase and lipase every other day.
If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume 
atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
238/Protocol CO40151, Version 6
Table 5
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
If event resolves to Grade 1 or better, resume 
atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
239/Protocol CO40151, 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 are provided in Table 6 below.
Table 6
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 
Continue atezolizumab.
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 
Continue atezolizumab.
Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to dermatologist for evaluation and, if indicated, 
biopsy.
Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
240/Protocol CO40151, Version 6
Table 9
Management Guidelines for Dermatologic Events (cont.)
Dermatologic 
event, Grade 4
Permanently discontinue atezolizumab 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 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 7 below.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
241/Protocol CO40151, Version 6
Table 7
Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1
Continue atezolizumab.
Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 
Withhold atezolizumab for up to 12 weeks after event onset. a
Investigate etiology.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to neurologist.
Initiate treatment as per institutional guidelines.
Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
242/Protocol CO40151, Version 6
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
below.
Table 8
Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades
Permanently discontinue atezolizumab and contact Medical Monitor. a
Refer patient to neurologist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function.  Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
243/Protocol CO40151, Version 6
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 below.
Table 9
Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
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.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
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 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
244/Protocol CO40151, Version 6
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 10.
Table 10 Management Guidelines for Immune- Mediated Myositis
Event
Management
Immune-
mediated
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
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.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
245/Protocol CO40151, Version 6
Table 10 Management Guidelines for Immune- Mediated Myositis (cont.)
Event
Management
Immune-
mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
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.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
246/Protocol CO40151, Version 6
Table 10 Management Guidelines for Immune- Mediated Myositis (cont.)
Event
Management
Immune-
mediated
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
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.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
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.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
247/Protocol CO40151, Version 6
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

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/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 11.


Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
248/Protocol CO40151, Version 6
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.
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Appendix 13
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Ipatasertib—F. Hoffmann-La Roche Ltd
249/Protocol CO40151, Version 6
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