Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 151
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, multicenter, pre-operative Phase II study designed to estimate the efficacy of ipatasertib combined with paclitaxel chemotherapy versus placebo combined with paclitaxel chemotherapy in women with Stage Ia - IIIa triple-negative breast adenocarcinoma. The anticipated time on study treatment is 12 weeks.

Detailed description:

Arms:
arm 1: Participants will receive ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses). arm 2: Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses).

Interventions: intervention 1: Ipatasertib intervention 2: Paclitaxel intervention 3: Placebo
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 3 cycles. intervention 2: Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) as IV infusion QW for 3 cycles. intervention 3: Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase II Randomized, Double-Blind, Study of Ipatasertib (GDC-
0068), an Inhibitor to AKT, in Combination With Paclitaxel as 
Neoadjuvant Treatment for Patients With Early Stage Triple 
Negative Breast Cancer 
NCT Number: 
NCT02301988 
Document Date: 
Protocol Version 3: 19 Jan 2016 
 
 
 


 
Title
19-Jan-2016 19:25:56
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
Ipatasertib (GDC-0068)—Genentech, Inc. 
Protocol GO29505, Version 3 
PROTOCOL 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND, 
STUDY OF IPATASERTIB (GDC-0068), AN 
INHIBITOR TO AKT, IN COMBINATION WITH 
PACLITAXEL AS NEOADJUVANT TREATMENT 
FOR PATIENTS WITH EARLY STAGE 
TRIPLE−NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: GO29505 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2014-003029-16 
IND NUMBER: 
111051 
TEST PRODUCT: 
Ipatasertib (GDC-0068; RO5532961) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  14 August 2014 
DATES AMENDED: 
Version 2:  23 July 2015 
Version 3:  See electronic date stamp below. 


Ipatasertib (GDC-0068)—Genentech, Inc. 
2/Protocol GO29505, Version 3 
PROTOCOL AMENDMENT, VERSION 3 
RATIONALE 
Protocol GO29505 has been amended to include the following changes: 
• 
Wording regarding dosing delay due to treatment-related toxicity (Section 5.1.5.1) 
has been added to clarify that when dosing delay to paclitaxel occurs, preferred 
dosing for ipatasertib/placebo is to align and resume with paclitaxel dosing 
• 
To clarify that dose reductions and dose modification(s) for ipatasertib/placebo and 
paclitaxel are independent (Table 1) 
• 
To provide further guidance and clarification to the management of diarrhea 
Dosing modification for ipatasertib and placebo (Section 5.1.5.2) 
Diarrhea management (Section 5.1.5.6) 
• 
To add Grade ≥ 3 diarrhea and Grade 2 diarrhea that persists for longer than 5 days 
despite optimal medical management (per diarrhea management in Section 5.1.5.6) 
as adverse event of special interest in Section 5.2.3 to improve monitoring of 
diarrhea events by the Sponsor 
• 
Wording regarding recording of persistent or recurrent adverse events 
(Section 5.3.5.3) has been modified/added to clarify data entry requirements for 
adverse event reporting 
• 
To add a sensitivity analysis that accounts for patients whose pCR assessment 
cannot be ascertained (Section 6.4.1). 
• 
To include additional information on the management guideline for diarrhea 
(Appendix 6) 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


Ipatasertib (GDC-0068)—Genentech, Inc. 
3/Protocol GO29505, Version 3 
PROTOCOL AMENDMENT, VERSION 3 
SUMMARY OF CHANGES 
GLOBAL CHANGE 
The Medical Monitor has been changed to 
 M.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1.2:  Joint Monitoring Committee 
A Joint Monitoring Committee (JMC) will be in place during the study and will provide 
oversight of safety and efficacy.  The primary responsibility of the JMC is to review the 
available safety data and to make a recommendation to continue, modify the study 
design as required for improved safety, or terminate the study.  While a JMC review is 
being conducted, patient accrual into the study will continue.  The JMC will be 
composed of a designated sponsor medical oncologist (who is not the study medical 
monitor), the drug safety officer, and the study biostatistician.  In addition, the JMC will 
also include at least two external medical oncologists who are not employees of 
Roche/Genentech and are not affiliated with the study team, to provide clinical and 
methodological expertise in early breast cancer.  The members of the JMC will not 
interact with the sites or investigators in terms of study conduct.   
The JMC will convene to review partially unblinded summaries of the safety data after 
approximately 20 patients have completed study treatment, including surgical resection.  
In addition, after approximately 90 patients have completed study treatment as well as 
surgery, the JMC will convene again to review data from an interim safety and efficacy 
analysis.  Additional details (e.g., JMC members, communication, affiliations) will be 
provided in the JMC Agreement.  While this review is being conducted, patient accrual 
into the study will continue.  The medical monitor may also request additional safety 
and/or efficacy analysis and may call for additional meetings of the JMC to review 
ongoing data to assess risk/benefit.  
The reviews the JMC will conduct are described in Section 6.8.1 and Section 6.8.2. 
SECTION 4.3.2.2:  Paclitaxel 
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
15, and 22 of each 4-week cycle, for a total of 3 cycles of treatment (12 total doses).… 
SECTION 5.1.2:  Safety Monitoring 
Safety will be evaluated in this current study through the monitoring of all serious 
adverse events, non-serious adverse events, and laboratory abnormalities, defined and 
graded according to NCI CTCAE, v4.0.  In addition, prespecified analyses of the safety 
and relevant efficacy data will be conducted by the JMC after approximately 20 patients 
have completed study treatment including surgery (safety only), and again after 


Ipatasertib (GDC-0068)—Genentech, Inc. 
4/Protocol GO29505, Version 3 
approximately 90 patients have completed study treatment including surgery (safety and 
efficacyIn addition, the JMC will conduct analyses of safety (see Section 6.8.1 and 
Section 6.8.2). 
SECTION 5.1.5.1:  General Guidelines 
General guidelines for dosage/schedule modification are summarized as follows: 
• 
If paclitaxel treatment component is delayed, the study cycle day count for each 
cycle continues and does not shift.  
• 
If ipatasertib or placebo treatment is delayed, paclitaxel treatment should continue 
as scheduled; however, if paclitaxel treatment is delayed and ipatasertib/placebo is 
scheduled to be administered at the same timepoint, it is preferred that 
ipatasertib/placebo is also delayed to align with paclitaxel dosing. 
• 
If the dose day of paclitaxel treatment is delayed, the ipatasertib or placebo may be 
delayed at the discretion of the investigator. 
 
SECTION 5.1.5.2:  Dosage Modification for Ipatasertib and Placebo 
If the patient does not tolerate the QD dosing of the ipatasertib or placebo, a BID 
regimen of the ipatasertib or placebo (with the total daily dose divided in half, without a 
dose reduction, and administered approximately every 12 hours) may be attempted 
(e.g., a 400 mg QD dose may be divided into 200 mg administered BID).  The BID 
regimen may be used to alleviate gastrointestinal symptoms, including nausea, and 
vomiting, and/or diarrhea.  Employment of a BID regimen should not be considered as a 
dose reduction.  No more than two dose reductions of ipatasertib or placebo per patient 
(lowest dose level to be administered will be 200 mg/day) will be allowed, and dose 
re-escalation of ipatasertib or placebo may be permitted in the study after discussion 
with the Medical Monitor. 
SECTION 5.1.5.6:  Diarrhea 
Diarrhea should be managed with loperamide or per institutional guidelines.local 
guidelines and standard of care, including but not limited to therapy with Lomotil 
(diphenoxylate and atropine), codeine, or octreotide.  Dose reductions for diarrhea 
should occur only if the symptoms persist despite treatment with adequate (combination) 
anti-diarrheal medications.  If persistent diarrhea (more than 48 hours despite optimal 
medical treatment or dose hold) is attributable to the ipatasertib or placebo, and/or 
paclitaxel, dosage modification guidelines for ipatasertib or placebo, and/or paclitaxel are 
outlined below: 
• 
Grade 2 diarrhea:  The investigator should initiate optimal medical management 
with loperamide as early as possible.  If diarrhea is persistent (lasting longer than 
48 hours despite medical management), second-line therapy may employ a BID 
regimeninclude (but not limited to) Lomotil (diphenoxylate and atropine), codeine 
or octreotide per local guidelines and standard of care.  Ipatasertib/placebo dosing 
should be interrupted until improvement of diarrhea to Grade ≤ 1, at which time 
ipatasertib administration (equivalent to/placebo may be resumed at the total 
dailysame dose divided by half), see Section 0.  Alternatively, the investigator may 


Ipatasertib (GDC-0068)—Genentech, Inc. 
5/Protocol GO29505, Version 3 
alsofor initial occurrence with consideration of maintenance loperamide dosing (i.e., 
2 mg, 2 to 4 times daily).  Investigators may reduce ipatasertib or placebo by one 
dose level (see Table 1) for recurrent Grade 2 diarrhea.  If diarrhea persists 
following up to two dose reductions of ipatasertib or placebo, consider dose hold or 
reduction of paclitaxel by one.  Dose intensity of paclitaxel should be maintained as 
much as is safely possible. Paclitaxel dose level reduction or discontinuation can be 
considered if diarrhea persists even after ipatasertib/placebo discontinuation (see 
Table 1). 
• 
Grade ≥ 3 diarrhea:  Medical management of diarrhea per Grade 2 diarrhea above 
should be initiated as early as possible.  Ipatasertib or placebo should be held until 
the diarrhea resolves to Grade ≤ 21, at which time maintenance loperamide dosing 
(i.e., 2 mg, 2 to 4 times daily) is recommended.  The dose of ipatasertib or placebo 
will be reduced by one dose level when treatment resumes (see Table 1).  If 
diarrhea persists following dose reduction of ipatasertib or placebo, consideran 
additional dose hold or reduction of paclitaxel by one dose levelwith 
ipatasertib/placebo should be considered (see Table 1).  Dose intensity of paclitaxel 
should be maintained as much as is safely possible.  Paclitaxel dose reduction or 
discontinuation can be considered if diarrhea persists even after ipatasertib/placebo 
discontinuation (see Table 1).  
 
Dose re-escalation of the ipatasertib or placebo, and/or paclitaxel may be permitted in 
subsequent cycles for patients who exhibit Grade ≤ 21 diarrhea for at least one cycle 
after discussion with the Medical Monitor.  
For additional information on the management guideline for diarrhea, see Appendix 6. 
SECTION 5.2.3:  Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) 
…Adverse events of special interest for this study include the following: 
• 
Grade ≥ 3 colitis or diarrhea 
• 
Grade 2 diarrhea that persists for longer than 5 days despite optimal medical 
management (per diarrhea management in Section 5.1.5.6) 
SECTION 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 , unless the severity (intensity or grade) of the event 
will be recorded at the time the event is first reported.increases.  If a persistent adverse 
event becomes more severe, the most extreme severityit should also be recorded as a 
separate event on the Adverse Event eCRF.  The initial (less severe) adverse event 
report should be updated to indicate that the event resolved on the date just prior to the 
day the event became more severe.  If thea persistent adverse event becomes serious, it 
should be recorded as a separate event on the Adverse Event eCRF and 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 


Ipatasertib (GDC-0068)—Genentech, Inc. 
6/Protocol GO29505, Version 3 
be updated by changing the event from "initial (non -serious" to ") adverse event report 
should be updated to indicate that the event resolved on the date just prior to the day 
the event became serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events.  
SECTION 6.4.1:  Primary Efficacy Endpoint 
In addition, a sensitivity analysis may be conducted to account for patients whose pCR 
assessment cannot be ascertained. 
Section 6.8.2:  Optional Interim Analysis 
In addition, the Medical Monitor may request additional safety analysis and may call 
for additional meetings of the JMC to review ongoing data to assess risk/benefit. 
Table 1:  Suggested Dose Reductions for Ipatasertib, Placebo, and/or 
Paclitaxel 
Table 1 has been updated to reflect changes to the protocol. 
Figure 2:  Study Schema 
Figure 2 has been updated to reflect changes to the protocol. 
APPENDIX 6:  Management Guideline for Diarrhea 
Appendix 6 has been added to the protocol. 


Ipatasertib (GDC-0068)—Genentech, Inc. 
7/Protocol GO29505, Version 3 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Breast Cancer............................................... 27 
1.1.1 
Molecular Classification of Breast Cancer, 
Including Triple-Negative Breast Cancer............................... 27 
1.1.2 
PI3K/Akt Signaling in Triple-Negative Cancer ....................... 28 
1.1.3 
Akt Activation and Chemoresistance ..................................... 28 
1.1.4 
Neoadjuvant Therapy for Breast Cancer ............................... 29 
1.2 
Background on Ipatasertib..................................................... 30 
1.2.1 
Summary of Ipatasertib Nonclinical Studies .......................... 30 
1.2.2 
Summary of Ipatasertib Clinical Studies ................................ 31 
1.2.2.1  Study PAM4743g-Phase I Study of 
Single-Agent Ipatasertib........................................................ 32 
1.2.2.2  Study PAM4983g-Phase Ib Study of Ipatasertib 
and Chemotherapy ............................................................... 33 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 35 
2. 
OBJECTIVES.............................................................................................. 36 
2.1 
Efficacy Objectives ................................................................ 36 
2.2 
Safety Objective .................................................................... 37 
2.3 
Pharmacokinetic Objective .................................................... 37 
2.4 
Exploratory Objectives........................................................... 37 
3. 
STUDY DESIGN ......................................................................................... 37 
3.1 
Description of Study .............................................................. 37 
3.1.1 
Surgery.................................................................................. 41 
3.1.2 
Joint Monitoring Committee................................................... 41 
3.2 
End of Study.......................................................................... 41 
3.3 
Rationale for Study Design.................................................... 42 
3.3.1 
Rationale for Conducting the Study in the 
Neoadjuvant Setting.............................................................. 42 
3.3.2 
Rationale for Starting Dose and Schedule of 
Ipatasertib ............................................................................. 42 


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8/Protocol GO29505, Version 3 
3.3.3 
Rationale for Treatment with Paclitaxel and 
Choice of Paclitaxel Regimen ............................................... 43 
3.3.4 
Rationale for Objective Response Assessed by 
MRI and Inclusion of Other MRI-Derived Metrics 
for Exploratory Purposes....................................................... 44 
3.3.5 
Rationale for Collection Tissue for Examining 
PTEN and Other AKT Pathway Components as 
Diagnostic Biomarkers .......................................................... 44 
3.3.6 
Rationale for Collection of Fresh Tumor Biopsies 
Following Progression for Exploratory Purposes .................. 45 
3.3.7 
Rationale for Collection of Blood Samples for 
Noninvasive Disease Monitoring........................................... 45 
3.3.8 
Rationale for the Pharmacokinetic Evaluation 
Schedule............................................................................... 46 
3.4 
Outcome Measures ............................................................... 46 
3.4.1 
Efficacy Outcome Measures.................................................. 46 
3.4.2 
Safety Outcome Measures .................................................... 46 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 46 
3.4.4 
Exploratory Outcome Measures ............................................ 47 
4. 
MATERIALS AND METHODS .................................................................... 47 
4.1 
Patients.................................................................................. 47 
4.1.1 
Inclusion Criteria.................................................................... 47 
4.1.2 
Exclusion Criteria................................................................... 48 
4.2 
Method of Treatment Assignment and Blinding..................... 50 
4.2.1 
Study Patients and Analysis Groups ..................................... 51 
4.2.2 
Control Groups ...................................................................... 51 
4.2.3 
Minimization of Bias............................................................... 51 
4.2.4 
Method of Unblinding............................................................. 52 
4.3 
Study Treatment.................................................................... 52 
4.3.1 
Formulation, Packaging, and Handling.................................. 52 
4.3.1.1  Ipatasertib (GDC-0068) and Placebo ................................... 52 
4.3.1.2  Paclitaxel.............................................................................. 52 
4.3.2 
Dosage, Administration, and Compliance.............................. 53 
4.3.2.1  Ipatasertib (GDC-0068) and Placebo ................................... 53 
4.3.2.2  Paclitaxel.............................................................................. 54 


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4.3.3 
Investigational Medicinal Product Accountability ................... 54 
4.3.4 
Post-Trial Access to Ipatasertib............................................. 55 
4.4 
Concomitant Therapy ............................................................ 56 
4.4.1 
Permitted Therapy ................................................................. 56 
4.4.2 
Prohibited Therapy ................................................................ 56 
4.5 
Study Assessments ............................................................... 57 
4.5.1 
Descriptions of Study Assessments ...................................... 57 
4.5.1.1  Informed Consent Forms and Screening Log....................... 57 
4.5.1.2  Medical History and Demographic Data............................... 57 
4.5.1.3  Physical Examinations ......................................................... 58 
4.5.1.4  Vital Signs ............................................................................ 58 
4.5.1.5  Distant Sites Tumor Assessment ......................................... 58 
4.5.1.6  Tumor and Response Evaluations ....................................... 59 
4.5.1.7  Laboratory, Biomarker, and Other Biological 
Samples............................................................................... 60 
4.5.1.8  Electrocardiograms .............................................................. 62 
4.5.1.9  Pathology Assessment at Surgery ....................................... 63 
4.5.2 
Timing of Study Assessments ............................................... 63 
4.5.2.1  Screening and Pretreatment Assessments .......................... 63 
4.5.2.2  Assessments during Treatment............................................ 63 
4.5.2.3  Post-Surgery/Early Termination Assessments ..................... 63 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 64 
4.6.1 
Patient Discontinuation.......................................................... 64 
4.6.2 
Study Treatment Discontinuation........................................... 64 
4.6.3 
Study and Site Discontinuation.............................................. 65 
5. 
ASSESSMENT OF SAFETY....................................................................... 65 
5.1 
Safety Plan ............................................................................ 65 
5.1.1 
Eligibility Criteria .................................................................... 65 
5.1.2 
Safety Monitoring................................................................... 66 
5.1.3 
Risks Associated with Ipatasertib .......................................... 66 
5.1.4 
Potential Safety Issues Associated with 
Paclitaxel............................................................................... 66 
5.1.5 
Dosage Modifications ............................................................ 67 


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5.1.5.1  General Guidelines............................................................... 67 
5.1.5.2  Dosage Modification for Ipatasertib and Placebo ................. 68 
5.1.5.3  Fasting Hyperglycemia......................................................... 69 
5.1.5.4  Neutropenia and/or Thrombocytopenia................................ 70 
5.1.5.5  Nausea and/or Vomiting....................................................... 70 
5.1.5.6  Diarrhea ............................................................................... 71 
5.1.5.7  Mucositis .............................................................................. 72 
5.1.5.8  Skin Toxicity ......................................................................... 72 
5.1.5.9  Peripheral Neuropathy ......................................................... 73 
5.1.5.10  Hypersensitivity .................................................................. 73 
5.1.5.11  Other Non-Hematologic Toxicities...................................... 74 
5.1.6 
Management of Specific Adverse Events .............................. 74 
5.1.6.1  Hyperglycemia ..................................................................... 74 
5.1.6.2  Hematologic Toxicity ............................................................ 75 
5.1.6.3  Gastrointestinal Toxicity ....................................................... 75 
5.1.6.4  Dermatologic Toxicity........................................................... 75 
5.2 
Safety Parameters and Definitions ........................................ 76 
5.2.1 
Adverse Events ..................................................................... 76 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ..................................................................... 77 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor).............................. 77 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78 
5.3.1 
Adverse Event Reporting Period ........................................... 78 
5.3.2 
Eliciting Adverse Event Information ....................................... 79 
5.3.3 
Assessment of Severity of Adverse Events ........................... 79 
5.3.4 
Assessment of Causality of Adverse Events ......................... 79 
5.3.5 
Procedures for Recording Adverse Events............................ 80 
5.3.5.1  Diagnosis versus Signs and Symptoms ............................... 80 
5.3.5.2  Adverse Events That Are Secondary to Other 
Events.................................................................................. 81 
5.3.5.3  Persistent or Recurrent Adverse Events .............................. 81 
5.3.5.4  Abnormal Laboratory Values................................................ 82 


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5.3.5.5  Abnormal Vital Sign Values.................................................. 82 
5.3.5.6  Abnormal Liver Function Tests............................................. 83 
5.3.5.7  Deaths.................................................................................. 83 
5.3.5.8  Preexisting Medical Conditions ............................................ 84 
5.3.5.9  Lack of Efficacy or Worsening of Breast Cancer .................. 84 
5.3.5.10  Hospitalization or Prolonged Hospitalization ...................... 84 
5.3.5.11  Adverse Events Associated with an Overdose 
or Error in Drug Administration........................................... 85 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 85 
5.4.1 
Emergency Medical Contacts................................................ 86 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ..................................................................... 86 
5.4.2.1  Events That Occur prior to Study Drug Initiation .................. 86 
5.4.2.2  Events That Occur after Study Drug Initiation ...................... 86 
5.4.3 
Reporting Requirements for Pregnancies.............................. 87 
5.4.3.1  Pregnancies in Female Patients........................................... 87 
5.4.3.2  Congenital Anomalies/Birth Defects and 
Abortions ............................................................................. 87 
5.5 
Follow-Up of Patients after Adverse Events .......................... 87 
5.5.1 
Investigator Follow-Up........................................................... 87 
5.5.2 
Sponsor Follow-Up ................................................................ 88 
5.6 
Post-Study Adverse Events................................................... 88 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 88 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 89 
6.1 
Determination of Sample Size ............................................... 89 
6.2 
Summaries of Conduct of Study............................................ 90 
6.3 
Summaries of Treatment Group Comparability ..................... 90 
6.4 
Efficacy Analyses .................................................................. 90 
6.4.1 
Primary Efficacy Endpoint...................................................... 90 
6.4.2 
Secondary Efficacy Endpoints............................................... 90 
6.5 
Safety Analyses..................................................................... 91 


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6.6 
Pharmacokinetic Analyses..................................................... 91 
6.7 
Exploratory Analyses............................................................. 92 
6.8 
Interim Analyses .................................................................... 92 
6.8.1 
Planned Interim Analyses...................................................... 92 
6.8.2 
Optional Interim Analysis....................................................... 92 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 92 
7.1 
Data Quality Assurance......................................................... 92 
7.2 
Electronic Case Report Forms............................................... 93 
7.3 
Source Data Documentation.................................................. 93 
7.4 
Use of Computerized Systems .............................................. 93 
7.5 
Retention of Records............................................................. 94 
8. 
ETHICAL CONSIDERATIONS.................................................................... 94 
8.1 
General Ethical Considerations ............................................. 94 
8.2 
Compliance with Laws and Regulations ................................ 94 
8.3 
Informed Consent .................................................................. 95 
8.4 
Institutional Review Board or Ethics Committee.................... 96 
8.5 
Confidentiality........................................................................ 96 
8.6 
Financial Disclosure .............................................................. 97 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 97 
9.1 
Study Documentation ............................................................ 97 
9.2 
Protocol Deviations................................................................ 97 
9.3 
Site Inspections ..................................................................... 98 
9.4 
Administrative Structure......................................................... 98 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 98 
9.6 
Protocol Amendments ........................................................... 99 
10.  REFERENCES ......................................................................................... 100 
 


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LIST OF TABLES 
Table 1 
Suggested Dose Reductions for Ipatasertib, Placebo, 
and/or Paclitaxel ......................................................................... 68 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 79 
Table 3 
Causal Attribution Guidance ....................................................... 80 
 
 
LIST OF FIGURES 
Figure 1 
Effect of Ipatasertib (GDC-0068) and Docetaxel on 
MCF7-Neo/HER2 Breast Tumor Xenografts in Nude Mice ......... 31 
Figure 2 
Study Schema............................................................................. 38 
Figure 3 
Evaluation of Clinical Suspicion of Progression or Significant 
Residual Disease........................................................................ 40 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 105 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 109 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 110 
Appendix 4 
ECOG Performance Status Scale............................................. 116 
Appendix 5 
New York Heart Association Classification 
of Functional Cardiac Capacity ................................................. 117 
Appendix 6 
Management Guideline for Diarrhea ........................................ 118 


Ipatasertib (GDC-0068)—Genentech, Inc. 
14/Protocol GO29505, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND, 
STUDY OF IPATASERTIB (GDC-0068), AN 
INHIBITOR TO AKT, IN COMBINATION WITH 
PACLITAXEL AS NEOADJUVANT TREATMENT 
FOR PATIENTS WITH EARLY STAGE 
TRIPLE−NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: GO29505 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2014-003029-16 
IND NUMBER: 
111051 
TEST PRODUCT: 
Ipatasertib (GDC-0068; RO5532961) 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
Genentech, Inc. 
 
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 to 
the contact provided by your local study monitor. 
 


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
15/Protocol GO29505, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND, STUDY OF 
IPATASERTIB (GDC-0068), AN INHIBITOR TO AKT, IN 
COMBINATION WITH PACLITAXEL AS NEOADJUVANT 
TREATMENT FOR PATIENTS WITH EARLY STAGE 
TRIPLE−NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
GO29505 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2014-003029-16 
IND NUMBER: 
111051 
TEST PRODUCT: 
Ipatasertib (GDC-0068; RO5532961) 
PHASE: 
II 
INDICATION: 
Breast cancer 
SPONSOR: 
Genentech, Inc. 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is to estimate the efficacy of ipatasertib combined 
with paclitaxel compared with placebo combined with paclitaxel in patients with early stage 
triple-negative breast cancer (TNBC), as measured by local pathology laboratory evaluation of 
pathological complete response (pCR) rate within the breast and axilla (ypT0/Tis ypN0) in all 
patients and in patients with phosphatase and tensin homolog (PTEN)-low tumors. 
The secondary efficacy objectives for this study are as follows: 
• 
To estimate the clinical activity of ipatasertib combined with paclitaxel compared with 
placebo combined with paclitaxel, as measured by local pathology laboratory evaluations of 
pCR within the breast (ypT0/Tis) in all patients and in patients with PTEN-low tumors 
• 
To evaluate objective response rate (ORR) assessed by breast magnetic resonance 
imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors (RECIST) of 
ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in all 
patients and in patients with PTEN-low tumors 
• 
To estimate the clinical activity, as measured by pCR (ypT0/Tis and ypT0/Tis ypN0) and 
ORR of ipatasertib combined with paclitaxel compared with placebo combined with 
paclitaxel in patients who are Akt diagnostic positive (Dx+) (defined by PTEN status, 
INPP4B status, and PI3K alterations) 
• 
To assess pCR rates according to subtypes of breast cancer defined by molecular profiles 
(e.g., the intrinsic subtypes of breast cancer defined by the PAM50 classifier) 
• 
To assess the rates of breast-conserving surgery (BCS) and conversion to BCS of 
ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in 
women with T2 or T3 tumors 
 
Safety Objective 
The safety objective for this study is to evaluate the safety and tolerability of ipatasertib 
combined with paclitaxel versus placebo combined with paclitaxel. 


 
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Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
GDC-0068 using a sparse sampling methodology, when given in combination with paclitaxel in 
early stage TNBC patients. 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To assess the effect of PI3K/Akt pathway alterations on pCR in patients treated with 
ipatasertib combined with paclitaxel versus placebo combined with paclitaxel, based on 
exploratory analysis of tumor tissue using molecular data obtained by one or more of the 
following analyses: 
Mutation and RNA/DNA copy number changes in oncogenes, tumor suppressors, 
and/or other genes associated with TNBC response to treatment and progression by 
DNA sequencing and/or in situ hybridization (ISH) 
Levels of Akt pathway proteins, as evaluated by reverse phase protein array 
Levels of tumor suppressors and/or receptor tyrosine kinases by immunohistochemistry 
(IHC) 
• 
To evaluate the changes in enhancing tumor volume from baseline to surgery as measured 
by breast MRI 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI  
• 
To assess the exposure-response relationships for efficacy, safety, and biomarker data 
 
Study Design 
Description of Study 
This is a randomized, double-blind, placebo-controlled, multicenter, pre-operative Phase II study 
designed to estimate the efficacy of ipatasertib combined with paclitaxel chemotherapy versus 
placebo combined with paclitaxel chemotherapy in women with Stage Ia−IIIa (primary 
tumors ≥ 1.5 cm) triple-negative breast adenocarcinoma.  Patients with cT4 or cN3 tumors are 
not eligible.  Patients and investigators will be blinded to study treatment.  Estrogen receptor 
(ER)- and Progesterone receptor (PgR)-negative is defined as < 1% of tumor cell expression of 
ER and PgR.  Patients who have an unknown ER, PgR, or human epidermal growth factor 2 
(HER2) status and for whom determination of status is not possible are also not eligible for this 
study.  Estimated benefit will be compared in all patients (independent of results from the 
diagnostic assessments of the tumor) and in patients with PTEN-low tumors. 
Approximately 150 patients will be enrolled at approximately 30 centers.  Patients will be 
randomized in a 1:1 ratio, stratified by the following three factors:  PTEN status (H score 0, vs. 
1 to ≤ 150, vs. > 150), node involvement (pathologically positive versus no known involvement), 
and T size (T1−2 vs. T3). 
For the purpose of enrollment, ER, PgR, and HER2 will be locally determined prior to beginning 
of study treatment.  Additionally, all enrolled patients must consent to provide sufficient and 
evaluable archival tissue for PTEN status determination.  In the absence of archival tissue, fresh 
tissue biopsy samples, excluding cytology and fine-needle aspiration (FNA) specimens, 
will be acceptable; however, evaluation of the patient’s tumor sample for PTEN status by a 
central laboratory should occur prior to the initiation of study treatment.  All patients will undergo 
pretreatment tumor tissue acquisition (snap-frozen, optimal cutting temperature [OCT], and 
formalin-fixed paraffin-embedded [FFPE] cores).  One pretreatment FFPE core biopsy and two 
freshly frozen core biopsies must be obtained for all patients prior to initiating study treatment.  
Pre-surgical FNA or core biopsy of suspicious node is allowed, but full excision lymph node 
biopsy (e.g., sentinel lymph node excisional biopsy [SLNB]) is not allowed. 
All patients will receive paclitaxel 80 mg/m2 every 7 days for a total of 12 doses (i.e., Days 1, 8, 
15, and 22 of each cycle).  Patients in the experimental arm will receive ipatasertib at a dose of 
400 mg administered orally once daily (QD) on Days 1 to 21 every 28 days and those in the 
control arm will receive placebo on the same days.  Each cycle will be 28 days in duration and 
study treatment will continue for a total of three cycles until disease progression, intolerable 


 
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toxicity, elective withdrawal from the study, or study completion or termination.  Following three 
cycles of treatment, patients will undergo surgery. 
Prior to administration of the second paclitaxel dose, a second research biopsy will be 
conducted for biomarker evaluation; at least one FFPE and at least two frozen OCT cores 
biopsy samples will be obtained.   
Primary breast tumor and axillary lymph nodes will be assessed every 4 weeks until Week 13 
by clinical breast exam (palpation and clinical measurement; caliper preferred).  Suspicion of 
progression based on clinical exam should be further evaluated.  Tumor measurement by MRI 
for disease evaluation will be performed at screening and prior to surgery (at approximately 
Weeks 10−12, following completion of neoadjuvant chemotherapy).  Early assessment by MRI 
is allowed for suspected progression.  Estimation of ORR will be by modified RECIST. 
Patients with clinical or radiologic evidence of significant residual or progressive disease, as 
defined by modified RECIST, can either proceed directly to surgery or be discontinued from the 
study, based on the investigator’s discretion.  Patients who discontinue study treatment prior to 
surgery will be required to have an additional research biopsy where at least one FFPE and at 
least two frozen OCT core biopsy samples will be obtained.   
Safety will be evaluated during the study through the monitoring of all serious and nonserious 
adverse events, graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE, v4.0).   
The pharmacokinetics of ipatasertib/placebo will be assessed in all patients. 
During Weeks 10−12 (approximately; i.e., near the time of completion of neoadjuvant 
chemotherapy), the patient will consult with the surgeon to plan the type of breast surgery to be 
performed (breast conservative vs. mastectomy) and to schedule the date for surgery. 
Following surgical resection of primary tumor, patients are expected to continue post-operative 
treatment with a standard adjuvant chemotherapy regimen such as 
5-FU/doxorubicin/cyclophosphamide (FAC), 5-FU/epirubicin/cyclophosphamide (FEC), or 
doxorubicin/cyclophosphamide (AC), if appropriate and as chosen by their treating physician.  
Post-operative treatment information (chemotherapy, radiotherapy, etc.) will be collected at the 
post-surgery visit. 
The primary efficacy endpoint, pCR within the breast and axilla (ypT0/Tis ypN0) in all patients 
and in patients with PTEN-low tumors will be assessed by local pathology evaluation following 
completion of neoadjuvant therapy and surgery. 
The trial is anticipated to have a recruitment period of approximately 24 months. 
Number of Patients 
Approximately 150 patients will be enrolled at approximately 30 centers.   
Target Population 
Patients with early stage (Stage Ia−IIIa; primary tumors ≥ 1.5 cm) triple-negative 
adenocarcinoma of the breast who have not received prior systemic therapy for this breast 
cancer may be eligible for this study. 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) 
• 
Premenopausal or postmenopausal women, age ≥ 18 years 
• 
Eastern Cooperative Oncology Group Performance Status of 0 or 1 
• 
Histologically documented triple-negative carcinoma of the breast with all of the following 
characteristics: 
Primary tumor ≥ 1.5 cm in largest diameter (cT1−3) by MRI.  In the case of a multifocal 
tumor (defined as the presence of two or more foci of cancer within the same breast 
quadrant), the largest lesion must be ≥ 1.5 cm and designated as the “index” lesion for 
all subsequent tumor evaluations.   
Stage I to operable Stage IIIa breast cancer 


 
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• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable 
for PTEN status by central histopathology laboratory 
Specimen may consist of a tissue block (preferred) or 10 unstained, serial slides.  
Cytologic or FNA samples are not acceptable. 
If archival tissue is either insufficient or unavailable, FFPE core sample from a 
pretreatment biopsy of the tumor may be used. 
Cytologic or FNA samples are not acceptable.   
• 
Adequate hematologic and organ function within 14 days before the first study treatment, 
defined by the following: 
Neutrophils (absolute neutrophil count [ANC] ≥ 1500/μL) 
Hemoglobin ≥ 9 g/dL 
Platelet count ≥100,000/μL 
Serum albumin ≥ 2.5 g/dL 
Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) with the following exception: 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be 
enrolled 
AST and ALT ≤ 2.0 × ULN 
Alkaline phosphatase ≤ 2 × ULN  
PTT and/or either international normalized ratio (INR) or prothrombin time (PT) 
≤ 1.5 × ULN (except for patients receiving anticoagulation therapy).   
Patients receiving heparin treatment should have an activated partial prothrombin 
time (aPTT) between 1.5 to 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.  
Fasting serum glucose ≤ 150 mg/dL (8.33 mmol/L) and HbA1C ≤ 8% 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of < 1% per year 
during the treatment period and for at least 6 months after the last dose of study drug 
Abstinence is acceptable only if it is in line with 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. 
Examples of contraceptive methods with a failure rate of  < 1% per year include tubal 
ligation, male sterilization, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as a condom and a cervical cap) may be combined to 
achieve a failure rate of < 1% per year.  Barrier methods must always be supplemented 
with the use of a spermicide. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known HER2-positive, ER-positive, or PgR-positive breast cancer 
HER2 positivity is defined as one of the following:  On IHC testing,  > 10% of contiguous 
and homogeneous tumor cells show protein overexpression (IHC 3+) or on ISH testing, 
or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on 
counting at least 20 cells within the area).  If results are equivocal, reflex testing should 
be performed using an alternative assay (IHC or ISH). 
ER and PgR positive are defined as ≥ 1% of cells expressing hormonal receptors via 
IHC analysis. 


 
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Patients who have not had HER2, ER, or PgR testing, and thus, the HER2, ER, and 
PgR status of the breast adenocarcinoma is unknown, are not eligible. 
• 
Any prior treatment for the current primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer (Note:  Staging exams are at the discretion of the 
investigator). 
• 
Bilateral invasive breast cancer 
• 
Multicentric breast cancer (the presence of more than one tumor in different quadrants of 
the breast) 
• 
Patients who have undergone excisional biopsy of primary tumor and/or axillary lymph 
nodes 
• 
Patients who have undergone excisional SLNB prior to study treatment 
Pre-surgical FNA or core biopsy of suspicious node is allowed. 
• 
Any contraindication to MRI examination, including the following: 
Neurostimulators 
Pacemakers 
Implanted metallic material or devices (metal implants or large tattoos in the field of 
view) 
Severe claustrophobia 
Physical characteristics (weight and/or size) that exceed the capabilities of the MRI 
scanner 
Known allergy or hypersensitivity reactions to gadolinium, versetamide, or any of the 
inert ingredients in gadolinium-based contrast agents 
Severe renal insufficiency, e.g., estimated glomerular filtration rate < 30 mL/min 
• 
Need for chronic corticosteroid therapy of ≥ 20 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease 
• 
Known hypersensitivity or contraindication to any component of the study treatments, 
including paclitaxel excipient macrogolglycerol ricinoleate 
• 
Grade ≥ 2 peripheral neuropathy 
• 
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 
• 
New York Heart Association (NYHA) Class II, III, or IV heart failure or left ventricular 
ejection fraction < 50%, or active ventricular arrhythmia requiring medication 
• 
Current unstable angina or history of myocardial infarction within 6 months prior to Cycle 1, 
Day 1 
• 
Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia 
• 
Congenital long QT syndrome or screening corrected QT interval (QTc) > 480 milliseconds 
• 
History of malabsorption syndrome, lack of physical integrity of the upper gastrointestinal 
tract, or other condition that would interfere with enteral absorption or results in the inability 
or unwillingness to swallow pills  
• 
Active infection requiring intravenous (IV) antibiotics  
• 
Known HIV infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis (e.g., Hepatitis B or Hepatitis C virus), current alcohol 
abuse, or cirrhosis  


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
20/Protocol GO29505, Version 3 
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile must have a negative serum pregnancy test result within 14 days 
prior to initiation of study drug. 
• 
Malignancies other than TNBC within 5 years prior to Cycle 1, Day 1, with the exception of 
those with a negligible risk of metastasis or death (such as adequately treated carcinoma 
in situ of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated 
surgically with curative intent); medical monitor will make final determination for cancers not 
mentioned here. 
• 
Active small or large intestine inflammation (such as Crohn’s disease or ulcerative colitis)  
• 
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 
 
Length of Study 
The length of the study is approximately 3 years, including an enrollment period of 
approximately 24 months, a 4-week screening period, and a 24-week study period. 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow up is received 
from the last patient, whichever occurs later.  LPLV is expected to occur approximately 
7 months after the last patient is enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure in all patients and in patients who have PTEN-low 
tumors is as follows: 
• 
pCR rate in breast and axilla as defined by ypT0/Tis ypN0 in the American Joint Committee 
on Cancer staging system by local pathology evaluation. 
The secondary efficacy outcome measures in all patients and in patients who have PTEN-low 
tumors or who are Akt Dx+, are as follows: 
• 
Objective tumor response by MRI, as assessed by the investigator per modified RECIST 
• 
pCR rate in breast as defined by ypT0/Tis in the American Joint Committee on Cancer 
staging system by local pathology evaluation 
• 
Comparison of the rates of BCS and conversion to BCS in patients with T2 or T3 tumors 
 
Safety Outcome Measures 
The safety and tolerability of ipatasertib when combined with paclitaxel will be assessed using 
the following outcome measures: 
• 
Incidence, nature, and severity of adverse events, graded according to the 
NCI CTCAE, v4.0 
• 
Clinically significant changes in vital signs, physical findings, and clinical laboratory results 
during and following ipatasertib administration 
 
Pharmacokinetic Outcome Measures 
For ipatasertib, the following PK parameters will be analyzed using a PopPK approach as data 
allow: 
• 
Exposure following first dose (AUC0-24) and steady-state (AUCss) 
• 
Minimum observed plasma concentration (Cmin; trough concentration) 
• 
Apparent clearance following oral dosing (CL/F) 
 


 
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Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Alterations in DNA and RNA, including but not limited to mutational status, RNA expression 
levels, DNA copy number, protein expression and modifications 
• 
Evaluation of changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI 
• 
Evaluation of changes in tumor cellular composition as assessed by diffusion-weighted MRI 
 
Investigational Medicinal Products 
Test Product 
Ipatasertib (GDC-0068) and Placebo 
Ipatasertib will be supplied by the Sponsor. 
Study treatment to either ipatasertib or placebo will be assigned by Interactive Web Response 
System (IWRS).  Ipatasertib or placebo will be administered orally QD, beginning on Cycle 1, 
Day 1 through Day 21 of each 28-day cycle for a total of 3 cycles of treatment.  Patients in the 
experimental arm will receive ipatasertib at a dose of 400 mg QD, and those in the control arm 
will receive placebo on the same days.  Ipatasertib or placebo will be administered prior to the 
IV infusion of paclitaxel.  Each dose of ipatasertib or placebo should be taken with a minimum of 
3 ounces (90 mL) of fluid.  Ipatasertib or placebo may be taken with or without food.  If a dose is 
missed (not taken within 8 hours after the scheduled dosing time), the patient should resume 
dosing with the next scheduled dose.  Missed or vomited doses will not be made up. 
The dose of ipatasertib or placebo will be taken at home, as directed on all days when there are 
no scheduled clinic visits.  Ipatasertib or placebo should be taken at approximately the same 
time each day.  On study visit days or visit days that require a blood draw for PK sampling, 
patients should not take their dose of ipatasertib or placebo at home before reporting to the 
clinic.  Patients will be instructed to take their oral dose of ipatasertib or placebo at the clinic 
after completion of the pretreatment assessments.  
A sufficient amount of ipatasertib or placebo should be provided to the patient to last for up to 
one treatment cycle (i.e., approximately 28 days).  In some cases, extra tablets may be 
dispensed if there is a possibility that the patient’s next visit may be delayed (e.g., due to 
holiday, inclement weather, or distance of patient’s home from study center).  Patients will also 
be given instructions for self-administration on dosing days that do not coincide with clinic visits. 
Patients will be asked to record the time and date they take each dose in a medication diary.  
Patients will be instructed to bring their bottles of ipatasertib or placebo (including all unused 
tablets) and their medication diaries to each study visit for assessment of compliance and 
medication disposal. 
The investigator (or designated representative) is responsible for keeping accurate records of 
the clinical supplies received from the Sponsor, including the amount dispensed to each patient 
and the amount returned by each patient.  Study drug accountability (verification of the total 
number of tablets administered) for each patient should be performed as indicated in the 
protocol. 
Any dose modification, overdose, or incorrect administration of ipatasertib or placebo should be 
noted on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF. 
Paclitaxel 
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 15, 
and 22 of each 4-week cycle, for a total of 3 cycles of treatment (12 total doses).  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, per institutional guidelines.   
On the planned day of treatment, chemotherapy may be administered if:  
• 
ANC ≥ 1500/μL (or per institutional guideline) 


 
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• 
Platelet count ≥ 100,000/μL (or per institutional guideline) 
• 
Grade ≤ 2 clinically significant chemotherapy-related gastrointestinal toxicity 
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophor® vehicle, precautions must be taken to decrease the risk of anaphylaxis.  Patients 
must be premedicated prior to paclitaxel per institutional practice with dexamethasone, 
diphenhydramine, and one of the following two H2-receptor blockers:  ranitidine or famotidine.  
Other H2-receptor antagonists, such as cimetidine, which are known to inhibit cytochrome P450, 
are excluded.  An H1-receptor antagonist, such as diphenhydramine 50 mg IV, may be given as 
well. 
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional 
guidelines and administered after the oral dose of ipatasertib or placebo. 
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 and decrease any potential peripheral neuropathy) according to institutional 
and/or local standards and per manufacturer’s instructions. 
Any dose modification, overdose, or incorrect administration of paclitaxel should be noted on 
the Paclitaxel Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of paclitaxel should be recorded on the Adverse Event eCRF. 
Comparator 
Ipatasertib placebo is the comparator in this study.  See Test Product section above for details. 
Statistical Methods 
Primary and secondary efficacy analyses will be based on randomized patients, with patients 
allocated to the treatment arm to which they were randomized. 
Safety analyses will include treated patients (i.e., patients who received at least one dose of 
ipatasertib, placebo, or paclitaxel), with patients allocated to the treatment arm associated with 
the regimen that they actually received. 
No adjustments will be made for multiple comparisons when addressing primary and secondary 
efficacy endpoints.  Multiple comparison adjustments will be used for selected exploratory 
endpoints to account for genome-wide correlative comparisons.   
The primary analysis will be performed after LPLV and subsequent data cleaning, expected to 
occur approximately 7 months after the last patient has been randomized to the study. 
Primary Analysis 
The primary efficacy analyses will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization. 
The primary efficacy endpoint is the rate of locally assessed pCR in breast and axilla (ypT0/Tis 
ypN0).  The primary efficacy analyses will be performed on randomized patients, with the 
patients allocated to the treatment arm according to the randomization.  The pCR endpoint will 
be analyzed for all randomized patients and for patients with PTEN-low tumors.  Patients whose 
pCR assessment is missing are counted as not achieving a pCR. 
An estimate of the pCR rate and its 90% CI (Blyth-Still-Casella method) will be calculated for 
each treatment arm for all randomized patients and for patients with PTEN-low tumors.  The 
difference in pCR rates will also be provided with 90% CIs, using the normal approximation to 
the binomial distribution.  Stratified Cochran-Mantel-Haenszel tests will be used to compare 
treatment arms. 
In addition, a sensitivity analysis may be conducted to account for patients whose pCR assessment 
cannot be ascertained. 
Determination of Sample Size 
This study is designed to evaluate the safety and preliminary evidence of activity of ipatasertib 
and paclitaxel.  This trial is hypothesis-generating and is able to detect only a large benefit from 
combination therapy with ipatasertib and paclitaxel versus placebo and paclitaxel.   
A total of 150 patients will be enrolled in the study (75 per arm).  Assuming a 60% prevalence of 
PTEN-low status in TNBC, it is expected that 90 patients with PTEN-low tumors will be enrolled.  
This trial will not have adequate power to detect minimum clinically meaningful differences 


 
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between treatment arms at a statistically significant α (type 1) error level of 5%.  Instead, the 
90% confidence intervals (CIs) for the difference in pCR rate will be calculated with the 
expectation that for clinically meaningful outcomes, the lower limit of the two-sided 90% CI will 
be greater than 0. 
For example, a true improvement of greater than 20% in pCR rate (from 20% to 40%) would be 
considered a clinically meaningful outcome when comparing ipatasertib and paclitaxel versus 
placebo and paclitaxel.  Given at least 90 patients (45 per arm) with PTEN-low tumors and a 
targeted improvement of 20% in pCR rate, the corresponding lower limit of the two-sided 
90% CI is 2.3%.  Also, for 150 patients (75 per arm) in ITT population with a targeted 
improvement of 15% in pCR rate, the corresponding lower limit of the two-sided 90% CI is 1.5%. 
Interim Analyses 
Planned Interim Analyses 
The Joint Monitoring Committee (JMC) will convene for a review of partially unblinded 
summaries of the safety data after approximately 20 patients have completed study treatment, 
including surgery.  In addition, after approximately 90 patients have completed study treatment 
as well as surgery, the JMC will reconvene to perform an interim safety and efficacy analysis.  
This efficacy interim analysis is for administrative purposes and is not intended to lead to an 
early termination of the trial if efficacy results appear favorable in a particular treatment arm. 
The members, roles, responsibilities, and communication processes of the JMC will be outlined 
in a separate charter. 
Optional Interim Analysis 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct an 
additional interim efficacy analysis.  The decision to conduct an optional interim analysis and the 
timing of the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed and reviewed by the JMC and will 
follow the communication plan described in the JMC charter. 
In addition, the Medical Monitor may request additional safety analysis and may call for additional 
meetings of the JMC to review ongoing data to assess risk/benefit. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial prothrombin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve (total exposure) 
AUC0−24 
exposure following first dose and steady-state 
BCS 
breast-conserving surgery 
BID 
twice daily 
BUN 
blood urea nitrogen 
Cmax 
maximum observed concentration 
Cmin 
minimum observed plasma concentration 
CALGB 
Cancer and Leukemia Group B 
CEP17 
chromosome 17 centromere 
CL/F 
apparent clearance following oral dosing 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DCIS 
ductal carcinoma in situ 
DDI 
drug-drug interaction 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity  
Dx+ 
diagnostic positive 
EBC 
early breast cancer 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
EORTC 
European Organisation for the Research and Treatment of Cancer 
ER 
estrogen receptor 
EU 
European Union 
FDA 
U.S. Food and Drug Administration 
FNA 
fine needle aspiration 
FFPE 
formalin-fixed paraffin-embedded 


 
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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HbA1C 
glycosylated hemoglobin 
H&E 
hematoxylin and eosin 
HER2 
human epidermal growth factor 2  
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
HR 
hormone receptor 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INPP4B 
inositol polyphosphate 4-phosphatase, type  II 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISH 
in situ hybridization 
IV 
intravenous 
IWRS 
Interactive Web Response System 
JMC 
Joint Monitoring Committee 
LPLV 
last patient, last visit 
MBC 
metastatic breast cancer  
mRNA 
messenger RNA 
MTD 
maximum tolerated dose 
mTNBC 
metastatic triple-negative breast cancer 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
pCR 
pathological complete response 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PopPK 
population PK methodology  


 
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Abbreviation 
Definition 
pPRAS40 
phosphorylated PRAS40 
PgR 
progesterone receptor  
PRO 
patient-reported outcome 
PRP 
platelet-rich plasma 
pS6 
phosphorylated S6 
PT 
prothrombin time 
PTEN 
phosphatase and tensin homolog 
PTT 
partial thromboplastin time 
QD 
once daily 
QLQ 
quality of life questionnaire 
QOL 
quality of life 
QLQ-C30 
Quality of Life Questionnaire-Core 30  
qRT-PCR 
quantitative real-time polymerase chain reaction  
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RP2D 
recommended Phase II dose  
RPPA 
reverse phase protein array 
RTK 
receptor tyrosine kinase 
S6RP 
S6 ribosomal protein 
SDV 
source data verification 
SEER 
Surveillance, Epidemiology and End Results  
SLNB 
sentinel lymph node excisional biopsy 
tmax 
time to peak concentration 
TNBC 
triple-negative breast cancer  
UGT1A1 
uridine diphosphate glucuronosyltransferase 1A1 
ULN 
upper limit of normal 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON BREAST CANCER 
According to the Surveillance, Epidemiology and End Results (SEER) database, over 
230,000 women were diagnosed with breast cancer and approximately 40,000 women 
died of breast cancer in 2013 in the United States (SEER 2013).  The lifetime probability 
of developing invasive breast cancer in the United States and Europe is one in eight 
(Sasieni et al. 2011).  Globally, breast cancer is the most common invasive malignancy 
with a prevalence of more than 1.3 million patients and a mortality rate of approximately 
450,000 deaths per year (Jemal et al. 2011). 
The treatment algorithm for patients with breast cancer is based on several 
considerations, for example, clinical factors and histopathology characteristics, including 
the presence or absence of human epidermal growth factor 2 (HER2) amplification, and 
hormone receptor status.  Most breast cancers in the Western world (approximately 
94−95% of patients in the U.S. and Europe) are diagnosed when the cancer is still 
confined to the breast, with or without locoregional lymph node spread (Sant et al. 2003; 
Howlader et al. 2011).  At this stage (early breast cancer [EBC]), the disease is usually 
operable and can be treated surgically with curative intent. 
Even with current optimum treatment, approximately 20−45% of patients with clinically 
localized disease at diagnosis relapse (EBCTCG 2011, 2012).  Upon relapse, patients 
with metastatic disease have a median survival of approximately 24 months and a 5-
year life expectancy of 18−23% in the U.S. and Europe (Sant et al. 2003; 
Howlader et al. 2011).  Thus, there is a substantial need to improve treatment outcomes 
for patients with early breast cancer to delay/prevent future relapse. 
1.1.1 
Molecular Classification of Breast Cancer, Including 
Triple-Negative Breast Cancer 
Breast cancer is a genetically heterogeneous and biologically diverse disease.  The long 
recognized clinical and phenotypic differences have been shown to correlate with 
differences at the gene expression level (van’t Veer et al. 2002).  Molecular profiling of 
breast cancers using cDNA array technology showed that breast cancer can be further 
sub-classified into Luminal A and B subgroups (with high expression of estrogen 
receptor/progesterone receptor [ER/PgR]), basal-like, HER2-enriched, and normal-like.  
The basal-like subtype was so named because the expression pattern of this subtype 
mimics that of basal epithelial cells of other parts of the body and normal breast 
myo-epithelial cells.  The molecular drivers underlying the pathogenesis of the basal-like 
subtype are not well-understood. 
Approximately 80% of basal-like breast cancers lack immuno-staining for hormone 
receptors and HER2 and are thus often referred to as triple-negative breast cancer 
(TNBC); approximately 15% of breast cancers are classified as TNBC.  TNBCs are more 
likely to exhibit an aggressive phenotype, including high genomic instability, rapid 


 
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proliferation rate, and tendency to become metastatic.  Although TNBC may respond to 
chemotherapy, including taxanes, there are no approved targeted therapies for patients 
with this disease in the U.S. or Europe.  Overall, the clinical outcome for patients with 
TNBC is poor, relative to other breast cancer subtypes; patients generally experience 
rapid clinical progression and poor survival.  Additional clinically active agents are 
needed for early TNBC. 
1.1.2 
PI3K/Akt Signaling in Triple-Negative Cancer 
Akt is the central node of the PI3K-Akt-mammalian target of rapamycin (mTOR) 
signaling axis and represents a major downstream effector of receptor tyrosine kinases 
(RTKs).  Activation of the PI3K/Akt pathway results in essential cellular functions 
including cell survival, growth, and proliferation, which are properties that underlie 
human cancers.  The PI3K/Akt pathway can be activated through loss of the tumor 
suppressor phosphatase and tensin homolog (PTEN) (Li et al. 1997), through activating 
mutations and/or amplifications in PIK3CA (Bachman et al. 2004), or through loss of the 
phosphatase inositol polyphosphate 4-phosphatase, type II (INPP4B) (Fedele et al.2010); 
all these events are frequently observed in TNBC. 
As demonstrated by the TCGA study (Cancer Genome Atlas Network 2012), among the 
breast cancer subtypes, basal-like-/triple-negative breast cancer was associated with the 
highest activity of PI3K/Akt pathway signaling as demonstrated by DNA copy 
number/mutation analysis, reverse-phase phosphoproteomic analysis (RPPA) and by 
gene expression signature.  Genetically, mutations in the PIK3CA gene are found in 
approximately 9% of basal-like breast cancers; in addition, PTEN and INPP4B gene 
losses occur in approximately one-third of samples as evaluated by DNA copy number 
changes.  Furthermore, deficient expression of tumor suppressors PTEN and INPP4B 
was found in > one-third of the basal-like breast cancers.  These alterations were 
associated with a higher degree of Akt pathway activation (as determined by pAKT and 
pS6 levels RPPA) in the basal subtype relative to other breast cancer subtypes.  
Inactivation of PTEN using tissue-specific gene knockout experiments drives the 
development of basal-like breast cancer in animal models (Dourdin et al. 2008; 
Saal et al. 2008).  
 
 
 
).  Given that 
the Akt pathway in TNBC is frequently activated (by PTEN-dependent and -independent 
mechanisms), inhibition of Akt represents a compelling and rational potential treatment 
strategy. 
1.1.3 
Akt Activation and Chemoresistance 
Activation of Akt signaling (whether intrinsic or induced following chemotherapy) leads to 
chemoresistance across several cancer models, including breast cancer.  One reported 


 
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mechanism of Akt-mediated chemoresistance, in response to genotoxic stress, is that 
DNA-dependent protein kinase and Akt can cross-regulate DNA repair via 
non-homologous end-joining (Toulany et al. 2008).  Additionally, Akt activation can lead 
to abrogation of the G1-S checkpoint (via MDM2 phosphorylation) and the G2-M 
checkpoint (in part via Chk1 activation) (Xu et al. 2012).  Taxanes and other 
chemotherapeutic agents can induce up−regulation of Akt in cancer cell lines via multiple 
proposed mechanisms, resulting in chemo-resistance (Winograd-Katz and Levitzki 2006).  
Thus, up−regulation of Akt signaling represents a potentially important survival pathway 
in response to genotoxic stress, and activation of Akt signaling following chemotherapy 
(including taxanes) may promote cell survival (Isakoff et al. 2005). 
Several studies have shown that inhibition of the PI3K/Akt pathway in diverse cancers 
leads to radiosensitization and/or chemosensitization (Brognard et al. 2001, 
Wallin et al. 2010).  In contrast, overexpression/activation of Akt across several tumor 
models leads to chemoresistance (Clark et al. 2002; Liu et al. 2007), including to 
paclitaxel (Isakoff et al. 2005).  Given that up−regulation of Akt signaling may lead to 
chemoresistance, targeting TNBC with an Akt inhibitor in combination with 
chemotherapy may increase treatment efficacy. 
1.1.4 
Neoadjuvant Therapy for Breast Cancer 
The use of neoadjuvant therapy for breast cancer has been studied in several large 
randomized trials that have compared neoadjuvant chemotherapy with standard 
adjuvant treatment (Mauriac et al. 1991; Scholl et al. 1994; Semiglazov et al. 1994; 
Powles et al. 1995; Fisher et al. 1997; Wolff et al. 2000).  Neoadjuvant therapy results in 
similar rates of disease-free survival (DFS) or overall survival (OS) compared with 
adjuvant therapy.  A meta-analysis of nine randomized studies comparing adjuvant with 
neoadjuvant systemic therapy for breast cancer showed no difference in rates of death, 
disease progression or disease recurrence based upon the timing of the systemic 
therapy (Mauri et al. 2005).  Rather, the major role of neoadjuvant treatment historically 
has been to reduce the size of unresectable tumors, allowing surgery to be performed; 
for example for operable tumors, neoadjuvant treatment allows for greater conservation 
of the breast and a decreased need for mastectomy (Hortobagyi et al. 1988; 
Fisher et al. 1997; Mieog et al. 2007).  Because neoadjuvant therapy has comparable 
efficacy and safety to adjuvant therapy, the concept of neoadjuvant therapy is now 
well-established option for patients with EBC. 
Across multiple neoadjuvant trials, patients who achieve a pathological complete 
response (pCR; and especially pCR defined as no residual disease present in both the 
breast and axilla) have an improved prognosis compared with those who have residual 
invasive disease present in the surgical specimen after completion of preoperative 
therapy (non-pCR).  For example, in National Surgical Adjuvant Breast and Bowel 
Project (NSABP studies B-18 and B-27, HRs for DFS for patients who achieved a pCR 
relative to those who did not were 0.47 and 0.49, respectively in the two trials; the HRs 


 
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for OS were 0.32 and 0.36, respectively (Rastogi et al. 2008).  In addition, the 
Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis was 
conducted in 2012, evaluating over 12,000 patients treated with neoadjuvant 
chemotherapy as part of clinical trials (Cortazar et al. 2012).  The results confirm an 
association between pCR and both event-free survival (EFS: hazard ratio [HR] 0.48, 
95% CI 0.43–0.54) and OS (HR 0.36, 0.31–0.42).  The association between pathological 
complete response and long-term outcomes was especially strong in patients with triple-
negative breast cancer (EFS:  HR 0.24, 95% CI 0.18–0.33; OS: HR 0.16, 0.11–0.25).  In 
addition to benefit in TNBC patients noted above in the Cortazar et al. (2012) meta-
analysis, Liedtke et al. (2008) found that pCR rates were higher with neoadjuvant 
treatment in patients with TNBC compared with those with non-TNBC (22% versus 11%; 
p = 0.034).  The prognosis for patients who experience a pCR is excellent, with less than 
10% developing a distant recurrence at 5 years, and equivalent to that for patients with 
other breast cancer subtypes who experience a pCR.  However, those patients with 
TNBC who do not experience a pCR with the same chemotherapy have a much poorer 
prognosis.  Interestingly, evaluation of residual tissue from TNBC patients who do not 
achieve a pCR demonstrated mutations affecting the PI3K–Akt pathway were enriched 
in post–neoadjuvant chemotherapy tumors compared with pretreatment tumors, 
suggesting Akt pathway contributes to chemoresistance (Blako et al. 2014). 
1.2 
BACKGROUND ON IPATASERTIB 
Ipatasertib (GDC-0068) is a novel, selective, ATP-competitive small molecule inhibitor of 
all three isoforms of the serine/threonine kinase Akt and is potent in nonclinical models, 
including tumors with loss of PTEN (PTEN-low, PTEN-null, or PTEN-mutated) or 
mutations of PIK3CA both in vitro and in vivo.  Ipatasertib inhibits the kinase activity of 
Akt and suppresses the phosphorylation of its direct substrates, including PRAS40, and 
additional downstream targets, such as S6 ribosomal protein (S6RP), resulting in G1 
arrest and/or apoptosis in human cancer cells (Lin et al. 2012). 
See the Ipatasertib Investigator's Brochure for additional details on nonclinical and 
clinical studies. 
1.2.1 
Summary of Ipatasertib Nonclinical Studies 
Daily and intermittent dosing of ipatasertib has demonstrated tumor growth inhibition in 
nonclinical models of multiple tumors.  In vitro studies showed that high levels of pAkt, 
often through inactivation of PTEN, predicted response to ipatasertib.  
 
 
 
and the Ipatasertib Investigator’s 
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1.2.2.1 
Study PAM4743g⎯Phase I Study of Single-Agent Ipatasertib 
Ipatasertib is currently tested in a Phase I open-label dose-escalation study (PAM4743g), 
in patients with refractory solid tumors, using a 3 + 3 design to assess the safety, 
tolerability, and pharmacokinetics of ipatasertib administered orally once daily (QD) for 
3 weeks, followed by a 1-week observation period.  Ipatasertib was well tolerated in the 
first six cohorts (25, 50, 100, 200, 400, and 600 mg daily); 800 mg daily resulted in 
dose-limiting toxicity (DLT; fatigue and gastrointestinal intolerance).  A patient in the 
expansion arm continues to receive treatment at an ipatasertib dose of 600 mg daily.  No 
patients in the first six cohorts receiving 25 to 600 mg of ipatasertib experienced a DLT.  
The maximum tolerated dose (MTD) of ipatasertib was determined to be 600 mg orally 
QD on a 21-day-on and 7-day-off (21/7) schedule. 
Study PAM4743g:  Preliminary Safety Data  
As of 31 March 2014, enrollment in Study PAM4743g was completed, with 52 patients 
enrolled and 51 patients treated with ipatasertib (GDC-0068), including 30 patients in the 
dose-escalation stage and 21 patients in the dose-expansion stage.  The most 
frequently reported adverse events in ≥ 10% of patients that were assessed by the 
investigators as related to ipatasertib were nausea (70.6%), diarrhea (68.6%), vomiting 
(51%), asthenia (37.3%), hyperglycemia (33.3%), decreased appetite (23.5%), 
dyspepsia (19.6%), dysgeusia (11.8%), rash (11.8%), and upper abdominal pain 
(11.8%).  In the 800-mg cohort, 2 patients experienced a DLT of Grade 3 asthenia.  
No DLTs were reported in the 600-mg cohort; thus, 600 mg was determined to be the 
MTD on this schedule.  Grade ≥ 3 adverse events in ≥ 5% of patients that were assessed 
as related to ipatasertib were diarrhea (n = 4, 7.8%), and asthenia (n = 3, 5.9%).  There 
were no ipatasertib−related Grade 4 or Grade 5 adverse events. 
Study PAM4743g:  Preliminary Pharmacokinetic Data  
Pharmacokinetic (PK) data are available from 30 patients treated with ipatasertib during 
the dose-escalation stage from dose cohorts 1 to 7 (25 to 800 mg) on a 21/7 schedule, 
with PK data available from the single dose on Day 1 and following multiple doses 
(on Day 8 of continuous dosing).  The preliminary PK profile of ipatasertib shows that 
ipatasertib is rapidly absorbed with time to peak concentration (tmax) ranging from 
0.5 to 3 hours across all doses.  The mean terminal half-life ranged from 
21.7 to 31.4 hours at doses above 100 mg.  Mean maximum concentration (Cmax) and 
total exposure (area under the curve [AUC]) were dose-proportional in the range from 
25 to 800 mg.  Preliminary data also show that the pharmacokinetics of ipatasertib are 
comparable between the fed and fasted states.  The transient increase in glucose and 
insulin are also comparable between the fed and fasted states of dosing following 
ipatasertib administration (for additional information, see the Ipatasertib Investigator’s 
Brochure). 
Study PAM4743g:  Preliminary Pharmacodynamic Data  
The pharmacodynamics of ipatasertib were assessed in Study PAM4743g on the basis 
of changes in the Akt pathway, including phosphorylated GSK3β (pGSK3β) in 


 
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platelet-rich plasma (PRP) and phosphorylated PRAS40 (pPRAS40) in predose and 
postdose tumor biopsies.  GSK3β and PRAS40 are substrates of Akt (Yan et al. 2013).  
In PRP experiments, the pGSK3β level decreased by more than 60% at doses ≥ 200 mg 
and by more than 80% at the 600 mg dose, demonstrating a dose- and 
concentration-dependent pharmacologic response.  Examination of multiple protein 
substrates of Akt in pre- and on-treatment tumor biopsies showed phosphorylation 
decreases of Akt pathway proteins, including more than 60% decrease in pPRAS40 
(compared with baseline) in all three patients treated at 400 mg (see the Ipatasertib 
Investigator’s Brochure for additional information). 
1.2.2.2 
Study PAM4983g⎯Phase Ib Study of Ipatasertib and 
Chemotherapy 
Study PAM4983g is a Phase Ib, dose-escalation study, in patients with advanced solid 
tumors, to determine the MTD and recommended Phase II dose (RP2D) of ipatasertib 
administered QD orally in combination with docetaxel on a 14-day-on and 7-day-off (14/7) 
dosing schedule (Arm A), with mFOLFOX6 (Arm B; see the Ipatasertib Investigator’s 
Brochure for details), and with paclitaxel (90 mg/m2 administered weekly [3 week on and 
1 week off]) with ipatasertib on a 21/7 dosing schedule (Arm C).   
Study PAM4983g:  Preliminary Safety Data for Ipatasertib + Taxanes in 
Arm A (Ipatasertib + Docetaxel) and Arm C (Ipatasertib + Paclitaxel) 
As of 31 March 2014, enrollment in Study PAM4983g was completed for Arm A, with 
27 patients enrolled in Arm A (ipatasertib combined with docetaxel), and enrollment was 
completed for Arm C, with 27 patients enrolled (ipatasertib combined with paclitaxel).   
Ipatasertib in combination with docetaxel was well tolerated in the 27 patients in all 
dosing cohorts (100, 200, 400, and 600 mg); no patients receiving 100 to 600 mg of 
ipatasertib experienced a DLT.  The adverse events reported in ≥ 10% of patients that 
were assessed by the investigators as related to ipatasertib (GDC-0068) in combination 
with docetaxel were nausea (74.1%), diarrhea (70.4%), vomiting (66.7%), decreased 
appetite (25.9%), asthenia (22.2%), fatigue (18.5%), dyspepsia (14.8%), hyperglycemia 
(14.8%), rash (14.8%), hypomagnesemia (11.1%), and mucosal Inflammation (11.1%).  
These adverse events were predominantly Grade 1 or 2.  There were no 
ipatasertib-related Grade 4 or Grade 5 adverse events with the ipatasertib + docetaxel 
combination.   
As of 31 March 2014, preliminary safety data from Study PAM4983g were available for 
27 treated patients in Arm C (ipatasertib combined with paclitaxel 90 mg/m2 
administered weekly [3 week on and 1 week off]), including 21 patients treated at a 
400 mg of ipatasertib and 6 patients treated at 600 mg of ipatasertib.  No patients 
receiving ipatasertib in combination with paclitaxel experienced a DLT.  The adverse 
events reported in ≥ 10% of patients that were assessed by the investigators as related 
to ipatasertib in combination with paclitaxel were diarrhea (77.8%), nausea (55.6%), 
vomiting (37%), fatigue (33.3%), decreased appetite (14.8%), rash maculo-papular 


 
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(14.8%), abdominal pain (11.1%), dehydration (11.1%), hyperglycemia (11.1%), and 
rash (11.1%).  These adverse events were predominantly Grade 1 or 2.  Grade 3 
adverse events related to ipatasertib in combination with paclitaxel occurred mostly at 
600 mg (in 5 of 6 patients or 83%), versus 400 mg of ipatasertib (in 3 of 21 patients or 
14%), including diarrhea (n = 6), hyperglycemia (n = 3), dehydration (n = 2), anemia (n = 1), 
neutropenia (n = 1), and rash (n = 1).  There were no Grade 4 or Grade 5 adverse events 
related to ipatasertib in combination with paclitaxel as assessed by the investigators.  
Three patients in the 600 mg ipatasertib + paclitaxel cohort were dose reduced for 
ipatasertib-related recurrent adverse events, including Grade 3 dehydration (n = 1), 
Grade 3 diarrhea (n = 1), and Grade 2 diarrhea (n = 1), while 1 patient in the 400 mg 
ipatasertib + paclitaxel cohort was dose reduced for ipatasertib-related Grade 1 
iron-deficiency anemia.  As of 31 March 2014, no patients in the 400 mg cohort had 
discontinued from the study for ipatasertib-related adverse events.  In addition, no 
patients in the 400 mg cohort a had dose reduction or delay of paclitaxel due to 
ipatasertib-related adverse events. 
As of 31 March 2014, 10 additional HER2-negative breast cancer patients enrolled in 
Arm C (400 mg ipatasertib +paclitaxel) of Study PAM4983g.  All 10 patients completed 
Cycle 1 with no DLT, and the majority of the adverse events were Grade 1 and 2.  The 
preliminary safety profile for this expansion cohort is consistent with that described 
above.  
Based on the overall safety data from Arm C, the RP2D of ipatasertib is 400 mg daily on 
a 21/7 dosing schedule in combination with paclitaxel administered every 7 days. 
Study PAM4983g:  Preliminary Pharmacokinetic Data 
As of 31 March 2014, preliminary PK data from Study PAM4983g were available for 
patients treated with ipatasertib combined with docetaxel (Arm A) or paclitaxel (Arm C).  
Ipatasertib exposures in both the docetaxel-treated and paclitaxel-treated arms were 
comparable to the Phase I single-agent data from Study PAM4743g.  
 
 
 
and the Ipatasertib Investigator’s Brochure). 
Study PAM4983g:  Preliminary Clinical Activity 
As of 31 March 2014, 12 patients in Study PAM4983g had a radiographic response by 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST, v1.1) criteria on 
computed tomography (CT) scans:  3 patients (11.1%) in Arm A (ipatasertib in 
combination with docetaxel), 3 patients (8.8%) in Arm B (ipatasertib in combination with 
mFOLFOX6), and 6 patients (22.2%) in Arm C (ipatasertib in combination with 
paclitaxel).  All 3 patients in Arm A had previously received taxane (docetaxel or 
paclitaxel) chemotherapy, all 3 patients in Arm B had previously received FOLFOX or 
platinum (cisplatin or carboplatin) chemotherapy, and 4 of 6 patients in Arm C had 
previously received taxane (docetaxel or paclitaxel) chemotherapy.  Molecular analysis 


 
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of archival tumor tissues is ongoing.  At least 7 of the 12 patients (58%) with 
radiographic responses had tumors with alterations in the PI3K/Akt pathway, including 
low expression of PTEN (immunohistochemical H-score ≤ 200), PIK3CA mutations 
(E545K or H1047R), and 1 patient with an AKT1 E17K mutation (site information). 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
An estimated 1.3 million cases of breast cancer are diagnosed annually worldwide.  Of 
these, approximately 200,000 are of the triple-negative (ER–/PR–/HER2–) phenotype.  
Improving the results of chemotherapy when the disease is still localized to the breast 
and regional lymph nodes offers the chance of potentially curing the disease, as well as 
delaying disease recurrence and death in those who are not cured.  In neoadjuvant 
setting, pCR correlates with a favorable outcome in TNBC; thus pCR is a useful tool to 
enable rapid and effective evaluation of much needed new targets and treatments for 
TNBC.  Evaluation of residual tissue from TNBC patients who do not achieve a pCR 
demonstrated mutations affecting the PI3K–Akt pathway were enriched in 
post-neoadjuvant chemotherapy tumors compared with pretreatment tumors, suggesting 
activation of the Akt pathway contributes to chemoresistance (Blako et al. 2014). 
As demonstrated by the TCGA study (Cancer Genome Atlas Network 2012), TNBC 
often exhibits activation of PI3K/Akt signaling, relative to other breast cancer subtypes.  
For example, > 50% of patients with TNBC exhibit low RNA expression of INPP4B and/or 
increased expression of AKT3. 
 
 
  
 
 
 Ipatasertib Investigator’s Brochure). 
Clinical safety profile of ipatasertib as a single-agent in the Phase Ia study (PAM4743g) 
and in combination with paclitaxel in the Phase Ib study (PAM4983g) supports 
development in breast cancer.  As a single-agent, ipatasertib has a predictable PK 
profile with a half-life of approximately 24 hours, and ipatasertib significantly 
downregulates the PI3K/Akt pathway at doses ≥ 200 mg.  In the Phase Ib 
study (PAM4983g), ipatasertib 400 mg daily was well-tolerated when combined with 
paclitaxel, exhibiting primarily Grade 1 to 2 gastrointestinal adverse events (e.g., nausea, 
vomiting, and diarrhea) and did not exacerbate the known adverse events attributable to 
paclitaxel. 
The study population eligible for this trial is at high risk for relapse (≥ 20% over 5 years); 
the addition of effective and tolerable therapy to conventional neoadjuvant regimen may 
increase pCR rates and thereby improve longer-term outcomes for these patients.  In 
addition, there may be additional benefits such as improved chances of 
breast-conserving surgery (BCS) in patients who desire this, and reduced rates of 


 
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re-operation for residual disease following primary surgery.  The addition of ipatasertib to 
taxane-based neoadjuvant regimen is expected to be generally well tolerated.  
Significant increases in leukopenia, febrile neutropenia, or cardiac toxicity are not 
anticipated but will be monitored during the trial.  Given the data to date, the benefit-risk 
assessment for administration of ipatasertib as part of a neoadjuvant treatment regimen 
within this clinical trial is considered positive. 
Given that activation of the PI3K/Akt pathway is frequent in TNBC and may lead to 
chemoresistance, and ipatasertib can be safely combined with paclitaxel, this Phase II 
trial is designed to test the hypothesis that inhibition of PI3K/Akt signaling will enhance 
the efficacy of paclitaxel chemotherapy in the neoadjuvant treatment of patients with 
TNBC.  The primary endpoint of this study will estimate the magnitude of benefit via 
pathologic complete response (pCR) in the breast and axilla of ipatasertib in combination 
with paclitaxel for patients with TNBC, as well as to prospectively evaluate whether 
patients whose tumors harbor a low/absent PTEN expression (by IHC) derive greater 
benefit from this regimen relative to the overall intent-to-treat population.  Other 
hypothesis generating exploratory analyses will be conducted as appropriate to evaluate 
molecular signatures that could predict patient response. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is to estimate the efficacy of ipatasertib 
combined with paclitaxel compared with placebo combined with paclitaxel in patients 
with early stage TNBC, as measured by local pathology laboratory evaluation of pCR 
rate within the breast and axilla (ypT0/Tis ypN0) in all patients and in patients with 
PTEN-low tumors. 
The secondary efficacy objectives for this study are as follows: 
• 
To estimate the clinical activity of ipatasertib combined with paclitaxel compared 
with placebo combined with paclitaxel, as measured by local pathology laboratory 
evaluations of pCR within the breast (ypT0/Tis) in all patients and in patients with 
PTEN-low tumors 
• 
To evaluate objective response rate (ORR) assessed by breast MRI via modified 
Response Evaluation Criteria in Solid Tumors (RECIST) of ipatasertib combined 
with paclitaxel compared with placebo combined with paclitaxel in all patients and in 
patients with PTEN-low tumors 
• 
To estimate the clinical activity, as measured by pCR (ypT0/Tis and ypT0/Tis ypN0) 
and ORR of ipatasertib combined with paclitaxel compared with placebo combined 
with paclitaxel in patients who are Akt diagnostic positive (Dx+) (defined by PTEN 
status, INPP4B status, and PI3K alterations) (see Section 4.5.1.7) 


 
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• 
To assess pCR rates according to subtypes of breast cancer defined by molecular 
profiles (e.g., the intrinsic subtypes of breast cancer defined by the PAM50 
classifier) 
• 
To assess the rates of BCS and conversion to BCS of ipatasertib combined with 
paclitaxel compared with placebo combined with paclitaxel in women with T2 or T3 
tumors 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of ipatasertib 
combined with paclitaxel versus placebo combined with paclitaxel. 
2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the 
pharmacokinetics of GDC-0068 using a sparse sampling methodology, when given in 
combination with paclitaxel in early stage TNBC patients. 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To assess the effect of PI3K/Akt pathway alterations on pCR in patients treated with 
ipatasertib combined with paclitaxel versus placebo combined with paclitaxel, based 
on exploratory analysis of tumor tissue using molecular data obtained by one or 
more of the following analyses: 
Mutation and RNA/DNA copy number changes in oncogenes, tumor 
suppressors, and/or other genes associated with TNBC response to treatment 
and progression by DNA sequencing and/or in situ hybridization (ISH) 
Levels of Akt pathway proteins, as evaluated by RPPA 
Levels of tumor suppressors and/or RTKs by IHC 
• 
To evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
To evaluate changes in tumor cellular composition as assessed by 
diffusion-weighted MRI 
• 
To assess the exposure-response relationships for efficacy, safety, and biomarker 
data 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomized, double-blind, placebo-controlled, multicenter, pre-operative 
Phase II study designed to estimate the efficacy of ipatasertib combined with paclitaxel 
chemotherapy versus placebo combined with paclitaxel chemotherapy in women with 
Stage Ia−IIIa (primary tumors ≥ 1.5 cm) triple-negative breast adenocarcinoma.  Patients 
with cT4 or cN3 tumors are not eligible.  Patients and investigators will be blinded to 
study treatment.  ER- and PgR-negative is defined as < 1% of tumor cell expression of 


 
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ER and PgR.  Patients who have an unknown ER, PgR, or HER2 status and for whom 
determination of status is not possible are also not eligible for this study.  Estimated 
benefit will be compared in all patients (independent of results from the diagnostic 
assessments of the tumor) and in patients with PTEN-low tumors.  The study schema is 
shown in Figure 2. 
Figure 2 Study Schema 
 
IV = intravenous; PO = orally; QD = once daily; QW = once weekly.  
 
Approximately 150 patients will be enrolled at approximately 30 centers.  Patients will be 
randomized in a 1:1 ratio, stratified by the following three factors:  PTEN status (H score 
0, vs. 1 to ≤ 150, vs. > 150), node involvement (pathologically positive versus no known 
involvement), and T size (T1−2 vs. T3). 
For the purpose of enrollment, ER, PgR, and HER2 will be locally determined prior to 
beginning of study treatment.  Additionally, all enrolled patients must consent to provide 
sufficient and evaluable archival tissue for PTEN status determination.  In the absence of 
archival tissue, fresh tissue biopsy samples, excluding cytology and fine-needle 
aspiration (FNA) specimens, will be acceptable; however, evaluation of the patient’s 
tumor sample for PTEN status by a central laboratory should occur prior to the initiation 
of study treatment.  All patients will undergo pretreatment tumor tissue acquisition 
(snap-frozen, optimal cutting temperature [OCT], and formalin-fixed paraffin-embedded 
[FFPE] cores).  One pretreatment FFPE core biopsy and two freshly frozen core 
TNBC 
T ≥ 1.5 cm, N 0−2 
R 1:1 
ARM 1: 
• 
Paclitaxel 80 mg/m2 IV QW 
• 
GDC-0068 400 mg PO daily on 
Days 1−21, every 28 days for 
3 cycles 
ARM 2: 
• 
Paclitaxel 80 mg/m2 IV QW 
• 
Placebo PO daily on 
Days 1−21, every 28 days for 
3 cycles 
S
U
R
G
E
R
Y 
Stratify by: 
• 
PTEN status (H score 0, vs. 1 to ≤ 150, vs. > 150) 
• 
Node involvement (pathologically positive versus no known 
involvement) 
• 
T size (T1−2 vs. T3) 
pCR 
N = 150 


 
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biopsies must be obtained for all patients prior to initiating study treatment.  Pre-surgical 
FNA or core biopsy of suspicious node is allowed, but full excision lymph node biopsy 
(e.g., sentinel lymph node excisional biopsy [SLNB]) is not allowed. 
All patients will receive paclitaxel 80 mg/m2 (see Table 1 for regimen and dose 
adjustments) every 7 days for a total of 12 doses (i.e., Days 1, 8, 15, and 22 of each cycle).  
Patients in the experimental arm will receive ipatasertib at a dose of 400 mg 
administered orally QD on Days 1 to 21 every 28 days and those in the control arm will 
receive placebo on the same days.  Each cycle will be 28 days in duration and study 
treatment will continue for a total of three cycles until disease progression, intolerable 
toxicity, elective withdrawal from the study, or study completion or termination.  
Following three cycles of treatment, patients will undergo surgery. 
Prior to administration of the second paclitaxel dose, a second research biopsy will be 
conducted for biomarker evaluation; at least one FFPE and at least two frozen OCT 
cores biopsy samples will be obtained.   
Primary breast tumor and axillary lymph nodes will be assessed every 4 weeks until 
Week 13 by clinical breast exam (palpation and clinical measurement; caliper preferred).  
Suspicion of progression based on clinical exam should be further evaluated 
(see Figure 3).  Tumor measurement by MRI for disease evaluation will be performed at 
screening and prior to surgery (at approximately Weeks 10−12, following completion of 
neoadjuvant chemotherapy).  Early assessment by MRI is allowed for suspected 
progression.  Estimation of ORR will be by modified RECIST (see Appendix 3).   
Patients with clinical or radiologic evidence of significant residual or progressive disease, 
as defined by modified RECIST, can either proceed directly to surgery or be 
discontinued from the study based on the investigator’s discretion.  Patients who 
discontinue study treatment prior to surgery will be required to have an additional 
research biopsy where at least one FFPE and at least two frozen OCT core biopsy 
samples will be obtained.   
Safety will be evaluated during the study through the monitoring of all serious and 
nonserious adverse events, graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE, v4.0).   
The pharmacokinetics of ipatasertib/placebo will be assessed in all patients. 


 
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Figure 3 Evaluation of Clinical Suspicion of Progression or Significant 
Residual Disease 
Clinical suspicion of 
progression
Breast MRI
Fine Needle Aspiration 
(FNA) of suspected 
node
Suspected PD, 
including apparent 
progression of 
previously normal 
node, i.e., node with 
negative/unknown 
status at baseline
Suspected PD in breast only
Continue on study
No PD 
confirmed on 
MRI AND no 
change in 
node status 
via FNA, if 
done
PD observed on MRI OR 
cytologic confirmation of 
change in node status
Patient proceed to 
surgery or additional 
chemotherapy and 
discontinue from study 
(with biopsy to be 
obtained prior to 
additional systemic 
therapy)
 
FNA = fine-needle aspiration; MRI = magnetic resonance imaging; PD = progressive disease. 
 
During Weeks 10−12 (approximately; i.e., near the time of completion of neoadjuvant 
chemotherapy), the patient will consult with the surgeon to plan the type of breast 
surgery to be performed (breast conservative vs. mastectomy) and to schedule the date 
for surgery (see Section 3.1.1). 
Following surgical resection of primary tumor, patients are expected to continue post-
operative treatment with a standard adjuvant chemotherapy regimen such as 
5-FU/doxorubicin/cyclophosphamide (FAC), 5-FU/epirubicin/cyclophosphamide (FEC), 
or doxorubicin/cyclophosphamide (AC), if appropriate and as chosen by their treating 
physician.  Post-operative treatment information (chemotherapy, radiotherapy, etc.) will 
be collected at the post-surgery visit. 
The primary efficacy endpoint, pCR within the breast and axilla (ypT0/Tis ypN0) in all 
patients and in patients with PTEN-low tumors will be assessed by local pathology 
evaluation following completion of neoadjuvant therapy and surgery. 
The trial is anticipated to have a recruitment period of approximately 24 months.   
A schedule of assessments is provided in Appendix 1. 


 
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3.1.1 
Surgery 
The patient should be evaluated at baseline and during approximately Weeks 10−12 of 
treatment to plan the surgical procedure (BCS or mastectomy); both the physician 
recommendation and final patient decision should be documented in the electronic Case 
Report Form (eCRF). 
Surgery will take place no more than 5 weeks after the last dose of paclitaxel.  Breast 
and axillary surgery will follow local practice.  However, pre-surgical SLNB is not allowed.  
Information on the type of surgery will be collected and recorded.  Representative 
surgery specimens will be sent to a central laboratory for assessment of Akt pathway 
markers. 
Following surgery, patients are expected to continue post-operative treatment according 
to local and institutional standards, including the use of adjuvant chemotherapy.   
A post-surgery visit will be performed within approximately 4 weeks after surgery for 
assessment of adverse events and general safety.  In addition, follow-up adjuvant 
chemotherapy and radiation therapy should be recorded, once known, in the eCRF. 
3.1.2 
Joint Monitoring Committee 
A Joint Monitoring Committee (JMC) will be in place during the study and will provide 
oversight of safety and efficacy.  The primary responsibility of the JMC is to review the 
available safety data and to make a recommendation to continue, modify the study 
design as required for improved safety, or terminate the study.  While a JMC review is 
being conducted, patient accrual into the study will continue.  The JMC will be 
composed of a designated sponsor medical oncologist (who is not the study medical 
monitor), the drug safety officer, and the study biostatistician.  In addition, the JMC will 
also include at least two external medical oncologists who are not employees of 
Roche/Genentech and are not affiliated with the study team, to provide clinical and 
methodological expertise in early breast cancer.  The members of the JMC will not 
interact with the sites or investigators in terms of study conduct.   
The reviews the JMC will conduct are described in Section 6.8.1 and Section 6.8.2. 
3.2 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis or safety follow up 
is received from the last patient, whichever occurs later.  LPLV is expected to occur 
approximately 7 months after the last patient is enrolled. 


 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Conducting the Study in the Neoadjuvant Setting 
Neoadjuvant therapy, a systemic therapy administered prior to breast cancer surgery, 
has become an increasingly popular approach in the systemic treatment of early breast 
cancer patients. Outcomes of patients receiving neoadjuvant therapy have been shown 
to be equivalent to those of adjuvant therapy (Mauri et al. 2005), and the former offers 
clear advantages to patients, particularly for patients with larger tumors; patients with 
smaller breast tumors (1−2 cm) also have been shown to benefit.  Tumor shrinkage prior 
to surgery may allow breast conservation surgery (Coudert et al. 2006), and since the 
response to therapy can be monitored, the patient might be also spared further 
treatment with inactive medications.  Upon completion of neoadjuvant treatment and 
surgery, patients are expected to continue to receive further adjuvant therapy 
(e.g., radiation and additional chemotherapy), if appropriate, following discussion with 
the treating physician. 
The neoadjuvant setting provides a unique opportunity to identify predictive biomarkers 
of response to novel therapeutic agents.  Pretreatment biopsies are easily accessible, 
usually from the diagnostic specimens.  On-treatment biopsies may also be pre-specified 
in order to monitor pharmacodynamic markers of treatment response at a biological level.  
Finally, the surgical specimen, if pCR is not reached, can be utilized as well to 
understand mechanisms of resistance.  The biological information obtained from all 
these biological specimens can be correlated with clinical data, such as pCR, a 
surrogate endpoint that demonstrates strong association with disease-free and overall 
patient survival in some subtypes of breast cancer (Cortazar et al. 2012; 
von Minckwitz and Fontanella 2013). 
Of note, at the completion of study treatment in this study, patients are expected to 
continue post-operative treatment with a standard anthracycline-based chemotherapy 
regimen such as FAC, FEC, or AC.  The specific regimen will be chosen by the treating 
physician per local guideline, and should be recorded in the eCRF. 
3.3.2 
Rationale for Starting Dose and Schedule of Ipatasertib 
For ipatasertib, the starting dose of 400 mg QD and the starting schedule of 21 days on 
and 7 days off (21/7) were selected on the basis of safety data from Arm C of 
Study PAM4983g, the Phase Ib trial of ipatasertib combined with paclitaxel 
(see Section 1.2.2.2).  In Arm C of Study PAM4983g, ipatasertib was generally well 
tolerated when administered at a dose of 400 mg QD on a 21/7 dosing schedule, in 
combination with paclitaxel 90 mg/m2 administered weekly (3 week on and 1 week off).  
A relative bioavailability study (Study GP29066) has been conducted in healthy 
volunteers and showed that 400-mg tablet dose of ipatasertib to be used in this study will 
provide exposures similar to the Phase II 400-mg dose of ipatasertib in the capsule 
formulation used in Study PAM4983g. 


 
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3.3.3 
Rationale for Treatment with Paclitaxel and Choice of 
Paclitaxel Regimen 
No globally accepted standard treatment exists specifically for neoadjuvant TNBC; rather, 
widely divergent chemotherapy followed by surgery (and radiation therapy) remain the 
cornerstone of treatment.  The role of paclitaxel in the treatment of breast cancer has 
been well established in both the adjuvant and metastatic settings.  Multiple trials 
demonstrated an increase in DFS in breast cancer patients who received 
paclitaxel-based therapy in the adjuvant setting (Hayes et al. 2007; Mackey et al 2013).  
In addition, taxanes are among the most active chemotherapy agents for the treatment 
of MBC in terms of response rates or survival, based on a meta-analysis of three 
randomized trials comparing a taxane with an anthracycline (Piccart-Gebhart et al. 2008).  
The pCR response rate of single agent paclitaxel is approximately 15−25% for TNBC 
patients treated in the neoadjuvant setting (Llombart et al. 2012); this pCR rate with 
paclitaxel is comparable to pCR in large single institution studies across diverse 
regimens (Ju et al. 2012).  Two Phase III studies showed that addition of bevacizumab 
results in a modest increase in pCR, particularly in patients with TNBC; however the 
addition of bevacizumab did not alter rate of BCS and was associated with increased 
Grades 3 and 4 toxicity and treatment discontinuation.  The role of adding platinum 
therapy to standard neoadjuvant regimen has recently been tested in GeparSixto and 
Cancer and Leukemia Group B (CALGB) 40603 trials (Sikov et al. 2013; 
von Minckwitz et al. 2014).  These trials also showed that although the addition of 
platinum resulted in improvement in pCR, there were substantial hematologic and other 
toxicities, leading to dose reductions and early treatment discontinuations.  It is unknown 
at this time whether the modest improvement in pCR observed in these trials (10−15%) 
will result in improved DFS or OS.  Paclitaxel results in reasonable pCR rate with 
manageable adverse event profile, allowing completion of the neoadjuvant treatment 
course and is thus a widely used and appropriate therapy for patients treated in this 
setting. 
Dose and regimen for paclitaxel in neoadjuvant and metastatic setting has been tested 
in several clinical trials.  In the neoadjuvant setting, weekly paclitaxel was also shown to 
improve the likelihood of pathologic complete remission in the breast and axillary lymph 
nodes (28.2% vs. 15.7%; p = 0.02), as well as the opportunity for BCS (p = 0.02), when 
compared with paclitaxel administered every 3 weeks in the neo-adjuvant setting 
(Green et al. 2005).  In the metastatic setting, results of the CALGB 9840 showed that 
paclitaxel 80 mg/m2 administered weekly had superior efficacy to and was better 
tolerated than paclitaxel 175 mg/m2 administered every 3 weeks in patients with MBC 
(Seidman et al. 2004).  This Phase II study (GO29505) will use a similar regimen of 
paclitaxel 80 mg/m2 administered weekly that was tested in the above referenced trials, 
as well as that used in the SOLTI NeoPARP trial (NCT01204125). 
Upon completion of study treatment in this study, patients are expected to continue 
post-operative treatment with a standard anthracycline-based chemotherapy regimen 


 
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such as FAC, FEC, or AC.  The specific regimen will be chosen by the treating physician 
per local guidelines, and should be recorded on the eCRF. 
3.3.4 
Rationale for Objective Response Assessed by MRI and 
Inclusion of Other MRI-Derived Metrics for Exploratory 
Purposes 
ORR is based on criteria related to changes in tumor size (e.g., RECIST) and is 
generally defined as the sum of partial and complete responses.  ORR is a robust 
indicator of antitumor activity in new anticancer agents and is considered to be an 
established surrogate marker for clinical benefit.  It has been used as a primary endpoint 
in multiple neoadjuvant trials (Smith et al. 2005; Ellis and Ma 2007; Baselga et al. 2009).  
Guidelines for RECIST 1.1 state that MRI is the preferred modality to follow breast 
lesions in a neoadjuvant setting, and it has advantages over CT and mammography 
(Eisenhauer et al. 2009).  In addition, MRI has been shown to be more accurate than 
clinical palpation, ultrasound, and mammography for measuring residual tumor size after 
neoadjuvant therapy in several prospective trials (Balu-Maestro et al. 2002; 
Yeh et al. 2005; Akazawa et al. 2006), including the I-SPY trial (Hylton et al. 2012).  
Results from the I-SPY trial also showed that tumor volume measurements based on the 
percent of tumor with enhancing signal after MR contrast agent administration may be a 
more sensitive measure of response during neoadjuvant treatment than longest 
dimension measures.  Enhancing tumor volume, along with other MRI-derived metrics 
acquired within the same MRI exam such as the apparent diffusion coefficient (ADC; a 
measure of tumor cellular composition derived from diffusion-weighted imaging), 
(Partridge et al. 2013), may serve as additional prognostic and/or predictive biomarkers 
of neoadjuvant therapy.  
3.3.5 
Rationale for Collection Tissue for Examining PTEN and Other 
AKT Pathway Components as Diagnostic Biomarkers 
Akt pathway activation in tumors, as demonstrated by PTEN loss, INPP4B loss, PIK3CA 
mutations, etc., may be an important predictive diagnostic for efficacy of ipatasertib.  
PTEN loss is an important cause of constitutively active Akt, and represents a potentially 
important predictive biomarker.  Activation of PI3K/Akt signaling frequently occurs in 
TNBCs; approximately 60% of TNBC samples exhibit low expression of PTEN.  In this 
Phase II study, PTEN status will be performed prospectively from archival tissue (or 
fresh biopsy if archival is not available), and the results will be used to stratify patients in 
this study.   
 
 
 Activation of the Akt results in 
increased levels of phosphorylated down-stream effector proteins, including pPRAS40, 


 
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pS6, pGSK3b; these proteins can be evaluated by IHC and/or reverse phase protein 
array from archival and/or fresh biopsy samples.  Collectively, these data could elucidate 
if the detection of alterations in the PI3K/Akt pathway, including low PTEN expression, 
loss of INPP4B activity, activating mutation in PIK3CA, and/or AKT3 overexpression, can 
be used to identify patients who may especially benefit from the combination of 
ipatasertib with paclitaxel. 
Taken together, these considerations support the collection of tissue from patients to 
evaluate the activity of ipatasertib combined with paclitaxel in patients with early TNBC 
in order to assess the clinical impact of these biomarkers. 
3.3.6 
Rationale for Collection of Fresh Tumor Biopsies Following 
Progression for Exploratory Purposes 
Exploratory assessments of biologic markers will be performed.  If tumor biopsies can be 
obtained with minimal risk and discomfort to patients who progressed during therapy, 
tissue may be collected at the end of the study (e.g., following disease progression prior 
to start of next therapy) from patients who consent to this procedure.  Tissue samples 
will be assessed for alterations in the PI3K/Akt pathway, as this may help predict which 
patients may benefit from ipatasertib and may also help identify potential causes of 
acquired resistance to ipatasertib.  Tumor biopsies may be used to explore PI3K/Akt 
pathway marker levels, gene copy number changes, and mutations to evaluate potential 
mechanisms of resistance to the combination of ipatasertib and paclitaxel. 
3.3.7 
Rationale for Collection of Blood Samples for Noninvasive 
Disease Monitoring 
Circulating tumor DNA (ctDNA) can be detected in the blood of cancer 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, as well as in breast cancer 
(Shinozaki et al. 2007).  An assay has been developed to identify major mutations in the 
PIK3CA gene through analysis of ctDNA in plasma.  In this study, blood samples will be 
collected at screening and during the study to evaluate oncogenic mutations at baseline 
and to assess for possible emergence of new mutations after treatment with ipatasertib 
and paclitaxel.  Mutations will be evaluated in relevant genes in the PI3K/Akt pathway, 
including but not limited to PIK3CA.  It is estimated that up to 10% of TNBCs may harbor 
PIK3CA mutations (Zang et al. 2012).  Identifying potential discordances in the PIK3CA 
status from baseline to post-surgery/end-of-study through exploratory analysis of 
archival tumor samples and ctDNA may help clarify the prognostic and predictive 
significance of PIK3CA mutations in patients with TNBC treated with ipatasertib and 
paclitaxel. 


 
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3.3.8 
Rationale for the Pharmacokinetic Evaluation Schedule 
A sparse sampling strategy will be applied in this study (see Appendix 2 for schedule).  
The sampling schedule is designed to enable characterization of GDC-0068 PK 
following first dose and at steady-state using population PK methodology (PopPK).  In 
addition, the PK data will allow comparison to single agent GDC-0068 PK data from the 
single agent Phase Ia Study PAM4743g and to combination data with paclitaxel from the 
Phase Ib Study PAM4983g.  Individual PK parameters estimated from the sparse 
sampling scheme will be used for exploratory exposure-response analyses.  
Paclitaxel concentrations will not be measured as a PK interaction between GDC-0068 
and paclitaxel is not expected, based on results from Study PAM4983g. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure in all patients and in patients who have 
PTEN-low tumors is as follows: 
• 
pCR rate in breast and axilla as defined by ypT0/Tis ypN0 in the American Joint 
Committee on Cancer staging system by local pathology evaluation. 
 
The secondary efficacy outcome measures in all patients and in patients who have 
PTEN-low tumors or who are Akt Dx+, are as follows: 
• 
Objective tumor response by MRI, as assessed by the investigator per modified 
RECIST (see Appendix 2)  
• 
pCR rate in breast as defined by ypT0/Tis in the American Joint Committee on 
Cancer staging system by local pathology evaluation 
• 
Comparison of the rates of BCS and conversion to BCS in patients with T2 or T3 
tumors 
 
3.4.2 
Safety Outcome Measures 
The safety and tolerability of ipatasertib when combined with paclitaxel will be assessed 
using the following outcome measures: 
• 
Incidence, nature, and severity of adverse events, graded according to the 
NCI CTCAE, v4.0 
• 
Clinically significant changes in vital signs, physical findings, and clinical laboratory 
results during and following ipatasertib administration 
 
3.4.3 
Pharmacokinetic Outcome Measures 
For ipatasertib, the following PK parameters will be analyzed using a PopPK approach 
as data allow: 
• 
Exposure following first dose (AUC0-24) and steady-state (AUCss) 
• 
Minimum observed plasma concentration (Cmin; trough concentration) 


 
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• 
Apparent clearance following oral dosing (CL/F) 
 
3.4.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Alterations in DNA and RNA, including but not limited to mutational status, 
RNA expression levels, DNA copy number, protein expression and modifications 
• 
Evaluation of changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
Evaluation of changes in tumor cellular composition as assessed by 
diffusion-weighted MRI 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Patients with early stage (Stage Ia−IIIa; primary tumors ≥ 1.5 cm) triple-negative 
adenocarcinoma of the breast who have not received prior systemic therapy for this 
breast cancer may be eligible for this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) 
• 
Premenopausal or postmenopausal women, age ≥ 18 years 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(see Appendix 4) 
• 
Histologically documented triple-negative carcinoma of the breast with all of the 
following characteristics: 
Primary tumor ≥ 1.5 cm in largest diameter (cT1−3) by MRI.  In the case of a 
multifocal tumor (defined as the presence of two or more foci of cancer within 
the same breast quadrant), the largest lesion must be ≥ 1.5 cm and designated 
as the “index” lesion for all subsequent tumor evaluations.   
Stage I to operable Stage IIIa breast cancer 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as 
evaluable for PTEN status by central histopathology laboratory 
Specimen may consist of a tissue block (preferred) or 10 unstained, 
serial slides.  Cytologic or FNA samples are not acceptable. 
If archival tissue is either insufficient or unavailable, FFPE core sample from a 
pretreatment biopsy of the tumor may be used. 
Cytologic or FNA samples are not acceptable.   
• 
Adequate hematologic and organ function within 14 days before the first study 
treatment, defined by the following: 
Neutrophils (absolute neutrophil count [ANC] ≥ 1500/μL) 


 
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Hemoglobin ≥ 9 g/dL 
Platelet count ≥ 100,000/μL 
Serum albumin ≥ 2.5 g/dL 
Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) with the following exception: 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN 
may be enrolled 
Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.0 × ULN 
Alkaline phosphatase ≤ 2 × ULN  
Partial thromboplastin time (PTT) and/or either international normalized ratio 
(INR) or prothrombin time (PT) ≤ 1.5 × ULN (except for patients receiving 
anticoagulation therapy).   
Patients receiving heparin treatment should have an activated partial 
prothrombin time (aPTT) between 1.5 to 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.  
Fasting serum glucose ≤ 150 mg/dL (8.33 mmol/L) and HbA1C ≤ 8% 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 6 months 
after the last dose of study drug 
Abstinence is acceptable only if it is in line with 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. 
Examples of contraceptive methods with a failure rate of  < 1% per year include 
tubal ligation, male sterilization, and certain intrauterine devices.  Alternatively, 
two methods (e.g., two barrier methods such as a condom and a cervical cap) 
may be combined to achieve a failure rate of < 1% per year.  Barrier methods 
must always be supplemented with the use of a spermicide. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known HER2-positive, ER-positive, or PgR-positive breast cancer 
HER2 positivity is defined as one of the following:  On IHC testing,  > 10% of 
contiguous and homogeneous tumor cells show protein overexpression (IHC 3+) 
or on ISH testing, or gene amplification (HER2 copy number or HER2/CEP17 
ratio by ISH based on counting at least 20 cells within the area).  If results are 


 
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equivocal, reflex testing should be performed using an alternative assay (IHC or 
ISH). 
ER and PgR positive are defined as  ≥ 1% of cells expressing hormonal 
receptors via IHC analysis. 
Patients who have not had HER2, ER, or PgR testing, and thus, the HER2, ER, 
and PgR status of the breast adenocarcinoma is unknown, are not eligible. 
• 
Any prior treatment for the current primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer (Note:  Staging exams are at the discretion of 
the investigator). 
• 
Bilateral invasive breast cancer 
• 
Multicentric breast cancer (the presence of more than one tumor in different 
quadrants of the breast) 
• 
Patients who have undergone excisional biopsy of primary tumor and/or axillary 
lymph nodes 
• 
Patients who have undergone excisional SLNB prior to study treatment 
Pre-surgical FNA or core biopsy of suspicious node is allowed. 
• 
Any contraindication to MRI examination, including the following: 
Neurostimulators 
Pacemakers 
Implanted metallic material or devices (metal implants or large tattoos in the 
field of view) 
Severe claustrophobia 
Physical characteristics (weight and/or size) that exceed the capabilities of the 
MRI scanner 
Known allergy or hypersensitivity reactions to gadolinium, versetamide, or any 
of the inert ingredients in gadolinium-based contrast agents 
Severe renal insufficiency, e.g., estimated glomerular filtration rate < 30 mL/min 
• 
Need for chronic corticosteroid therapy of ≥ 20 mg of prednisone per day 
or an equivalent dose of other anti-inflammatory corticosteroids 
or immunosuppressants for a chronic disease 
• 
Known hypersensitivity or contraindication to any component of the study treatments, 
including paclitaxel excipient macrogolglycerol ricinoleate 
• 
Grade ≥ 2 peripheral neuropathy 
• 
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 


 
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• 
New York Heart Association (NYHA) Class II, III, or IV heart failure (see Appendix 5) 
or left ventricular ejection fraction < 50%, or active ventricular arrhythmia requiring 
medication 
• 
Current unstable angina or history of myocardial infarction within 6 months prior to 
Cycle 1, Day 1 
• 
Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia 
• 
Congenital long QT syndrome or screening corrected QT interval (QTc) 
> 480 milliseconds 
• 
History of malabsorption syndrome, lack of physical integrity of the upper 
gastrointestinal tract, or other condition that would interfere with enteral absorption 
or results in the inability or unwillingness to swallow pills  
• 
Active infection requiring intravenous (IV) antibiotics  
• 
Known HIV infection 
• 
Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis (e.g., Hepatitis B or Hepatitis C 
virus), current alcohol abuse, or cirrhosis  
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 14 days prior to initiation of study drug. 
• 
Malignancies other than TNBC within 5 years prior to Cycle 1, Day 1, with the 
exception of those with a negligible risk of metastasis or death (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, ductal 
carcinoma in situ treated surgically with curative intent); medical monitor will make 
final determination for cancers not mentioned here. 
• 
Active small or large intestine inflammation (such as Crohn’s disease or ulcerative 
colitis)  
• 
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 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the Interactive Web Response System (IWRS).  Once eligibility 
has been established, the patient will be enrolled, and the study site will obtain the 
patient’s identification number from the IWRS. 
The patient will be randomized, and the site will obtain the blinded study drug kit number 
from the IWRS.  


 
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4.2.1 
Study Patients and Analysis Groups 
This study is a randomized, double-blind, placebo-controlled, multicenter, clinical trial 
designed to estimate the effect on pCR of the addition of ipatasertib to paclitaxel (Arm 1) 
compared with placebo plus paclitaxel (Arm 2).  This comparison (Arm 1 vs. Arm 2) will 
be performed in all patients (independent of results from the diagnostic assessments of 
the tumor) and in specific subsets of patients with PTEN-low tumors (see Section 6.4) to 
estimate the clinical effect of PTEN status and to provide information for the design of 
future confirmatory studies. 
4.2.2 
Control Groups 
All patients will receive paclitaxel chemotherapy for the treatment of triple-negative 
breast adenocarcinoma and will receive either QD dosing of ipatasertib or a placebo 
control.  A placebo will be used to maintain treatment blinding and will be formulated to 
appear identical to ipatasertib but will not contain any active ingredient. 
4.2.3 
Minimization of Bias 
Patients will be allocated to each of the treatment arms (Arm 1 or Arm 2) through the use 
of a stratified permuted block randomization to ensure within-stratum balance of patient 
characteristics between treatment arms.  Randomization will be stratified by the following 
three factors: PTEN status (H score 0, vs. 1 to ≤ 150, vs. > 150), Node involvement 
(pathologically positive versus no known involvement), and T size (T1-2 vs. T3).  These 
three stratification factors were chosen because of their known or suspected prognostic 
value and/or potential to affect efficacy of paclitaxel with/without ipatasertib.  Prospective 
stratification by these factors will minimize differences in the two treatment arms as a 
result of sources other than ipatasertib. 
Placebo tablets will be identical in shape and in color to the ipatasertib tablets and will be 
undistinguishable (see Section 4.3.1.1 for details).  Tablet bottles and drug kits for 
placebo will also be identical to those for ipatasertib, except for the unique kit numbers 
on the kit boxes.  
To minimize bias from potential unblinding, an IWRS provider will conduct randomization 
and hold treatment assignment codes.   
Because of the size of the study, use of IWRS, randomization, blinding, and expected 
lack of substantial emergency unblinding, collected data will be protected from any 
biases that would arise from subjectivity in the reporting of the outcome measures.  
To further protect the integrity of the study, the results of interim safety and efficacy 
analyses will not be made known to the investigators, and the PTEN loss status or other 
AKT pathway alterations within the tumor samples will not be disclosed to the 
investigators. 
The addition of ipatasertib to paclitaxel is not expected to affect planned laboratory tests 
or adverse reactions to a degree that would significantly unblind patients or investigators.  


 
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All laboratory tests of blood specimens will be performed by a local laboratory, a central 
laboratory, or the Sponsor, as appropriate.  To maintain blinding, patient-specific plasma 
concentration data for ipatasertib will not be made known to either investigators or the 
contract research organizations (CROs). 
The investigator and the patient will be blinded to treatment assignment.   
4.2.4 
Method of Unblinding 
Emergency unblinding of treatment assignment by the investigator is permitted and may 
be performed by the investigator through the IWRS system.  This emergency unblinding 
may occur without prior authorization from the Sponsor.  However, the investigator 
should promptly notify, document, and provide an explanation to the Sponsor for this 
premature unblinding. 
If a JMC safety review is necessary, as outlined in the guidelines of the JMC Agreement, 
the JMC will instruct the IWRS to provide the treatment assignment for those patients of 
interest to evaluate unbalanced toxicity. 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Ipatasertib (GDC-0068) and Placebo 
Ipatasertib will be supplied by the Sponsor.   
Ipatasertib drug product is intended for oral administration and will be supplied as 
100 and 200 mg tablets.  Ipatasertib and placebo tablets should be in the original 
high-density polyethylene bottles that includes the desiccant; do not store above 30°C 
(86°F); do not freeze.  During dispensing of the tablet from the primary container, if the 
desiccant is removed, it should be placed back into the primary container until the last 
tablet is consumed.  The period between 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. 
For information on the formulation, packaging, and handling of ipatasertib, see the 
pharmacy manual and the Ipatasertib Investigator's Brochure. 
4.3.1.2 
Paclitaxel 
For information on the formulation, packaging, and handling of paclitaxel, see the local 
prescribing information for paclitaxel. 


 
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4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Ipatasertib (GDC-0068) and Placebo 
Study treatment to either ipatasertib or placebo will be assigned by IWRS.  Ipatasertib or 
placebo will be administered orally QD, beginning on Cycle 1, Day 1 through Day 21 of 
each 28-day cycle for a total of 3 cycles of treatment.  Patients in the experimental arm 
will receive ipatasertib at a dose of 400 mg QD, and those in the control arm will receive 
placebo on the same days.  Ipatasertib or placebo will be administered prior to the IV 
infusion of paclitaxel.  Each dose of ipatasertib or placebo should be taken with a 
minimum of 3 ounces (90 mL) of fluid.  Ipatasertib or placebo may be taken with or 
without food.  If a dose is missed (not taken within 8 hours after the scheduled dosing 
time), the patient should resume dosing with the next scheduled dose.  Missed or 
vomited doses will not be made up. 
The dose of ipatasertib or placebo will be taken at home, as directed on all days when 
there are no scheduled clinic visits.  Ipatasertib or placebo should be taken at 
approximately the same time each day.  On study visit days or visit days that require a 
blood draw for PK sampling, patients should not take their dose of ipatasertib or placebo 
at home before reporting to the clinic.  Patients will be instructed to take their oral dose 
of ipatasertib or placebo at the clinic after completion of the pretreatment assessments 
outlined in Appendix 1.  
A sufficient amount of ipatasertib or placebo should be provided to the patient to last for 
up to one treatment cycle (i.e., approximately 28 days).  In some cases, extra tablets 
may be dispensed if there is a possibility that the patient’s next visit may be delayed 
(e.g., due to holiday, inclement weather, or distance of patient’s home from study center).  
Patients will also be given instructions for self-administration on dosing days that do not 
coincide with clinic visits. 
Patients will be asked to record the time and date they take each dose in a medication 
diary.  Patients will be instructed to bring their bottles of ipatasertib or placebo (including 
all unused tablets) and their medication diaries to each study visit for assessment of 
compliance and medication disposal. 
The investigator (or designated representative) is responsible for keeping accurate 
records of the clinical supplies received from the Sponsor, including the amount 
dispensed to each patient and the amount returned by each patient.  Study drug 
accountability (verification of the total number of tablets administered) for each patient 
should be performed as indicated in Appendix 1. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5. 
Any dose modification, overdose, or incorrect administration of ipatasertib or placebo 
should be noted on the Study Drug Administration electronic Case Report Form (eCRF).  


 
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Adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  Section 5.3.5.11 summarizes available 
safety data related to overdosing of ipatasertib. 
4.3.2.2 
Paclitaxel 
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
15, and 22 of each 4-week cycle, for a total of 3 cycles of treatment (12 total doses).  
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, per institutional 
guidelines.   
On the planned day of treatment, chemotherapy may be administered if:  
• 
ANC ≥ 1500/μL (or per institutional guideline) 
• 
Platelet count ≥ 100,000/μL (or per institutional guideline) 
• 
Grade ≤ 2 clinically significant chemotherapy-related gastrointestinal toxicity 
 
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophor® vehicle, precautions must be taken to decrease the risk of anaphylaxis.  
Patients must be premedicated prior to paclitaxel per institutional practice with 
dexamethasone, diphenhydramine, and one of the following two H2-receptor blockers:  
ranitidine or famotidine.  Other H2-receptor antagonists, such as cimetidine, which are 
known to inhibit cytochrome P450, are excluded.  An H1-receptor antagonist, such as 
diphenhydramine 50 mg IV, may be given as well. 
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per 
institutional guidelines and administered after the oral dose of ipatasertib or placebo. 
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 and decrease any potential peripheral neuropathy) 
according to institutional and/or local standards and per manufacturer’s instructions. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.5. 
Any dose modification, overdose, or incorrect administration of paclitaxel should be 
noted on the Paclitaxel Administration eCRF.  Adverse events associated with an 
overdose or incorrect administration of paclitaxel should be recorded on the 
Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(ipatasertib/placebo) will be provided by the Sponsor where required by local health 


 
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authority regulations.  The remaining IMP (paclitaxel) will either be provided by the 
Sponsor or sourced commercially by the site.  The study site will acknowledge receipt of 
IMPs and confirm the shipment condition and content.  Any damaged shipments will be 
replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Ipatasertib 
The Sponsor (Genentech) is a member of the Roche group and is subject to Roche’s 
global policies.  The Sponsor will offer post-trial access to the study drug (ipatasertib) 
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 study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for TNBC 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for TNBC 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
28 days prior to screening to the end of the study visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  
Patients who experience toxicities may be treated symptomatically as clinically indicated.  
Patients treated with anti-convulsant medications (see Section 4.4.2) should have levels 
monitored regularly. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study (within 7 days prior to Day 1 
until end of study treatment) unless otherwise specified below or in the exclusion criteria 
in Section 4.1.2: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer agents 
such as chemotherapy (with the exception of paclitaxel), immunotherapy, targeted 
therapy, biological response modifiers, or endocrine therapy will be allowed.  
• 
Radiation therapy:  Radiation therapy should not be administered to the breast 
and/or regional lymph nodes prior to surgery in this study.   
• 
Bone-targeted therapy:  treatment including bisphosphonates and receptor activator 
of nuclear factor kappa-B ligand inhibitors are prohibited except for the management 
of osteoporosis in patients who have been receiving them at a stable dose for at 
least 2 weeks prior to randomization.  
• 
Quinidine and/or other anti-arrhythmic agents, with the following exception: 
Stable doses of beta-blockers and/or calcium-channel blockers are permitted. 
• 
Vaccination with a live vaccine should be avoided in patients receiving paclitaxel 
because of the potential for serious or fatal infections 
 
Patients who require the use of any of these agents will be permanently discontinued 
from treatment with ipatasertib or placebo and will be followed for safety outcomes for 
30 days after their last dose of ipatasertib or placebo or until they receive another 
anti-cancer therapy, whichever occurs first. 
A clinical study in patients shows that ipatasertib at a dose of 600 mg QD is a moderate 
inhibitor of CYP3A, which resulted in a 2.2-fold increase in midazolam exposures.  
Midazolam is a sensitive CYP3A substrate.  Therefore, the following drugs should be 
used with caution.  If use of one of these drugs is necessary, the risks and benefits 


 
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should be discussed with the Medical Monitor prior to its concomitant use with 
ipatasertib or placebo: 
• 
Strong CYP3A4/5 inhibitors:  Such as but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandamycin, voriconazole, and/or grapefruit juice or grapefruit 
supplements 
• 
Strong CYP3A4/5 inducers:  Such as but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin 
• 
CYP3A4 substrates with a narrow therapeutic index:  Such as but not limited to 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, ergot alkaloids ergotamine, and/or 
dihydroergotamine 
 
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is a strong CYP3A4/5 inhibitor or inducer or a CYP3A4 substrate with a 
narrow therapeutic index.  In addition, the investigator should contact the Medical 
Monitor if questions arise regarding medications not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study. 
All patients will be closely monitored for safety throughout the study and during the 
adverse event reporting period (see Section 5.3.1).  Study assessments will be 
performed at screening, during treatment, and at the treatment completion visits.  
Screening assessments will be performed within 28 days before first dose of study 
treatment, unless otherwise specified.  A post-surgery assessment should be performed 
within 4 weeks of the patient’s surgery.   
4.5.1 
Descriptions of Study Assessments 
4.5.1.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
4.5.1.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer treatments, cancer procedures, and history of weight loss), 
disease characteristics (histologic subtype, stage of disease, and immunostaining or 


 
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in-situ hybridization results), and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, and nutritional supplements) 
used by the patient within 28 days prior to the ICF signature. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.1.3 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat; cardiovascular; dermatological; musculoskeletal; respiratory; gastrointestinal; 
and neurological systems, clinical breast examination and regional lymph node 
examination, as well as measurement of weight and height (height at screening only).  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Vital Signs eCRF. 
At subsequent visits (or as clinically indicated), targeted physical examination (including 
clinical breast examination and regional lymph node examination) should be performed 
to assess and record changes from baseline abnormalities and any treatment-emergent 
signs or symptoms.  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.  See Section 4.5.1.6 for the clinical breast 
examination requirements. 
As part of tumor assessment, physical examinations should also include evaluation of 
the presence and degree of enlarged lymph nodes, as well as a breast examination. 
ECOG performance status and weight will be recorded at baseline and throughout the 
study, as scheduled.  
4.5.1.4 
Vital Signs 
Vital signs will include measurements of heart rate; systolic and diastolic blood pressure 
while the patient is in a seated position after resting for at least 5 minutes; respiratory 
rate; and oral, axillary, or tympanic temperature. 
On paclitaxel dosing days, vital signs will be recorded prior to dosing and at the end of 
the infusion. 
4.5.1.5 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed at the discretion of 
the treating investigator.  As a reference, per National Comprehensive Cancer Network 
(NCCN) guidelines, metastatic evaluation can be informed from clinical stage as follows:  
• 
For Stage II and Stage IIIA:  bone scan is to be performed in presence of bone pain 
and/or elevated alkaline phosphatase; abdominal/pelvic CT in case of elevated 
alkaline phosphatase, abnormal liver function tests, abdominal symptoms or 
abnormal physical examination; chest CT if pulmonary symptoms. 
 


 
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In addition, liver function tests, bone scans, chest X-rays/diagnostic CT, liver imaging, 
and/or other radiographic modalities may be considered when clinically indicated to 
exclude metastatic disease. 
4.5.1.6 
Tumor and Response Evaluations 
All measurable disease must be documented at screening and re-assessed at 
subsequent tumor evaluation (see Appendix 3).  Response will be assessed by the 
investigator on the basis of clinical breast examinations and breast MRI.  Whenever 
possible, assessments should be performed by the same evaluator to ensure internal 
consistency across visits. 
Mammogram 
Bilateral mammograms must be obtained at baseline within 90 days prior to enrollment, 
if not already performed per standard of care within this timeframe.  Mammographic 
tumor measurements must be recorded in the eCRF.  
Clinical Breast Examination 
Assessment of primary breast tumor and regional lymph nodes must be done by 
physical examination (palpation) at baseline and as specified in Appendix 1.  Breast 
tumor measurement by caliper (preferred) or ruler will be performed and recorded in the 
eCRF. 
Axillary lymph node status (and other regional lymph nodes if clinically indicated) will 
also be assessed as clinically positive or negative at each timepoint.  The main purpose 
of performing this examination is to rule out progressive disease that would lead to study 
treatment discontinuation. 
Breast MRI 
Contrast-enhanced breast MRI scans is mandatory for all patients at baseline (within 
28 days prior to start of study treatment, Cycle 1 Day 1) and at the presurgical visit.  
Timing and location of any clip or marker placement during study biopsies should be 
recorded for reference when MRI scans are read.  If the screening breast MRI scan is 
not evaluable for RECIST measurement due to technical limitations of the scan itself, the 
scan may be repeated.  Other MRI acquisition sequences, such as diffusion-weighted 
imaging, may be acquired during this study during the MRI scan visits for each patient. 
If at any time there is suspicion of progression based on physical examination, then the 
algorithm provided in Figure 3 must be followed for further evaluation of the suspected 
progression. 
For information about patient preparation, scanner requirements and settings, and image 
acquisition, refer to the imaging manual.  Standard site practice may be followed for the 
use of mild sedatives or anti-anxiolytics for claustrophobic patients prior to MRI. 


 
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An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient imaging scans throughout the trial.  The review facility 
will retain copies of scans for potential centralized assessments of MRI-related 
endpoints. 
4.5.1.7 
Laboratory, Biomarker, and Other Biological Samples 
Adequate hematologic and organ function within 14 days before the first study treatment 
must be determined.   Predose laboratory samples should be drawn within 
approximately 3 days prior to study drug administration on Day 1 of each cycle, and 
results available before dosing.  Postdose laboratory samples should be drawn 
according to the schedule in Appendix 1. 
Local Laboratory Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  Complete blood count, including red blood cell (RBC) count, ANC, 
hemoglobin, hematocrit, and white blood cell (WBC) count with differential 
(neutrophils, bands, eosinophils, basophils, lymphocytes, monocytes, and other 
cells), and platelet count 
• 
Coagulation:  INR, PT, and aPTT/PTT 
• 
Fasting (≥ 8-hour fast) serum chemistry:  sodium, potassium, chloride, bicarbonate, 
glucose, blood urea nitrogen (BUN)/urea, creatinine, calcium, phosphorus, 
magnesium, total bilirubin, total protein, albumin, LDH, ALT, AST, and alkaline 
phosphatase. 
• 
Fasting (≥ 8-hour fast) lipid profile and amylase:  Total cholesterol, high-density 
lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase 
• 
Fasting insulin  
• 
Glycosylated hemoglobin (HbA1c) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• 
Pregnancy test:  All women who are not postmenopausal (≥ 12 months of 
non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy 
test at screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits, and as clinically indicated.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
 


 
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Central Laboratory Samples 
Instruction manuals outlining sampling procedures, storage conditions, and shipment 
instructions and supply kits will be provided for all central laboratory assessments.  
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Mandatory tumor tissue:  All biopsies collected for study purposes, whether it is 
required or optional, should be from safely accessible tissue and be minimally 
invasive 
• 
Specimens will be used for assessment of several biomarkers.  It is likely that not all 
assays will be performed on samples provided by each patient (possibly because of 
insufficient tumor material or inadequate sample quality).  Therefore, assays will be 
performed with the following priority to ensure a high likelihood of generating data to 
support the objectives of the study, including but not limited to hematoxylin and 
eosin (H&E) stains, PTEN status by IHC, INPP4B status by IHC, RNA isolation for 
gene expression analysis, PIK3CA alteration analysis, AKT3 analysis, Ki67 staining, 
DNA isolation for additional mutation detection and copy number analyses, and 
RPPAs.  In addition, other exploratory assessments, including but not limited to, 
AKT/PTEN signaling pathways may be evaluated, including protein expression and 
molecular profiling studies such as next-generation sequencing (NGS) and 
gene-expression. 
Archival tumor tissue for PTEN status:  Tissue should be of good quality based 
on total and viable tumor content.  Evaluation of the patient’s tumor sample for 
PTEN status by a central laboratory must occur prior to initiation of study 
treatment.  A minimum of 10 unstained slides from a prior diagnostic FFPE core 
biopsy would be required for enrollment eligibility purposes.  Cytologic or FNA 
samples are not acceptable.  
If archival tissue is either insufficient or unavailable, FFPE core sample from a 
pretreatment biopsy of the tumor may be used; however, evaluation of the 
patient’s tumor sample for PTEN status by a central laboratory should occur 
prior to the initiation of study treatment.   
Screening and on-treatment tumor tissue biopsy:  FFPE and non-FFPE 
samples will be prepared from newly collected (fresh) tumor biopsies.  At least 
one FFPE core needle biopsy and at least two freshly frozen OCT core needle 
biopsies are required at baseline and Cycle 1, Day 8.  
Tissue from surgery (see Section 3.1.1):  A FFPE tumor block and/or 
representative tissue sample slides from the scheduled surgical resection are 
required for additional pathway marker evaluation.   
If a tumor block and/or slides cannot be obtained for various reasons (e.g., 
the tumor tissue is not sufficient at surgical resection), the site should 
discuss with the Sponsor. 
Mandatory tissue biopsy if patient will have additional systemic therapy prior to 
surgery:  FFPE and non-FFPE samples will be prepared from newly collected 
(fresh) tumor biopsies.  At least one FFPE core needle biopsy and at least two 


 
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freshly frozen OCT core needle biopsies are required prior to initiation of 
additional systemic therapy. 
• 
Optional tumor tissue from biopsies at progression:  Optional FFPE tumor biopsy 
collection is strongly recommended and may be obtained if the patient progresses 
during neoadjuvant treatment.  Patients must have provided specific consent to 
allow collection and retention of optional samples. 
• 
Plasma samples for exploratory research on candidate biomarkers including, but not 
limited, to ctDNA 
• 
At Cycle 1, Day 1, a whole blood sample will be taken for DNA analysis and will be 
collected as part of the central laboratory samples. 
• 
Plasma samples for PK assessment:  Plasma samples will be collected to measure 
ipatasertib concentrations (see Appendix 1 and Appendix 2).   
• 
Any remaining samples collected for PK and biomarker assays may be used for 
exploratory biomarker profiling, metabolite profiling and identification, and 
pharmacodynamic assay development purposes as appropriate. 
Residual samples will be destroyed no later than 5 years after the date of final 
closure of the clinical database. 
 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.5. 
4.5.1.8 
Electrocardiograms 
Triplicate 12-lead ECG recordings will be obtained at specified timepoints, as outlined in 
the schedule of assessments (see Appendix 1).  Three interpretable ECG recordings 
(e.g., without artifacts) must be obtained at each timepoint (± 5 minutes).  The average of 
the three readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  Single 
ECG recordings may be obtained at unscheduled timepoints as indicated.  
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 triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate ECG monitoring should continue until QTcF has stabilized on 


 
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two successive ECGs.  The Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained and 
collected subsequent to the ECG reading.  A decision on study drug discontinuation 
should be made, as described in Section 5.1.5.1.  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). 
4.5.1.9 
Pathology Assessment at Surgery 
Determination of pathological complete response (pCR) will be as measured by local 
pathology laboratory evaluation of the breast and lymph node sampling from the axilla.  
Pathologic response within the breast and axilla will be assessed per local guidelines. 
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the treating physician to 
confirm that patients meet all eligibility criteria before initiation of study treatment.  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. 
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding Cycle 1, Day 1, unless otherwise specified.  Results of tests and/or 
examinations performed as standard of care prior to obtaining informed consent and 
within 28 days prior to the first dose of study treatment may be used rather than 
repeating required tests.  Additional informed consent (with a separate ICF) is required 
for collection of optional samples. 
4.5.2.2 
Assessments during Treatment 
All visits must occur within 3 days (± 3 days) of schedule visits after Cycle 1, Day 1, 
unless otherwise noted.  All assessments will be performed on the day of the specified 
visit unless a time window is specified.  Assessments scheduled on the day of study 
drug administration of each cycle should be performed prior to study drug administration, 
unless otherwise noted.   
The surgery visit should take place no more than 5 weeks after the last dose of 
paclitaxel. 
4.5.2.3 
Post-Surgery/Early Termination Assessments 
A treatment completion visit should be scheduled within approximately 4 weeks after 
surgery.  The treatment completion visit procedures and assessments should be 
performed after patients permanently discontinue all study treatments (i.e., ipatasertib or 
placebo, and paclitaxel). 


 
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Patients who receive additional neoadjuvant systemic treatment for significant residual 
disease or progressive disease will be followed for pathologic complete response after 
definitive surgery. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
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 at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance (e.g., missed doses, visits) 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
Adverse events that are ongoing at the post-surgery/early termination visit and thought 
to be related to ipatasertib or placebo, and/or paclitaxel, will be followed until the event 
has resolved to baseline grade, the event is assessed by the investigator as stable for a 
minimum of 60 days, new anti-tumor treatment is initiated, the patient is lost to follow up, 
the patient withdraws consent, or it has been determined that the study treatment or 
participation is not the cause of the adverse event. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Disease progression, per investigator assessment 
• 
Intolerable toxicity to ipatasertib or placebo, and/or paclitaxel 
• 
Change in patient eligibility 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
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4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Ipatasertib is not approved and is currently in clinical development.  Thus, the entire 
safety profile is not known at this time.  The following information is based on nonclinical 
data and limited clinical data from the Phase I studies. 
Nonclinical and Phase I clinical data for ipatasertib as a single agent and in combination 
with chemotherapy have identified limited overlap with the well-defined safety profile of 
paclitaxel.  The combination of ipatasertib and paclitaxel has been well tolerated in the 
Phase Ib study (PAM4983g), including ipatasertib administered at the RP2D of 400 mg 
in combination with paclitaxel.  However, given that both ipatasertib and paclitaxel may 
result in gastrointestinal toxicity, there may be an increased risk of nausea, vomiting, and 
diarrhea with this combination.  The potential for a clinically meaningful change in the 
exposure of ipatasertib and/or paclitaxel because of drug−drug interaction (DDI) is 
anticipated to be low, based on the PK data from the Phase Ib study (PAM4983g). 
The safety plan for this study is designed to ensure patient safety and will include 
specific eligibility criteria and monitoring assessments as detailed below. 
5.1.1 
Eligibility Criteria 
Eligibility criteria for this study (see Section 4.1) were selected to enhance the safety of 
patients in this trial.  A number of exclusion criteria are specifically based on the known 


 
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safety profiles of the study treatments, including the known safety profile of paclitaxel, as 
well as the nonclinical and clinical data for ipatasertib.   
5.1.2 
Safety Monitoring 
Safety will be evaluated in this current study through the monitoring of all serious 
adverse events, non-serious adverse events, and laboratory abnormalities, defined and 
graded according to NCI CTCAE, v4.0.  In addition, the JMC will conduct analyses of 
safety (see Section 6.8.1 and Section 6.8.2). 
5.1.3 
Risks Associated with Ipatasertib 
As of 31 March 2014, single-agent ipatasertib had been given to 30 patients with cancer 
in the dose-escalation stage.  The following adverse events have been assessed as 
related to ipatasertib and occurred in ≥ 10% of the patients:  nausea, diarrhea, vomiting, 
asthenia, hyperglycemia, decreased appetite, dyspepsia, dysgeusia, and rash.  Grade 3 
adverse events that were assessed as related to ipatasertib were diarrhea, asthenia, 
hypercholesterolemia, hyperglycemia, hypophosphatemia, nausea, and toxic skin 
eruption (see Section 1.2.2 and Ipatasertib Investigator’s Brochure for more details). 
The combination of ipatasertib with paclitaxel has also been tested in Arm C of the 
ongoing Phase Ib study (PAM4983g).  The types and frequencies of adverse events 
assessed by investigators to be related to ipatasertib in Study PAM4983g are 
comparable to the single-agent Study PAM4743g.  The following adverse events in 
Arm C (ipatasertib in combination with paclitaxel) have been assessed as related to 
ipatasertib in combination with paclitaxel and occurred in ≥ 10% of the patients:  diarrhea, 
nausea, fatigue, vomiting, rash, abdominal pain, anemia, dehydration, dermatitis 
acneiform, dizziness, dyspnea, and hyperglycemia.  Grade 3 adverse events assessed 
as related to ipatasertib in Arm C were diarrhea, dehydration, hyperglycemia, anemia, 
neutropenia, and rash.  Of note, no patients in Arm C experienced a Grade 4 or Grade 5 
adverse event assessed as related to ipatasertib.  A more comprehensive list of adverse 
events observed in Study PAM4983g is provided in Section 1.2.2. 
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. 
5.1.4 
Potential Safety Issues 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 (every 4 weeks) or sooner if clinically 
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Peripheral neuropathy has not been observed to date with single-agent ipatasertib in the 
Phase Ia study (PAM4743g).  Patients with Grade ≥ 2 peripheral neuropathy will be 
excluded from this study.  Patients will be monitored throughout the study for new 
peripheral neuropathy through assessment of adverse events and physical examinations.  
Modifications of paclitaxel administration in response to neuropathy are described below. 
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 
Package Insert or Summary of Product Characteristics 
5.1.5 
Dosage Modifications 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided below. 
5.1.5.1 
General Guidelines 
Dose modifications for paclitaxel chemotherapy will be performed according to standard 
practice or institutional guidelines; details in this section can be used as guidance.  
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcome will be documented in the patient's chart and recorded in the eCRF.  
General guidelines for dosage/schedule modification are summarized as follows: 
• 
All effort should be made to provide 12 total doses of paclitaxel, if risk/benefit 
assessment allows. 
• 
If ipatasertib or placebo treatment is delayed, paclitaxel treatment should continue 
as scheduled; however, if paclitaxel treatment is delayed and ipatasertib/placebo is 
scheduled to be administered at the same timepoint, it is preferred that 
ipatasertib/placebo is also delayed to align with paclitaxel dosing. 
• 
If toxicity causes paclitaxel treatment to be delayed, clinic visits (and study 
procedures) associated with each cycle of therapy, as defined by the administration 
of paclitaxel chemotherapy, will also be delayed.  However, laboratory assessments 
and clinical visits shall be scheduled as needed for adverse events follow-up.  Once 
the toxicity has resolved to the required level, study treatment and study procedures 
will be resumed, according to the study cycle day count. 
• 
For any concomitant conditions at baseline, the dose modifications will 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 will be considered a shift of one grade and will be treated as 
Grade 1 toxicity for dose-modification purposes. 
• 
For toxicities assessed by the investigator to be unlikely to develop into serious 
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. 


 
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• 
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 across three or more doses (i.e., at least 21 days) may be allowed to increase 
back to a 100% dose at the treating physician’s discretion.   
• 
Chemotherapy may be delayed to manage toxicity.  Delays up to 4 weeks 
(approximately 28 days) are permitted.  Any delay longer than 4 weeks for a 
treatment-related adverse event will require permanent discontinuation of paclitaxel.  
All effort should be made to provide 12 total doses of paclitaxel, if risk/benefit allows. 
 
Criteria for treatment modifications and guidelines for the management of toxicities 
attributable to ipatasertib, placebo, and/or paclitaxel are summarized below, along with 
recommended dose reductions for ipatasertib, placebo, and/or paclitaxel (see Table 1).  
The suggested reduction instructions provided in Table 1 are intended to serve as a 
guideline to allow ongoing treatment for patients.   
Table 1 
Suggested Dose Reductions for Ipatasertib, Placebo, 
and/or Paclitaxel 
Dose Level a 
Ipatasertib/Placebo 
Paclitaxel 
Starting dose 
400 mg 
80 mg/m2 
First dose reductionb 
300 mg 
65 mg/m2 
Second dose reductionb 
200 mg 
50 mg/m2 
Third dose reductionb 
Discontinue  
Discontinue 
a If the patient continues to experience specified drug-related adverse events after 
second reduction, the treatment should be discontinued. 
b Note that dose modification(s) for ipatasertib/placebo and paclitaxel are 
independent (e.g., adverse event may lead to dose reduction for ipatasertib/placebo 
with no dose modification for paclitaxel). 
 
5.1.5.2 
Dosage Modification for Ipatasertib and Placebo 
Patients may hold the ipatasertib or placebo 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 the ipatasertib or placebo is discontinued at any time 
during the study, patients may have the option of continuing on study with chemotherapy 
alone. 
If the patient does not tolerate the QD dosing of the ipatasertib or placebo, a BID 
regimen of the ipatasertib or placebo (with the total daily dose divided in half, without a 
dose reduction, and administered approximately every 12 hours) may be attempted 
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regimen may be used to alleviate gastrointestinal symptoms, including nausea and 
vomiting.  Employment of a BID regimen should not be considered as a dose reduction.  
No more than two dose reductions of ipatasertib or placebo per patient (lowest dose 
level to be administered will be 200 mg/day) will be allowed, and dose re-escalation of 
ipatasertib or placebo may be permitted in the study after discussion with the Medical 
Monitor. 
5.1.5.3 
Fasting Hyperglycemia 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 4 hours.  Dosage modification guidelines for fasting hyperglycemia attributable to 
ipatasertib or placebo are outlined below: 
• 
Grade 1 fasting hyperglycemia (Range:  > ULN−160 mg/dL [> ULN−8.9 mmol/L]):  
The patient may continue treatment with the ipatasertib or placebo, and 
chemotherapy.  The patient may receive education on a diabetic diet and consider 
beginning home glucose monitoring at the discretion of the investigator.  If glucose 
home monitoring is instituted, the ipatasertib or placebo treatment decision should 
be based on the morning fasting glucose value obtained prior to the dose of 
ipatasertib or placebo.  The patient may be started on an oral anti-diabetic 
medication (e.g., metformin) at the discretion of the investigator. 
• 
Grade 2 fasting hyperglycemia (Range:   > 160−250 mg/dL [> 8.9−13.9 mmol/L]):  The 
patient should be started on an oral anti-diabetic medication (e.g., metformin) and 
should receive education on a diabetic diet.  The ipatasertib or placebo treatment 
decision should be based on the morning fasting glucose value obtained prior to the 
dose of ipatasertib or placebo.  The patient may also continue treatment with the 
ipatasertib or placebo, and/or chemotherapy. 
• 
Grade ≥ 3 fasting hyperglycemia (Range:   > 250−500 mg/dL [> 13.9−27.8 mmol/L]):  
The ipatasertib or placebo should be held until fasting hyperglycemia has resolved 
to Grade ≤ 2, but may continue chemotherapy.   The patient should start a diabetic 
diet and should start an oral anti-diabetic medication (e.g., metformin).  The patient 
may begin home glucose monitoring (with fasting glucose checked prior to the 
ipatasertib daily dose).  If fasting glucose levels recover to Grade ≤ 2 within 3 days, 
the ipatasertib or placebo may be resumed at the same dose; alternatively, the dose 
of ipatasertib or placebo may be reduced by one dose level (see Table 1) at the 
discretion of the investigator.  If Grade ≥ 3 fasting hyperglycemia recurs within the 
same cycle, or if recovery of fasting glucose levels to Grade ≤ 2 takes 4 or more 
days, the dose of ipatasertib or placebo must be reduced by one dose level when 
treatment resumes.   
 
If patients develop Grade ≥ 3 fasting hyperglycemia associated with severe neurological 
symptoms (e.g., lethargy, focal signs, and obtundation), hyperventilation, abdominal pain 
or hypotension, discontinuation of study treatment with ipatasertib or placebo should be 
considered and discussed with the Medical Monitor.  Patients should be educated on the 
symptoms of hyperglycemia so that they can be promptly and appropriately managed. 


 
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In order to diminish the risk of hypoglycemia, insulin should not be administered for 
asymptomatic hyperglycemia of any grade. 
5.1.5.4 
Neutropenia and/or Thrombocytopenia 
Addition of hematopoietic growth factors is allowed.  Dosage modification guidelines for 
neutropenia and/or thrombocytopenia attributable to paclitaxel are outlined below: 
• 
Grade 2 neutropenia or thrombocytopenia:  Paclitaxel may be administered at the 
previous dose when ANC has recovered to ≥ 1500/μL (or per institutional guideline) 
and when the platelet count has recovered to ≥ 100,000/μL (or per institutional 
guideline).  If the hematologic parameters do not recover to levels required for 
dosing per guidelines within 14 days, the paclitaxel dose should be reduced.  
• 
Grade ≥ 3 neutropenia or thrombocytopenia:  Paclitaxel should be held.  Dose for 
subsequent paclitaxel treatments should be reduced by one dose level (see 
Table 1).  Following a treatment delay of 4 weeks, if recovery to ANC of ≥ 1500/μL 
(or per institutional guideline) or if recovery to platelet count of ≥ 100,000/μL (or per 
institutional guideline) does not occur before the next scheduled paclitaxel dose, the 
patient will permanently discontinue paclitaxel treatment. 
• 
Febrile neutropenia (ANC < 1000/μL and fever ≥ 38.5°C [101°F]):  Paclitaxel should 
be held until adequate recovery and for up to 4 weeks.  If the neutropenia recovers 
to ANC ≥ 1500/μL within 4 weeks, paclitaxel should be reduced by one level.  
Following a treatment delay of up to 4 weeks, if recovery to ANC of ≥ 1500/μL does 
not occur, the patient will permanently discontinue paclitaxel treatment. 
 
If a dose delay is required as a result of neutropenia at any grade, patients should 
receive prophylactic granulocyte colony-stimulating factor (G-CSF) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) per institutional standards. 
Patients should be counseled as to the risk of fever and infection and to the importance 
of contacting their treating physician immediately if these conditions occur, so that they 
can be promptly and appropriately managed. 
5.1.5.5 
Nausea and/or Vomiting 
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti-emetic 
treatment(s), including ondansetron (or equivalent anti-emetic).  If the nausea and/or 
vomiting are attributable to the ipatasertib or placebo, the investigator may employ a BID 
dosing of the ipatasertib or placebo administration (equivalent to the total daily dose 
divided by half; see Section 5.1.5.2).  For persistent nausea and/or vomiting attributable 
to the ipatasertib or placebo, and/or paclitaxel, dosage modification guidelines for 
ipatasertib or placebo, and/or paclitaxel are outlined below: 
• 
Grade 1 nausea and/or vomiting:  Maximum supportive care should be administered 
as needed at the discretion of the investigator.  
• 
Grade 2 nausea and/or vomiting:  Ondansetron (or equivalent anti-emetic) should 
be administered as needed.   


 
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• 
Grade ≥ 3 nausea and/or vomiting:  Ondansetron (or equivalent anti-emetic) should 
be administered as needed.  If the nausea and/or vomiting are attributable to 
ipatasertib or placebo, the investigator may employ a BID dosing of 
ipatasertib/placebo administration (equivalent to the total daily dose divided by half; 
see Section 5.1.5.2); alternatively, the dose of ipatasertib or placebo may be 
reduced by one dose level (see Table 1).  If nausea and/or vomiting is attributable to 
chemotherapy, paclitaxel may be given at a reduced dose during subsequent cycles. 
 
Dose re-escalation of the ipatasertib or placebo, and/or paclitaxel may be permitted in 
subsequent cycles for patients who exhibit Grade ≤ 1 nausea/vomiting through at least 
one cycle. 
5.1.5.6 
Diarrhea 
Diarrhea should be managed with loperamide or per local guidelines and standard of 
care, including but not limited to therapy with Lomotil (diphenoxylate and atropine), 
codeine, or octreotide.  Dose reductions for diarrhea should occur only if the symptoms 
persist despite treatment with adequate (combination) anti-diarrheal medications.  
If persistent diarrhea (more than 48 hours despite optimal medical treatment or dose 
hold) is attributable to the ipatasertib or placebo, and/or paclitaxel, dosage modification 
guidelines for ipatasertib or placebo, and/or paclitaxel are outlined below: 
• 
Grade 2 diarrhea:  The investigator should initiate optimal medical management 
with loperamide as early as possible.  If diarrhea is persistent (lasting longer than 
48 hours despite medical management), second-line therapy may include (but not 
limited to) Lomotil (diphenoxylate and atropine), codeine or octreotide per local 
guidelines and standard of care.  Ipatasertib/placebo dosing should be interrupted 
until improvement of diarrhea to Grade ≤ 1, at which time ipatasertib/placebo may 
be resumed at the same dose for initial occurrence with consideration of 
maintenance loperamide dosing (i.e., 2 mg, 2 to 4 times daily).  Investigators may 
reduce ipatasertib or placebo by one dose level (see Table 1) for recurrent Grade 2 
diarrhea.  If diarrhea persists following up to two dose reductions of ipatasertib or 
placebo, consider dose hold of paclitaxel.  Dose intensity of paclitaxel should be 
maintained as much as is safely possible. Paclitaxel dose reduction or 
discontinuation can be considered if diarrhea persists even after ipatasertib/placebo 
discontinuation (see Table 1). 
• 
Grade ≥ 3 diarrhea:  Medical management of diarrhea per Grade 2 diarrhea above 
should be initiated as early as possible.  Ipatasertib or placebo should be held until 
the diarrhea resolves to Grade ≤ 1, at which time maintenance loperamide dosing 
(i.e., 2 mg, 2 to 4 times daily) is recommended.  The dose of ipatasertib or placebo 
will be reduced by one dose level when treatment resumes (see Table 1).  If 
diarrhea persists following dose reduction of ipatasertib or placebo, an additional 
dose hold or reduction with ipatasertib/placebo should be considered (see Table 1).  
Dose intensity of paclitaxel should be maintained as much as is safely possible.  
Paclitaxel dose reduction or discontinuation can be considered if diarrhea persists 
even after ipatasertib/placebo discontinuation (see Table 1).  
 


 
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Dose re-escalation of the ipatasertib or placebo, and/or paclitaxel may be permitted in 
subsequent cycles for patients who exhibit Grade ≤ 1 diarrhea for at least one cycle after 
discussion with the Medical Monitor.  
Gastroenterologists should be counseled as to the risk of colitis and infection upon 
prolonged diarrhea condition, and patients should be educated on the symptoms of 
dehydration, so that patients can be promptly and appropriately managed. 
For additional information on the management guideline for diarrhea, see Appendix 6. 
5.1.5.7 
Mucositis 
Dosage modification guidelines for mucositis attributable to the ipatasertib or placebo, 
and/or paclitaxel are outlined below: 
• 
Grade 1 or Grade 2 mucositis:  Maximum supportive care should be administered 
as needed at the discretion of the investigator.  If Grade ≥ 2 mucositis recurs in 
subsequent 4-week cycles, despite maximal supportive care, the dose of ipatasertib 
or placebo should be reduced by one dose level, and/or the dose of paclitaxel may 
be reduced for subsequent 4-week cycles (see Table 1).   
• 
Grade ≥ 3 mucositis:  If the mucositis resolves to Grade ≤ 2 during the current cycle, 
the dose of ipatasertib or placebo should be reduced by one dose level, and/or the 
dose of paclitaxel may be reduced by one dose level for subsequent cycles 
(see Table 1).  If the mucositis does not resolve to Grade ≤ 2 during the current 
cycle, paclitaxel should be held for a maximum of 4 weeks (approximately 28 days).  
If the mucositis resolves to Grade ≤ 2 within a maximum of 4 weeks, dosing of 
paclitaxel may resume at dose reduced by one level for subsequent cycles 
(see Table 1).  If recovery of mucositis to Grade ≤ 2 does not occur within a 
maximum of 4 weeks, the patient will permanently discontinue paclitaxel and may 
continue the ipatasertib or placebo after discussion with the Medical Monitor. 
 
Dose re-escalation of the ipatasertib or placebo, and/or paclitaxel may be permitted in 
subsequent cycles for patients who exhibit Grade ≤ 1 mucositis for at least one cycle. 
5.1.5.8 
Skin Toxicity 
Dosage modification guidelines for skin toxicity attributable to the ipatasertib or placebo, 
and/or paclitaxel are outlined below:  
• 
Grade 1 or Grade 2 skin toxicity, asymptomatic:  Investigator may prescribe topical 
or oral steroids or per institutional guidelines. 
• 
Grade 2 skin toxicity, symptomatic:  Investigator should consider topical or oral 
steroids per institutional guidelines.  The ipatasertib or placebo, and/or paclitaxel 
treatment may be held until resolution to Grade ≤ 1 or resolution such that the skin 
toxicity is no longer clinically significant. 


 
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• 
Grade ≥ 3 skin toxicity attributable to ipatasertib or placebo:  The ipatasertib or 
placebo should be held for a maximum of 4 weeks (approximately 28 days).  During 
this time, the patient may continue treatment with paclitaxel at the discretion of the 
investigator.  If the skin toxicity resolves to Grade ≤ 2 or resolution such that the skin 
toxicity is no longer clinically significant in less than 4 weeks, dosing of the 
ipatasertib or placebo may resume, but the dose of ipatasertib or placebo should be 
reduced by one dose level (see Table 1).  If recovery of the skin toxicity to Grade ≤ 2 
or resolution such that the skin toxicity is no longer clinically significant does not 
occur within a maximum of 4 weeks, the patient will permanently discontinue the 
ipatasertib or placebo but may continue paclitaxel. 
• 
Grade ≥ 3 skin toxicity attributable to paclitaxel:  Paclitaxel treatment should be held 
for a maximum of 4 weeks (approximately 28 days).  If the skin toxicity resolves to 
Grade ≤ 2 within a maximum of 4 weeks, paclitaxel treatment may resume with 
paclitaxel dose reduced by one dose level (see Table 1).  If recovery of the skin 
toxicity to Grade ≤ 2 does not occur within a maximum of 4 weeks, the patient will 
permanently discontinue paclitaxel but may continue the ipatasertib or placebo. 
 
Dose re-escalation of the ipatasertib or placebo, and/or paclitaxel may be permitted in 
subsequent cycles for patients who exhibit Grade ≤ 1 skin toxicity for at least one cycle.  
The ipatasertib or placebo, and/or paclitaxel should be permanently discontinued for 
rash due to Stevens-Johnson syndrome, toxic epidermal necrolysis, or other suspected 
severe hypersensitivity or allergic reaction that is related to ipatasertib or placebo, and/or 
paclitaxel. 
5.1.5.9 
Peripheral Neuropathy 
If Grade ≥ 3 peripheral neuropathy attributable to paclitaxel develops in patients, 
paclitaxel should be held until the neuropathy recovers to Grade ≤ 2 or resolution such 
that the peripheral neuropathy is no longer clinically significant.  During this time, the 
patient may continue the ipatasertib or placebo at the discretion of the investigator.  
If the peripheral neuropathy recovers to Grade ≤ 2 within 4 weeks or resolution such that 
the peripheral neuropathy is no longer clinically significant, dosing of paclitaxel may 
resume reduced by one dose level (see Table 1).  If recovery of the peripheral 
neuropathy to Grade ≤ 2 or resolution such that the peripheral neuropathy is no longer 
clinically significant does not occur within a maximum of 4 weeks, the patient will 
permanently discontinue paclitaxel but may continue the ipatasertib or placebo. Dose of 
paclitaxel may be reduced at discretion of the investigator for clinically significant 
neuropathy not reaching grade 3. 
5.1.5.10 
Hypersensitivity 
If a hypersensitivity reaction due to infusion of paclitaxel develops in patients, treatment 
for the hypersensitivity reaction, including the possibility of rechallenge with paclitaxel, 
should be administered as per institutional guidelines or at the discretion of the 
investigator.  The patient may continue the other study treatment components not 
associated with the toxicity (i.e., ipatasertib or placebo). 


 
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5.1.5.11 
Other Non-Hematologic Toxicities 
If other Grade ≥ 3 non-hematologic toxicities not described above develop in patients, 
treatment with the ipatasertib or placebo, and/or paclitaxel may be held, depending on 
the attribution of the toxicity, at the discretion of the investigator.  During this time, 
treatment may continue with the other non-attributable treatment agent (i.e., either the 
ipatasertib or placebo, or paclitaxel).  The Grade ≥ 3 non-hematologic toxicity should be 
monitored at least weekly.  If the toxicity resolves to Grade ≤ 1 within 2 weeks, treatment 
may resume with the attributable agent.  If the toxicity resolves to Grade ≤ 1 in 
2−4 weeks, the dose of the attributable drug should be reduced by one level per the 
suggested guidelines in Table 1.  Depending on the nature and the severity of the 
adverse event, if recovery to Grade ≤ 1 takes > 4 weeks, treatment may resume with the 
attributable agent with dose reduction, or the attributable agent may be permanently 
discontinued, at the discretion of the investigator and after discussion with the Medical 
Monitor.   
For Grade ≥ 3 toxicities associated primarily with laboratory abnormalities only 
(e.g., elevation of ALT, AST, lipase, or amylase, or decreases in phosphorus without 
clinical or other evidence of pancreatitis or other hepatic dysfunction), study treatment 
may continue without interruption and/or dose-reduction at the discretion of the 
investigator per institutional practice. 
5.1.6 
Management of Specific Adverse Events 
Guidelines for the management of specific adverse events are provided below. 
5.1.6.1 
Hyperglycemia 
Concomitant administration of the ipatasertib with food increased plasma glucose and 
insulin levels in the single-agent Phase Ia study (PAM4743g).  Grade 1 or Grade 2 
fasting hyperglycemia events were observed among fasting patients and were relieved 
with a combination of oral anti-diabetic therapy (e.g., metformin) and diet modifications.  
Patients who at baseline show early signs of insulin resistance, based on an elevated 
homeostasis model of estimated insulin resistance, may be treated with an oral 
anti-diabetic drug (e.g., metformin) and will still be allowed to participate in the trial.  
To prevent the risk of hypoglycemia, management of any asymptomatic hyperglycemia 
with insulin should be avoided. 
Use of glucocorticoid pretreatment for paclitaxel may influence glucose metabolism 
in patients in this study.  Institutions may use glucocorticoid premedications per 
institutional policies and as described in the package insert. 
Patients who currently require the use of insulin or have a fasting glucose > 150 mg/dL 
or HbA1C > 8% at baseline will be excluded from this study.  Fasting glucose levels and 
HbA1C will be obtained at selected study visits from all patients as described in 
Appendix 1.  For the purposes of dose modification decisions, glucose measurements 


 
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should be in a fasting state, defined as a glucose level obtained ≥ 4 hours after the most 
recent caloric intake. 
Any patient experiencing fasting hyperglycemia should be managed per standard 
medical practice for hyperglycemia and sequelae, such as dehydration and acidosis.  
Suggested dose modifications of the ipatasertib or placebo for hyperglycemia are 
outlined in Section 5.1.5.3. 
Other metabolic effects observed with the class of PI3K/mTOR inhibitors include 
hypercholesterolemia and hypertriglyceridemia; therefore, patients with Grade ≥ 2 
uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia will be excluded 
from the study.  Fasting plasma lipid profiles will be obtained at selected study visits from 
all patients as described in Appendix 1.  
5.1.6.2 
Hematologic Toxicity 
Lymphocyte depletion has been observed in nonclinical toxicity studies in animals 
treated with ipatasertib; therefore, patients will be required to have adequate 
hematologic function, with resolution of any acute hematologic toxicities from prior 
therapies, before initiation of ipatasertib or placebo.  Patients with conditions that affect 
lymphocyte counts, such as HIV infection or immunosuppressive therapy, will be 
excluded from the study.  Patients will have standard hematologic parameters monitored 
throughout the study as described in Appendix 1.  
5.1.6.3 
Gastrointestinal Toxicity 
Nausea, vomiting, and diarrhea have been observed in the Phase Ia study (PAM4743g) 
with single-agent ipatasertib.  These symptoms are generally transient and relieved by 
supportive medications (e.g., ondansetron for nausea and loperamide for diarrhea).  
Class effects from other PI3K/Akt pathway inhibitors have included stomatitis and 
diarrhea and are generally reversible.   
Any potential gastrointestinal effects will be monitored by weekly evaluations of clinical 
history and physical examination findings.  Patients with known active inflammatory 
diseases, including those with small or large intestinal inflammation (e.g., Crohn’s 
disease or ulcerative colitis), will be excluded from the study.   
Gastrointestinal toxicities should be managed according to institutional guidelines, with 
appropriate supportive care as clinically indicated.  Suggested dose modifications of 
ipatasertib or placebo, and/or paclitaxel for gastrointestinal toxicities are outlined in 
Section 5.1.5.5 for nausea/vomiting, Section 5.1.5.6 for diarrhea, and Section 5.1.5.7 
for mucositis. 
5.1.6.4 
Dermatologic Toxicity 
Treatment-related rash occurred in approximately 12% of patients who received 
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a maculopapular-type rash, with or without pruritus.  The majority of cases were mild in 
severity and self-limited.  The incidence and severity of the rash appeared to be 
dose-dependent and may occur during or upon stopping ipatasertib administration.  
Isolated cases of Grade 3 rash have been observed. 
Rash and other dermatologic events should be closely monitored and managed 
according to institutional guidelines, with appropriate supportive care as clinically 
indicated.  For severe rash, dosing of ipatasertib or placebo should be interrupted, and 
patients should be treated with supportive therapy according to standard-of-care practice.  
Suggested dose modifications of ipatasertib or placebo, and/or paclitaxel for 
dermatologic toxicity are outlined in Section 5.1.5.8.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
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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) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions).  Adverse events of special interest 
for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
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considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Grade 4 fasting hyperglycemia or symptomatic Grade 3 fasting hyperglycemia 
• 
Grade ≥ 4 hepatotoxicity 
• 
Grade ≥ 3 colitis or diarrhea 
• 
Grade 2 diarrhea that persists for longer than 5 days despite optimal medical 
management (per diarrhea management in Section 5.1.5.6) 
• 
Grade ≥ 3 rash 
• 
Grade ≥ 2 pneumonitis 
• 
Any grade acute coronary syndrome or myocardial infarction 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1, 
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4, 5.5, and 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 30 days after the last dose of study drug, or initiation of 
another anti-cancer therapy, whichever occurs first.  After this period, the investigator is 
not required to actively monitor patients for adverse events; however, the Sponsor 
should be notified if the investigator becomes aware of any post-study serious adverse 
events with a suspected causal relationship (see Section 5.6). 


 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 2 
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 or 
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"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 3): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
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 3 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 


 
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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, unless the severity increases.  If a persistent adverse event 
becomes more severe, it should be recorded as a separate event on the Adverse Event 
eCRF.  The initial (less severe) adverse event report should be updated to indicate that 
the event resolved on the date just prior to the day the event became more severe.  If a 
persistent adverse event becomes serious, it should be recorded as a separate event on 
the Adverse Event eCRF and 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 initial (non-serious) adverse event report should be updated to 
indicate that the event resolved on the date just prior to the day the event became 
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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 if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
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 
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• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
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.  
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 a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of TNBC. 
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.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
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and stable.  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. 
If the death is attributed to progression of TNBC, "TNBC progression" should be 
recorded on the Adverse Event eCRF. 
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.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
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) 


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
• 
Perform an efficacy measurement for the study 
• 
Receive scheduled therapy for the target disease of the study 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events 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.  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). 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Non-serious adverse events of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 




 
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5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche 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.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (because the 
Sponsor considers abortions to be medically significant). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
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All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period and that is 
believed to be related to prior study drug treatment.  The adverse event reporting period 
is defined as 30 days after the last dose of study drug or initiation of another anti-cancer 
therapy, whichever occurs first (see Section 5.3.1). 
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event / Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Ipatasertib Investigator's Brochure 
• 
Local prescribing information for paclitaxel 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Primary and secondary efficacy analyses will be based on randomized patients, with 
patients allocated to the treatment arm to which they were randomized. 
Safety analyses will include treated patients (i.e., patients who received at least one 
dose of ipatasertib, placebo, or paclitaxel), with patients allocated to the treatment arm 
associated with the regimen that they actually received. 
No adjustments will be made for multiple comparisons when addressing primary and 
secondary efficacy endpoints.  Multiple comparison adjustments will be used for selected 
exploratory endpoints to account for genome-wide correlative comparisons.   
The primary analysis will be performed after LPLV and subsequent data cleaning, 
expected to occur approximately 7 months after the last patient has been randomized to 
the study. 
The primary, secondary, and exploratory efficacy analyses and safety analyses are 
described in Sections 6.4, 6.5, and 6.7.  
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is designed to evaluate the safety and preliminary evidence of activity of 
ipatasertib and paclitaxel.  This trial is hypothesis-generating and is able to detect only a 
large benefit from combination therapy with ipatasertib and paclitaxel versus placebo 
and paclitaxel.   
A total of 150 patients will be enrolled in the study (75 per arm).  Assuming a 60% 
prevalence of PTEN-low status in TNBC, it is expected that 90 patients with PTEN-low 
tumors will be enrolled.  This trial will not have adequate power to detect minimum 
clinically meaningful differences between treatment arms at a statistically significant α 
(type 1) error level of 5%.  Instead, the 90% confidence intervals (CIs) for the difference 
in pCR rate will be calculated with the expectation that for clinically meaningful outcomes, 
the lower limit of the two-sided 90% CI will be greater than 0. 
For example, a true improvement of greater than 20% in pCR rate (from 20% to 40%) 
would be considered a clinically meaningful outcome when comparing ipatasertib and 
paclitaxel versus placebo and paclitaxel.  Given at least 90 patients (45 per arm) with 
PTEN-low tumors and a targeted improvement of 20% in pCR rate, the corresponding 
lower limit of the two-sided 90% CI is 2.3%.  Also, for 150 patients (75 per arm) in ITT 
population with a targeted improvement of 15% in pCR rate, the corresponding lower 
limit of the two-sided 90% CI is 1.5%. 


 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized overall and by treatment arm.  The reasons for study treatment 
discontinuation will be tabulated, and major protocol violations will be summarized. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, region, 
weight, baseline ECOG performance status, tumor PTEN status, and tumor PIK3CA 
status will be summarized by treatment arm. 
Continuous variables will be summarized using means, standard deviations, medians, 
and ranges.  Categorical variables will be summarized by counts and by proportions. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the rate of locally assessed pCR in breast and axilla 
(ypT0/Tis ypN0).  The primary efficacy analyses will be performed on randomized 
patients, with the patients allocated to the treatment arm according to the randomization.  
The pCR endpoint will be analyzed for all randomized patients and for patients with 
PTEN-low tumors.  Patients whose pCR assessment is missing are counted as not 
achieving a pCR. 
An estimate of the pCR rate and its 90% CI (Blyth-Still-Casella method) will be 
calculated for each treatment arm for all randomized patients and for patients with 
PTEN-low tumors.  The difference in pCR rates will also be provided with 90% CIs, using 
the normal approximation to the binomial distribution.  Stratified Cochran-Mantel-
Haenszel tests will be used to compare treatment arms. 
In addition, a sensitivity analysis may be conducted to account for patients whose pCR 
assessment cannot be ascertained. 
6.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows. 
• 
The rate of pCR in breast in all patients and in patients with PTEN-low tumors 
assessed by local evaluation 
• 
Tumor ORR assessed by breast MRI via modified RECIST criteria, in all patients 
and in patients with PTEN-low tumors  
• 
The rate of pCR and ORR in patients whose tumors are Akt Dx+ (defined by PTEN 
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• 
The rate of pCR according to subtypes of breast cancer defined by molecular 
profiles; e.g., PAM50 classifier 
• 
The rate of BCS and conversion to BCS in patients with T2 or T3 tumors 
 
These endpoint measures will be summarized by their point estimates and 90% CIs for 
each treatment arm, and will be compared between the two treatment arms for each 
population using the normal approximation to the binomial distribution.  In addition, the 
locally-assessed pCR rate in breast and axilla will also be compared between the two 
treatment arms based on Cochran-Mantel-Haenszel test. 
6.5 
SAFETY ANALYSES 
The safety analyses will include all treated patients (i.e., randomized patients who 
received at least one dose of ipatasertib, placebo, or paclitaxel), with patients grouped 
according to the treatment actually received.  
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and ipatasertib or placebo, and paclitaxel exposures.  
Treated patients will be included in the safety analyses. 
Verbatim descriptions of adverse events will be mapped to thesaurus terms.  
Treatment-emergent events (defined as events occurring on or after the first dose of 
ipatasertib, placebo, or paclitaxel) will be summarized by thesaurus term, appropriate 
thesaurus levels, and NCI CTCAE, v4.0 grade.  Serious adverse events, including 
deaths, will be listed separately and will be summarized.  
Relevant laboratory values will be displayed by time, with NCI CTCAE Grade 3 
and Grade 4 values identified, where appropriate.  Laboratory abnormalities will also 
be summarized by NCI CTCAE grade.  Vital signs will be summarized by each 
treatment arm. 
6.6 
PHARMACOKINETIC ANALYSES 
GDC-0068 levels will be measured on Day 1 and Day 8 of Cycle 1. GDC-0068 plasma 
concentration versus time data, together with information on dosing and patient 
characteristics, will be pooled and analyzed using a PopPK analysis approach, as 
appropriate.  Nonlinear mixed-effect modeling will be used for the estimation of PopPK 
parameters for GDC-0068.  Covariates such as patient demographics (e.g., age, sex, 
body size), may be tested for significance on PK parameters of interest. 
The PK data may be combined with the safety, efficacy, and biomarker data for 
exposure-response modeling as an exploratory objective.  PK and PK/pharmacodynamic 
analyses may be reported in separate stand-alone reports.  Additional analyses may be 
explored as warranted by the data. 


 
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6.7 
EXPLORATORY ANALYSES 
The exploratory endpoints, including the effects of PI3K/Akt pathway alterations in the 
archival tumor samples will be evaluated with appropriate methods. 
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Analyses 
The JMC will convene for a review of partially unblinded summaries of the safety data 
after approximately 20 patients have completed study treatment, including surgery.  In 
addition, after approximately 90 patients have completed study treatment as well as 
surgery, the JMC will reconvene to perform an interim safety and efficacy analysis.  This 
efficacy interim analysis is for administrative purposes and is not intended to lead to an 
early termination of the trial if efficacy results appear favorable in a particular treatment 
arm. 
The members, roles, responsibilities, and communication processes of the JMC will be 
outlined in a separate charter. 
6.8.2 
Optional Interim Analysis 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct an additional interim efficacy analysis.  The decision to conduct an optional 
interim analysis and the timing of the analysis will be documented in the Sponsor’s trial 
master file prior to the conduct of the interim analysis.  The interim analysis will be 
performed and reviewed by the JMC and will follow the communication plan described in 
the JMC charter. 
In addition, the Medical Monitor may request additional safety analysis and may call 
for additional meetings of the JMC to review ongoing data to assess risk/benefit. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  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 a Data Quality Plan that describes the quality checking to be 
performed on the data.  Electronic data will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 


 
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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 to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor (or designee) 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 


 
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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, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
GENERAL ETHICAL CONSIDERATIONS 
All patients in this study will receive paclitaxel chemotherapy, given that paclitaxel has 
been extensively tested in multiple clinical trials for breast cancers in neoadjuvant, 
adjuvant and metastatic settings and represents an internationally recognized 
appropriate treatment for this disease.   An important aspect of neoadjuvant therapy in 
TNBC is to decrease tumor size, allowing for breast conservation surgery; in addition, 
pCR following neoadjuvant chemotherapy is prognostic of favorable long-term outcome.  
An important consideration for neoadjuvant regimen is good tolerability, allowing 
completion of the regimen and safe surgical resection.   
Taxane-based therapy can improve pCR in the neoadjuvant setting.  In addition, 
single-agent taxane therapy is safer relative to multidrug combinations, exhibiting lower 
frequency of Grade 3 and 4 events, and lower treatment discontinuation rate 
(see Section 3.3.3).  Notably, only a limited number of patients achieve pCR; thus there 
is a need for safe and effective regimen in early TNBC (as well as within biomarker 
subsets of TNBC). 
8.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 


 
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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 (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.3 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
A separate sample Research Informed Consent Form that addresses the use of 
remaining mandatory samples for optional exploratory research will be provided to each 
site.  The investigator or authorized designee will explain to each patient the objectives 
of the exploratory research.  Patients will be told that they are free to refuse to 
participate and may withdraw their specimens at any time and for any reason during the 
storage period.  A signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not sign the Research ICF. 
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. 


 
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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 of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.5 
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. 


 
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Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
Biologic samples obtained in this study will be identified using unique patient identifiers 
and sample identification numbers.  Samples will be linked with clinical data in the 
clinical database using the sample identification number.   
This clinical research involves the procurement of samples of blood and tissue for tumor 
DNA testing (e.g., mutational status of PIK3CA) as well as genomic DNA testing 
(e.g., polymorphisms in genes related to metabolic enzymes).  DNA samples will not be 
identified with patients’ names, pictures, or any government-issued identification 
numbers (e.g., Social Security numbers).  Samples will be identified using unique 
sample identification numbers only, which are considered patient identifiers under the 
Health Insurance and Portability and Accountability Act (HIPAA).  Samples will be linked 
with clinical data in Genentech’s clinical study database (including outcome data) by the 
patient’s year of birth and by the study identification number. 
8.6 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
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. 


 
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech and 
SOLTI (a cooperative group located in Spain).  The SOLTI group will provide clinical 
operations management in Spain and potentially in Portugal.  Approximately 30 U.S. and 
international sites will participate to enroll approximately 150 patients. 
A JMC will be in place during the study and will provide oversight of safety (see 
Section 3.1.2). 
An IWRS will be used to assign screening numbers, randomize patients, monitor 
enrollment and patient status, and to manage ipatasertib and placebo inventory, 
requests, and shipments.  
Patient data will be recorded via an EDC system from 
 
 using eCRFs (see Section 7).  
Central laboratories, including Genentech and Genentech’s collaborators, will be used 
for PIK3CA mutation detection and/or PTEN status determination and will provide kits for 
PK, tissue, whole blood, and plasma sample analyses to be conducted at central 
laboratories or Genentech.  PTEN evaluation will be conducted prior to randomization, 
and the results will be used for stratification. 
Treatment decisions will be based on local reading of ECGs obtained during the study. 
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient imaging scans throughout the trial.  The review facility 
will retain copies of scans for potential centralized assessments of MRI-related 
endpoints. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf  


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
99/Protocol GO29505, Version 3 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
100/Protocol GO29505, Version 3 
10. 
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Ipatasertib (GDC-0068)—Genentech, Inc. 
105/Protocol GO29505, Version 3 
Appendix 1  
Schedule of Assessments 
Assessment 
Screening a
Cycle 1 
Cycle 2 
Cycle 3 
Day −28 to –1 
1 
8 
15
22 
1 
8 
15
22 
1 
8 
15 
22 
Pre-
surgery Surgery b
Post-
surgery c
Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
~10-12
~14−19 
~ ≤ 4 
Weeks 
Early 
Termination 
Visit d 
Signed informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer-related medications 
and surgical procedures 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Complete physical 
examination e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Targeted physical  
examination f 
 
x 
 
 
 
x 
 
 
 
x 
 
  
 
x 
 
 
 
Weight 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs g 
x 
x 
x  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECOG performance status 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
x 
Hematology h 
x 
x i
x 
x 
x 
x i 
 
 
 
x i 
 
 
 
x 
 
x 
x 
INR, PT, and aPTT/PTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Fasting serum chemistry j 
x 
x i
 
 
 
x i 
 
 
 
x i 
 
 
 
x 
 
x 
x 
Fasting lipid profile, amylase 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
HbA1c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Urinalysis 
x 
 
 
 
 
x 
 
 
 
x  
 
 
 
 
 
 
 
Pregnancy test k 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
106/Protocol GO29505, Version 3 
Assessment 
Screening a
Cycle 1 
Cycle 2 
Cycle 3 
Day −28 to –1 
1 
8 
15
22 
1 
8 
15
22 
1 
8 
15 
22 
Pre-
surgery Surgery b
Post-
surgery c
Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
~10-12
~14−19 
~ ≤ 4 
Weeks 
Early 
Termination 
Visit d 
12-lead ECG l 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Mandatory tumor tissue 
x m 
 
x m
 
 
 
 
 
 
 
 
 
 
x n 
x o 
 
 
Optional tumor biopsy p,q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x r 
Circulating tumor DNA r 
x r 
 
 
 
 
 
 
 
 
x r 
 
 
 
x r 
 
 
x s 
Breast MRI s 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x s 
 
 
x 
Breast  
mammogram t 
x t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pCR determination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x o 
 
 
PK sample u 
 
x u x u
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for DNA analysis  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications v 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
x 
Adverse events w, x  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
x 
Paclitaxel administration 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Fasting insulin 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ipatasertib/placebo 
dispensation y 
See footnote s 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; ctDNA = circulating tumor DNA; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed paraffin-embedded; HbA1c = glycosylated 
hemoglobin; INR = international normalized ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; pCR = pathologic complete 
response; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time. 
 


Appendix 1  
Schedule of Assessments (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
107/Protocol GO29505, Version 3 
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 Cycle 1 Day 1 unless otherwise 
noted (e.g., for archival tissue processing, screening assessments may be extended to 8 weeks).  Except for Cycle 1 Day 1, all other study visits 
during the treatment period should be performed within ± 3 days of the scheduled date.  Screening eligibility labs done within 7 days of Cycle 1 
Day 1 may be used for Cycle 1 Day 1 labs.  Study assessments may be delayed or moved ahead of the window to accommodate holidays, 
vacations, and unforeseen delays.  All assessments or procedures are to be performed predose unless otherwise specified. 
a Adequate hematologic and organ function within 14 days before the first study treatment must be determined. 
b The surgery visit should take place no more than 5 weeks after last dose of paclitaxel. 
c 
Perform post-surgery visit approximately within 4 weeks after the surgery. 
d The early termination visit should occur within 4 weeks after the last administration of ipatasertib or placebo, or paclitaxel, whichever is 
discontinued last.  Note that early termination visit is required only if patients discontinue study treatment prior to protocol specified treatments. 
e The clinical breast examination and regional lymph node examination shall be performed as part of both the complete physical examination and 
targeted physical examination. 
f 
The clinical breast examination and regional lymph node examination shall be performed as part of both the complete physical examination and 
targeted physical examination. 
g Includes heart rate, systolic and diastolic blood pressure while patient is in a seated position after resting for at least 5 minutes; respiratory rate; 
and oral, axillary, or tympanic and temperature.  On paclitaxel dosing days, vital signs to be recorded prior to dosing and at the end of the 
infusion. 
h Includes RBC count, WBC count, WBC differential count (neutrophils, bands, lymphocytes, eosinophils, basophils, monocytes, and other cells), 
absolute neutrophil count, hemoglobin, hematocrit, and platelet count. 
i 
Measured prior to dosing. 
j 
Includes sodium, potassium, chloride, bicarbonate, glucose, BUN/urea, creatinine, calcium, phosphorus, magnesium, total bilirubin, total 
protein, albumin, LDH, ALT, AST, and alkaline phosphatase. 
k 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile.  Screening pregnancy test 
must be within 14 days of planned cycle day 1.  In addition pregnancy tests (serum or urine) are to be performed within approximately 3 days of 
Day 1 of each treatment cycle ≥ Cycle 2, and a pregnancy test should also be performed when clinically indicated.  For all other women, 
documentation must be present in medical history confirming that patient is not of childbearing potential. 
l 
Triplicate 12-lead ECG measurements. 
m Archival tissue (either FFPE tumor specimens or minimum of 10 unstained paraffin slides) and an associated pathology report must be 
confirmed to be available prior to entry into the study.  If archival tissue is either insufficient or unavailable, FFPE core sample from a 
pretreatment biopsy of the tumor may be used.  FFPE and non-FFPE samples will be prepared from newly collected (fresh) tumor biopsies and 
surgical resection.  All patients must consent to the collection of newly collected tumor biopsies (frozen and FFPE) for PTEN Akt-pathway 
testing and other biomarker assessments at baseline, Cycle 1 Day 8, and at surgery.  At least one FFPE core needle biopsy and at least two 


Appendix 1  
Schedule of Assessments (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
108/Protocol GO29505, Version 3 
freshly frozen OCT core needle biopsies are required at baseline and Cycle 1 Day 8 (Week 2). 
n Patients with significant residual or progressive disease can either proceed directly to surgery or be discontinued from the study, based on the 
investigator’s decision.  Patients who will receive additional systemic therapy prior to surgery are required to have an additional research 
biopsy. 
o FFPE tumor block/slides from surgical resection (at approximately Weeks 14−19) is required for local assessment of pCR; in addition 
block/slides are required for analysis of pathway biomarkers by the Sponsor.  If a tumor block/slides cannot be obtained for various reasons 
(e.g., the tumor tissue is not sufficient at surgical resection), the site should discuss with the Sponsor. 
p Tumor biopsy collection at disease progression is optional and only for patients who provide specific consent, one FFPE tumor biopsy will be 
collected.  
q All biopsies collected for study purposes, whether it is required or optional, should be from safely accessible tissue and be minimally invasive. 
r 
Blood will be collected for ctDNA analysis at screening, on Cycle 3 Day 1, at the pre-surgery visit, and at the study drug discontinuation or early 
termination visit. 
s 
MRI evaluation is mandatory at screening, pre-surgical visit (approximately weeks 10−12), early termination visit, as well as in cases where 
disease progression is suspected.  MRI scans will be centrally collected and held. 
t 
Mammography evaluation at baseline is mandatory if not already acquired as per standard of care between 90 days prior to screening and 
Day 1. 
u PK samples should be collected on Cycle 1, Days 1 and 8.  See Appendix 2 for schedule of PK assessments. 
v 
At screening and Day 1 of Cycle 1, record all concomitant medications taken between 28 days prior to screening and Day 1, Cycle 1; at 
subsequent timepoints, record new concomitant medications and any changes to the daily dosing. 
w Record serious adverse events, adverse events leading to ipatasertib, placebo, or paclitaxel discontinuation, and protocol-defined selected 
adverse events 
x 
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.  
y 
Patients will take ipatasertib/placebo on Days 1−21 every 28 days of all cycles.  Dispense a sufficient number of ipatasertib/placebo tablets to 
last until the next visit and provide a medication diary.  Extra study drug may be dispensed if there is a reasonable possibility that the patient’s 
next visit may be delayed (e.g., because of inclement weather or distance of patient’s home from study center).  Instruct patient to record the 
time and date they take each study drug dose in the diary and to return all unused study drug at each study visit to assess compliance.  Collect 
and review medication diary, collect unused tablets, and assess compliance at each subsequent visit. 
 


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
109/Protocol GO29505, Version 3 
Appendix 2  
Schedule of Pharmacokinetic Assessments 
Plasma samples for GDC-0068/placebo concentration measurement will be collected in 
Cycle 1 only.  The following information will need to be captured to allow PK analysis:  
1. 
Actual dose amount, dose time, and sampling time on Day 1 
2. 
Actual dose amount and dose time on the previous day 
3. 
Actual dose amount and dose time on the day of sampling (e.g., if the PK sampling 
occurs on Day 7, the dose time will need to be collected on Day 6 and on Day 7) 
4. 
Actual sampling times at each sample collection 
 
Study Visit 
Sampling Time Window 
0.5 to 2 hours post−GDC-0068/placebo 
Cycle 1, Day 1 
4 to 6 hours post−GDC-0068/placebo 
0 to 2 hours prior to GDC-0068/placebo 
Cycle 1, Day 8 
2 to 5 hours post−GDC-0068/placebo 
 
 


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
110/Protocol GO29505, Version 3 
Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer 
Conventional response criteria may not be ideal for the assessment of response in the 
setting of neoadjuvant therapy in early breast cancer. Therefore, RECIST 1.1 criteria 
have been modified to specifically address assessment of primary breast lesions along 
with axillary lymph node disease, using a range of breast imaging modalities.  Selected 
sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.11 
are presented below, with modifications and the addition of explanatory text as needed 
for clarity. For detailed information on the read methodology including how imaging data 
should be processed prior to reads, please refer to the Study Imaging Charter.  
 
RECIST v1.1 
Modified RECIST Early Breast 
Cancer Neoadjuvant Therapy 
Modalities 
CT as primary modality, 
ultrasound not 
recommended 
No CT; primary assessments by MRI; 
also assessments by ultrasound, 
mammography, and clinical exam  
Lymph nodes 
May be considered 
target lesions based on 
size criteria (≥ 15 mm in 
SAD) 
Only axillary lymph nodes assessed; 
nodes that are considered abnormal 
on imaging (based on morphological 
factors including, but not limited to 
SAD) to be followed as non-target 
lesions 
Possibility of having only 
non-target disease 
Allowed 
Not allowed; primary breast lesions 
must be measurable by MRI and/or 
ultrasound 
CT = computed tomography; MRI = magnetic resonance imaging; SAD = short axis dimension. 
 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
Method of Measurement 
According to RECIST 1.1 guidelines, MRI is the preferred modality to follow breast 
lesions in a neoadjuvant setting.  CT is currently the preferred modality for assessing 
metastatic disease, but should not be used in this focused setting of neoadjuvant 
                                            
 
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. 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
111/Protocol GO29505, Version 3 
therapy in early breast cancer.  Ultrasound, mammography, and clinical exam are all 
common and useful modalities for assessing breast lesions, and will also be used to 
assess response in this protocol, adhering to response criteria as presented in this 
appendix.  
Target Lesions 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should lend themselves to reproducible repeated measurements. Up to 
2 lesions in the breast may be identified as target lesions. A sum of the diameters of all 
target lesions will be calculated and reported as the baseline sum of diameters. 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. Lesions that 
meet the criteria for radiographically defined simple cysts should not be considered 
malignant lesions (neither target nor non-target) since they are, by definition, simple 
cysts. Pathologic axillary lymph nodes are not to be designated at target lesions, and 
lymph node measurements are not to be included in the sum of diameters (see below for 
more detail). 
Bilateral breast imaging studies should be conducted at each study assessment. The 
same method of measurement and the same technique should be used to characterize 
each target lesion at baseline and during the study, and all measurements should be 
recorded in metric notation.  Care must be taken in measurement of target lesions with 
different modalities, since the same lesion may appear to have a different size with 
each modality. If for some reason the same imaging modality cannot be used at a 
scheduled assessment time point, then the case should be discussed with the radiologist 
to determine if substitution of any other approach is possible and, if not, the patient 
should be considered not evaluable at that timepoint, for that particular type of imaging 
assessment. 
Non-Target Lesions 
Non-target lesions may include any other measurable breast lesions not identified as 
target lesions, as well as truly non-measurable lesions, such as diffuse skin thickening or 
other lesions not measurable by reproducible imaging techniques. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  Axillary lymph nodes are 
known to vary widely in size, and signs of abnormality in axillary lymph nodes on 
imaging include other morphological findings often in addition to changes in nodal size.  
For these reasons, pathologic axillary lymph nodes on imaging should be identified as 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
112/Protocol GO29505, Version 3 
non-target lesions at baseline.  Change in short-axis dimension may be considered in 
the assessment of pathology, but measurements are not required, and these lesions 
should be followed qualitatively, as described below at each response assessment 
timepoint.   
Signs of lymph node pathology on imaging include the following:  
• 
Increase in short axis dimension 
• 
Thickened cortex, either diffusely or asymmetrically enlarged 
• 
Thinning, or replaced fatty hilum 
• 
Irregular margins or spiculations 
• 
Rim enhancement 
• 
Decreased echogenicity of cortex 
• 
Perinodal edema 
 
EVALUATION OF RESPONSE 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target breast lesions: 
• 
Complete response (CR):  disappearance of all target lesions 
• 
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 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
113/Protocol GO29505, Version 3 
Special Notes on the Assessment of Target Lesions 
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions that are recorded as target lesions at baseline become so faint on imaging 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 
accurately measure, BML (below measurable limit) should be indicated.  
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, 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 for the coalesced lesion should be 
recorded. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for any non-target lesions identified at baseline.  Although some non-target lesions may 
actually be measurable, they need not be measured and, instead, should be assessed 
only qualitatively at the timepoints specified in the protocol. 
• 
CR: disappearance of all non-target lesions 
– 
All lymph nodes must be non-pathologic in appearance 
• 
Non-CR/Non-PD:  persistence of one or more non-target lesion(s) 
• 
PD: unequivocal progression of existing non-target lesions.  For pathologic axillary 
lymph nodes, this may be based on a combination of morphological factors, 
including a potential increase in short-axis dimension 
 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
114/Protocol GO29505, Version 3 
Special Notes on Assessment of Progression of Non-Target Disease 
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. 
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. 
This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a breast lesion may be reported on an 
MRI 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. 
Timepoint Response (Overall Response) 
Table 1 provides a summary of the overall response status calculation at each protocol-
specified timepoint for which a response assessment occurs.  


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
Ipatasertib (GDC-0068)—Genentech, Inc. 
115/Protocol GO29505, Version 3 
Table 1: Timepoint Response:  Patients with Target Lesions 
(with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR, or no non-target lesions 
identified at baseline 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Any except PD 
No 
PR 
SD 
Any except PD 
No 
SD 
NE (Any lesion) 
Any except 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. 
 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response. Similarly, if one or more non-target 
lesions are not assessed, the response for non-target lesions should be “not evaluable” 
except where there is clear progression in non-target lesions that are assessed.  
Special Notes on Response Assessment 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1.   


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
116/Protocol GO29505, Version 3 
Appendix 4  
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair 
> 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
 


 
Ipatasertib (GDC-0068)—Genentech, Inc. 
117/Protocol GO29505, Version 3 
Appendix 5  
New York Heart Association Classification 
of Functional Cardiac Capacity 
Class 
Description 
I 
No limitation:  Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity:  Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, or 
angina. 
III 
Marked limitation of physical activity:  Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort:  Symptoms of 
congestive heart failure are present even at rest.  With any physical 
activity, increased discomfort is experienced. 
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114.