Clinical trial NCT02273973
Conditions: Breast Cancer
Sponsor: Genentech, Inc.
Start date: 2014-11-12; Completion date: 2017-03-13
Enrollment: 334 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the effect of combining letrozole and GDC-0032 (also known as taselisib) versus letrozole and placebo in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2) untreated, Stage I-III operable breast cancer. Participants will be randomized into one of the two treatment arms with a 1:1 randomization ratio. Letrozole at 2.5 milligrams (mg) will be dosed once daily plus either Taselisib at 4 mg (two 2-mg tablets) or placebo on a 5 days-on/ 2 days-off schedule for a total of 16 weeks.

Detailed description:

Arms: arm 1: Participants will receive 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks. arm 2: Participants will receive 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.
Interventions: intervention 1: Letrozole intervention 2: Placebo intervention 3: Taselisib
Intervention descriptions: intervention 1: Letrozole tablets will be administered orally at 2.5 mg QD for 16 weeks. intervention 2: Placebo tablets matched to taselisib formulation will be administered orally daily on 5 days-on/2 days-off schedule for up to 16 weeks. intervention 3: Taselisib will be administered orally at 4 mg (two 2 mg tablets) daily.

Protocol documents:
Prot_000.pdf: 
Document Type:         Protocol and Amendments 
Official Title: 
A Phase II Randomized, Double-Blind Study of Neoadjuvant 
Letrozole Plus GDC-0032 Versus Letrozole plus Placebo in 
Postmenopausal Women with ER-positive/HER2-negative, Early 
Stage Breast Cancer 
NCT Number: 
NCT02273973 
Document Date: 
Protocol Amendment Version 4: 27-July-2015 
Protocol Amendment Version 3: 22-May-2014 
Protocol Amendment Version 2: 09-Apr-2014 
Protocol Amendment Version 1: 23-Dec-2013 
 
 
 




GDC-0032—Genentech, Inc. 
2/Protocol GO28888, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
The following changes have been made in this amendment:  
• 
Adverse Event of Special Interest (AESI) Grade ≥ 3 diarrhea has been changed to 
Grade ≥ 2 diarrhea  
• 
Grade ≥ 1 diarrhea that persists for more than 2 weeks despite antidiarrheals (e.g., 
loperamide) has been added as an AESI  
• 
Recommendation to Management of Gastrointestinal Toxicities that patients 
experiencing Grades ≥ 1 diarrhea be contacted at least weekly (e.g., by telephone) 
has been added 
• 
Adverse Event assessments at Weeks 7 and 11 by telephone have been added for 
a general assessment of adverse events 
 
Rationale:  The above changes were prompted by the number of suboptimally managed 
cases of diarrhea, one of which resulted in colitis.  These changes, including the addition 
of adverse event assessments at Weeks 7 and 11, have been made to increase 
monitoring of diarrhea.  
Other changes are as follows:  
• 
Added collection of additional blood sample at 4-week Post-Surgical Follow-Up visit 
for ctDNA and plasma protein biomarkers analysis. 
Rationale:  This is aimed to enable correlation of response with biomarkers and 
potential identification of high-risk population(s)  
• 
Requirement added for Target Lesion #2, if selected, to be ≥ 10 mm.  
Rationale:  No minimum size was previously defined; therefore, this change 
was made to improve clarity.  
• 
Added additional restriction to the following exclusion criterion: “History of prior or 
currently active small or large intestine inflammation (such as Crohn’s disease or 
ulcerative colitis).  Any patient with a baseline medical condition involving the 
gastrointestinal (GI) tract or who may have a predisposition for GI toxicity requires 
prior approval from the Medical Monitor.”  
Rationale:  This was added with the intention that it may further prevent patients 
with potential predispositions to GI side effects from being enrolled.  
• 
Included “Investigational Agents” amongst prohibited Concomitant Therapies.    
Rationale:  This was not previously specified; therefore, this change was made 
to improve clarity.  
• 
Added specification that there is a 4-week “wash-out” period for any other 
Investigational Agents prior to initiation of treatment with GDC-0032.    
Rationale:  This was not previously specified; therefore, this change was made 
to improve clarity  
 


 
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Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.  


 
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PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
Non-serious has been deleted from “non-serious adverse event of special interest” 
throughout the protocol.   
IND number has changed from 110184 to 121658 
Medical Monitor has changed from 
 to 
, M.D. Ph.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
LIST OF AUTHORS 
, and 
 were 
added and 
 was removed from the list.   
SECTION 1.3:  BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Genes in the PI3K/AKT/mTOR signaling pathway are frequently mutated or amplified in 
breast cancer, especially in the ER+ subtype (Cancer Genome Atlas Network [CGAN] 
2012).  Molecular alterations of the PI3K/AKT/mTOR pathway include the following: 
(1) Mutations or amplifications in PIK3CA, the gene encoding the alpha catalytic subunit 
of PI3K (p110α) (Saal et al. 2005; Wu et al. 2005); (2) Alterations in the tumor 
suppressor gene PTEN, either by loss of protein expression (PTEN null), inactivation 
mutations and/or epigenetic deregulation through promoter hypermethylation 
(García et al. 2004); (3) PDKP1 amplification and/or overexpression (Brugge et al. 2007); 
(4) AKT1 somatic gain-of-function mutations (Stemke-Hale et al. 2008) and AKT2 
amplifications (Bellacosa et al. 1995).  Overall, it is estimated that up to 70% of breast 
cancers can have some form of molecular aberration of the PI3K/AKT/mTOR pathway 
(CGAN 2012).   
SECTION 1.4:  BACKGROUND ON REVERSING HORMONAL RESISTANCE 
BY INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, the PI3K signaling pathway seems to play an 
important role in mediating hormonal resistance and is a viable therapeutic target.  
Hyperactivation of this signaling pathway was proved to promote both de novo (primary) 
and acquired (secondary) resistance to hormone therapy in ER+ breast cancer cell lines 
and xenograft models (Sabnis et al. 2007), and. simultaneous  Simultaneous blocking of 
the PI3K/AKT/mTOR pathway with everolimus, an mTOR inhibitor, and the ER pathway 
with letrozole enhances antitumor activity of either agent alone (Boulay et al. 2005).  
Importantly, a baseline protein signature of PI3K activation was found to be predictive of 
a poor prognosis after adjuvant endocrine therapy (Miller et al. 2010). 


 
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In the clinical setting, impressive results of the combination of exemestane and 
everolimus, an mTOR inhibitor,  were reported in the BOLERO-2 trial 
(Baselga et al. 2009).… 
SECTION 1.5:  BACKGROUND ON NEOADJUVANT THERAPY IN BREAST 
CANCER 
…In September 2013, the Food and Drug Administration (FDA) granted accelerated 
approval of pertuzumab (Perjeta®) as part of a complete treatment regimen for patients 
with HER2-positive, locally advanced, inflammatory, or early stage breast cancer in the 
neoadjuvant setting. 
SECTION 1.6:  BACKGROUND ON GDC-0032 
GDC-0032 has demonstrated activity in preclinical models of PIK3CA-mutant breast 
tumors in vivo as a single agent and in combination with standard of care (e.g., paclitaxel 
or docetaxel) or endocrine therapies (e.g., letrozole or fulvestrant).… 
SECTION 3:  STUDY DESIGN 
In addition to the safety assessments conducted at the scheduled follow-up visits, 
patients will be contacted by telephone for a general assessment of adverse events at 
Weeks 7 and 11. 
Blood samples for exploratory endpoint analysis will be collected on Day 1 prior to 
dosing, at Week 9, and prior to surgery (Week 16 visit,) and at the 4-weeks postsurgical 
follow-up visit. 
SECTION 3.3.1:  Rationale for Conducting the Study in the Neoadjuvant 
Setting 
…Known as the intrinsic subtypes of breast cancer, these groups of tumors have 
revealed critical differences in incidence, survival, and response to treatment 
(Sotiriou et al. 2003).  As genomic studies evolve, further sub-classifications of breast 
tumors are expected to emerge.  Thus, a major challenge in breast cancer management 
is how to prospectively select patients who will derive the maximum benefit from a given 
drug regimen and minimizing unnecessary toxicities for patients with non-responsive 
disease. 
SECTION 3.3.3:  Rationale for Control Group 
The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen 
(IMPACT) trial was a randomized, Phase II, double-blind, double-dummy, multicenter 
trial that randomly assigned 330 postmenopausal women with ER+ operable or locally 
advanced, potentially operable breast cancer in a 1:1:1 ratio to receive a daily dose of 
anastrozole 1 mg and tamoxifen placebo, tamoxifen 20 mg and anastrozole placebo, or 
a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks before surgery.… 


 
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The American College of Surgeons Oncology Group (ACOSOG) Z1031 trial compared 
three AIs in a randomized, Phase II, neoadjuvant trial designed to select agents for 
Phase III investigations.… 
SECTION 3.3.4.1:  Rationale for Efficacy Outcome Measure of Pathologic 
Complete Response 
In trials of neoadjuvant hormonal therapy, pCR is an unlikely event.  For instance, in the 
neoadjuvant trial comparing everolimus plus letrozole to letrozole plus placebo, pCR 
rates were 1.4% and 0.8%, respectively (Baselga et al. 2009). 
In September of 2013, the FDA granted accelerated approval of pertuzumab (Perjeta®), 
an HER2 dimerization inhibitor, as part of a complete treatment regimen for patients 
with HER2-positive, locally advanced, inflammatory or early stage breast cancer in the 
neoadjuvant setting.   
SECTION 3.3.7:  Rationale for GDC-0032 Dosage 
As of 5 July 2013, 34 patients have been enrolled into the dose-escalation stage of 
Study PMT4979g, and 56 patients have been enrolled into the single-agent expansion 
cohorts at 9 mg in Stage 2 (Cohorts A-D and G).  All patients received GDC-0032 in 
capsules.  Five dose-escalation cohorts (i.e., 3, 5, 8, 12, and 16 mg daily) were tested 
(see Section 1.7.1).  The maximal administered dose was 16 mg.  To obtain more safety 
data on long-term tolerability, the recommended single-agent dose and schedule for the 
single-agent GDC-0032 expansion stage is was 9-mg capsules daily. 
Of the 19 efficacy-evaluable patients treated with GDC-0032 in combination with 
letrozole, one patient at 6 mg capsule had a cPR.  The PIK3CA mutation status of this 
patient is unknown.  Since efficacy has been observed at 6 mg capsules, and the 
long-term safety suggests that 6 mg capsule is better tolerated, the neoadjuvant study 
will utilize 6-mg GDC-0032 capsules in combination with letrozole.  
Of the 27 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 2 confirmed partial responses were observed at 6 mg capsules and 
1 confirmed partial response at 9 mg capsules. 
Colitis has been observed with an incidence rate of 6.2% (10/160 patients).  The time 
(from the first dose of study treatment) to onset of colitis ranged from approximately 
82−248 days as either a single agent or in combination with letrozole or fulvestrant.  
Most of the colitis cases have been observed at the 9-mg capsule dose level or higher. 
To mitigate the late-onset adverse events, such as colitis, an intermittent dosing 
schedule will be applied. With the 40-hour half-life, a limited impact on efficacy is 
anticipated.… 
SECTION 3.3.8:  Rationale for Biomarker Assessments 
Next generation sequencing (NGS) techniques, like deep genome sequencing, may offer 
a unique opportunity to identify such biomarkers of response.  For example, using whole 


 
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genome sequencing, a two base-pair deletion in the tuberous sclerosis 1 (TSC1) gene 
was found in a patient with metastatic bladder cancer with a prolonged response 
(> 2 years) to everolimus as single agent (Iyer et al. 2012).  Among 13 additional patients 
with bladder cancer treated with everolimus in the same trial, those with TSC1 mutant 
tumors remained on therapy longer than those with WT tumors (7.7 vs. 2.0 months, 
p = 0.004), suggesting that mTORC-1 directed therapies may be most effective in 
patients with cancer whose tumors harbor TSC1 somatic mutations.  Furthermore, 
interesting data was recently reported from an autopsy case study from a patient with 
metastatic breast cancer that received an alpha-isoform PI3K blocking agent and 
succumbed to her disease after a lasting clinical response (Juric et al. 2015).  Extensive 
metastatic sampling was performed post-mortem, with the main finding being the 
emergence of molecular aberrations leading to loss of PTEN; thus, indicating a new 
mechanism of secondary resistance to PI3K blockade.  Similar approaches could be of 
great value when analyzing responses to agents targeting the PI3K/AKT/mTOR pathway, 
especially in the neoadjuvant setting. 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of prior or currently active small or large intestine inflammation (such as 
Crohn’s disease or ulcerative colitis).  Any patient with a baseline medical 
condition involving the gastrointestinal (GI) tract or who may have a 
predisposition for GI toxicity requires prior approval from the Medical Monitor.  
SECTION 4.5.10:  Laboratory Assessments 
The following assessments will be performed at the local laboratory.  The frequency of 
assessments is provided in Appendix 1. 
• 
Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, and other cells, if applicable]), and 
platelet count.   
 
The following assessments will be performed at a central laboratory.  Instruction 
manuals outlining sampling procedures, storage conditions, and shipment instructions 
and supply kits will be provided for all central laboratory assessments: 
• 
Tumor tissue should be from the primary tumor (not lymph nodes) and of good 
quality based on total and viable tumor content.  Evaluation of the patient’s tumor 
sample for adequate tumor tissue content by a central laboratory must occur prior to 
initiation of study treatment.  A minimum of ten unstained slides from a prior 
diagnostic FFPE core biopsy would be required for enrollment eligibility purposes. 
A formalin-fixed, paraffin-embedded tumor block from surgical resection 
(Weeks 17−18) is required.  If a tumor block cannot be obtained for various 
reasons (e.g., the tumor tissue is not sufficient at surgical resection), the site 
should discuss with the central study team.  In such cases, paraffin-embedded, 
unstained slides (a minimum of 20 and up to 40 unstained slides) from a 


 
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surgical specimen are required at surgery (Weeks 17−18).  Except in the case 
of pCR, every effort should be made to obtain a fresh-frozen tumor tissue 
sample at surgery. 
 
SECTION 4.5.11.1:  Mutational Analysis for PIK3CA  
Somatic mutations in the PIK3CA gene are found in approximately 35%−40% of 
ER-positive breast cancers and occur most commonly in Exons 9 and 20 (helical and 
kinase domain, respectively) in the codons encoding amino acids E542, E545, and 
H1047 (Saal et al. 2005).… 
SECTION 5.1.1.3:  Management of Rash 
Rash and other dermatological events should be closely monitored, and patients with 
severe rash should be monitored for associated signs and symptoms such as fever and 
hypotension that may be suggestive of a systemic hypersensitivity reaction.  For severe 
rash, dosing of GDC-0032/placebo should be interrupted, and patients should be treated 
with supportive therapy per standard of care.  Use of antihistamines, as well as topical or 
systemic corticosteroids, may be considered (see Table 4).   
SECTION 5.1.1.4.1:  Management of Diarrhea and Colitis 
Patients should be closely monitored for gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea, abdominal pain, stomatitis, and changes in stool, including checking 
for blood in stool if clinically indicated).  Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is mild.  Weekly patient contact (e.g., 
telephone call) for all events of diarrhea Grades ≥1 is recommended to closely follow 
until resolution of symptoms.  Gastrointestinal symptoms should be managed per 
protocol guidelines and institutional standard of care.  For example, prompt management 
of diarrhea with antidiarrheal medications should be implemented.  Because of the 
approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032/placebo for Grade ≥ 2 diarrhea.     
Perforated duodenal ulcer has been observed in 2 patients (one patient at 6 mg capsule 
in combination with letrozole; another patient at 6 mg capsule in combination with 
fulvestrant).  Appropriate caution should be taken with the administration of medications 
such as aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids that can 
increase the risk of gastritis, peptic ulcers, or gastrointestinal perforation. 
SECTION 5.2.3:  Non Serious Adverse Events of Special Interest 
(Immediately Reportable to ABCSG) 
Non serious aAdverse events of special interest are required to be reported by the 
investigator to ABCSG safety department 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: 
• 
Grade ≥ 3 2 diarrhea 


 
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• 
Grade ≥ 1 diarrhea for > 2 weeks after following medical management guidelines in 
Section 5.1.1.4  
 
SECTION 5.4.1:  Emergency Medical Contacts 
Genentech’s Medical Monitor Contact Information: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No. 
 
 
SECTION 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.  With regard to the adverse event of 
special interest of diarrhea, it is recommended that investigators follow every adverse 
event of ≥ Grade 1 diarrhea with weekly patient contacts (e.g., telephone calls) and 
follow up until resolution.  Cases that do not resolve within 1−2 weeks should be 
aggressively managed per protocol recommendations for gastrointestinal toxicities. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators directly to the Sponsor 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. (see "Protocol Administrative and Contact Information & List of 
Investigators”). 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
To control an overall, two-sided, family-wise error rate under 20% for each analysis 
population, we use a two-sided significance level of 16% and 4% for the co-primary 
endpoints MRI ORR, and pCR, respectively. 
SECTION 6.4.1:  Primary Efficacy Endpoint 
…The pCR rate will also be calculated and compared at a two-sided alpha of 4% based 
on the same analytical approach as ORR.  The two alpha values account for a 
family-wise type I error rate of 20% for each analysis population.  Patients with early 
study termination and hence missing efficacy outcome will be considered as 
non-responders. 
TABLE 2:  Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) 
Table 2 has been updated to include placebo throughout:  GDC-0032/placebo. 


 
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TABLE 3:  Dose Modification and Management Guidelines for Pneumonitis 
Table 3 has been updated to include placebo throughout:  GDC-0032/placebo. 
TABLE 4:  GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Table 4 has been updated to include placebo throughout:  GDC-0032/placebo. 
TABLE 5:  GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis 
Table 5 has been updated to include placebo throughout:  GDC-0032/placebo.  The 
following was also added to the table:  For any grade of diarrhea (≥ 1), contact patient 
at least weekly to monitor until resolution of symptoms.  If symptoms persist beyond 
2 weeks despite antidiarrheal treatment (e.g., loperamide), escalate to Grade 2 
management. 
TABLE 6:  GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Table 6 has been updated to include placebo throughout:  GDC-0032/placebo.   
TABLE 7:  GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events 
Table 7 has been updated to include placebo throughout:  GDC-0032/placebo.   
APPENDIX 1:  Schedule of Assessments  
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 3:  MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS:  ASSESSMENT OF RESPONSE OF NEOADJUVANT 
THERAPY IN EARLY BREAST CANCER 
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.  Per this protocol, target 
lesion #1 must be ≥ 2 cm and, if selected, target lesion #2 must be ≥ 10 mm.   
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 19 
PROTOCOL SYNOPSIS .................................................................................... 21 
1. 
BACKGROUND .......................................................................................... 35 
1.1 
Background on the Phosphatidylinositol-3-Kinase 
Pathway................................................................................. 35 
1.2 
Background on Estrogen Receptor-Positive, 
HER2-Negative Breast Cancer.............................................. 35 
1.3 
Background on the PI3K/AKT/MTOR Pathway 
and Breast Cancer................................................................. 36 
1.4 
Background on Reversing Hormonal Resistance 
by Inhibiting the PI3K/MTOR/AKT Pathway........................... 36 
1.5 
Background on Neoadjuvant Therapy in Breast 
Cancer................................................................................... 37 
1.6 
Background on GDC-0032 .................................................... 38 
1.6.1 
Toxicology ............................................................................. 40 
1.7 
Summary of Clinical Data for GDC-0032............................... 41 
1.7.1 
Clinical Safety Data with GDC-0032...................................... 41 
1.7.1.1 
Preliminary Pharmacokinetics ............................................... 42 
1.7.1.2 
Preliminary Pharmacodynamics ............................................ 43 
1.8 
Study Rationale and Benefit-Risk Assessment...................... 44 
2. 
OBJECTIVES.............................................................................................. 46 
2.1 
Efficacy Objectives ................................................................ 46 
2.2 
Safety Objectives................................................................... 46 
2.3 
Patient-Reported Outcome Objectives .................................. 47 
2.4 
Exploratory Objectives........................................................... 47 
3. 
STUDY DESIGN ......................................................................................... 47 
3.1 
Description of Study .............................................................. 47 
3.1.1 
Surgery.................................................................................. 51 
3.1.2 
Independent Data Monitoring Committee .............................. 52 
3.2 
End of Study.......................................................................... 52 
3.3 
Rationale for Study Design.................................................... 53 


 
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3.3.1 
Rationale for Conducting the Study in the 
Neoadjuvant Setting .............................................................. 53 
3.3.2 
Rationale for Patient Population ............................................ 53 
3.3.3 
Rationale for Control Group................................................... 54 
3.3.4 
Rationale for the Efficacy Outcome Measure of 
Response Rate Assessed by Magnetic 
Resonance Imaging............................................................... 55 
3.3.4.1 
Rationale for Efficacy Outcome Measure of 
Pathologic Complete Response ............................................ 56 
3.3.4.2 
Rationale for Ki67 Measurements ......................................... 56 
3.3.4.3 
Rationale for Using the Preoperative Endocrine 
Prognostic Index Score.......................................................... 57 
3.3.4.4 
Rationale for Assessing ORR by Clinical Breast 
Exam (Palpation), Mammography, and Breast 
Ultrasound ............................................................................. 58 
3.3.4.5 
Rationale for Assessing Enhancing Tumor 
Volume by Breast Magnetic Resonance Imaging.................. 58 
3.3.5 
Rationale for Independent Review Facility............................. 58 
3.3.6 
Rationale for Interim Safety Review ...................................... 58 
3.3.7 
Rationale for GDC-0032 Dosage........................................... 58 
3.3.8 
Rationale for Biomarker Assessments................................... 59 
3.3.9 
Rationale for Day 15 Biopsy .................................................. 60 
3.3.10 
Rationale for Collection of Blood Sample for the 
Detection of Plasma Protein Biomarkers ............................... 61 
3.3.11 
Rationale for Collection of Blood Sample for DNA 
Sequencing to Identify Mutations in Plasma.......................... 61 
3.3.12 
Rationale for Collection of Blood Sample for Next 
Generation Sequencing......................................................... 61 
3.3.13 
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 61 
3.3.14 
Rationale for the Collection of DNA for 
Exploratory Pharmacogenetic Polymorphisms ...................... 62 
3.3.15 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 63 
3.4 
Outcome Measures ............................................................... 63 
3.4.1 
Efficacy Outcome Measures.................................................. 63 
3.4.1.1 
Co-Primary Efficacy Outcome Measures............................... 63 


 
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3.4.1.2 
Secondary Efficacy Outcome Measures................................ 63 
3.4.2 
Safety Outcome Measures .................................................... 64 
3.4.3 
Patient-Reported Outcome Measures ................................... 64 
3.4.4 
Exploratory Outcome Measures ............................................ 65 
4. 
MATERIALS AND METHODS .................................................................... 65 
4.1 
Patients.................................................................................. 65 
4.1.1 
Inclusion Criteria.................................................................... 66 
4.1.2 
Exclusion Criteria................................................................... 67 
4.2 
Method of Treatment Assignment and Blinding..................... 68 
4.2.1 
Patient Randomization........................................................... 68 
4.2.2 
Stratification........................................................................... 69 
4.2.3 
Blinding.................................................................................. 69 
4.3 
Study Treatment.................................................................... 69 
4.3.1 
Formulation, Packaging, and Handling.................................. 69 
4.3.1.1 
GDC-0032 and Placebo......................................................... 69 
4.3.1.2 
Letrozole................................................................................ 70 
4.3.2 
Dosage, Administration, and Compliance.............................. 70 
4.3.2.1 
GDC-0032 and Placebo......................................................... 70 
4.3.2.2 
Letrozole................................................................................ 70 
4.3.3 
Investigational Medicinal Product Accountability ................... 71 
4.3.4 
Post-Trial Access to GDC-0032............................................. 71 
4.4 
Concomitant Therapy ............................................................ 72 
4.4.1 
Permitted Therapy ................................................................. 72 
4.4.2 
Prohibited Therapy ................................................................ 73 
4.5 
Study Assessments ............................................................... 73 
4.5.1 
Informed Consent Forms and Screening Log........................ 73 
4.5.2 
Medical History and Demographic Data ................................ 74 
4.5.3 
Physical Examination ............................................................ 74 
4.5.4 
Vital Signs.............................................................................. 74 
4.5.5 
Electrocardiograms................................................................ 74 
4.5.6 
Distant Sites Tumor Assessment........................................... 74 
4.5.7 
Tumor and Response Evaluations......................................... 75 
4.5.8 
Surgical Treatment Plan ........................................................ 76 


 
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4.5.9 
Surgical Specimen–Pathology............................................... 76 
4.5.10 
Laboratory Assessments ....................................................... 76 
4.5.11 
Assay Methods...................................................................... 78 
4.5.11.1 
Mutational Analysis for PIK3CA............................................. 78 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor 
Tissues .................................................................................. 78 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog 
Expression............................................................................. 79 
4.5.11.4 
Confirmation of Estrogen Receptor, 
Progesterone Receptor, and HER2 Status............................ 79 
4.5.11.5 
Circulating Tumor DNA Analysis ........................................... 79 
4.5.11.6 
Messenger RNA Expression Profiling.................................... 79 
4.5.11.7 
Next Generation Sequencing................................................. 79 
4.5.11.8 
Copy Number Analysis .......................................................... 79 
4.5.11.9 
Plasma Biomarker Analyses.................................................. 79 
4.5.11.10 
Plasma Pharmacokinetic Samples ........................................ 80 
4.5.11.11 
Pharmacogenetic Polymorphism Assay ................................ 80 
4.5.11.12 
Electrocardiograms................................................................ 80 
4.5.11.13 
DLCO Testing.......................................................................... 80 
4.5.11.14 
Osteoporosis Assessment and Monitoring ............................ 80 
4.5.12 
Patient-Reported Outcomes .................................................. 81 
4.5.13 
Samples for Clinical Repository............................................. 82 
4.5.13.1 
Confidentiality........................................................................ 82 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 83 
4.6.1 
Patient Discontinuation.......................................................... 83 
4.6.2 
Study Treatment Discontinuation........................................... 83 
4.6.3 
Conditions for Terminating the Study .................................... 83 
5. 
ASSESSMENT OF SAFETY....................................................................... 84 
5.1 
Safety Plan ............................................................................ 84 
5.1.1 
Management of Specific Adverse Events of 
GDC-0032 ............................................................................. 84 
5.1.1.1 
Management of Hyperglycemia............................................. 85 
5.1.1.2 
Management of Pneumonitis................................................. 86 


 
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5.1.1.3 
Management of Rash ............................................................ 87 
5.1.1.4 
Management of Gastrointestinal Toxicity............................... 88 
5.1.2 
Management of Abnormal Liver Function Tests .................... 91 
5.1.3 
Management of Asymptomatic Lipase and/or 
Amylase Elevations ............................................................... 91 
5.1.4 
Management of Other Clinically Significant 
Adverse Events ..................................................................... 92 
5.1.5 
General Guidance for Dose Modifications and 
Delays for Letrozole............................................................... 92 
5.1.6 
Management of Increases in QT Interval............................... 92 
5.1.7 
Safety Monitoring for Letrozole.............................................. 93 
5.2 
Safety Parameters and Definitions ........................................ 93 
5.2.1 
Adverse Events ..................................................................... 94 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to ABCSG)............................................................................. 94 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to ABCSG) .......................................................... 95 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 95 
5.3.1 
Adverse Event Reporting Period ........................................... 95 
5.3.2 
Eliciting Adverse Event Information ....................................... 96 
5.3.3 
Assessment of Severity of Adverse Events ........................... 96 
5.3.4 
Assessment of Causality of Adverse Events ......................... 97 
5.3.5 
Procedures for Recording Adverse Events............................ 97 
5.3.5.1 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 98 
5.3.5.2 
Persistent or Recurrent Adverse Events................................ 98 
5.3.5.3 
Abnormal Laboratory Values ................................................. 99 
5.3.5.4 
Abnormal Vital Sign Values ................................................... 99 
5.3.5.5 
Reporting of Abnormal Liver Function Tests as 
Hy’s Law.............................................................................. 100 
5.3.5.6 
Deaths ................................................................................. 100 
5.3.5.7 
Preexisting Medical Conditions............................................ 101 
5.3.5.8 
Hospitalization or Prolonged Hospitalization........................ 101 
5.3.5.9 
Adverse Events Associated with an Overdose .................... 101 


 
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5.3.5.10 
Patient-Reported Outcome Data ......................................... 102 
5.4 
Immediate Reporting Requirements from 
Investigator to ABCSG......................................................... 102 
5.4.1 
Emergency Medical Contacts.............................................. 102 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 103 
5.5 
Follow-Up of Patients after Adverse Events ........................ 103 
5.5.1 
Investigator Follow-Up......................................................... 103 
5.5.2 
Sponsor Follow-Up .............................................................. 104 
5.6 
Post-Study Adverse Events................................................. 104 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 104 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 105 
6.1 
Determination of Sample Size ............................................. 105 
6.2 
Summaries of Conduct of Study.......................................... 106 
6.3 
Summaries of Treatment Group Comparability ................... 106 
6.4 
Efficacy Analyses ................................................................ 106 
6.4.1 
Primary Efficacy Endpoint.................................................... 106 
6.4.2 
Secondary Efficacy Endpoints............................................. 107 
6.5 
Safety Analyses................................................................... 107 
6.6 
Pharmacodynamic Analyses ............................................... 108 
6.7 
Pharmacokinetic Analyses................................................... 108 
6.8 
Patient-Reported Outcome Analyses .................................. 108 
6.9 
Exploratory Analyses........................................................... 109 
6.10 
Interim Analyses.................................................................. 109 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 109 
7.1 
Data Quality Assurance....................................................... 109 
7.2 
Data(Base) Management..................................................... 110 
7.3 
Electronic Case Report Forms............................................. 110 
7.4 
Source Data Documentation................................................ 111 
7.5 
Use of Computerized Systems ............................................ 111 
7.6 
Retention of Records........................................................... 112 


 
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8. 
ETHICAL CONSIDERATIONS.................................................................. 112 
8.1 
Compliance with Laws and Regulations .............................. 112 
8.2 
Informed Consent ................................................................ 112 
8.3 
Institutional Review Board or Ethics Committee.................. 113 
8.4 
Data Privacy ........................................................................ 114 
8.5 
Financial Disclosure ............................................................ 114 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 115 
9.1 
Study Documentation .......................................................... 115 
9.2 
On Site Quality Control (Monitoring).................................... 115 
9.3 
Protocol Deviations.............................................................. 115 
9.4 
Site Inspections ................................................................... 115 
9.5 
Administrative Structure....................................................... 116 
9.6 
Protocol Amendments ......................................................... 116 
10. REFERENCES ......................................................................................... 117 
 
 
LIST OF TABLES 
Table 1 
Overall Dose Modification Guideline for GDC-0032-Related 
Adverse Events........................................................................... 85 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose)..................... 85 
Table 3 
Dose Modification and Management Guidelines for 
Pneumonitis ................................................................................ 86 
Table 4 
GDC-0032 Dose Modification and Management Guidelines 
for Rash ...................................................................................... 88 
Table 5 
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis ............................................................... 89 
Table 6 
GDC-0032 Dose Delay and Modification Guidelines for 
Stomatitis and Oral Mucositis...................................................... 91 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events .......................................... 92 
Table 8 
Adverse Event Severity Grading Scale ....................................... 96 
Table 9 
Causal Attribution Guidance ....................................................... 97 
 


 
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LIST OF FIGURES 
Figure 1 
GDC-0032 Potency in Non-PIK3CA Mutant Breast Cancer 
Cell Lines .................................................................................... 39 
Figure 2 
Combination Effects between Letrozole and GDC-0032 in 
the Aromatase-Expressing MCF7.2x3 Breast Cancer Cell 
Line ............................................................................................. 39 
Figure 3 
Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse 
Xenografts................................................................................... 40 
Figure 4 
Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT 
and WT Tumors .......................................................................... 43 
Figure 5 
Study Schema............................................................................. 49 
Figure 6 
Schematic Representing Confirmation of Progression................ 51 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 123 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 128 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 129 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 
Measures .................................................................................. 135 
Appendix 5 
New York Heart Association Classifications.............................. 139 
Appendix 6 
American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ..................................................................... 140 
Appendix 7 
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume...................................................................................... 150 


GDC-0032—Genentech, Inc. 
19/Protocol GO28888, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY 
OF NEOADJUVANT LETROZOLE PLUS GDC-0032 
VERSUS LETROZOLE PLUS PLACEBO IN 
POSTMENOPAUSAL WOMEN WITH 
ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE 
BREAST CANCER 
PROTOCOL NUMBER: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
121658 
TEST PRODUCT: 
GDC-0032 
MEDICAL MONITOR: 
, M.D., Ph.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 return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 




 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY OF 
NEOADJUVANT LETROZOLE PLUS GDC-0032 VERSUS 
LETROZOLE PLUS PLACEBO IN POSTMENOPAUSAL WOMEN 
WITH ER-POSITIVE/HER2- NEGATIVE, EARLY STAGE BREAST 
CANCER 
PROTOCOL NUMBER: 
GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
121658 
TEST PRODUCT: 
GDC-0032 
PHASE: 
II 
INDICATION: 
Early stage breast cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Efficacy Objectives 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus 
letrozole plus placebo in women with estrogen receptor-positive/human epidermal growth factor 
receptor 2-negative (ER +/HER2 −) early stage breast cancer, as measured by the following 
co-primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA mutant (MT) patients 
• 
Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local 
evaluation in all enrolled patients and PIK3CA MT patients 
The secondary efficacy objectives of this study are the following: 
• 
Tumor objective response rate (ORR), assessed by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA 
wildtype (WT) patients  
The following secondary objectives will be performed in all enrolled patients and separated by 
PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally assessed 
ORR as measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery.  


 
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• 
Compare the centrally derived, preoperative endocrine prognostic index (PEPI) score upon 
treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, 
ypNX (breast pCR). 
Safety Objective 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
Patient-Reported Outcome Objectives  
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL) between treatment arms as measured by the 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23) 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited to 
somatic cancer associated mutations, PTEN expression, pro-survival pathways (such as 
PI3K/AKT, MAPK etc.), apoptotic markers, and levels of RNA and DNA expression are 
predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream 
markers in tumor tissue and to examine the relationship to anti-tumor activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline biopsy 
and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole and 
GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or letrozole 
on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in letrozole 
plus GDC-0032 versus letrozole plus placebo. 
Study Design 
Description of Study 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the 
effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal 
women with ER +/HER2 − untreated, Stage I-III operable breast cancer whose primary tumors 
are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  Standard of care 
assessments/procedures (e.g., bilateral mammogram) performed within 28 days of Day 1 
dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal cutting 
temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]).  Two pretreatment 
FFPE core biopsies and one freshly frozen core biopsy must be obtained for all patients prior to 
beginning study drug treatment.  Prior diagnostic FFPE core biopsies may be used for 
enrollment eligibility purposes.  For the purpose of enrollment, ER, progesterone receptor (PR), 
and HER2 will be locally determined prior to beginning of study treatment.  ER, PR, HER2, and 


 
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the percentage of Ki67-positive cells will also be centrally assessed, but the results do not have 
to be available prior to enrollment in the study.  Remaining tissue will be retained for future 
translational studies.  Pre-surgical sentinel lymph node biopsy (SLNB) is not allowed. 
Patients will be randomized into one of the two treatment arms with a 1:1 randomization ratio.  
Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 4 mg (two 2-mg tablets) or 
placebo on a 5−days-on/ 2−days-off schedule for a total of 16 weeks (see Figure 5).  A 
maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be continued up to 
surgery per the investigator’s discretion. 
After confirmation of all the eligibility criteria, patients will be randomized to one of the treatment 
arms.  A second biopsy will be performed on Day 15 (Week 3) for biomarker analyses.  Biopsies 
should be performed at least 2 hours after GDC-0032 dose administration. 
Randomization will be stratified according to 2 factors: 
1. 
Tumor size (T1-T2 vs. T3) 
2. 
Nodal status (cytologically positive vs. radiologically or cytologically negative) 
The study will enroll approximately 330 patients at approximately 110 global sites. 
At Weeks 1, 5, 9, 13, and 16 the primary breast tumor and axillary lymph nodes will be 
assessed by clinical breast examination (palpation and caliper measurement).  Suspicion of 
progression based on clinical exam at any time should be further evaluated (Figure 6).  
In addition to the safety assessments conducted at the scheduled follow-up visits, patients will 
be contacted by telephone for a general assessment of adverse events at Weeks 7 and 11. 
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive disease 
and for the purpose of surgery planning.  Suspicion of progressive disease on breast ultrasound 
should be confirmed by investigator-assessed breast MRI.  Patients with primary disease not 
evaluable by ultrasound at baseline should be assessed by MRI at Week 9.  Suspected 
progression in nodes should also be confirmed by fine needle aspiration (FNA) if these nodes 
had not been previously shown to be cytologically positive for cancer.  Patients with progressive 
disease (as defined by modified RECIST, Appendix 3), can either proceed directly to surgery or 
be taken off of the study, according to the investigator’s decision.  If the patient goes off-study 
every reasonable effort should be made to obtain a new biopsy sample prior to beginning 
another systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis.  Clinical 
breast exam, breast ultrasound, and mammography will also be conducted prior to surgery for 
the purpose of the secondary endpoint analysis.  
Blood samples for exploratory endpoint analysis will be collected on Day 1 prior to dosing, at 
Week 9, prior to surgery (Week 16 visit,) and at the 4-weeks postsurgical follow-up visit. 
Surgery 
Surgery will take place after at least 16 weeks of treatment, during Weeks 17−18.  Surgery 
should be performed within 4 days after the last dose of GDC-0032, if possible, to best observe 
pharmacodynamic knockdown with GDC-0032 in the surgical specimen.  Surgery may be 
delayed due to toxicity or other safety issues, upon discussion with the Medical Monitor (see 
Section 5.4.1) or recommendations from the Independent Data Monitoring Committee (IDMC; 
see below).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be 
continued up to surgery per the investigator’s discretion.   
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.  Surgery specimens will be 
collected for histological examination to assess for pCR and for other endpoint analyses. 
Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 


 
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A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the end of 
the study.  Assessment of adverse events and general safety will be collected at this visit and 
the plan for future treatment will be recorded. 
The patient should be evaluated at baseline and after Week 13 of treatment for planning the 
surgical procedure (BCS or mastectomy), and both the planned and actual surgical treatment 
should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pathological complete response (pCR–ypT0/is, ypN0) will be 
established via a local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and directions 
for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  IRF 
procedures are detailed in the IRF charter. 
Number of Patients 
The study will enroll approximately 330 patients at approximately 110 global sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age ≥ 18 years. Postmenopausal status is defined as follows: 
– 
Age ≥ 60 years or 
– 
Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) 
and plasma estradiol levels within postmenopausal range by local laboratory 
assessment or 
– 
Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated as the “target” lesion for 
all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as determined by 
institutional practice (in patients where there may be a reasonable suspicion of 
advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and 
symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable 
for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥ 100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5 × the upper limit of normal (ULN) 


 
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– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be 
enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase 
≤ 1.5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis 
of the Cockcroft−Gault glomerular filtration rate estimation: 
(140−age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × ULN and activated partial thromboplastin time 
(aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is 
required.  If anticoagulation is required for a prosthetic heart valve, then INR should be 
between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply with the 
protocol, in the investigator’s judgment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as optimal 
neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric absorption 
• 
History of prior or currently active small or large intestine inflammation (such as Crohn’s 
disease or ulcerative colitis).  Any patient with a baseline medical condition involving the 
gastrointestinal (GI) tract or who may have a predisposition for GI toxicity requires prior 
approval from the Medical Monitor. 
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
> 470 msec 
• 
Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% of the predicted values 
(see Appendix 7 for calculations) 
• 
Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II-IV (New York Heart 
Association, Appendix 5), or any other that in the judgment of the investigator could 
jeopardize patient safety or study outcomes 
• 
Any contraindication to MRI examination, including the following: 
– 
Neurostimulators 
– 
Pacemakers 


 
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– 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, that may affect 
the interpretation of the results, or renders the patients at high risk from treatment 
complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer 
 
Concomitant 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 7 days prior to 
screening to the study completion/discontinuation visit.  All concomitant medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak 
time-dependent inhibitor of CYP3A4.  Although in vitro induction studies in human hepatocytes 
suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, preliminary data 
from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 daily for 2 weeks in 
patients had no apparent effect on the pharmacokinetics of midazolam (a sensitive CYP3A4 
substrate).  Therefore, GDC-0032 may be administered concomitantly with CYP3A4 substrates 
without the risk of a pharmacokinetic drug-drug interaction (DDI).  
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy (other than letrozole permitted in this protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is receiving 
these at the moment of registration, treatment should be discontinued prior to 
randomization.  
• 
Radiation therapy:  Radiation therapy should not be administered to the breast and/or 
regional lymph nodes prior to surgery in this study.   


 
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• 
Bone-targeted therapy:  treatment including bisphosphonates and receptor activator 
of nuclear factor kappa-B ligand inhibitors are prohibited except for the management of 
osteoporosis.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an alternate 
medication with no or minimal potential to inhibit CYP3A4.  If a strong CYP3A4 inhibitor is 
co-administered with GDC-0032, patients should be closely monitored for adverse reactions. 
• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, rifampin, phenobarbital) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to induce CYP3A4.  If a strong CYP3A4 
inducer is co-administered with GDC-0032, patients should be closely monitored for 
adverse reactions. 
Length of Study 
The total duration of the study is expected to be approximately 24 months for enrollment, plus 
5.5 months after last patient in. 
End of Study 
The end of the study is defined as the date when the last patient has her postsurgery visit.  
Outcome Measures 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR via centrally assessed breast MRI (centrally assessed) via modified RECIST 
(Appendix 3) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the American Joint 
Committee on Cancer staging system (Appendix 6) by local evaluation in all enrolled 
patients and PIK3CA MT patients 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST (Appendix 3) 
in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients 
The following secondary outcome measures will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery 
• 
Compare the centrally derived PEPI score upon treatment with letrozole plus GDC-0032 
with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) yoT0/is, 
ypNX (breast pCR) 


 
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Safety Outcome Measures 
The safety and tolerability of GDC-0032 will be assessed using the following primary safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during the 
adverse event reporting period (see Section 5.3.1) 
Patient-Reported Outcome Measures  
The PRO outcome measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty swallowing, 
diarrhea, skin problems), and patient functioning as measured using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ–C30) and the modified breast cancer module QLQ–BR23 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are not 
limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
Circulating tumor DNA (ctDNA) 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 versus 
letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug safety 
response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing enzymes and 
transporters and other patient-specific covariates with PK of GDC-0032 or letrozole and/or 
drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a marker of 
tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, diffusion 
metrics], ultrasound, mammography) in measuring tumor response 
Investigational Medicinal Products 
Study treatment is neoadjuvant (pre-operative) therapy.   
Test Product 
The test product for this study is GDC-0032.  Patients will receive an oral, daily dose of 4 mg 
(two 2-mg tablets) GDC-0032 or placebo on a schedule of 5 days on/2 days off for a maximum 
of 16 weeks.  Patients will take GDC-0032 at the same time of day ± 2 hours, unless otherwise 
instructed.  Patients will be instructed as to the number of tablets to take.  


 
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Information on the formulation, packaging, handling, and administration of GDC-0032 are 
provided in the GDC-0032 Investigator’s Brochure. 
Non-Investigational Medicinal Products 
Letrozole 
Letrozole is a marketed product that is approved in the European Union and the United States 
for the treatment of hormone receptor-positive breast cancer.  Based upon the different 
mechanisms of action of GDC-0032 and the well-established safety profile of letrozole, there 
are no expected overlapping, significant toxicities between letrozole and GDC-0032.   
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of surgery 
at the investigator’s discretion).   
Statistical Methods 
Primary Analysis 
This study is designed for testing the effect of GDC-0032 on the two co-primary endpoints in all 
enrolled patients and in the PIK3CA MT patients and plans to enroll 330 patients in total. 
Assuming the PIK3CA mutation status will not be available (unknown) for approximately 10% of 
the patients and the prevalence of PIK3CA mutant is 40%, there will be approximately 
120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, there 
might be a possible imbalance between treatment arms within the PIK3CA MT cohort, which 
may reduce the statistical power in this cohort. To ensure the study provides sufficient statistical 
power even when the treatment assignment is imbalanced, the sample size was calculated 
based on a conservative scenario by assuming that the treatment assignment imbalance in 
PIK3CA MT is 40% vs. 60%. The sample size was calculated based on a chi²-test using 
continuity correction (Ury and Fleiss 1980). 
To control an overall two-sided, family-wise error rate under 20% for each analysis population, 
we use a two-sided significance level of 16% and 4% for the co-primary endpoints MRI ORR, 
and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 enrolled 
patients and 108 patients in the PIK3CA MT cohort will be evaluable for analyses. This sample 
size allows us to detect an absolute percentage increase of 24% in MRI ORR rate in the 
GDC-0032 plus letrozole arm (64%) versus the letrozole-only arm (40%; Smith et al. 2005; 
Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power and 16% two-sided significance 
level.  The minimal detectable difference for ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled patients and 
120 in the PIK3CA MT cohort), this sample size provides 80% power to detect an absolute 
percentage increase of 18% in pCR in the GDC-0032 plus letrozole arm (19%) versus the 
letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at the 
4% two-sided significance level.  The minimal detectable difference for pCR rate is 
approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more substantial 
treatment assignment imbalance in the PIK3CA MT cohort than assumed, or there is an 
increased number of unevaluable patients for the MRI ORR, the sample size may be increased 
to obtain the level of power at 80%, and the enrollment may be limited to patients with PIK3CA 
MT.   
Secondary Analysis 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by 
breast MRI (centrally assessed) in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT 
patients.  
These endpoint measures will be summarized by treatment arm and will be analyzed analogue 
to the primary efficacy endpoint. 


 
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The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status (centrally assessed): 
• 
ORR using modified RECIST criteria by the following methods: by clinical breast 
examination, mammography and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery 
(centrally assessed) 
• 
PEPI score (centrally derived) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
These endpoint measures will be summarized by treatment arm and will be compared between 
the two treatment arms within each population based on appropriate statistical analyses: ORR 
will be compared using a Cochrane Mantel-Haenszel test, stratified by tumor size and nodal 
status; PEPI, Ki67, and tumor volume change will be compared by regression analyses, 
adjusted for tumor size and nodal status. All secondary endpoints will be tested at a two-sided 
type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
Determination of Sample Size   
Please refer to the primary analysis in the Statistical Methods section. 
 Interim Analyses 
An independent Data Monitoring Committee (iDMC) will monitor accumulating patient safety 
data at a minimum of once every 6 months until the last patient has completed study treatment.  
Additional details (e.g., DMC members, communication, affiliations) will be provided in the iDMC 
charter.   
The iDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day follow-up visit after the surgery, or 2) been on 
study for 20 weeks after the randomization date (for those who do not receive the surgery).  The 
iDMC will create and review unblinded, pooled summaries of the safety and available PK 
summaries (all interim analyses).  While this review is being conducted, patient accrual into the 
study will continue.  The Medical Monitor may also request additional safety analysis and may 
call for additional meetings of the iDMC to review ongoing safety data.  
The iDMC will share results from interim safety analyses with the study team.  The study team 
will share interim safety results with study investigators as needed for the conduct of the study 
and the safety of the patients.  Specific potential safety issues anticipated in this trial, as well as 
measures intended to avoid, minimize, and manage such toxicities, are outlined in the following 
sections.  All available information of all enrolled patients with all available assessments at the 
respective timepoint will be included in the interim analyses. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABCSG 
Austrian Breast and Colorectal Cancer Study Group 
ADC 
apparent diffusion coefficient 
AE 
adverse events 
AI 
aromatase inhibitors 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ASCO-CAP 
American Society of Clinical Oncology-College of 
American Pathologists 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-24 
area under the concentration–time curve from 0 to 24 
hours 
AUC0-inf 
area under the concentration–time curve from 0 to 
infinity 
BCS 
breast conserving surgery 
BIG 
Breast International Group 
BUN 
blood urea nitrogen 
CD 
compact disc 
CI 
confidence interval 
Cmax 
maximum plasma concentration observed  
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
cPR 
confirmed partial responses 
CRA 
clinical research associate 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTNeoBC 
Collaborative Trials in Neoadjuvant Breast Cancer 
DCR 
data clarification request 
DDI 
drug-drug interaction 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DMP 
data management plan 
DXA 
dual-energy X-ray absorptiometry 
DVD 
digital video disk 
EC 
Ethics Committee 


 
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Abbreviation 
Definition 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER+ 
estrogen receptor-positive 
E.U. 
European Union 
FFPE 
formalin-fixed paraffin-embedded 
FDA 
Food and Drug Administration 
FNA 
fine needle aspiration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HLM 
human liver microsomes 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IGF-1R 
insulin-like growth factor-1 receptor 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
ISH 
in situ hybridization 


 
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Abbreviation 
Definition 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LDL 
low-density lipoprotein 
LPLV 
last patient, last visit 
MAPK 
mitogen-activated protein kinase 
MDD 
minimum detected difference 
MP 
monitoring plan 
MRI 
magnetic resonance imaging 
MT 
mutant 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSCLC 
non − small-cell lung cancer 
nu/nu 
immunocompromised nune (mice) 
OCT 
Optimal cutting temperature 
ORR 
objective response rate 
pAKT 
phosphorylated form of AKT 
pCR 
pathologic complete response 
PD 
progressive disease 
PEPI 
preoperative endocrine prognostic index 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PI3K 
phosphatidylinositol-3-kinase 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, 
catalytic subunit alpha 
PIP2 
phosphatidylinositol-4,5-bisphosphate 
PIP3 
phosphatidylinositol 3,4,5 trisphosphate 
PO 
oral 
PR 
progesterone receptor 
PRO 
patient-reported outcome 
PTEN 
phosphatase tensin homolog 
QD 
once daily 
QLQ-BR23 
Quality of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 


 
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Abbreviation 
Definition 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
relapse-free survival 
RPPA 
reverse phase protein array 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
source data verification 
SLNB 
sentinel lymph node biopsy 
SOLTI 
Spanish Breast Cancer Research Group 
SOP 
standard operating procedure 
SmPC 
summary of product characteristics 
t1/2 
terminal half-life 
TSC1 
Tuberous Sclerosis 1 
TGI 
tumor growth inhibition 
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
WT 
wildtype 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON THE PHOSPHATIDYLINOSITOL-3-KINASE 
PATHWAY 
Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase involved in tumor cell proliferation, 
survival, and migration upon activation by growth factor receptors and integrins.  
PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) 
to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Cantley 2002), 
a second messenger involved in the phosphorylation of AKT and associated proteins in 
the AKT-mammalian target of rapamycin (mTOR) pathway (Guertin and Sabatini 2007).  
Activating and transforming mutations, as well as amplification, in the p110α subunit of 
PI3K are commonly found in solid and hematological tumors (Li et al. 1997).  In addition, 
the PI3K-AKT pathway is activated in numerous types of cancer by receptor tyrosine 
kinase signaling, the loss of the phosphatase tensin homolog (PTEN) and Inositol 
Polyphosphate 4-phosphatase type II (INPP4B), or RAS mutations 
(Shayesteh et al. 1999; Cantley 2002; Massion et al. 2004; Wu et al. 2005). 
1.2 
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE, 
HER2-NEGATIVE BREAST CANCER 
Breast cancer is the most frequently diagnosed cancer worldwide and the leading cause 
of cancer death among females, accounting for 23% of the total cancer cases and 14% 
of total cancer deaths (Jemal et al. 2011).  As a large proportion of breast cancer cases, 
especially in developed countries, are now diagnosed in early stages, they are amenable 
to cure with a stage-appropriate combination of surgery, systemic therapy 
(chemotherapy and/or hormonal therapy), and radiotherapy. 
Estrogen receptor-positive (ER +)/human epidermal growth factor receptor 2-negative 
(HER2 −) breast cancer accounts for about 60%−70% of all breast cancers.  However, 
not all ER+ breast cancers respond optimally to endocrine therapy (Davies et al. 2011).  
There are several mechanisms that can lead to primary and/or secondary hormonal 
resistance in ER+ breast cancer:  decrease of ER expression, loss of ER expression, or 
upregulation of growth factor signaling pathways, such as the epidermal growth factor 
receptor (EGFR)/HER2, the mitogen-activated protein kinase (MAPK), or the 
PI3K/AKT/mTOR pathways (Johnston 2009). 
In the setting of ER+ /HER2-negative breast cancer, the PI3K/AKT/mTOR pathway plays 
an important role in mediating hormonal resistance and is a viable therapeutic target to 
explore (Miller et al. 2010). 


 
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1.3 
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Genes in the PI3K/AKT/mTOR signaling pathway are frequently mutated or amplified in 
breast cancer, especially in the ER+ subtype (Cancer Genome Atlas Network [CGAN] 
2012).  Molecular alterations of the PI3K/AKT/mTOR pathway include the following: 
(1) Mutations or amplifications in PIK3CA, the gene encoding the alpha catalytic subunit 
of PI3K (p110α) (Saal et al. 2005; Wu et al. 2005); (2) Alterations in the tumor 
suppressor gene PTEN, either by loss of protein expression (PTEN null), inactivation 
mutations and/or epigenetic deregulation through promoter hypermethylation 
(García et al. 2004); (3) PDKP1 amplification and/or overexpression (Brugge et al. 2007); 
(4) AKT1 somatic gain-of-function mutations (Stemke-Hale et al. 2008) and AKT2 
amplifications (Bellacosa et al. 1995).  Overall, it is estimated that up to 70% of breast 
cancers can have some form of molecular aberration of the PI3K/AKT/mTOR pathway 
(CGAN 2012).   
1.4 
BACKGROUND ON REVERSING HORMONAL RESISTANCE BY 
INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, the PI3K signaling pathway seems to play an 
important role in mediating hormonal resistance and is a viable therapeutic target.  
Hyperactivation of this signaling pathway was proved to promote both de novo (primary) 
and acquired (secondary) resistance to hormone therapy in ER+ breast cancer cell lines 
and xenograft models (Sabnis et al. 2007).  Simultaneous blocking of the 
PI3K/AKT/mTOR pathway with everolimus, an mTOR inhibitor, and the ER pathway 
with letrozole enhances antitumor activity of either agent alone (Boulay et al. 2005).  
Importantly, a baseline protein signature of PI3K activation was found to be predictive of 
a poor prognosis after adjuvant endocrine therapy (Miller et al. 2010). 
In the clinical setting, impressive results of the combination of exemestane and 
everolimus were reported in the BOLERO-2 trial (Baselga et al. 2009).  This trial 
compared everolimus and exemestane with placebo and exemestane in 
724 postmenopausal patients with ER + advanced breast cancer who had experienced 
recurrence or progression while receiving previous therapy with a nonsteroidal 
aromatase inhibitor in the adjuvant setting and/or in advanced disease.  Median 
progression-free survival (PFS) in the everolimus group was 6.9 months, as compared to 
2.8 months in the placebo group.  Hazard ratio (HR) for progression or death was 0.43, 
with a 95% confidence interval (CI) of 0.35−0.54 (< 0.001), as per the investigator’s 
assessment, and the magnitude of the effect was even greater as per central 
assessment (HR, 0.36, 95% CI, 0.27−0.47; p< 0.001).  In the open-label Phase II 
TAMRAD trial, patients with aromatase inhibitors (AI) resistant metastatic breast cancer 
received tamoxifen plus everolimus or tamoxifen alone (Bachelot et al. 2012).  The 
6-month clinical benefit rate was 61% (95% CI, 47%−74%) with tamoxifen plus 
everolimus and 42% (95% CI, 29%−56%) with tamoxifen alone.  Time to progression 
increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus 


 
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everolimus, corresponding to a 46% reduction in risk of progression with the combination 
(HR, 0.54; 95% CI, 0.36−0.81).  Risk of death was reduced by 55% with tamoxifen plus 
everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24−0.81). 
In the neoadjuvant setting, combination of letrozole and everolimus also resulted in 
improved responses over letrozole alone in patients with ER+ breast cancer 
(Baselga et al. 2009).  In this study, 270 postmenopausal patients with operable ER + 
breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment 
with letrozole and either everolimus or placebo.  The primary endpoint of the trial, clinical 
response by palpation, was higher in the everolimus arm than in the control arm (68.1% 
vs. 59.1%, p = 0.062), a statistically significant result (one-sided, α = 0.1 level). 
An important finding in trials with mTOR-targeting drugs like everolimus is that they 
produce a pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the phosphorylated form of AKT (pAKT), resulting in feedback 
PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009).  This finding suggests that 
alternative pharmacologic strategies to effectively shut down the pathway upstream of 
AKT should be pursued.  One of these strategies is inhibiting the PI3K/AKT/mTOR 
pathway at the level of PI3K. 
1.5 
BACKGROUND ON NEOADJUVANT THERAPY IN 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 and Smith 2003; Scholl et al. 1994; Semiglazov et al. 2004; 
Fisher et al. 2012; Wolff and Davidson 2000).  The randomized studies evaluating 
neoadjuvant therapy as well as meta-analyses of these studies have shown that 
neoadjuvant therapy can improve breast conservation rates, decreasing the number of 
women obligated to undergo mastectomy (Mieog et al. 2007; Fisher et al. 2012).  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 distant disease recurrence based upon the timing of the systemic 
therapy (Mauri et al. 2005).  The concept of neoadjuvant therapy is now well established 
and a standard treatment option for patients with early breast cancer.  The Collaborative 
Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis was recently conducted 
evaluating over 12,000 patients treated with neoadjuvant chemotherapy as part of 
clinical trials (Cortazar et al. 2014).  The results of this meta-analysis confirmed an 
association of pCR with favorable long-term outcomes in high-risk populations (i.e., 
HER2-positive, high-grade hormone receptor positive and triple negative subtypes), 
although the magnitude of pCR improvement predictive of the long-term survival benefits 
could not be determined.  In September 2013, the Food and Drug Administration (FDA) 
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regimen for patients with HER2-positive, locally advanced, inflammatory, or early stage 
breast cancer in the neoadjuvant setting. 
1.6 
BACKGROUND ON GDC-0032 
GDC-0032 (also known as taselisib) is a potent selective inhibitor of Class I PI3K alpha, 
delta, and gamma isoforms, with 30-fold less potent inhibition of the beta isoform that is 
being developed as a therapy for human cancers.  Nonclinical studies with GDC-0032 
demonstrate that GDC-0032 inhibits proliferation of p110α-mutant breast cell lines, 
inhibits tumor growth in human breast xenograft models harboring PIK3CA mutations, 
and results in a substantial reduction of PI3K pathway markers, including pAkt, 
pPRAS40, and pS6.   
GDC-0032 has demonstrated activity in preclinical models of PIK3CA-mutant breast 
tumors in vivo as a single agent and in combination with standard of care (e.g., paclitaxel 
or docetaxel) or endocrine therapies (e.g., letrozole or fulvestrant).  GDC-0032 has a 
favorable in vitro and nonclinical in vivo absorption, distribution, metabolism, and 
elimination profile that has characteristics consistent with a compound that can be 
delivered orally to achieve clinical exposure similar to the nonclinical efficacy findings 
described herein.  Additional studies, including 16-week toxicity studies in rats and dogs, 
phototoxicity studies, and an embryo-fetal development study, support the Phase II 
neoadjuvant trial with GDC-0032 in combination with endocrine therapy.   
In vitro, single-agent GDC-0032 potency is also observed in cell lines that do not harbor 
PIK3CA mutations (see Figure 1).  In in vitro combination studies, the 
aromatase-expressing breast cancer cell line (MCF7X2.3.ARO) showed positive 
combination effects between GDC-0032 and endocrine therapies (see Figure 2).  In this 
cell line, GDC-0032 alone caused growth inhibition (50% effective concentration 
[EC50] = 95 nM).  Effects on growth were also observed with letrozole and fulvestrant.  
Combined treatment of cells with GDC-0032 and letrozole caused dose-dependent 
inhibition of cell viability at lower concentrations of either GDC-0032 or letrozole resulting 
in enhanced activity for the combination.  In addition, combination activity was 
demonstrated in the PIK3CA wild-type (WT) cell line ZR75-1 when GDC-0032 was 
added to either fulvestrant or tamoxifen endocrine therapies (combination with letrozole 
not available in this cell line).  However, in vivo data in a PIK3CA WT model are not 
available because these cell lines do not grow as xenografts. 




 
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tolerated with no increase in mortality and no greater body weight loss than single 
agents alone. 
Figure 3 Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse Xenografts 
 
QD = once daily; PO = oral gavage. 
Vehicle was MCT (0.5% methycellulose/0.2% Tween-80). 
Tamoxifen pellets (5 mg/pellet, 60-day release) were implanted on Day 0 of dosing (8 days post 
tumor implantation).  Tumor volumes after QD oral administration of GDC-0032 for 21 days are 
depicted by dose group. 
 
Please refer to the GDC-0032 Investigator’s Brochure for additional nonclinical data for 
GDC-0032 supporting this clinical trial.    
1.6.1 
Toxicology 
Please refer to the GDC-0032 Investigator’s Brochure for details on the toxicology 
program to support this clinical trial.   


 
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1.7 
SUMMARY OF CLINICAL DATA FOR GDC-0032  
1.7.1 
Clinical Safety Data with GDC-0032 
As of 5 July 2013, a total of 144 patients have been treated with GDC-0032 capsules, in 
the Phase I/II PMT4979g study, either as single agent (n = 90, 63%) or in combination 
with endocrine therapy (n = 54, 37%). 
As of 5 July 2013, enrollment into the dose-escalation stage of Study PMT4979g had 
been completed with 34 patients enrolled at GDC-0032 doses ranging from 3−16 mg 
daily.  GDC-0032 was well tolerated in the first three cohorts (3, 5, and 8 mg), with no 
patients experiencing a dose-limiting toxicity (DLT).  At the 16-mg dose level, 2 of the 
11 safety-evaluable patients experienced a DLT (Grade 4 hyperglycemia and Grade 3 
fatigue).  At the 12-mg dose level, 1 of the 10 safety-evaluable patients experienced a 
DLT of Grade 3 acute renal failure.  Although the single-agent GDC-0032 maximum 
tolerated dose (MTD) was not exceeded at the 16-mg dose level, the recommended 
GDC-0032 dose and schedule for the single-agent expansion cohorts is 9 mg daily on 
the basis of long-term safety data through multiple treatment cycles.  As of the cutoff 
date, a total of 53 patients had been enrolled in the 9-mg daily dosing expansion cohorts. 
As of 5 July 2013, adverse events of any grade that occurred in ≥ 10% of the 87 patients 
treated with daily single-agent GDC-0032 capsules and were investigator-assessed as 
related to GDC-0032 were as follows:  diarrhea (47%), hyperglycemia (38%), nausea 
(36%), fatigue (35%), decreased appetite (31%), rash (25%), stomatitis (13%), vomiting 
(13%), and mucosal inflammation (12%).  Grade 3 and 4 adverse events assessed by 
the investigator as GDC-0032 related included hyperglycemia (12%), colitis (6%), rash 
(5%), diarrhea (3%), fatigue (3%), pneumonitis (3%), pruritus (2%), stomatitis (2%), 
increased alanine aminotransferase levels (1%), anemia (1%), increase in blood 
creatinine (1%), exfoliative rash (1%), hypokalemia (1%), hypophosphatemia (1%), lung 
infection (1%), pneumonia (1%), erythematous rash (1%), generalized rash (1%), 
maculopapular rash (1%) and skin exfoliation (1%), and acute renal failure (1%).    
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (19 patients at 6 mg, and 8 patients at 
9 mg) daily in combination with letrozole (Cohort E).  No DLTs were observed at either 
dose level.  Adverse events of any grade and assessed by the investigator as drug 
related that occurred in ≥ 10% of the 27 safety-evaluable patients assessed as related to 
GDC-0032 were diarrhea (67%), fatigue (30%), nausea (30%), rash (30%), decreased 
appetite (26%), hyperglycemia (26%), stomatitis (26%), dysgeusia (22%), mucosal 
inflammation (19%), asthenia (15%), pruritis (15%), vomiting (15%), and dry mouth 
(11%).  Grade 3 and 4 adverse events assessed by the investigator as GDC-0032 
related include diarrhea (11%), mucosal inflammation (7%), increased amylase (4%), 
hyperglycemia (4%), increased AST (4%), stomatitis (3.7%), increased blood alkaline 
phosphate (4%), fatigue (4%), increased gamma-glutamyltransferase in the blood (4%), 
hypokalemia (4%), increased lipase in the blood, (4%), and papilloedema (4%). 


 
GDC-0032—Genentech, Inc. 
42/Protocol GO28888, Version 4 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (21 patients at 6 mg and 6 patients at 9 mg) 
in combination with fulvestrant (Cohort F).  No DLTs were observed at either dose level.  
One patient has been enrolled in the Phase II part of the study with 6 mg GDC-0032 in 
combination with fulvestrant.  Adverse events assessed by the investigator as 
GDC-0032 related and of any grade that occurred in ≥ 10% of the 27 patients and were 
assessed as related to GDC-0032 were diarrhea (48%), hyperglycemia (33%), nausea 
(33%), decreased appetite (26%), fatigue (26%), rash (26%), stomatitis (22%), asthenia 
(19%), muscle spasms (15%), vomiting (15%), dysgeusia (11%), gastroesophageal 
reflux disease (11%) and mucosal inflammation (11%).  Grade 3 and 4 adverse events 
assessed by the investigator as related to GDC-0032 included hyperglycemia (15%), 
diarrhea (7%), dyspnea (4%), flank pain (4%), hyponatremia (4%), neutropenia (4%), 
rash (4%) and vomiting (4%). 
Please refer to the GDC-0032 Investigator’s Brochure for additional information. 
1.7.1.1 
Preliminary Pharmacokinetics 
Pharmacokinetic (PK) data are available from 34 patients treated with GDC-0032 at 3, 5, 
8, 12, and 16 mg in the ongoing Phase I/II clinical trial (Study PMT4979g).  The cohort 
mean apparent clearance and the terminal half-life (t1/2) following a single, oral dose of 
GDC-0032 had a range of 4.77−9.17 L/hour and 36.7−43.8 hours, respectively.  
Following daily oral dosing for 8 days, there was a 2- to 4-fold accumulation of 
GDC-0032.  The pharmacokinetics of GDC-0032 appears to be dose linear and 
time-independent.  Preliminary PK data from Cohort E suggest there is no drug-drug 
interaction (DDI) between letrozole plus GDC-0032.  Mean plasma exposure of letrozole 
when given in combination with GDC-0032 (maximum concentration observed 
[Cmax] = 0.407 μM and area under the concentration–time curve from 0 to 24 hours 
[AUC0-24 ] = 8.01 μM*hr) was comparable with the historical single-agent exposure 
(Cmax = 0.495 μM and AUC0-24 = 10.1 μM*hr) (Awada et al. 2008).  Similarly, plasma 
concentrations of GDC-0032, when given in combination with letrozole, were within the 
range predicted by the population PK model.  Therefore, letrozole plus GDC-0032 can 
be co-administered without the risk of a DDI.  
GDC-0032 was metabolized primarily by CYP3A4 in human liver microsomes (HLMs) 
and appeared to be a weak time-dependent inhibitor of CYP3A4.  Although in vitro 
induction studies in human hepatocytes suggested that GDC-0032 has low to moderate 
potential to induce CYP3A4, preliminary data from the Phase I/II study (PMT4979g) 
indicate that 9 mg of GDC-0032 daily for 2 weeks in patients had no apparent effect on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate).  Therefore, 
GDC-0032 may be administered concomitantly with CYP3A4 substrates without the risk 
of a PK DDI.  
Preliminary data from a healthy volunteer study showed that the 3-mg GDC-0032 tablet 
produces an estimated geometric mean ratio (90% CI) of 196% (177.1−217.0) for Cmax 


 
GDC-0032—Genentech, Inc. 
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and 152.2% (141.9−163.2) for AUC time 0 to infinity (AUC0-inf) when compared with the 
3-mg Phase I capsule.  For this reason, a new 2-mg tablet has been formulated to 
deliver GDC-0032 exposure similar to the 3-mg capsule formulation.   
The drug exposure (AUC) for GDC-0032 in a healthy volunteer study was minimally 
affected by the consumption of a high-fat meal.  Therefore, GDC-0032 may be taken 
without regard to the timing of the administration of food.   
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.7.1.2 
Preliminary Pharmacodynamics 
Paired tumor biopsies were obtained from both PIK3CA MT and PIK3CA WT non-small 
cell lung cancer (NSCLC) patients treated at either the 3-mg or 16-mg GDC-0032 dose 
level, respectively, at screening (pretreatment biopsy) and during Cycle 1 in 
Study PMT4979g (on-treatment biopsy).  Inhibition of PI3K pathway markers, including 
decreases of > 60% in pAKT and pS6 (compared with baseline), were demonstrated in 
these patients’ paired tumor biopsies (see Figure 4).  
Figure 4 Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT and WT 
Tumors 
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
(16mg): NSCLC adeno 
PIK3CA wt, EGFR (exon 19 del) 
 (3mg): NSCLC (squam) 
PIK3CA (H1047R) 
 
MT = mutant; NSCLC = non − small-cell lung cancer; WT = wild type. 
 
As of 5 July 2013, metabolic partial responses via FDG-PET (≥ 20% decrease in 
maximum standardized uptake value) were observed in 23 out of 38 patients assessed 
(61%) and included patients from the lowest dose tested (3 mg).  Thirteen of these 23 
were patients with breast cancer.  Of the 13 response-evaluable patients treated with 
GDC-0032 plus letrozole, 10 patients (77%) had a partial metabolic response.  Of the 


 
GDC-0032—Genentech, Inc. 
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15 response-evaluable patients treated with GDC-0032 plus fulvestrant, 11 (73%) had a 
partial metabolic response.  
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.8 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Cancer is one of the leading causes of death worldwide, with solid tumors accounting for 
the majority of these deaths.  An estimated 1.38 million women across the world were 
diagnosed with breast cancer in 2008, accounting for 23% of all cancers diagnosed in 
women.  Breast cancer is the most common cause of death from cancer in women 
worldwide, estimated to be responsible for almost 460,000 deaths in 2008 
(Ferlay et al. 2010). 
A neoadjuvant study in a similar patient population with the combination of letrozole and 
the mTOR inhibitor everolimus has already been completed (Baselga et al. 2009).  
Please refer to Sections 1.4, 1.5, and 3.3 for further rationale supporting the proposed 
trial design of combining GDC-0032 with letrozole in the neoadjuvant setting for this 
patient population.  In postmenopausal women with hormone receptor-positive 
metastatic breast cancer, it is hypothesized that the combination of decreasing estrogen 
levels with letrozole and inhibition of the PI3K pathway with GDC-0032 may have 
improved anti-tumor activity as compared to endocrine therapy alone.  This is supported 
by the nonclinical and clinical data outlined below. 
GDC-0032 is a potent, selective small molecule inhibitor of Class 1 PI3K that is being 
developed by Roche/Genentech as an anti-cancer therapeutic agent.  Activating and 
transforming mutations in the p110 alpha subunit of PI3K are commonly found in tumors.  
GDC-0032 has been shown to be a potent inhibitor of growth in various human cancer 
cell lines, and especially in nonclinical models of PIK3CA MT tumors.  In addition, 
combination activity was demonstrated in the PIK3CA WT cell line ZR75-1 when 
GDC-0032 was added to either fulvestrant or tamoxifen endocrine therapies 
(combination with letrozole not available in this cell line).   
GDC-0032 has also shown additive efficacy in combination with endocrine therapy in a 
hormone receptor-positive breast cancer xenograft model as outlined in Section 1.6.  
Nonclinical data support the investigation of GDC-0032 as a single-agent in solid tumors 
and in combination with endocrine therapy in patients with hormone receptor-positive 
breast cancer.  
Available clinical data with single-agent GDC-0032 suggest that GDC-0032 has 
dose-linear pharmacokinetics with a half-life of approximately 37−44 hours.  
Pharmacodynamic markers of PI3K pathway inhibition upon treatment with GDC-0032 
have been observed.  These include decreases in phospho-S6 in platelet-rich plasma 
and decreases in F-flurodeoxyglucose-positron emission tomography uptake.  Available 
clinical data also include multiple confirmed partial responses in patients treated with 


 
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GDC-0032.  These include a patient with PIK3CA MT lung adenocarcinoma treated at 
the 3-mg daily dose and another patient with PIK3CA MT, hormone receptor-positive, 
HER2-positive metastatic breast cancer treated at the 5-mg daily dose.  In addition, a 
patient with PIK3CA WT lung cancer treated at the 3-mg daily dose has had prolonged 
stable disease and remained on study for over 11 months.  These data show that 
single-agent GDC-0032 doses below 6 mg have been shown to have anti-tumor activity.  
These aggregate data support the use of 6 mg in combination with letrozole.   
Letrozole is a marketed product that is approved in the European Union (E.U.) and the 
United States (U.S.) for the treatment of hormone receptor-positive breast cancer.  
Based upon the different mechanisms of action of GDC-0032 and the well-established 
safety profile of letrozole, there are no expected overlapping, significant toxicities 
between letrozole and GDC-0032.  
As of 5 July 2013, efficacy data are available for 24 patients treated with GDC-0032 
capsules in combination with letrozole; 3 patients (12.5%) had a partial response as best 
overall response, 2 of which were confirmed partial responses (cPRs) (1 cPR at 6 mg; 
1 cPR at 9 mg).  Of the 25 efficacy-evaluable patients treated with GDC-0032 in 
combination with fulvestrant, 7 patients (28%) had a partial response as best overall 
response, of which 3 were cPRs (1 cPR at 6 mg; 1 partial response at 9 mg).  cPRs 
have been observed in both PIK3CA mutant and PIK3CA WT patients with breast 
cancer.  Maintenance of cPR has been observed in a patient who had a dose reduction 
from 6 mg to 3 mg for an adverse event.  In addition, no additional safety concerns have 
been observed with GDC-0032 in combination with letrozole in the ongoing Phase I 
study compared to GDC-0032 given as single agent. 
A number of clinically appropriate strategies to minimize risk to patients have been built 
into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, 
protocol design, and management guidelines.  These will also be clearly highlighted and 
discussed in detail at investigator meetings and site visits.  In addition, please refer to 
the GDC-0032 Investigator’s Brochure for details regarding potential risks, associated 
precautions, and other relevant nonclinical and clinical safety information. 
Due to the need to develop improved therapies to reverse or delay resistance to current 
endocrine therapy in HER2-negative, hormone receptor-positive breast cancer and on 
the basis of the clinical and nonclinical data available for GDC-0032, Genentech/Roche 
feels that the risk-benefit profile of GDC-0032 in combination with letrozole in 
postmenopausal patients with HER2-negative, hormone receptor-positive early stage 
breast cancer is favorable for proceeding with the proposed randomized Phase II clinical 
trial. 


 
GDC-0032—Genentech, Inc. 
46/Protocol GO28888, Version 4 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 
versus letrozole plus placebo in women with ER +/HER2 − early stage breast cancer, as 
measured by the following co-primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled 
patients and PIK3CA MT patients  
 
The secondary efficacy objectives of this study are the following: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via RECIST in PIK3CA 
WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in 
PIK3CA WT patients  
 
The following secondary objectives will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR as measured by modified RECIST criteria (Appendix 3) using the 
following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally derived, preoperative endocrine prognostic index (PEPI) 
score upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
 


 
GDC-0032—Genentech, Inc. 
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2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, 
and health-related quality of life (HRQoL) between treatment arms as measured by 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module 
(QLQ-BR23) 
 
2.4 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by 
diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited 
to somatic cancer associated mutations, PTEN expression, pro-survival pathways 
(such as PI3K/AKT, MAPK etc.), apoptotic markers, hormone receptor expression 
levels, and levels of RNA and DNA expression are predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to anti-tumor 
activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline 
biopsy and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, 
enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor 
response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole 
and GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or 
letrozole on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in 
letrozole plus GDC-0032 versus letrozole plus placebo. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate 
the effect of combining letrozole and GDC-0032 versus letrozole and placebo in 
postmenopausal women with ER+/HER2- untreated, Stage I−III operable breast cancer 
whose primary tumors are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  


 
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Standard of care assessments/procedures (e.g., bilateral mammogram) performed 
within 28 days of Day 1 dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal 
cutting temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]).  Two 
pretreatment FFPE core biopsies and one freshly frozen core biopsy must be obtained 
for all patients prior to beginning study drug treatment.  Tumor tissue from prior 
diagnostic FFPE core biopsies may be used for enrollment eligibility purposes.  For the 
purpose of enrollment, ER, progesterone receptor (PR), and HER2 will be locally 
determined prior to beginning of study treatment.  Remaining tissue will be retained for 
future translational studies.  Presurgical sentinel lymph node biopsy (SLNB) is not 
allowed.   
Patients will be randomized into one of the two treatment arms with a 1:1 randomization 
ratio.  Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 4 mg (two 
2-mg tablets) or placebo on a 5−days-on/2−days-off schedule for a total of 16 weeks 
(see Figure 5).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole 
can be continued up to surgery per the investigator’s discretion. 




 
GDC-0032—Genentech, Inc. 
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Suspicion of progression based on clinical exam at any time should be further evaluated 
(see Figure 6).   
In addition to the safety assessments conducted at the scheduled follow-up visits, 
patients will be contacted by telephone for a general assessment of adverse events at 
Weeks 7 and 11. 
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive 
disease and for the purpose of surgery planning.  Suspicion of progressive disease on 
breast ultrasound should be confirmed by investigator-assessed breast MRI.  Patients 
with primary disease not evaluable by ultrasound at baseline should be assessed by 
MRI at Week 9.  Suspected progression in nodes should also be confirmed by fine 
needle aspiration (FNA) if these nodes had not been previously shown to be 
cytologically positive for cancer.  Patients with progressive disease (as defined by 
modified RECIST, Appendix 3) can either proceed directly to surgery or be taken off of 
the study, according to the investigator’s decision.  If the patient goes off-study, every 
reasonable effort should be made to obtain a new biopsy sample prior to beginning 
another systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis.  
Clinical breast examination, breast ultrasound, and mammography will also be 
conducted prior to surgery for the purpose of the secondary endpoint analysis.  
Blood samples for exploratory endpoint analysis will be collected on Day 1 prior to 
dosing, at Week 9, prior to surgery (Week 16 visit,) and at the 4-weeks postsurgical 
follow-up visit. 




 
GDC-0032—Genentech, Inc. 
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Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice.  
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the 
end of the study.  Assessment of adverse events and general safety will be collected at 
this visit and the plan for future treatment will be recorded. 
The patient should be evaluated at baseline and after Week 13 of treatment for planning 
the surgical procedure (BCS or mastectomy), and both the planned and actual surgical 
treatment should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pCR (pCR–ypT0/is, ypN0) will be established via a 
local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and 
directions for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  
IRF procedures are detailed in the IRF charter. 
3.1.2 
Independent Data Monitoring Committee  
An iDMC will monitor accumulating patient safety data at a minimum of once every 
6 months until the last patient has completed study treatment.  Additional details 
(e.g., iDMC members, communication, affiliations) will be provided in the iDMC charter.   
The iDMC will review the unblinded safety data after the first 20 patients have either 1) 
finished the 30-day follow-up visit after the surgery, or 2) been in the study for 20 weeks 
after the randomization date (for those who do not receive the surgery), whichever 
occurs first.  While this review is being conducted, patient accrual into the study will 
continue.  The Medical Monitor may also request additional safety analysis and may call 
for additional meetings of the iDMC to review ongoing safety data.   
3.2 
END OF STUDY  
The end of the study is defined as the date when the last patient has her postsurgery 
visit.  The total duration of the study is expected to be approximately 24 months for 
enrollment, plus 5.5 months after last patient in.   


 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Conducting the Study in the Neoadjuvant Setting 
Breast cancer is a heterogeneous disease, and not every breast tumor responds equally 
to a specific agent.  Studies based on global gene expression analyses have provided 
additional insights into this complex scenario.  Over the past 10 years, four major 
classes of breast cancer (Luminal A, Luminal B, HER2-enriched, and basal-like) have 
been identified and intensively studied (Perou et al. 2000; Sørlie et al. 2001).  Known as 
the intrinsic subtypes of breast cancer, these groups of tumors have revealed critical 
differences in incidence, survival, and response to treatment (Sotiriou et al. 2003).  As 
genomic studies evolve, further sub-classifications of breast tumors are expected to 
emerge.  Thus, a major challenge in breast cancer management is how to prospectively 
select patients who will derive the maximum benefit from a given drug regimen and 
minimizing unnecessary toxicities for patients with non-responsive disease. 
Neoadjuvant therapy, a systemic therapy administered prior to breast cancer surgery, is 
now widely used in the treatment of patients with early breast cancer.  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, 
especially those with larger tumors.  The tumor may shrink prior to surgery, thus 
increasing the rate of BCS (Coudert et al. 2006), and since the response to therapy can 
be monitored, the patient might be also spared further treatment with inactive 
medications.  
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 prespecified 
in order to monitor treatment response at a biological level.  Finally, the surgical 
specimen, if pCR is not reached, can be utilized as well.  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 (von Minckwitz and 
Fontanella 2013; Cortazar et al. 2012). 
3.3.2 
Rationale for Patient Population 
Postmenopausal patients with HER2-negative, ER+, early stage breast cancer will be 
enrolled in this study.  This patient population is usually treated with a combination of 
surgery, anti-hormonal therapy, and/or chemotherapy, according to staging and 
biological features.  
Recently, everolimus was approved by the FDA and European Medicines Agency in 
combination with exemestane for the treatment of advanced or metastatic breast cancer 
in patients after recurrence or progression following treatment with nonsteroidal 
aromatase inhibitors (AIs).  In the neoadjuvant setting, a combination of letrozole and 


 
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everolimus resulted in improved responses over letrozole alone in patients with ER+ 
breast cancer (Baselga et al. 2009). 
Important findings in trials with drugs targeting mTOR, like everolimus, confirm a 
previously identified pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the pAKT, resulting in feedback PI3K/AKT/mTOR pathway activation 
through an insulin-like growth factor-1 receptor (IGF-1R) mediated feedback loop 
(Tabernero et al. 2009).  This finding suggests that alternative pharmacologic strategies 
to shut down the pathway upstream of AKT should be pursued.  One of these strategies 
is to inhibit the PI3K/AKT/mTOR pathway at the PI3K level.  PI3K-inhibitors are central 
regulators of the mTOR signaling pathway, and nonclinical findings show that 
PI3K-inhibitors and dual PI3K-mTOR inhibitors induce a greater amount of apoptosis 
than everolimus in estrogen-deprived in vitro models (Sanchez et al. 2011); therefore, it 
is hypothesized that PI3K-inhibitors may be active and demonstrate greater anti-tumor 
activity as compared to AIs alone in the neoadjuvant setting. 
3.3.3 
Rationale for Control Group 
AIs have been found to be more effective than tamoxifen as a neoadjuvant endocrine 
therapy for postmenopausal women with ER+ breast cancer. 
Several trials have assessed the efficacy and safety of neoadjuvant endocrine therapy 
using AIs in patients with postmenopausal breast cancer (Eiermann et al. 2001; 
Smith et al. 2005; Ellis et al. 2011). 
The P024 trial was a worldwide, prospective, randomized, multicenter trial that 
randomized 337 postmenopausal patients with ER+ breast cancer to receive either 
4 months of neoadjuvant letrozole or tamoxifen (Eiermann et al. 2001).  The primary 
endpoint of P024 was the percentage of patients in each treatment arm with objective 
response as determined by clinical palpation.  Secondary endpoints included ORR 
determined by mammogram and ultrasound and included the percentage of patients in 
each arm who had become eligible for BCS.  The trial demonstrated a significantly 
higher clinical response rate for letrozole when compared with tamoxifen (55% vs. 36%; 
p < 0.001) in the intent-to-treat (ITT) population.  An improved ORR for letrozole was also 
observed with ultrasound (35% vs. 25%; p < 0.042) and mammogram (34% vs. 16%; 
p < 0.001).  The higher response rate assessed by clinical palpation translated into a 
significantly higher rate of women undergoing BCS in tumors that had initially been 
considered unsuitable for this procedure (45% vs. 35%; p = 0.022).  Median 
time-to-response was 66 days in the letrozole group and 70 days in the tamoxifen group, 
and both treatments were well tolerated. 
The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen 
(IMPACT) trial was a randomized, Phase II, double-blind, double-dummy, multicenter 
trial that randomly assigned 330 postmenopausal women with ER+ operable or locally 
advanced, potentially operable breast cancer in a 1:1:1 ratio to receive a daily dose of 


 
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anastrozole 1 mg and tamoxifen placebo, tamoxifen 20 mg and anastrozole placebo, or 
a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks before surgery.  
The tumor ORR was assessed by both caliper and ultrasound.  No significant 
differences in ORR in the ITT population between patients receiving tamoxifen, 
anastrozole, or the combination were seen.  However, in a predefined analysis, there 
was a nonsignificant trend towards more patients requiring mastectomy at baseline 
actually receiving BCS with anastrozole than with tamoxifen (44% vs. 31%, respectively; 
p = 0.23); this difference became significant for patients deemed by their surgeon to be 
eligible for BCS after treatment (46% vs. 22%, respectively; p = 0.03).  All treatments 
were well tolerated. 
The American College of Surgeons Oncology Group (ACOSOG) Z1031 trial compared 
three AIs in a randomized, Phase II, neoadjuvant trial designed to select agents for 
Phase III investigations.  Three hundred seventy-seven postmenopausal women with 
clinical Stage II−III ER+ breast cancer were randomly assigned to receive neoadjuvant 
exemestane, letrozole, or anastrozole.  The primary endpoint was clinical response.  No 
formal comparison between arms was prespecified in the statistical plan.  ORR was 
62.9%, 74.8%, and 69.1% for the exemestane, letrozole, and anastrozole arms, 
respectively.  On the basis of clinical response rates, letrozole and anastrozole were 
selected for further investigation; however, no other differences in surgical outcome, 
PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only 
patients at presentation was 51%. 
Results from these trials suggest that neoadjuvant endocrine therapy can be beneficial 
in postmenopausal patients with hormone-sensitive breast cancer and that it offers an 
alternative to neoadjuvant chemotherapy. 
3.3.4 
Rationale for the Efficacy Outcome Measure of Response Rate 
Assessed by Magnetic Resonance Imaging  
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, non-registrational, neoadjuvant trials in combination with endocrine therapy 
(Smith et al. 2005; Ellis and Ma 2007; Baselga et al. 2009).  
Guidelines for RECIST v1.1 state that MRI is the preferred modality to follow breast 
lesions in a neoadjuvant setting, and it has advantages over computed tomography (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 
(Akazawa et al. 2006; Balu-Maestro et al. 2002; Yeh et al. 2005), including the I-SPY 
trial (Hylton et al. 2012).  For these reasons, ORR as assessed by breast MRI has been 
chosen as a co-primary endpoint for this trial.  


 
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3.3.4.1 
Rationale for Efficacy Outcome Measure of Pathologic 
Complete Response 
pCR is a recognized efficacy endpoint of neoadjuvant trials, especially those with 
neoadjuvant chemotherapy, as it has been correlated with long-term outcomes, such as 
event-free survival (von Minckwitz and Fontanella 2013).  
In trials of neoadjuvant hormonal therapy, pCR is an unlikely event.  For instance, in the 
neoadjuvant trial comparing everolimus plus letrozole to letrozole plus placebo, pCR 
rates were 1.4% and 0.8%, respectively (Baselga et al. 2009). 
In the ongoing Phase I/II trial that combines letrozole with GDC-0032, tumor shrinkage 
has been observed, and some patients presented sustained partial responses.  As pCR 
is a recognized indicator of activity to a given regimen, it would be useful to assess it as 
a co-primary efficacy endpoint of this trial.  Furthermore, for the same trial size, this 
would represent a minimal increase in the minimum detected difference (MDD) of the 
co-primary endpoint for pCR ORR (from MDD of 12% to MDD of 13%). 
In September of 2013, the FDA granted accelerated approval of pertuzumab (Perjeta®), 
an HER2 dimerization inhibitor, as part of a complete treatment regimen for patients 
with HER2-positive, locally advanced, inflammatory or early stage breast cancer in the 
neoadjuvant setting.   
3.3.4.2 
Rationale for Ki67 Measurements 
Ki67 is a well-established proliferation biomarker with prognostic value in ER+ breast 
cancer (Dowsett et al. 2011).  Efficacy of endocrine therapy relies on induction of 
cell-cycle arrest, and during neoadjuvant treatment, Ki67 levels reflect the ability of 
endocrine agents to suppress proliferation (Smith et al. 2005; Ellis et al. 2011).  In the 
neoadjuvant trial of letrozole with everolimus, by using the definition that patients with 
natural log (Ki67) < 1 at Day 15 have an antiproliferative response, 57% of 
everolimus-treated patients were responders versus 30% in the placebo arm, with a 
significant p value of < 0.01 (Baselga et al. 2009).  Furthermore, the mean reduction in 
the percentage of Ki67-positive tumor cells at Day 15 relative to baseline was greater in 
the everolimus-treated patients (90.7% ± 3.2%) than in the placebo group (74.8% ± 6.8%; 
p = 0.0002).  In the IMPACT trial, Ki67 was assessed at baseline, on Day 15, and at 
surgery (Smith et al. 2005).  For each treatment arm, the reduction in geometric mean 
Ki67 levels was significantly higher for anastrozole than for tamoxifen at both timepoints 
(p = 0.004, p = 0.001, respectively), but no differences were found between tamoxifen and 
the combination.  In the ASCOSOG Z1031 trial (Ellis et al. 2011), although no data on 
Ki67 at Day 15 were available, no differences were found between treatments at 
baseline and at surgery (after 16−18 weeks of therapy).  The geometric mean 
percentage change in Ki67 for each treatment was similar between the arms 
(anastrozole 78%, exemestane 81.2%, and letrozole 87.1%). 


 
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The issue of whether Ki67 decrease at surgery or at any timepoint during treatment 
correlates with long-term efficacy outcomes has been addressed in the P024 trial 
(Eiermann et al. 2001).  Treatment with letrozole led to higher, treatment-induced 
reduction of Ki67 levels in the tumor at surgery (87% reduction in the letrozole arm vs. 
75% in the tamoxifen arm; analysis of covariance p = 0.0009) based on the 
185 specimens with available data on Ki67 (Ellis et al. 2003).  With a median follow-up of 
61.2 months, low levels of Ki67 in the biopsy at the end of treatment were significantly 
associated with better relapse-free survival (RFS; HR 1.4 per natural log increase in the 
Ki67 value, 95% CI 1.2−1.6, p < 0.001), and breast cancer specific survival (HR 1.4, 95% 
CI 1.1−1.7, p =  0.009).  Finally, in the IMPACT trial, higher Ki67 expression after 
2 weeks of endocrine therapy was statistically significantly associated with lower RFS 
(p = 0.004), whereas higher Ki67 expression at baseline was not (Smith et al. 2005). 
Importantly, the Ki67 suppression in these hormonal neoadjuvant trials mirrored efficacy 
outcomes in large adjuvant trials: adjuvant BIG1-98 trial (n = 8,010) showed the superior 
efficacy of letrozole over tamoxifen (Regan et al. 2011), similar to the neoadjuvant P024 
trial (n = 185); the adjuvant ATAC trial (n = 9,366) showed that anastrozole was better 
than tamoxifen and the combination of anastrozole plus tamoxifen (Cuzick et al. 2010), 
similar to neoadjuvant IMPACT (n = 259); and the adjuvant MA27 trial (n = 7,576) showed 
similar efficacy of anastrozole and exemestane (Goss et al. 2013), mirroring neoadjuvant 
ACOSOG Z1031 (n = 266).  These results suggest that a biological superiority 
hypothesis generated by a neoadjuvant study may help the design of future adjuvant 
hormonal therapy trials. 
In summary, reduction in Ki67 after neoadjuvant treatment with AIs is a good marker of 
suppression of cellular proliferation, correlates with long term efficacy outcomes, and 
mirrors results of large adjuvant endocrine trials, which make it an attractive endpoint to 
assess in the present trial. 
3.3.4.3 
Rationale for Using the Preoperative Endocrine Prognostic 
Index Score 
In addition to Ki67, pathologic tumor size (T1 or T2 versus T3 or T4), node status 
(positive or negative), and the ER status (positive Allred score 3−8 versus negative 
Allred score 0−2) of the surgery specimen were also determined to have independent 
prognostic value for relapse and death after relapse in the P024 trial (Ellis et al. 2008).  
A PEPI score, prognostic for RFS, which weighs each of these factors according to their 
associated hazard ratios, was developed and subsequently validated in an independent 
data set from the IMPACT trial (Ellis et al. 2008).  No relapses were recorded in either 
trial in patients with tumors classified as T1N0 and with a PEPI score of 0 (residual 
tumor with a Ki67 level ≤ 2.7%, and with maintained ER expression) or in the rare patient 
with a pCR. 
In this trial, the PEPI score will be derived centrally.  


 
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3.3.4.4 
Rationale for Assessing ORR by Clinical Breast Exam 
(Palpation), Mammography, and Breast Ultrasound 
Objective overall response rate will also be assessed by clinical breast exam, 
mammography, and breast ultrasound during screening and prior to surgery.  These 
data will allow for more direct comparison of results to other neoadjuvant trials with 
endocrine therapy as described in Section 3.3.3.  The concurrent acquisition of ORR 
data with these techniques, in addition to MRI-based measures, will also provide 
valuable comparative information on these methods, which will be important for both 
future neoadjuvant studies and GDC-0032 clinical development.  
3.3.4.5 
Rationale for Assessing Enhancing Tumor Volume by Breast 
Magnetic Resonance Imaging  
As shown in the I-SPY trial, tumor volume measurements based on the percent of tumor 
with enhancing signal after contrast agent administration may be a more sensitive 
measure of response during neoadjuvant treatment than longest dimension measures 
(Hylton et al. 2012).  However, there are no established response criteria for volumetric 
data, and the extrapolation of current one- and two-dimensional criteria to volumetric 
data based on a spherical model may not be appropriate given the range of tumor 
morphologies expected in this population of patients (Loo et al. 2011).  Additionally, 
there are only very limited data on the clinical relevance of any particular range in 
change in tumor volume during the course of neoadjuvant treatment.  For these reasons, 
changes in enhancing tumor volume as measured by breast MRI will be a secondary 
endpoint in the trial.     
3.3.5 
Rationale for Independent Review Facility 
Due to the relatively novel nature of using MRI as an imaging endpoint, a central 
assessment by an IRF for the co-primary endpoint of response rate via MRI will be 
performed to ensure consistency across all sites participating in the study.  
3.3.6 
Rationale for Interim Safety Review 
The first 20 patients will be assessed for safety following surgery and 30 days beyond.  
This will allow the iDMC to review all safety data during the treatment period and to 
evaluate any surgery complications that may be attributed to GDC-0032. 
3.3.7 
Rationale for GDC-0032 Dosage 
As of 5 July 2013, 34 patients have been enrolled into the dose-escalation stage of 
Study PMT4979g, and 56 patients have been enrolled into the single-agent expansion 
cohorts at 9 mg in Stage 2 (Cohorts A-D and G).  All patients received GDC-0032 in 
capsules.  Five dose-escalation cohorts (i.e., 3, 5, 8, 12, and 16 mg daily) were tested 
(see Section 1.7.1).  The maximal administered dose was 16 mg.  To obtain more safety 
data on long-term tolerability, the recommended single-agent dose and schedule for the 
single-agent GDC-0032 expansion stage was 9-mg capsules daily. 


 
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Of the 19 efficacy-evaluable patients treated with GDC-0032 in combination with 
letrozole, one patient at 6 mg capsule had a cPR.  The PIK3CA mutation status of this 
patient is unknown.  Since efficacy has been observed at 6 mg capsules, and the 
long-term safety suggests that 6 mg capsule is better tolerated, the neoadjuvant study 
will utilize 6-mg GDC-0032 capsules in combination with letrozole.  
Of the 27 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 2 confirmed partial responses were observed at 6 mg capsules and 
1 confirmed partial response at 9 mg capsules. 
Colitis has been observed with an incidence rate of 6.2% (10/160 patients).  The time 
(from the first dose of study treatment) to onset of colitis ranged from approximately 
82−248 days as either a single agent or in combination with letrozole or fulvestrant.  
Most of the colitis cases have been observed at the 9-mg capsule dose level or higher. 
To mitigate late-onset adverse events, such as colitis, an intermittent dosing schedule 
will be applied. With the 40-hour half-life, a limited impact on efficacy is anticipated.  PK 
modeling has shown that a schedule of 5 days on/2 days off will maintain GDC-0032 
drug exposure levels within an efficacious range as assessed by various breast cancer 
cell lines.  There has also been data presented for another PI3K inhibitor, BKM120, with 
a similar half-life in combination with letrozole in a Phase Ib study that demonstrated 
improved tolerability with similar efficacy for a schedule of 5 days on/2 days off as 
compared with daily continuous dosing of the PI3K inhibitor (Mayer et al. 2012). 
3.3.8 
Rationale for Biomarker Assessments  
Breast cancer is a heterogeneous disease, and PIK3CA mutations have been shown to 
vary among patients (CGAN 2012).  Therefore, all patients may not equally likely benefit 
from treatment with GDC-0032.  Predictive biomarker samples collected prior to dosing 
will be assessed in an effort to identify those patients with PIK3CA-driven pathogenesis 
who are most likely to respond to GDC-0032.  Pharmacodynamic biomarkers will be 
evaluated to assess the biologic activity of the addition of GDC-0032 to letrozole.  
It has been suggested that not all molecular alterations in the PI3K/AKT/mTOR pathway 
result in pathway activation.  In a comprehensive analysis of tumors from 850 patients 
with breast cancer, protein markers of PI3K/AKT/mTOR pathway activation (pAKT, pS6, 
and p4EBP1) correlated strongly with INPP4B and PTEN loss, to a degree with PIK3CA 
amplification but were not elevated in PIK3CA- MT luminal A cancers (CGAN 2012).  
This apparent disconnect between the presence of PIK3CA mutations and biomarkers of 
pathway activation had been previously noted (Loi et al. 2010) and stress the need to 
find innovative and robust predictive biomarkers to PI3K/AKT/mTOR pathway inhibiting 
agents (Saini et al. 2013). 
Next generation sequencing (NGS) techniques, like deep genome sequencing, may offer 
a unique opportunity to identify such biomarkers of response.  For example, using whole 
genome sequencing, a two base-pair deletion in the tuberous sclerosis 1 (TSC1) gene 


 
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was found in a patient with metastatic bladder cancer with a prolonged response 
(> 2 years) to everolimus as single agent (Iyer et al. 2012).  Among 13 additional patients 
with bladder cancer treated with everolimus in the same trial, those with TSC1 mutant 
tumors remained on therapy longer than those with WT tumors (7.7 vs. 2.0 months, 
p = 0.004), suggesting that mTORC-1 directed therapies may be most effective in 
patients with cancer whose tumors harbor TSC1 somatic mutations.  Furthermore, 
interesting data was recently reported from an autopsy case study from a patient with 
metastatic breast cancer that received an alpha-isoform PI3K blocking agent and 
succumbed to her disease after a lasting clinical response (Juric et al. 2015).  Extensive 
metastatic sampling was performed post-mortem, with the main finding being the 
emergence of molecular aberrations leading to loss of PTEN; thus, indicating a new 
mechanism of secondary resistance to PI3K blockade.  Similar approaches could be of 
great value when analyzing responses to agents targeting the PI3K/AKT/mTOR pathway, 
especially in the neoadjuvant setting. 
In addition to mutational activation of proteins, levels of RNA and DNA can also activate 
the PI3K pathway.  For example, increases in DNA copy number in receptor tyrosine 
kinases such as FGFR1/2 and IGF-1R, which occur at some frequency in breast cancer, 
can activate downstream PI3K pathway.  Hormone receptor positive breast cancer can 
be divided into luminal A and luminal B subtype, with the luminal B subtype displaying a 
higher proliferative index.  Therefore, profiling the RNA and DNA expression of tumors 
will allow intrinsic subtyping of patients enrolled onto study.  In addition, PI3K 
transcription activation signatures may identify additional patients who could respond to 
PI3K inhibitors outside of PIK3CA mutations.  
The use of circulating tumor DNA (ctDNA) to monitor response to treatment is an area of 
great interest.  It could allow for an early, non-invasive, and quantifiable method for use 
in the clinical setting to identify candidates for specific therapies and monitoring of 
disease mutation status over time (Higgins et al. 2012).  The neoadjuvant setting is ideal 
to prospectively test these approaches. 
3.3.9 
Rationale for Day 15 Biopsy 
On-study biopsies can provide valuable information regarding target engagement and 
downstream pathway suppression.  Assessing how GDC-0032 interacts with letrozole in 
this previously untreated patient population provides a unique opportunity to understand 
the interaction between two anti-cancer molecules.  When available, FFPE tumor 
samples will be assessed for pathway modulation using immunohistochemistry (IHC) 
methodologies, and fresh frozen OCT samples will be assessed using reverse phase 
protein array (RPPA) technologies, or equivalent.  Measurement of Ki67 after 2 weeks of 
continuous letrozole and GDC-0032 combination treatment versus letrozole and placebo 
will give a good benchmark to prior neoadjuvant studies that demonstrated a larger 
decrease in Ki67 at this 2-week timepoint for a combination of letrozole and everolimus 
as compared with letrozole and placebo (Baselga et al. 2009).  This Day 15 biopsy will 


 
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also be useful in identifying potential biomarkers that may help predict a tumor response 
for patients treated with GDC-0032.   
3.3.10 
Rationale for Collection of Blood Sample for the Detection 
of Plasma Protein Biomarkers 
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate response 
to drugs, particularly targeted agents such as GDC-0032 (Wilson et al. 2012).  Assays 
to assess the expression of soluble, systemic cytokines and chemokines from the 
plasma of patients will be carried out using ELISA-based mass spectrometry or 
equivalent methodologies.   
3.3.11 
Rationale for Collection of Blood Sample for DNA Sequencing 
to Identify Mutations in Plasma 
There is increasing evidence that circulating DNA obtained from blood specimens of 
patients with cancer is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008; Maheswaran et al. 2008).  Assays are available that can detect the 
major PI3K mutations (and other cancer-related genes) in plasma, and results from this 
analysis will be correlated with tumor specimens. 
3.3.12 
Rationale for Collection of Blood Sample for Next Generation 
Sequencing 
Next generation sequencing (NGS) technologies generate a large quantity of 
sequencing data.  Tumor DNA can contain both reported and unreported chromosomal 
alterations due to tumorigenesis process.  To help control for sequencing calls in 
previously unreported genomic alterations, a normal blood sample will be taken during 
prescreening to determine whether the alteration is somatic or germline.  
3.3.13 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected from patients with early breast cancer in this study to 
assess the pharmacokinetics of GDC-0032 and possible DDI between letrozole and 
GDC-0032 in this population.  Considering the lack of DDI between GDC-0032 and 
letrozole upon concomitant administration in the 24 patients with metastatic breast 
cancer in the Phase I study (preliminary data), this drug interaction in patients with early 
breast cancer is unlikely.  Hence, extensive PK sample collection is not needed; sparse 
PK sampling from patients enrolled in this study is adequate.  The proposed PK sample 
collection schedule will also enable assessment of a concentration and response 
relationship to better understand the following:  pharmacokinetics/pharmacodynamics 
(efficacy), PK/safety correlation, and population pharmacokinetics.  Additional PK 
samples may be collected for safety concerns (e.g., severe adverse event) in order to 
better characterize drug levels in these patients at the time of the adverse event.   


 
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3.3.14 
Rationale for the Collection of DNA for Exploratory 
Pharmacogenetic Polymorphisms 
One sample (approximately 3 mL of whole blood) will be collected from all patients using 
K3-EDTA collection tubes.  Samples will be used for the evaluation of genetic 
polymorphisms of drug metabolic enzymes including, but not limited to, CYP2C9, 
CYP3A4/5, and UGT1A1, and transporters (e.g., OATP1B1) and for genetic variants, 
which could contribute to potentially drug-related rash and/or colitis safety assessments 
(including but not limited to human leukocyte antigen [HLA]).  For sample handling 
procedures, storage conditions, and shipment instructions, see the laboratory manual.  
Only in circumstances where there is concern for collection of this genetic material for 
above evaluations, can this assessment be considered not mandatory as part of study 
assessments in this study.  Results of any analyses from these samples will be reported 
outside the clinical study report. 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affects their safety and efficacy.  For 
example, patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN 38 
(the active metabolite of irinotecan), are at higher risk for adverse effects associated with 
the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  Preliminary 
results from in vitro metabolism studies with GDC-0032 suggest that they are partially 
metabolized by multiple Phase I cytochrome P450 enzymes, including CYP3A4.  
Although in vitro studies can help elucidate the roles of enzymes in the metabolism of 
the drug, these results are not always predictive of in vivo metabolism for a number of 
reasons, such as differences in drug concentrations that the enzymes encounter in vitro 
and in vivo.  For this reason, a blood sample for DNA isolation is proposed to be 
collected from all patients in this study for potential pharmacogenetic analysis of genes 
or biomarkers that may affect the pharmacokinetics or response to GDC-0032.  The 
decision to analyze the samples will be based on a review of the pharmacokinetics and 
response data.  Most recently, the role of HLA has been demonstrated to play an 
important role in the development of drug-induced rash for some drugs (carbamazepine, 
abacavir, and allopurinol).  Therefore, evaluation of genetic variants of genes that may 
regulate the immune response (including but not limited to HLA) may also be 
investigated to characterize unusual safety responses that are not predicted by 
GDC-0032 pharmacokinetics. 
The analysis will be performed on identifiable DNA samples, because it is necessary to 
link a patient’s PK data with genotype.  This analysis would be restricted to the 
evaluation of genes that may be involved in the pharmacokinetics of GDC-0032, drug 
metabolism, disposition, or elimination and/or response of patients who develop severe 
adverse reactions such as colitis or rash.  Samples may be stored and analyzed up to 
15 years after the completion of the study, at which time all DNA samples collected for 
this analysis will be destroyed. 


 
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3.3.15 
Rationale for Patient-Reported Outcome Assessments  
A PRO is “any report on the status of a patient’s health condition that comes directly 
from the patient, without any interpretation of the patient’s response by a clinician or 
anyone else” (FDA Guidance for Industry 2007).  PRO measures are able to 
contextualize a patient’s experience on trial, elucidating symptom and treatment burden.  
Since early breast cancer is often asymptomatic, the PRO objective is to evaluate and 
compare PROs of treatment-related symptoms, patient functioning, and the 
health-related quality of life between treatment arms (Lemieux et al. 2011).  
The EORTC QLQ-C30 and associated breast cancer module, QLQ-BR23, were selected 
because they were specifically developed to assess the most salient constructs and 
experiences with breast cancer and its treatment.  The EORTC QLQ-C30 is a widely and 
frequently used PRO measure in oncology trials that contains a global health status 
scale, functional scales (physical, role, emotional, cognitive, and social), and general 
cancer symptom scales/items with a recall period of ‘the past week.’  
The second measure, the QLQ-BR23, is a breast cancer specific modular supplement to 
the EORTC QLQ-C30 and includes additional functioning scales and symptom 
scales/items relating to breast cancer.  
These instruments demonstrate strong psychometric properties, of both reliability and 
validity, and meet the requirements for this study (EORTC QLQ-C30 Scoring Manual, 
1999; see Appendix 4).  Therefore, PRO data will be collected from patients using the 
EORTC QLQ-C30 and modified QLQ-BR23 (Quinten et al. 2009). 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR, via centrally assessed breast MRI via modified RECIST (Appendix 3) 
in all enrolled patients and PIK3CA MT patients. 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the 
American Joint Committee on Cancer staging system (Appendix 6) by local 
evaluation in all enrolled patients and PIK3CA MT patients.  
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST 
(Appendix 3) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients. 
 


 
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The following secondary outcome measures will be performed in all enrolled patients 
and separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally derived PEPI score upon treatment with letrozole plus 
GDC-0032 with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
yoT0/is, ypNX (breast pCR) 
 
3.4.2 
Safety Outcome Measures  
The safety and tolerability of GDC-0032 will be assessed using the following primary 
safety outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE, v4.0  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, 
or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during 
the adverse event reporting period (see Section 5.3.1) 
 
3.4.3 
Patient-Reported Outcome Measures   
The PRO measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty 
swallowing, diarrhea, skin problems), and patient functioning as measured using the 
EORTC QLQ–C30 and the modified breast cancer module QLQ–BR23 
 


 
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3.4.4 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include but are 
not limited to the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Hormone receptor expression levels 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
ctDNA 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 
versus letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug 
safety response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing 
enzymes and transporters and other patient-specific covariates with PK of 
GDC-0032 or letrozole and/or drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a 
marker of tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response  
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients for this study include postmenopausal patients with ER+/HER2− untreated, 
Stage I−III operable breast cancer.  The size of the primary tumor should be ≥ 2 cm by 
MRI.   


 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age ≥ 18 years.  Postmenopausal status is defined as 
follows: 
– 
Age ≥ 60 years or 
– 
Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone 
(FSH) and plasma estradiol levels within postmenopausal range by local 
laboratory assessment or 
– 
Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following 
characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated 
as the “target” lesion for all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as 
determined by institutional practice (in patients where there may be a 
reasonable suspicion of advanced disease [e.g., large tumors, clinically positive 
axillary lymph nodes] signs and symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional 
definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as 
evaluable for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5 ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may 
be enrolled 
• 
AST, ALT, alkaline phosphatase ≤ 1.5 × ULN  


 
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• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of the 
Cockcroft−Gault glomerular filtration rate estimation: 
(140−age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × ULN and aPTT < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR 
between 2 and 3 is required.  If anticoagulation is required for a prosthetic heart 
valve, then INR should be between 2.5 and 3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply 
with the protocol, in the investigator’s judgment 
 
4.1.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as optimal 
neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric 
absorption 
• 
History of prior or currently active small or large intestine inflammation (such as 
Crohn’s disease or ulcerative colitis).  Any patient with a baseline medical 
condition involving the gastrointestinal (GI) tract or who may have a 
predisposition for GI toxicity requires prior approval from the Medical Monitor.  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula 
(QTcF) > 470 msec 
• 
DLCO < 60% of the predicted values (see Appendix 7 for calculations)  


 
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• 
Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II−IV (New 
York Heart Association, Appendix 5), or any other that in the judgment of the 
investigator could jeopardize patient safety or study outcomes 
• 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, 
current alcohol abuse, or cirrhosis 
• 
Known HIV infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic 
dysfunction, physical examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug, that may affect the interpretation of the results, or renders the 
patients at high risk from treatment complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Patient Randomization 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain a patient’s identification number and treatment assignment 
using a permuted block randomization algorithm via an interactive voice or Web-based 
response system (IxRS).  


 
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4.2.2 
Stratification 
Patients will be randomized into one of the two treatment arms in a 1:1 ratio based on 
the following stratification factors: 
• 
Tumor size (T1−2 vs. T3) 
• 
Nodal status (cytologically positive vs. radiologically or cytologically negative).  If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then fine needle aspiration (FNA) or core biopsy is required to 
confirm nodal status. 
 
4.2.3 
Blinding 
Investigators and patients will be blinded to treatment assignment of GDC-0032 or 
placebo. 
For emergency situations, the investigator will be able to break the treatment code by 
contacting the IxRS.  The responsibility to break the treatment code in emergency 
situations resides solely with the investigator.  For non-emergency situations, the 
investigator needs to obtain approval from the Medical Monitor to break the treatment 
code.  Unblinding during the study will result in the withdrawal of a patient from the study.  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected, suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  The PK 
assay group will be unblinded to patients’ treatment assignments to identify appropriate 
PK samples to be analyzed and bioanalytical methodology to employ.  However, the PK 
scientist does not have access to the PK assay results and therefore stays blinded until 
the PK assay results need to be interpreted and reported.  Samples from patients 
assigned to the comparator arm will be analyzed for letrozole.  However, GDC-0032 
assay will be analyzed by request (i.e., to evaluate a possible error in dosing). 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0032 and Placebo  
GDC-0032 Drug Substance and Drug Product are manufactured according to current 
Good Manufacturing Practice guidelines for use in the clinical studies.  Each lot of 
GDC-0032 for clinical studies is subjected to a series of quality control tests to confirm 
its identity, purity, potency, and quality. 
GDC-0032 is provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 2 mg strength. 


 
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Placebo tablets will be identical in shape and color to the 2-mg tablets of GDC-0032 and 
will be indistinguishable from the 2-mg tablets of GDC-0032.  The ingredients in the 
placebo tablets are identical to those in the 2-mg tablets of GDC-0032, except for the 
absence of GDC-0032 active. 
The GDC-0032 active and placebo tablets are packaged in high-density polyethylene 
bottles, are labeled for clinical use, and should not be stored above 25°C. 
For further details, see the GDC-0032 Investigator’s Brochure. 
4.3.1.2 
Letrozole 
Letrozole will be labeled according to regulatory requirements in each country, as well as 
in accordance with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and will be labeled for investigational use only.  The Sponsor will provide 
letrozole free of charge to all study sites. 
Refer to the letrozole (e.g., Femara®) Package Insert or summary of product 
characteristics (SmPC) for details on the formulation and storage of letrozole. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0032 and Placebo 
Patients will receive an oral, daily dose of 4 mg (two 2-mg tablets) GDC-0032 or placebo 
on a schedule of 5 days on/2 days off for a maximum of 16 weeks.  Patients will take 
GDC-0032 or placebo at the same time of day ± 2 hours, unless otherwise instructed.  
Patients will be instructed as to the number of tablets to take.  Patients will be asked to 
record the time and date that they take each dose in a medication diary. 
If a patient misses a GDC-0032 or placebo dose or vomits up a tablet, she should be 
instructed to skip that dose and to resume dosing with the next scheduled dose.  Missed 
doses will not be made up.  Patients will be instructed to bring their medication diary to 
each study visit for assessment of compliance.  Patients will also be instructed to bring 
all unused tablets to each study visit for GDC-0032 or placebo accountability. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
4.3.2.2 
Letrozole 
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of 
surgery at the investigator’s discretion).  No dose modifications of letrozole are permitted.  
Any overdose or incorrect administration of letrozole should be noted on the letrozole 


 
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Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of letrozole should be recorded on the Adverse Event eCRF.  
Both GDC-0032 or placebo and letrozole should be taken together (in no particular order) 
at the same time each day ± 2 hours, unless otherwise instructed.   
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(letrozole and GDC-0032) will be provided by the Sponsor where required by local health 
authority regulations.  The investigational site will acknowledge receipt of IMPs, using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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 GDC-0032 
The Sponsor will offer post-trial access to the study drug (GDC-0032, letrozole, or other 
study interventions) 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 would not 
otherwise create a financial hardship for the patient) 


 
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• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for untreated, postmenopausal ER+/HER2−, early 
stage, operable breast cancer 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for untreated, postmenopausal postmenopausal ER+/HER2−, early stage, operable 
breast cancer 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at 
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 
7 days prior to screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak 
time-dependent inhibitor of CYP3A4.  Although in vitro induction studies in human 
hepatocytes suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, 
preliminary data from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 
daily for 2 weeks in patients had no apparent effect on the pharmacokinetics of 
midazolam (a sensitive CYP3A4 substrate).  Therefore, GDC-0032 may be administered 
concomitantly with CYP3A4 substrates without the risk of a pharmacokinetic DDI.  
Letrozole is mainly metabolized to a pharmacologically inactive carbinol metabolite by 
CYP2A6 and CYP3A4 in vivo. GDC-0032, which has the potential to induce CYP3A4 
based on in vitro induction studies, was administered in combination with letrozole in the 
expansion phase of Study PMT4979g to assess their DDI potential.  Preliminary data 
from 10 patients in this cohort indicated that steady state plasma concentrations of both 
letrozole and GDC-0032, following once daily administration of the combination (2.5 mg 
letrozole plus 6 or 9 mg GDC-0032), were similar to historical, single-agent data 
suggesting lack of DDI between GDC-0032 and letrozole.  These preliminary results 
suggest that GDC-0032 and letrozole combination may be administered without the risk 
of a pharmacokinetic DDI.  
In vitro CYP inhibition studies in HLMs and induction studies in human hepatocytes 
suggested a low to moderate potential of GDC-0032 to perpetrate DDIs.  A clinical DDI 
study with rifampin (CYP3A4 inducer) and itraconazole (CYP3A4 inhibitor), to 


 
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understand the effect of CYP inhibitors or inducers on the pharmacokinetics of 
GDC-0032, is currently ongoing (Study GP28617). 
4.4.2 
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer 
agents such as chemotherapy, immunotherapy, targeted therapy, biological 
response modifiers, or endocrine therapy (other than letrozole permitted in this 
protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent:  If a patient is 
receiving these at the moment of registration, treatment should be discontinued prior 
to randomization.  
• 
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.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to inhibit CYP3A4.  If a strong 
CYP3A4 inhibitor is co-administered with GDC-0032, patients should be closely 
monitored for adverse reactions. 
• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., 
phenytoin, carbamazepine, rifampin, phenobarbital) with GDC-0032 should be 
avoided.  Consider an alternate medication with no or minimal potential to induce 
CYP3A4.  If a strong CYP3A4 inducer is co-administered with GDC-0032, patients 
should be closely monitored for adverse reactions. 
 
4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments to be performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
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to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases that are currently active or that 
were active within the previous 5 years, surgeries, cancer history (including prior cancer 
therapies and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to the screening visit.   
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examination 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems as well as weight and height 
(height is measured at the screening visit 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), limited, symptom-directed physical 
examination may be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressure while the patient is in a seated position, and temperature.  Oxygen 
saturation is obtained by pulse oximetry after the patient has been in a seated position 
for ≥ 5 minutes.  Obtain vital signs predose. 
4.5.5 
Electrocardiograms 
Triplicate electrocardiogram (ECG) recordings will be obtained at each specified 
timepoint (see the schedule of assessments in Appendix 1).  
4.5.6 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to randomization.   
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage:  
• 
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 


 
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alkaline phosphatase, abnormal liver function tests, abdominal symptoms or 
abnormal physical examination; chest CT if pulmonary symptoms.   
• 
For Stage IIIB and Stage IIIC:  bone scan and CT of chest, abdomen, and pelvis 
should be conducted for all patients. 
 
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.   
4.5.7 
Tumor and Response Evaluations 
All measurable disease must be documented at screening and reassessed at 
subsequent timepoints as outlined in Appendix 1.  Responses based on clinical breast 
examination, breast ultrasound, and mammography will be investigator-assessed.  
Whenever possible, assessments should be performed by the same evaluator to ensure 
internal consistency across visits.  Response via breast MRI will be centrally assessed, 
and all assessments will be based on modified RECIST criteria (see Appendix 3).  
Clinical Breast Examination:  Assessment of primary breast tumor and regional lymph 
nodes must be done by physical examination (palpation) during baseline evaluation, 
Weeks 1, 5, 9, 13 and 16 during the treatment phase and prior to surgery.  Breast tumor 
measurement by caliper (preferred) or rule 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.  
Mammogram:  Bilateral mammograms must be obtained at baseline within 28 days 
prior to enrollment and again prior to surgery.  Mammographic tumor measurements are 
to be recorded in the eCRF.  
Breast Ultrasound:  Bilateral breast ultrasounds must be obtained at baseline within 
28 days prior to enrollment.  Investigator decision whether to perform unilateral or 
bilateral ultrasounds performed at Week 9 and prior to surgery (Week 16) may be 
unilateral or bilateral and per investigator discretion.  If on ultrasound examination there 
is evidence of suspicious axillary lymph nodes at the baseline examination, then FNA or 
core biopsy is required.  Sonographic tumor measurements are to be recorded in the 
eCRF.  The tumor site may be marked with a radiopaque clip or marker via radiographic 
guidance (e.g., ultrasound) prior to initiation of neoadjuvant therapy.  
Breast MRI:  Contrast-enhanced breast MRI scans will be mandatory for all study 
patients at baseline (within 28 days prior to enrollment) and prior to surgery (Week 16).  
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evaluable by ultrasound or if there are signs of disease progression on the Week 9 
ultrasound (see Figure 6).   
Breast MRI scans should not be acquired within 48 hours after biopsy, and the 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 as 
assessed by the central reading facility, the scan may be repeated, at least 48 hours 
after the first scan before the start of study treatment.  Other MRI acquisition sequences, 
such as diffusion-weighted imaging, may be acquired during this study during the MRI 
scan visits for each patient.  Additional MRI-derived metrics such as ADC value may 
provide additional insight into changes in tumor cellular composition.  
For information about patient preparation, scanner requirements and settings, and image 
acquisition, refer to the Study Imaging Manual.  Standard site practice may be followed 
regarding the use of mild sedatives or anti-anxiolytics for claustrophobic patients prior to 
MRI. 
4.5.8 
Surgical Treatment Plan 
The planned and actual surgical treatment (BCS or mastectomy) performed should be 
documented and reported in the eCRF.  Patients should be reassessed after completion 
of neoadjuvant therapy and prior to surgery.  
4.5.9 
Surgical Specimen–Pathology 
The co-primary endpoint of the study (pCR) will be as identified by local pathology 
review.  Guidelines regarding pathology specimen preparation, labeling, and review are 
outlined in the pathology manual. 
4.5.10 
Laboratory Assessments 
The following assessments will be performed at the local laboratory.  The frequency of 
assessments is provided in Appendix 1. 
• 
Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, and other cells, if applicable), and 
platelet count.   
• 
Coagulation (INR and aPTT/PTT) 
• 
Fasting serum chemistry (blood urea nitrogen [BUN], creatinine, sodium, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, serum 
bilirubin, alkaline phosphatase, glucose, AST, ALT), performed following ≥ 10-hour 
fast 
• 
Fasting lipid profile and amylase (total cholesterol, high-density lipoprotein [HDL], 
low-density lipoprotein [LDL], triglycerides, amylase, and lipase) performed following 
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• 
Fasting insulin and glucose  
• 
Glycosylated hemoglobin (HbA1c) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
The following assessments will be performed at a central laboratory.  Instruction 
manuals outlining sampling procedures, storage conditions, and shipment instructions 
and supply kits will be provided for all central laboratory assessments: 
• 
Mandatory tumor tissue 
• 
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 PIK3CA mutation testing as well as 
for other protocol-mandated exploratory assessments at baseline, Day 15, and at 
surgery. 
• 
Tumor tissue should be from the primary tumor (not lymph nodes) and of good 
quality based on total and viable tumor content.  Evaluation of the patient’s tumor 
sample for adequate tumor tissue content by a central laboratory must occur prior to 
initiation of study treatment.  A minimum of ten unstained slides from a prior 
diagnostic FFPE core biopsy would be required for enrollment eligibility purposes. 
Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly 
frozen OCT core needle biopsy are required at baseline and Day 15 (Week 3).   
A formalin-fixed, paraffin-embedded tumor block from surgical resection 
(Weeks 17−18) is required.  If a tumor block cannot be obtained for various 
reasons (e.g., the tumor tissue is not sufficient at surgical resection), the site 
should discuss with the central study team.  In such cases, paraffin-embedded, 
unstained slides (a minimum of 20 and up to 40 unstained slides) from a 
surgical specimen are required at surgery (Weeks 17−18).  Except in the case 
of pCR, every effort should be made to obtain a fresh-frozen tumor tissue 
sample at surgery. 
The specimens will be used for confirmatory central laboratory assessment of 
PIK3CA mutation status, Ki67, PTEN, ER/PgR and HER2 expression.  In 
addition, other exploratory assessments, including but not limited to, PI3K 
signaling pathways may be evaluated, including protein expression and 
molecular profiling studies such as NGS and gene-expression. 
• 
Plasma samples for exploratory research on candidate biomarkers include but are 
not limited to the following:  ctDNA and plasma protein biomarkers 
• 
Blood for NGS (if approved by local regulatory authorities) 
• 
Blood for pharmacogenomics (if approved by local regulatory authorities) 
• 
PK assessment  
Plasma samples will be collected to measure letrozole and GDC-0032 
concentrations (see Appendix 2).  Any remaining samples collected for PK and 
biomarker assays may be used for exploratory biomarker profiling, metabolite 


 
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profiling and identification, and pharmacodynamic assay development purposes 
as appropriate. 
 
4.5.11 
Assay Methods 
4.5.11.1 
Mutational Analysis for PIK3CA 
The PIK3CA mutation assay will be performed by a central laboratory. 
Somatic mutations in the PIK3CA gene are found in approximately 35%−40% of 
ER-positive breast cancers and occur most commonly in Exons 9 and 20 (helical and 
kinase domain, respectively) in the codons encoding amino acids E542, E545, and 
H1047 (Saal et al. 2005).  Real-time polymerase chain reaction (RT-PCR) assays that 
amplify exons that are commonly mutated in PIK3CA offer a sensitive and quantitative 
method to detect mutations from a tumor specimen.  DNA will be extracted from tumor 
samples and subjected to allele-specific PCR assays that detect the WT allele, as well 
as to assays for nucleotide substitutions that include but are not limited to the following 
amino acid changes:  R88Q, N345K, C420R, E542K, E545K/A/G/D, E546K/E/R/L, 
M1043I, H1047R/L/Y, H1049R.  Following histopathological review, samples with < 10% 
tumor content may not be evaluable for the PIK3CA assay.  Samples will be run on 
cobas z480 analyzer, and PIK3CA mutation status (mutant or WT) will be made using 
appropriate cutoffs and automated software.   
A designation of PIK3CA status unknown will be assigned to a sample wherein any one 
of the predefined mutations was not conclusively assessed. 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor Tissues 
Ki67 antigen is an important cell cycle-related nuclear protein that is expressed by 
proliferating cells in all phases of the active cell cycle (G1, S, G2, and M phase).  As 
such, it is a useful marker of the proliferative state of a tumor.  Ki67 protein levels will be 
determined by IHC through the use of standard techniques.   
PI3K pathway, and other pro-survival, biomarkers will be tested in the fresh tumor 
biopsies by IHC including but not limited to phospho-S6, phospho-AKT, phospho-4EBP1, 
and phospho-ERK.  If tissue quantity permits, change in expression of pathway 
biomarkers will be measured by the RPPA using OCT fixed tissue.  The basis of the 
technology is to immobilize small amounts of lysate from a tumor biopsy sample in serial 
dilution on a microarray slide.  Multiple samples are thus arrayed on a slide and can be 
probed with antibodies that detect a particular phospho-epitope.  Using this technology, 
we will profile approximately 80 key signaling nodes representing a number of pathways 
known to be dysregulated in cancer, including receptors in the HER family, multiple 
components of PI3K/mTor signaling, as well as key members of the RAS/MAP kinase 
pathway. 


 
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4.5.11.3 
Analysis of Phosphatase Tensin Homolog Expression 
PTEN status will be examined by IHC using a protocol that has been validated for 
specificity using several available cell line controls at a central laboratory.  Tumor 
specimen will be scored only if appropriate staining is observed in internal control 
stromal or normal (non-tumor) tissue elements.  
4.5.11.4 
Confirmation of Estrogen Receptor, Progesterone Receptor, 
and HER2 Status 
ER, PR, and HER2 status will be determined at a central laboratory according to the 
American Society of Clinical Oncology-College of American Pathologists 
(ASCO-CAP) guidelines. 
4.5.11.5 
Circulating Tumor DNA Analysis 
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations using appropriate technologies.  The prevalence of 
the mutations measured at baseline and post-treatment may provide information on 
response or resistance to therapy. 
4.5.11.6 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression will be 
performed using gene expression assays conducted on the NanoString platform or 
equivalent.  Analysis may include but is not limited to a panel of genes important for 
intrinsic subtyping, breast cancer biology, and PI3K signaling.  The goal will be to 
generate a database of expression status to examine whether there are gene expression 
patterns that are associated with clinical response to GDC-0032. 
4.5.11.7 
Next Generation Sequencing 
In cases where there is sufficient material to isolate DNA, NGS will be performed using 
NGS platforms, such as Illumina or equivalent.  The goal will be to determine whether 
the percentages of genetic mutations are associated with clinical response to GDC-0032. 
4.5.11.8 
Copy Number Analysis  
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically using chromosomal in situ hybridization 
(ISH), using next-generation sequencing platforms or by RT-PCR-based or equivalent 
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(fluorescence in situ hybridization assay) or chromogenic-based (chromogenic in situ 
hybridization).  Increased copy number of PI3K pathways activating genes may provide 
information on response or resistance to therapy.  
4.5.11.9 
Plasma Biomarker Analyses 
Assays to assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be carried out using appropriate methodologies, such as 
enzyme-linked immunosorbent assay (ELISA)-based or mass spectrometry-based or 
equivalent technologies.   


 
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4.5.11.10 
Plasma Pharmacokinetic Samples 
Plasma GDC-0032 and letrozole samples will be analyzed using a validated liquid 
chromatography tandem mass spectrometry. 
After the plasma samples are analyzed, any remaining samples may be used for 
exploratory metabolite profiling and identification, ex vivo protein binding, and PK, or 
pharmacodynamic assay development purposes. 
4.5.11.11 
Pharmacogenetic Polymorphism Assay 
If approved by the local regulatory authority, gene mutations will be assayed using 
multiplex PCR, allele-specific PCR, direct sequencing, or other acceptable methods.  
Results may be correlated to population PK parameters or other clinical measures in order 
to better understand the impact of genetic variants on drug metabolism, exposure, adverse 
events, and/or response.   
A sample will also be utilized as a source of normal DNA to determine whether sequence 
variants in the PIK3CA gene and in other relevant oncogenes in the tumor DNA are 
somatic mutations or single nucleotide polymorphisms. 
4.5.11.12 
Electrocardiograms 
Triplicate ECG recordings will be obtained at each specified timepoint (see the schedule 
of assessments in Appendix 1).  
4.5.11.13 
DLCO Testing 
A diffusion capacity of the lung for carbon monoxide (DLCO) test will be required at 
baseline and at the end of study-drug treatment (prior to surgery) for all patients.  The 
DLCO test should be repeated if there is clinical suspicion of pneumonitis.  Further 
guidance regarding DLCO testing is contained in Appendix 7 and in the management 
guidelines for pneumonitis (Section 5.1.1.2).   
4.5.11.14 
Osteoporosis Assessment and Monitoring 
Treatment with aromatase inhibitors results in bone loss due to estrogen deficiency 
(Gaillard and Stearns 2011).  For patients who have a history of osteoporosis and/or 
fractures, or who are at increased risk of osteoporosis, a bone mineral density 
assessment will be required at baseline prior to initiating study treatment.  Baseline bone 
mineral density will be measured via dual-energy X-ray absorptiometry (DXA).  DXA 
measurement of both the hip and lumbar spine is suggested.  When either the hip or 
lumbar spine is not a valid skeletal site for a bone mineral density measurement, then 
the 33% (one-third) radius should be measured.  In some patients, measurement of the 
hip alone could be sufficient. 
Appropriate monitoring in these patients will occur per institutional guidelines.  
Assessment for fractures is already included as part of the scheduled physical 
examinations.  Determination of patients who are at increased risk for osteoporosis will 
be per institutional guidelines.  Clinical risk factors for fracture include advancing age, 


 
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previous fracture, glucocorticoid therapy, parental history of hip fracture, low body weight, 
current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, and 
conditions predisposing to secondary osteoporosis (e.g., hypogonadism or premature 
menopause, malabsorption, chronic liver disease, inflammatory bowel disease) 
(Kanis et al. 2005).   
4.5.12 
Patient-Reported Outcomes  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of GDC-0032.  The PRO questionnaires, translated as required in the local 
language, will be distributed by the investigator staff and completed in their entirety by 
the patient.  To ensure instrument validity and that data standards meet health authority 
requirements, PRO questionnaires should be self-administered at the investigational site 
prior to the completion of other study assessments and the administration of study 
treatment.  
The EORTC QLQ-C30 and the Modified Breast Cancer module QLQ-BR23 
questionnaires will be used to assess HRQoL, including side-effects of systemic therapy 
(e.g., sore mouth/tongue, difficulty swallowing, diarrhea, skin problems) and patient 
functioning during the neoadjuvant period (refer to schedule of assessments in 
Appendix 1 for a detailed description of timepoints) and post-surgery follow-up.  
The EORTC QLQ-C30 is a widely used HRQoL measure in oncology trials with excellent 
psychometric properties demonstrating both reliability and validity.  The measure 
consists of “five functional scales (physical, role, cognitive, emotional, and social); three 
symptom scales (fatigue, pain, and nausea and vomiting); and a global health and 
quality-of-life scale” with a recall period of “the past week” (Aaronson et al. 1993).  Scale 
scores can be obtained for each of the multi-item scales, global health status/QoL scale, 
and six single items by using a liner transformation for standardization of the calculated 
raw score.   
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of “the past week,” and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment).  As this 
trial will include patients in the neo-adjuvant setting, the last seven items of the original 
BR23 questionnaire, items numbered 47−53 that deal with symptoms and side effects 
not relevant to the population under study, will be removed.  These seven items 
addressed symptoms experienced by patients with metastatic breast cancer and those 
undergoing radiation.  Therefore, in consultation with the EORTC, these items were 
deleted, as the validity of the measure would not be compromised by their removal.  In 
addition, as “oral mucositis” and “skin problems” are key symptoms of this therapy not 
assessed by currently available tools, validated items from the EORTC item bank were 
added to assess the presence and bothersomeness of oral mucositis (2 items:  sore 
mouth/tongue, difficulty swallowing) and skin problems (2 items).  Data analysis will be 
performed on the final modified BR23 data set in parallel with the final data analysis to 


 
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assess the psychometric properties of the modified instrument and will be reported along 
with the clinical trial results.  Scale scores can be obtained for each of the multi-item and 
single-item scales by using a linear transformation for standardization of the calculated 
raw score. 
The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient.  Patients must 
complete these instruments in the clinic (cannot be taken home) prior to any healthcare 
provider interactions (i.e., prior to administration of study drug and prior to any other 
study assessment) to ensure that the validity of the instruments are not compromised 
and to ensure that data quality meet regulatory requirements. 
Refer to Appendix 4 for the EORTC QLQ-C30 and the modified QLQ-BR23. 
4.5.13 
Samples for Clinical Repository 
All residual samples (or leftover biologic samples after protocol-defined studies are 
completed) obtained during the study (FFPE, fresh-frozen, plasma, etc.) will be stored in 
an academic central repository.  The specimens in the study repository will be made 
available for future biomarker research towards further understanding of treatment with 
GDC-0032, of breast cancer, related diseases, and adverse events, and for the 
development of potential, associated diagnostic assays.  The implementation of study 
repository specimens is governed by the Study Steering Committee, with guidance from 
a dedicated Translational Research Committee to ensure the appropriate use of the 
study specimens. 
All biomarker specimens will be retained for new research related to this study and/or 
disease in accordance with the recommendations and approval of the Study Steering 
Committee.  Samples will be only destroyed if required by local laws relating to the 
collection, storage, and destruction of biological specimens. 
Specimens will be stored up to 15 years or until they are exhausted.  The storage period 
will be in accordance with the institutional review board/ethics committee 
(IRB/EC)-approved ICF and applicable laws (e.g., health authority requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.13.1 
Confidentiality 
Patient medical information associated with biologic specimens is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 


 
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Data derived from biologic specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using biologic specimens will be available 
in accordance with the effective Translational Reseach Committee policy on study data 
publication. 
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 
 
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. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Disease progression 
• 
Unacceptable toxicity 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Conditions for Terminating the Study 
Both the Sponsor and the investigator reserve the right to terminate their participation in 
the study under the circumstances agreed upon in the site agreement.  Should this be 
necessary, both parties will arrange the procedures on an individual basis after review 
and consultation.  In terminating the study, the Sponsor and investigator will assure that 
adequate consideration is given to the protection of the patients’ interest. 


 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
GDC-0032 is not approved and is currently in early clinical development.  Thus, the 
entire safety profile is not known at this time.  Human experience is currently limited.  
The following information is based on results from ongoing clinical studies.  The safety 
plan for this study is designed to ensure patient safety and will include specific eligibility 
criteria and monitoring assessments as detailed below.  
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events, and laboratory abnormalities (see Section 5.3.5.3), defined 
and graded according to NCI CTCAE, v4.0.  General safety assessments will include 
serial interval histories, physical examinations, and specific laboratory studies, including 
serum chemistry and blood counts.  All serious adverse events and adverse events of 
special interest will be reported in an expedited fashion, via fax to Austrian Breast and 
Colorectal Cancer Study Group (ABCSG) safety department and also captured in the 
electronic data capture (EDC) system.  In addition, the Sponsor and the investigators will 
review and evaluate observed adverse events on a regular basis. 
All adverse events will be recorded during the trial and for 30 days after the last dose of 
study treatment or until the end of study visit, whichever occurs later.  Patients who have 
an ongoing study treatment-related adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the adverse event. 
All adverse events should be attributed by the investigator to study drug or to another 
clearly identified etiology by the investigator (see Table 9).  
Specific potential safety issues anticipated in this trial, as well as measures intended to 
avoid, minimize, and manage such toxicities, are outlined in the following sections. 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
5.1.1 
Management of Specific Adverse Events of GDC-0032  
Guidelines for management of specific adverse events are outlined in Table 1.  
Additional guidelines are provided in the subsections below.  
Due to the approximately 40-hour half-life for GDC-0032, investigators should consider 
holding GDC-0032 for certain Grade 2 toxicities until the adverse event resolves to 
Grade ≤ 1 as discussed below (e.g., stomatitis/mucositis, colitis, rash, diarrhea, 
pneumonitis).  Certain toxicities can occur within 1−2 weeks of holding or discontinuing 


 
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GDC-0032 drug (e.g., pneumonitis, colitis, rash).  In these cases, the adverse event 
eventually resolves.  Investigators should follow management guidelines and dose 
modifications for toxicities as described below, including administration of topical or 
systemic corticosteroids as appropriate.   
Table 1 Overall Dose Modification Guideline for GDC-0032-Related 
Adverse Events 
 
GDC-0032 
Starting dose 
4 mg at 5 days on/2 days off 
First reduction 
2 mg at 5 days on/2 days off  
Second reduction  
2 mg at 3 days on/4 days off a 
 a If the patient continues to experience specified drug-related adverse 
events after the second dose reduction, the treatment should be 
discontinued. 
 
5.1.1.1 
Management of Hyperglycemia 
Metformin is the first antihyperglycemic medication of choice because of the lower risk of 
hypoglycemia with this agent.  Because metformin in some patients may also cause 
diarrhea and not be well tolerated, other antihyperglycemic medications such as 
sulfonylureas (e.g., glimepiride, glipizide) can be used.  Extra caution should be used 
with other drugs such as sulfonylureas because of the increased risk for hypoglycemia 
with these agents.  Consultation with an endocrinologist can be helpful in managing 
hyperglycemia.   
Specific dose modification and management guidelines for hyperglycemia are provided 
in Table 2. 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) 
Grade 
Dose Modification and Management Guidelines for Hyperglycemia 
(based on fasting blood glucose) 
Grade 2 
Initiation of an anti-hyperglycemic agent (e.g., metformin) and 
additional glucose monitoring will be implemented.   
Dosing with GDC-0032/placebo may either be held or continued per 
investigator evaluation. 
Grade 3  
(asymptomatic) 
GDC-0032/placebo dosing will be suspended and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of an anti-hyperglycemic therapy (e.g., metformin).   
If the hyperglycemic event does not improve to Grade ≤  1 within 
28 days, GDC-0032/placebo will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032/placebo dosing may resume at one dose level lower, 
with approval by the Medical Monitor. 


 
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Grade 
Dose Modification and Management Guidelines for Hyperglycemia 
(based on fasting blood glucose) 
Grade 3  
(symptomatic) a, 
Grade 3 
(requiring 
hospitalization),  
or Grade 4 
GDC-0032/placebo dosing will be suspended, and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of anti-hyperglycemic therapy.   
If the hyperglycemic event does not improve to Grade ≤ 1 within 
28 days, GDC-0032/placebo will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032/placebo dosing may resume at one dose level lower, 
with approval by the Medical Monitor. 
a For example, blurred vision, frequent urination, excessive thirst. 
 
5.1.1.2 
Management of Pneumonitis 
Patients who require any daily supplemental oxygen are not eligible for the study.  
Patients who have DLCO values < 60% will be excluded from the study.  Patients will be 
assessed for pulmonary signs and symptoms throughout the study.  The DLCO test 
should be repeated if there is clinical suspicion of pneumonitis.  The DLCO test will also 
be repeated presurgery after completion of study treatment.  Management guidelines for 
patients with possible pneumonitis are listed in Table 3. 
Table 3 
Dose Modification and Management Guidelines for Pneumonitis 
Grade 
Intervention 
Investigations 
GDC-0032 a  
Dose Adjustment 
1 
No specific therapy 
required. 
CT scan.  Consider DLCO. b 
Repeat CT scan every 
8 weeks until return to 
baseline. 
No change. 
2 
Symptomatic only.  
Prescribe 
corticosteroids if 
cough is troublesome. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks until 
return to baseline.  Consider 
bronchoscopy. 
Interrupt GDC-0032/placebo 
treatment until improvement to 
Grade ≤ 1. Interrupt treatment as 
long as corticosteroids are being 
given. 
Restart GDC-0032/placebo at the 
same dose if clinical benefit 
evident.  Consider restarting at 
reduced dose if recurrent event or 
per discussion with Medical 
Monitor. 
Discontinue treatment if recovery 
to Grade ≤ 1 is not evident within 
28 days. 


 
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Grade 
Intervention 
Investigations 
GDC-0032 a  
Dose Adjustment 
3 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks until 
return to baseline. c 
Bronchoscopy is 
recommended. 
Interrupt treatment until 
improvement to Grade ≤ 1. 
Restart therapy within 28 days at 
a reduced dose if clinical benefit 
is evident. 
Interrupt treatment as long as 
corticosteroids are being given. 
4 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks until 
return to baseline. 
Bronchoscopy is 
recommended. 
Permanently discontinue 
GDC-0032/placebo. 
Table modified from White et al. 2010.  
CT = computed tomography; DLCO = diffusion capacity of the lung for carbon monoxide.  
a Dose reductions per Section 5.1.1. 
b DLCO may be useful to monitor the effect of interventions such as dose 
reduction/discontinuation and corticosteroids, in conjunction with imaging (White et al. 2010). 
c Follow-up imaging and investigation should be coordinated with the local pulmonologist if no 
baseline scans are available.  
 
5.1.1.3 
Management of Rash 
Rash and other dermatological events should be closely monitored, and patients with 
severe rash should be monitored for associated signs and symptoms such as fever and 
hypotension that may be suggestive of a systemic hypersensitivity reaction.  For severe 
rash, dosing of GDC-0032/placebo should be interrupted, and patients should be treated 
with supportive therapy per standard of care.  Use of antihistamines, as well as topical or 
systemic corticosteroids, may be considered (see Table 4).   


 
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Table 4 
GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Grade of Rash 
GDC-0032/placebo  
Grade 1 
Continue dosing at current dose and monitor for change in severity.  
Consider prescribing topical corticosteroids a 
Grade 2 
Consider holding GDC-0032/placebo or reducing to the next lower 
dose if rash is troublesome.   
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b). 
Grade 3 
Hold GDC-0032/placebo until Grade ≤ 1. 
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b).  
Consider dermatological consultation.  
Consider obtaining photographs of rash if permitted by local 
regulations. 
After rash improves to Grade ≤ 1, restart GDC-0032/placebo at the 
next lower dose upon discussion with Medical Monitor, or 
permanently discontinue. 
Grade 4  
Permanently discontinue GDC-0032/placebo. 
AE = adverse event. 
AE grading is based on NCI CTCAE, v4.0. 
a Suggested topical steroids include hydrocortisone 2.5% to face twice daily, 
triamcinolone 0.1%, or fluocinonide 0.1% cream to body twice daily. 
b Suggested oral steroids include a methylprednisolone dose pack or prednisone 
60 mg daily followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, 
etc.). 
 
5.1.1.4 
Management of Gastrointestinal Toxicity 
5.1.1.4.1 
Management of Diarrhea and Colitis 
Patients should be closely monitored for gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea, abdominal pain, stomatitis, and changes in stool, including checking 
for blood in stool if clinically indicated).  Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is mild.  Weekly patient contact (e.g., 
telephone call) for all events of diarrhea Grades ≥ 1 is recommended to closely follow 
until resolution of symptoms.  Gastrointestinal symptoms should be managed per 
protocol guidelines and institutional standard of care.  For example, prompt management 
of diarrhea with antidiarrheal medications should be implemented.  Because of the 
approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032/placebo for Grade ≥ 2 diarrhea.     
Steroid-responsive diarrhea and colitis have been difficult to distinguish in patients 
treated with GDC-0032.  All cases of colitis have been reversible with corticosteroid 
treatment.  Prompt initiation of corticosteroids for persistent diarrhea despite 
antidiarrheal treatment can decrease the severity of the diarrhea and prevent the need 


 
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for hospitalizations.  Patients who develop severe steroid-responsive diarrhea usually 
have been on GDC-0032 treatment for at least 2 months, with an average onset 
between 4 and 6 months of treatment.  A stool culture is helpful in identifying concurrent 
infections, and patients have been successfully treated with concurrent steroids and 
appropriate antibiotics if needed.  
If a patient is being treated with corticosteroids, total parenteral nutrition is discouraged 
as this increases the risk for severe hyperglycemia.  Discontinuation of nonsteroidal 
inflammatory medications or other medications that exacerbate colitis are also 
recommended during colitis episodes.   
Perforated duodenal ulcer has been observed in 2 patients (one patient at 6 mg capsule 
in combination with letrozole; another patient at 6 mg capsule in combination with 
fulvestrant).  Appropriate caution should be taken with the administration of medications 
such as aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids that can 
increase the risk of gastritis, peptic ulcers, or gastrointestinal perforation. 
Specific dose modification and management guidelines for diarrhea and colitis are 
provided in Table 5.  
Table 5 GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis 
Grade of Diarrhea 
Dose Modification and Management Guidelines  
Grade 1 
• Manage per institutional standard of care that includes 
antidiarrheals.a 
• For persistent Grade 1 diarrhea occurring after Cycle 2, 
recommend evaluation for infectious causes via stool culture.b  
For noninfectious diarrhea, consider colonoscopy to evaluate for 
colitis. 
• 
For any grade of diarrhea (≥1), contact patient at least weekly 
to monitor until resolution of symptoms.  If symptoms persist 
beyond 2 weeks despite antidiarrheal treatment (e.g., 
loperamide), escalate to Grade 2 management. 
Grade 2 
• Hold GDC-0032/placebo and initially manage with antidiarrheals.a 
• Obtain stool culture for infectious workup. b  Infections (e.g., 
Clostridium difficile, enteric bacteria, CMV) should be treated 
with the appropriate antibiotic. 
• For persistent Grade 2 non-infectious diarrhea lasting longer 
than 48 hours despite treatment with antidiarrheals, treat with 
oral corticosteroids (20−40 mg prednisone QD starting dose with 
taper) or budesonide 9 mg PO QD. 
• If Grade 2 diarrhea occurred after Cycle 2, was a recurrent 
episode, or improved with corticosteroid treatment, resume 
GDC-0032/placebo treatment at one dose level lower upon 
improvement to Grade ≤ 1 and after completion of corticosteroid 
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Grade of Diarrhea 
Dose Modification and Management Guidelines  
• If Grade 2 diarrhea occurred before Cycle 2, did not require 
corticosteroid treatment, and was an initial episode, resume 
GDC-0032/placebo treatment at the same dose upon 
improvement to Grade ≤ 1.  
• For Grade 2 colitis, resume GDC-0032/placebo treatment at one 
dose level lower upon improvement to Grade ≤ 1 and after 
completion of corticosteroid treatment. 
• If Grade 2 diarrhea does not improve after 48 hours of 
corticosteroid treatment, a colonoscopy is recommended to 
evaluate for other causes of diarrhea (e.g., CMV colitis). 
Grade 3 (first 
episode)  
• Hold GDC-0032/placebo and initially treat with antidiarrheals. a   
• Obtain stool culture for infectious workup. b 
• For G3 diarrhea or colitis, treat with systemic corticosteroids 
(prednisone 60 − 80 mg QD equivalent or solumedrol 16−20 mg 
IV q8hr to start).  Can increase steroid dosage if diarrhea does 
not improve. 
• Concurrent infections (e.g., Clostridium difficile, enteric bacteria, 
CMV) should be treated with the appropriate antibiotic. 
• For patients who do not improve upon 48 hours of corticosteroid 
treatment, a colonoscopy is recommended to evaluate for other 
causes of diarrhea (e.g., CMV colitis).  
• If diarrhea or colitis improves to Grade ≤ 1 and upon completion 
of any steroid taper or antibiotic treatment, resume 
GDC-0032/placebo treatment at one dose level lower. 
Grade 3 (recurrent) 
or Grade 4 
• Permanently discontinue GDC-0032/placebo.   
• Workup and treatment algorithm as for Grade 3 (first episode). 
• If patient receiving endocrine therapy, upon recovery to 
Grade  ≤ 1, can resume endocrine therapy alone.   
CMV = cytomegalovirus; IV = intravenous; PO = oral; QD = once daily; q8hr = every 8 hours; 
SOC = standard of care. 
a Suggested antidiarrheals include the following: loperamide (initial: 4 mg, followed by 
2 mg after each loose stool, up to 16 mg/day); diphenoxylate and atropine 
(Diphenoxylate 5 mg 4 times/day until control achieved [maximum:  20 mg/day], then 
reduce dose as needed; some patients may be controlled on doses of 5 mg/day; tincture 
of opium (6 mg of undiluted opium tincture [10 mg/mL]) 4 times daily. 
b Non-infectious diarrhea can be diagnosed by stool culture with workup for various enteric 
bacteria and C. difficile. Fecal calprotectin is a possible marker for bowel inflammation.  
Blood-based CMV PCR test can also be used to detect CMV infection. 
 
5.1.1.4.2 
Management of Stomatitis and Oral Mucositis 
Aggressive mouth care for oral mucositis and stomatitis with mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal 
and/or antibiotics) may also be helpful in managing symptoms, and it is recommended 
that these are implemented with early signs of dry mouth, Grade 1 mucositis, or Grade 1 
stomatitis (see Table 6).  Avoidance of spicy foods may also be helpful.   


 
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Table 6 GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Grade of 
Stomatitis/Mucositis 
GDC-0032/placebo  
All grades 
• 
Aggressive mouth care that includes mouthwash 
formulations (e.g., combinations of local anesthetic, 
antihistamine, corticosteroid, antacid, antifungal and/or 
antibiotics)  
• 
Diet management (e.g., avoidance of spicy foods) 
Grade 1 
• 
Monitor symptoms and initiate management (see above). 
Re-evaluate within 48 − 72 hours.   
Grade 2 
• 
Hold GDC-0032/placebo and manage until Grade ≤ 1.   
• 
Restart GDC-0032/placebo at the same dose.   
• 
If Grade 2 stomatitis/oral mucositis recurs, hold 
GDC-0032/placebo until Grade ≤ 1.  Restart 
GDC-0032/placebo at the next lower dose. 
Grade 3 
• 
Hold GDC-0032/placebo and manage until Grade ≤ 1.  
Restart GDC-0032/placebo at the next lower dose.  
For Grade 3 event that was not adequately managed upon 
initial presentation, consider restarting at same dose upon 
discussion with Medical Monitor.   
Grade 4 
• 
Permanently discontinue GDC-0032/placebo. 
 
5.1.2 
Management of Abnormal Liver Function Tests 
Some patients have experienced elevations of liver function tests (e.g., AST or ALT). 
Patients will be monitored throughout the study treatment for changes in liver function 
tests.  Given the potential for hepatic toxicity, all patients must have adequate liver 
function as manifested by measurements of serum bilirubin, hepatic transaminases, and 
alkaline phosphatase for initial and continued dosing.  Separate criteria for eligibility, 
continued dosing, and DLT are given for patients with hepatic metastases and Grade 2 
hepatic transaminase and/or alkaline phosphatase levels at baseline to allow safety 
testing to be adequately assessed in this patient group.   
For new abnormal liver function tests (e.g., elevated AST or ALT), a standard clinical 
work-up to understand the etiology of the abnormality should take place per local 
guidelines.  In many cases, elevated liver function tests may be a result of liver 
metastases, concomitant medications, or biliary obstruction.  Dose modifications for 
elevated liver function tests are described in Table 7.  
5.1.3 
Management of Asymptomatic Lipase and/or Amylase 
Elevations 
Some patients treated with GDC-0032 have experienced asymptomatic lipase and/or 
amylase elevations in blood tests without any clinical or radiographic symptoms of 


 
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pancreatitis or another clear etiology for the abnormal laboratory values.  Upon 
discussion with the Medical Monitor and after a risk-benefit assessment, investigators 
can consider continuing GDC-0032 therapy in such patients at the same dose or one 
dose level lower.  Investigators should have a low threshold for interrupting GDC-0032 
for any concerning clinical gastrointestinal toxicities. 
5.1.4 
Management of Other Clinically Significant Adverse Events 
See Table 7 for the dose modifications for other clinically significant adverse events. 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events 
Grade 
GDC-0032/placebo  
Grade 3:  first event 
• 
Hold GDC-0032/placebo until Grade ≤ 1.  
• 
Consider restarting at next lower dose. 
Grade 3:  recurrent 
• 
Hold GDC-0032/placebo until Grade ≤ 1. 
Grade 4:  non-life-threatening 
• 
Restart at next lower dose. 
Grade 4:  life-threatening 
• 
Permanently discontinue GDC-0032/placebo.  
 
5.1.5 
General Guidance for Dose Modifications and Delays for 
Letrozole 
The letrozole dose level cannot be modified.  In general, the investigator can consider 
continuing letrozole if it is not thought to be letrozole-related.   
All dose modifications should be based on the adverse event requiring the greatest 
modification and should be properly documented in the source documents. 
5.1.6 
Management of Increases in QT Interval  
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
1. 
Sustained (at least two ECG measurements > 30 minutes apart) QTcF that is 
> 500 msec and > 60 msec longer than the baseline value 
2. 
Sustained absolute QTcF that is > 515 msec  
3. 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, as this represents an increase in 
QTcF unrelated to alterations in repolarization.  Also of note, it is not uncommon to 
record arrhythmias such as non-sustained ventricular tachycardia, supraventricular 
tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving placebo during 
periods of extended ECG monitoring.  Therefore, it is critical that expert 
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likelihood of a drug-induced arrhythmia versus the background occurrence of this 
arrhythmia.  In such a situation, saving all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients. 
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied. 
5.1.7 
Safety Monitoring for Letrozole 
Letrozole is a nonsteroidal AI indicated for first line treatment of hormone receptor 
positive, locally advanced, or metastatic breast cancer in postmenopausal women.  
Letrozole is also indicated for adjuvant treatment in postmenopausal hormone-receptor 
positive patients and for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following anti-estrogen therapy. 
The most frequently reported adverse events in a first line, breast cancer clinical trial 
with letrozole were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea.  
Clinically significant adverse events also include bone effects (osteoporosis and bone 
fractures) and hypercholesterolemia.  Discontinuations for adverse events other than 
progression of tumor occurred in 2% of patients on letrozole.  Refer to the U.S. letrozole 
Package Insert or SmPC for additional information.   
There are no expected significant overlapping toxicities between letrozole and 
GDC-0032. Routine safety monitoring and periodic laboratory tests for the letrozole and 
GDC-0032 combination will occur throughout the study. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and 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 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), 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 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to ABCSG) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (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). 


 
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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 ABCSG safety 
department immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
ABCSG)  
Adverse events of special interest are required to be reported by the investigator to 
ABCSG safety department 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: 
• 
Grade 4 hyperglycemia 
• 
Grade ≥ 3 symptomatic hyperglycemia 
• 
Grade ≥ 2 colitis or enterocolitis  
• 
Grade ≥ 2 diarrhea 
• 
Grade ≥ 1 diarrhea for > 2 weeks after following medical management guidelines in 
Section 5.1.1.4  
• 
Grade ≥ 3 rash 
• 
Grade ≥ 2 pneumonitis  
• 
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 5.3.5.5) 
• 
Suspected transmission of an infectious agent by the study drug  
 
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 additionally reported to ABCSG 
safety department in case they fulfill the criteria for expedited reported in accordance 
with instructions provided in this section and in Section 5.4−Section 5.6. 
For each adverse event recorded on the Adverse Event CRF, 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 
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 until the end of 
study visit, whichever occurs later.  After this period, investigators should report any 


 
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deaths, serious adverse events, or other adverse events of concern deemed related to 
prior study drug treatment or study procedures (Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE, v4.0 will be used for 
assessing adverse event severity.  Table 8 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 8 
Adverse Event Severity Grading Scale 
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 (v 4.0), 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 one's self, 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. 
 


 
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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 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 9): 
• 
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 (where 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 9 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 
Adverse events will be considered related, unless they fulfill the criteria as 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 
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If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.1 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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. 
5.3.5.2 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The progression (increase and decrease) of an adverse 
event must be documented in the Adverse Event eCRF.   
The initial severity of the event should be recorded, and the severity should be updated 
to reflect the most extreme severity any time the event worsens.  If the event becomes 
serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
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5.3.5.3 
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: 
• 
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 
• 
Clinically significant in the investigator’s judgment 
 
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 times the 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.4 
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: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 


 
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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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.5 
Reporting of Abnormal Liver Function Tests as Hy’s Law 
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 ABCSG safety department immediately (i.e., no more than 24 hours 
after learning of the event), either as serious adverse event or an adverse event of 
special interest (see Section 5.4.2). 
5.3.5.6 
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 ABCSG safety department 
(see Section 5.4.2).  This includes death attributed to progression of breast cancer. 
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 only be used 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 of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive 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 


 
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death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
5.3.5.7 
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 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”). 
5.3.5.8 
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: 
• 
Perform an efficacy measurement for the study 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol for breast cancer surgery  
• 
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 suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
• 
Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care 
• 
Hospitalization for protocol mandated biopsies 
 
5.3.5.9 
Adverse Events Associated with an Overdose 
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 serious 
criteria, the event should be reported to the ABCSG safety department immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 


 
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5.3.5.10 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO ABCSG 
Certain events require immediate reporting to allow ABCSG safety department to take 
appropriate measures to address potential new risks in a clinical trial.  The investigator 
must report such events to ABCSG safety department 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 
ABCSG safety department within 24 hours after learning of the event, regardless of 
relationship to study drug: 
• 
Serious adverse events 
• 
Adverse events of special interest (see Section 5.2.3) 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to 
ABCSG safety department immediately (i.e., no more than 24 hours after becoming 
aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
U.S. Medical Monitor Contact Information  
Genentech’s Medical Monitor Contact Information: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No. 
Alternate Telephone No.: 
 


 
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Medical Monitor Contact Information for Sites outside the United States:  
Please refer to the country/region-specific phone numbers provided in the study binder. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the paper Serious Adverse Event reporting form and transmit to ABCSG 
safety department via fax. In addition the serious adverse event and adverse event of 
special interest information will be captured in the EDC system.   
Worldwide Sites: 
ABCSG safety department  
Fax No.: 
+43 1 409 09 90 
Relevant follow-up information should be submitted to ABCSG safety department as 
soon as it becomes available and/or upon request. 
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.  With regard to the adverse event of 
special interest of diarrhea, it is recommended that investigators follow every adverse 
event of ≥ Grade 1 diarrhea with weekly patient contacts (e.g., telephone calls) and 
follow up until resolution.  Cases that do not resolve within 1−2 weeks should be 
aggressively managed per protocol recommendations for gastrointestinal toxicities. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification (SDV).  For follow-up reports of serious adverse events and adverse events 
of special interest, investigators should record all follow up information immediately (i.e., 
within 24 hours) on the paper Serious Adverse Event reporting form and transmit to 
ABCSG safety department via fax. In addition the serious adverse event and adverse 
event of special interest follow-up information will be captured in the EDC system.  If, 
after follow-up, return to baseline status or stabilization cannot be established, an 
explanation should be recorded on the Adverse Event eCRF and paper Serious Adverse 
Event form, if applicable.   
All pregnancies reported during the study should be followed until pregnancy outcome, 
and they should be reported according to the instructions provided in Section 5.4. 


 
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5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor and/or ABCSG safety department 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 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (30 days after the last dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or adverse event of special interest occurring 
after the end of the adverse event reporting period, regardless of causality.  The 
Sponsor should also be notified if the investigator becomes aware of the development of 
cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a 
female patient exposed to study drug or the female partner of a male patient exposed to 
study drug. 
The investigator should report these events directly to the Sponsor 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 (see "Protocol Administrative and Contact Information & List of 
Investigators”). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
GDC-0032 Investigator's Brochure  
• 
Local prescribing information for letrozole SmPC 
 


 
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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. 
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
Primary and secondary efficacy analyses will include all patients who were included 
in the randomization.  Final analysis will be performed after last patient, last visit (LPLV) 
and subsequent data cleaning, with patients allocated to the treatment arm associated 
by randomization. 
Safety analyses will include all patients who were included in the randomization and 
received at least one dose of study treatment, with patients allocated to the treatment 
arm associated with the regimen actually received.  
6.1 
DETERMINATION OF SAMPLE SIZE  
This study is designed for testing the effect of GDC-0032 on the two co-primary 
endpoints in all enrolled patients and in the PIK3CA MT patients and plans to enroll 
330 patients in total.  Assuming the PIK3CA mutation status will not be available 
(unknown) for approximately 10% of the patients and the prevalence of PIK3CA mutant 
is 40%, there will be approximately 120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, 
there might be a possible imbalance between treatment arms within the PIK3CA MT 
cohort, which may reduce the statistical power in this cohort.  To ensure the study 
provides sufficient statistical power even when the treatment assignment is imbalanced, 
the sample size was calculated based on a conservative scenario by assuming that the 
treatment assignment imbalance in PIK3CA MT is 40% versus 60%.  The sample size 
was calculated based on a chi²-test using continuity correction (Ury and Fleiss 1980). 
To control an overall, two-sided, family-wise error rate under 20% for each analysis 
population, we use a two-sided significance level of 16% and 4% for the co-primary 
endpoints MRI ORR, and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 
300 enrolled patients and 108 patients in the PIK3CA MT cohort will be evaluable for 
analyses.  This sample size allows us to detect an absolute percentage increase of 24% 
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arm (40%; Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power 
and 16% two-sided significance level.  The minimal detectable difference for ORR is 
approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled 
patients and 120 in the PIK3CA MT cohort), this sample size provides 80% power to 
detect an absolute percentage increase of 18% in pCR in the GDC-0032 plus letrozole 
arm (19%) versus the letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in 
the PIK3CA MT cohort at the 4% two-sided significance level.  The minimal detectable 
difference for pCR rate is approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more 
substantial treatment assignment imbalance in the PIK3CA MT cohort than assumed, or 
there is an increased number of unevaluable patients for the MRI ORR, the sample size 
may be increased to obtain the level of power at 80%, and the enrollment may be limited 
to patients with PIK3CA MT.   
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 incidence of study treatment 
discontinuation for reasons other than disease progression will be tabulated. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized by treatment arm. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the ITT population; that is, all 
randomized patients will be included in the analyses, with patients grouped according to 
the treatment assigned at randomization.  
6.4.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are (1) tumor ORR, assessed by modified RECIST 
criteria by breast MRI (centrally assessed) and (2) the rate of pCR in breast and axilla 
(total pCR) after completion of study drug. 
The tumor ORR will be calculated by treatment arm in all enrolled population and in 
PIK3CA MT population.  Within each population, the ORR for the two treatment arms will 
be compared at a two-sided alpha of 16% using a Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status.  The pCR rate will also be calculated and 
compared at a two-sided alpha of 4% based on the same analytical approach as ORR.  
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population.  Patients with early study termination and hence missing efficacy outcome 
will be considered as non-responders. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST 
criteria by breast MRI (centrally assessed) in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in 
PIK3CA WT patients.  
These endpoint measures will be summarized by treatment arm and will be 
analyzed analogue to the primary efficacy endpoint. 
 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status (centrally assessed): 
• 
ORR using modified RECIST criteria by the following methods:  clinical breast 
examination, mammography, and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to 
surgery (centrally assessed) 
• 
PEPI score (centrally derived) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast 
MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and 
b) ypT0/is, ypNX (breast pCR) 
 
These endpoint measures will be summarized by treatment arm and will be compared 
between the two treatment arms within each population based on appropriate statistical 
analyses:  ORR will be compared using a Cochrane Mantel-Haenszel test, stratified by 
tumor size and nodal status; PEPI, Ki67, and tumor volume change will be compared by 
regression analyses, adjusted for tumor size and nodal status.  All secondary endpoints 
will be tested at a two-sided type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study 
treatment, with patients allocated to the treatment arm associated with the regimen 
actually received.  
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and letrozole and GDC-0032 exposure. 


 
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Verbatim descriptions of adverse events will be mapped to thesaurus terms.  Adverse 
event data will be listed by study site, treatment arm, patient number, and study day, 
severity, relationship to study drug, outcome, and action taken with the study treatments.  
Events occurring on or after treatment on Day 1 of Week 1 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 and vital sign (heart rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE, v4.0 Grade 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized in tables by 
NCI CTCAE, v4.0 grade. 
6.6 
PHARMACODYNAMIC ANALYSES  
Ki67 biomarker analyses will include patients with at least one predose and one 
postdose biomarker assessment, with patients grouped according to the treatment 
actually received.  
6.7 
PHARMACOKINETIC ANALYSES  
Individual Cmax and trough plasma concentrations (Cmin) of GDC-0032 and letrozole from 
all patients enrolled will be reported.  Mean of trough plasma concentrations of 
GDC-0032 and letrozole will be tabulated.  The population pharmacokinetics of letrozole 
and GDC-0032 in this study will be compared with historical single-agent 
pharmacokinetics to assess the potential DDI between GDC-0032 and letrozole in this 
population.   
Additional PK analyses on metabolites of GDC-0032, letrozole, and/or other concomitant 
medications may be conducted as appropriate. 
6.8 
PATIENT-REPORTED OUTCOME ANALYSES 
Patient-reported outcomes of breast cancer symptoms, patient functioning, and HRQoL 
will be assessed by the EORTC QLQ-C30 and the modified Breast Cancer module 
(QLQ-BR23)  
Summary statistics (mean, standard deviation, median and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the modified QLQ-BR23 according to the EORTC scoring manual 
guidelines for each assessment time point.  The mean change of the linear transformed 
scores from baseline (and 95% CI using the normal approximation) will also be 
assessed.  Line charts depicting the mean changes (and standard errors) of items and 
subscales over time will be provided for each treatment arm from the baseline 
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Data analysis will be performed on the final modified BR23 data set in parallel with the 
final data analysis to assess the psychometric properties of the modified instrument and 
will be reported along with the clinical trial results.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data.  Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses.  The number and 
proportion of patients who improved, worsened, or remained stable for all of the 
symptom and functional domains, global QoL, and single items of the EORTC QLQ-C30 
and QLQ-BR23 will be summarized. 
6.9 
EXPLORATORY ANALYSES  
Additional details on analyses will be specified in the SAP. 
6.10 
INTERIM ANALYSES  
The iDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day follow-up visit after the surgery, or 2) been 
in the study for 20 weeks after the randomization date (for those who do not receive the 
surgery), whichever occurs first.  All available information of all enrolled patients with all 
available assessments at the respective timepoint will be included in the interim 
analyses.  In addition, the iDMC or the Medical Monitor may request additional ad hoc 
meetings of the iDMC at any time during the study to review safety data. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
ABCSG will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, ABCSG 
and/or all involved clinical research associates (CRAs) will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
ABCSG will produce a Data Management Plan that describes the quality checking to be 
performed on the data.  The Sponsor will perform oversight of the data management of 
this study, including review of the ABCSG’s data management plan and corresponding 
specifications.  Data will be transferred electronically from ABCSG to the Sponsor at the 
end of the study and whenever otherwise contractually agreed, and the Sponsor’s 
standard procedures will be used 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 at ABCSG and records retention for the study data will 
be consistent with the ABCSG’s standard procedures. 


 
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Data from paper PRO questionnaires will be entered into the EDC system by site staff. 
Original PRO questionnaires will be kept in the patient’s medical record as source 
documentation. 
7.2 
DATA(BASE) MANAGEMENT 
ABCSG Clinical Data Management will check all e-forms for plausibility and consistency 
by automatic edit checks and manual data review according to study-specific data 
management plan (DMP).  If necessary, web-based data queries (data clarification 
requests [DCRs]) will be generated and subsequently visible for the investigators, 
dedicated site staff, responsible CRAs, and responsible ABCSG staff.  For those eCRFs 
which pass all verification procedures and are regarded as correct and complete, they 
will be frozen subsequently by ABCSG clinical data management.  Consequently, no 
further data entries or changes on frozen eCRFs are possible.  The status of frozen 
eCRFs is flagged by the specific icon. 
Clinical Data Management ensures that the database is corrected for the following eCRF 
issues without immediate notification to site staff (self-evident corrections).  Notification 
of site staff is provided via a specific report after final data cleaning procedures and 
before final data confirmation by the investigator or a designee: 
• 
misspellings/typing errors that do not change the meaning of the word 
• 
location of data recorded at an incorrect variable field or eForm (e.g., moving lab 
data from general comments to the appropriate lab table) 
• 
standard time to 24-hour clock 
• 
correction of date format, if required (dd/mm/yyyy) 
• 
if equivalent units of terms are recorded instead of the acceptable ABCSG standard 
• 
data changes due to plausibility checks and eCRF content (e.g., combination of 
several variables and/or eCRFs) 
 
All data management workflows are described in detail in the relevant SOPs and 
working instructions of ABCSG. 
7.3 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using the Clinical Data Management System “MACRO,” a 
Web-interface DATAPORT.  Sites will receive training by the responsible CRAs and 
have access to a manual for appropriate eCRF completion (web data entry).   
All eCRFs should be completed by designated, trained site staff in a timely manner, 
usually within 2 weeks after the patient visit.  Electronic CRFs should be reviewed and 
respective data confirmation eCRF should be electronically signed and dated by the 
investigator or a designee at the end of the study.  


 
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a storage medium (compact disc [CD], digital video disk [DVD] etc.) 
that must be kept with the study records.  Acknowledgement of receipt of the storage 
medium is required. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors (CRAs) will perform ongoing SDV 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 7.6. 
To facilitate SDV, the investigators and institutions must provide the Sponsor/CRAs 
direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The investigational site must also allow inspection 
by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
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7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), ICFs, 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 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 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/European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs) 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 ICFs 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. 
The ICF will contain a separate section that addresses the consent for optional donation 
of remaining samples for the clinical repository.  Samples stored in the clinical repository 
may be used for future exploratory research.  Patients will be told that they are free to 
refuse to donate their remaining samples to the clinical repository.  If patients choose to 
donate remaining samples, they may withdraw their specimens at any time and for any 
reason during the storage period.  A separate, specific signature will be required to 
document a patient's agreement to allow any remaining specimens to be stored in the 
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The ICFs must be signed and dated by the patient or the patient’s legally 
authorized representative before 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 eCRF contains a section to document whether the patient has signed the ICF or not. 
The ICFs 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. 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion.  After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood.  The investigator or designee must also explain that the patients are 
completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason. 
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative.  All signed and dated ICFs 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 ICF 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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the sponsor, the affiliated 


 
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groups, or contract research organizations (CROs) according to the applicable local laws 
and regulations, if applicable 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 Sponsor, affiliated groups, or CROs are 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 local IRB/EC.  The 
Sponsor, affiliated groups, or CROs 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 local 
health authority requirements and the policies and procedures established by their 
IRB/EC, and archived in the site’s study file.  
8.4 
DATA PRIVACY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique 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 only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by local 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, provided 
the patient has given consent. 
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.  The patient will have to consent to such access by signing the informed 
consent form. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  


 
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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, ICFs, and documentation of IRB/EC and governmental (health authorities) 
approval.  In addition, at the end of the study, the investigator will receive the patient 
data, which includes an audit trail containing a complete record of all changes to data. 
9.2 
ON SITE QUALITY CONTROL (MONITORING) 
During the study, CRAs will visit their respective sites on a regular basis as outlined in 
the study specific monitoring plan (MP) and all other relevant specifications, in order to 
guarantee adherence to the protocol and to the principles of GCP and to check for the 
progress of enrolment, adequate storage conditions of IMP and adequate drug 
dispensing and accounting records.  
CRAs will review documented data in the eCRFs for completeness and accuracy 
according to the study-specific MP, subsequently flag all reviewed pages with a specific 
mark (“SDV done”) within the EDC system “MACRO,” Web-interface DATAPORT, 
developed by 
  The CRAs will raise data queries (“DCRs”) in cases of 
missing source data or incorrect data entries.  Immediately after electronic issue of the 
queries, they become visible to the investigator, the clinical data managers, and the 
ABCSG clinical safety officers (“raised DCRs”).  CRAs and/or clinical data managers 
and/or ABCSG clinical safety officers will follow up with trial site personnel until final data 
query resolution. 
9.3 
PROTOCOL DEVIATIONS 
The investigator should document and explain any deviations from the approved 
protocol.  The investigator should promptly report any deviations that might impact 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with 
established IRB/EC policies and procedures. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit international and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 


 
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9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech in 
collaboration with the Breast International Group (BIG), ABCSG, and the SOLTI Breast 
Cancer Research Group.  Genentech in collaboration with BIG, ABCSG, and SOLTI will 
provide clinical operations management, data management, and medical monitoring.  
Approximately 110 U.S. and international sites will participate to enroll approximately 
330 patients. 
An iDMC will be in place throughout the study and will provide oversight of safety and 
efficacy analyses (see Section 3.1.2). 
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the IxRS system.  Once eligibility has been established, the 
patient will be enrolled, and the study site will obtain the patient’s identification number 
from the IxRS.  Once results of the tissue analysis are made available, the patient will be 
randomized, and the site will obtain the blinded treatment assignment from the IxRS.  
The IxRS will manage GDC-0032/placebo drug inventory at all sites and letrozole drug 
inventory at all study sites outside the United States.  IxRS will be required to randomize 
patients, to monitor enrollment and patient status, and to manage study treatment 
requests and shipments.  
Patient data will be recorded via an electronic data capture (EDC) system from 
 
(
, United Kingdom), which will be managed by ABCSG using eCRFs 
(see Section 7.2).   
Central laboratories, including Genentech and Genentech collaborators, will be used for 
PIK3CA mutation detection, Ki67, and PTEN status and/or will provide kits for PK, 
pharmacogenomic, tissue, whole blood, and plasma sample analyses to be conducted at 
central laboratories, Genentech, or Genentech collaborators. 
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans throughout the trial.  The review facility will retain 
copies of scans for centralized assessments of MRI-related endpoints.   
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). 


 
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117/Protocol GO28888, Version 4 
10. 
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Appendix 1  
Schedule of Assessments 
Treatment Phase 
Surgery a,f 
Post-
Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
W16 
(Presurgical Visit) 
W17−W18
(Surgery) 
4 Weeks 
(± 1W) from 
Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
43 
(± 2) 
57 
(± 2) 
71 
(± 2) 
85 
(± 2) 
106−112 
113−126 
 
Informed consent a 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and  
demographic data b 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination c 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
Clinical breast and regional lymph 
node examination  
x 
x 
 
x 
 
x 
 
x 
x 
 
 
Vital signs d 
x 
x 
x 
x 
 
x 
 
x 
x 
 
x 
ECOG Performance Status 
x 
x 
x 
x 
 
x 
 
x 
x 
 
x 
12-Lead ECG e 
x 
 
x 
 
 
 
 
 
 
 
 
Mammography  
x 
 
 
 
 
 
 
 
x 
 
 
Breast ultrasound and axillary lymph 
node status f 
x 
 
 
 
 
x 
 
 
x 
 
 
Breast MRI g 
x 
 
 
 
 
 
 
 
x 
 
 
Collection of tumor samples h  
x 
 
x 
 
 
 
 
 
 
x 
 
Confirmation of receipt of adequate 
tissue for PIK3CA assessment 
x 
 
 
 
 
 
 
 
 
 
 
CBC with differential and  
platelet count i 
x 
x 
 
x 
 
x 
 
x 
x 
 
x 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
124/Protocol GO28888, Version 4 
Treatment Phase 
Surgery a,f 
Post-
Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
W16 
(Presurgical Visit) 
W17−W18
(Surgery) 
4 Weeks 
(± 1W) from 
Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
43 
(± 2) 
57 
(± 2) 
71 
(± 2) 
85 
(± 2) 
106−112 
113−126 
 
Fasting serum chemistry j 
x 
x 
 
x 
 
x 
 
x 
x 
 
x 
Glycosylated hemoglobin (HbA1c) 
x 
 
 
 
 
 
 
 
 
 
 
Fasting insulin and glucose k 
x 
x 
 
x 
 
x 
 
x 
x 
 
x 
Fasting lipid profile and amylase l 
x 
 
 
x 
 
 
 
x 
x 
 
x 
Coagulation (INR and aPTT)  
x 
 
 
x 
 
x 
 
x 
x 
 
x 
Urinalysis (laboratory) m 
x 
 
 
x 
 
x 
 
 
x 
 
x 
DLCO n 
x 
 
 
 
 
 
 
 
x 
 
 
Bone mineral density test o 
x 
 
 
 
 
 
 
 
 
 
 
Blood sample for plasma protein 
biomarkers p 
 
x 
 
 
 
x 
 
 
x 
 
x 
Blood sample for ctDNA q 
 
x 
 
 
 
x 
 
 
x 
 
x 
Blood sample for NGS r 
 
x 
 
 
 
 
 
 
 
 
 
Pharmacogenomic sample s  
 
x 
 
 
 
 
 
 
 
 
 
Concomitant medication t 
x 
x 
x 
x 
 
x 
 
x 
x 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Inclusion/exclusion criteria u 
x 
 
 
 
 
 
 
 
 
 
 
Visit with breast surgeon (may occur 
from Week 13) 
 
 
 
 
 
 
 
x 
 
 
 
Surgery v 
 
 
 
 
 
 
 
 
 
x 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
125/Protocol GO28888, Version 4 
Treatment Phase 
Surgery a,f 
Post-
Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
W16 
(Presurgical Visit) 
W17−W18
(Surgery) 
4 Weeks 
(± 1W) from 
Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
43 
(± 2) 
57 
(± 2) 
71 
(± 2) 
85 
(± 2) 
106−112 
113−126 
 
Randomization  
x 
 
 
 
 
 
 
 
 
 
 
Letrozole accountability/dispensation 
 
x 
x 
x 
 
x 
 
x 
x 
 
 
GDC-0032/placebo accountability/ 
dispensation  
 
x 
x 
x 
 
x 
 
x 
x 
 
 
Patient-reported outcomes w 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
Pharmacokinetic sample (see 
Appendix 2 ) 
 
x 
x 
 
 
x 
 
 
 
 
 
aPTT = activated partial thromboplastin time; CA-125 = cancer antigen 125; CTCs = circulating tumor cells; ctDNA = circulating tumor DNA; DLCO = diffusion capacity 
of the lung for carbon monoxide; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INR = international normalized ratio; MRI = magnetic 
resonance imaging; NGS = next-generation sequencing. 
Note:  All assessments should be performed before dosing, unless otherwise stated.  Some assessments may be performed outside the window indicated to 
accommodate holidays, unforeseen scheduling issues, or ongoing safety issues with the trial and the patient, after approval by the Medical Monitor. 
a Perform within 28 days prior to Day 1 of Cycle 1.  Signed informed consent must be provided prior to any study-specific evaluations.  Assessments performed 
as standard of care within the timeframe may be used. 
b Medical history includes clinically significant diseases that are currently active or that were active within the last 5 years, surgeries, cancer history (including 
date of diagnosis, primary tumor histology, grade, staging, prior cancer therapies, and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse. Demographic data include age, sex, and self-reported race/ethnicity. 
c A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; height is 
measured at the screening visit only).  Perform symptom-directed physical examination after baseline assessment. 
d Vital signs include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated position and 
temperature. Oxygen saturation is obtained by pulse oximetry after the patient has been in a seated position for ≥ 5 minutes. Obtain vital signs predose. 
e Triplicate ECG recordings will be obtained at each specified timepoint.  A window of  ± 30 minutes is acceptable for all timepoints.  Submit all ECGs to the 
diagnostic facility for central review. 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
126/Protocol GO28888, Version 4 
 
f Baseline evaluation of axillary lymph nodes assessed with ultrasound. 
g MRI evaluation is optional at Week 9.  MRI is mandatory at Week 9 in the event that disease progression is suspected, or if the primary lesion is not evaluable 
by ultrasound at baseline.  Send all scans to the central reading facility for evaluation. 
h Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen OCT core needle biopsy are required prior to initiation of treatment 
(pretreatment) and also on Day 15.  A formalin-fixed, paraffin-embedded tumor block from a surgical resection is required at surgery (Weeks 17−18).  Except in 
the case of pCR, every effort should be made to obtain a fresh-frozen tumor tissue sample at surgery. 
i Complete blood count includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells, if applicable), and platelet count. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to 
Week 1, Day 1. 
j Fasting (≥ 10-hour fast) serum chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, serum 
bilirubin, alkaline phosphatase, glucose, AST, and ALT. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, Day 1. 
k Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, Day 1. 
l Fasting lipid profile includes total cholesterol, HDL, LDL, triglycerides, amylase, and lipase. Screening results may be valid for Week 1, Day 1 if performed 
within 7 days prior to Week 1, Day 1. 
m Includes specific gravity, pH, glucose, protein, ketones, and blood. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, 
Day 1. 
n   DLCO is obtained at screening and prior to surgery.  The DLCO test should be repeated if there is clinical suspicion of pneumonitis.  DLCO calculations are 
described in Appendix 7 .  The hemoglobin value used for correcting DLCO should represent the patient’s actual hemoglobin level and should be obtained within 
7 days of the DLCO test. 
o Baseline bone mineral density will be measured via dual-energy X-ray absorptiometry (DXA) and will need to be obtained in women with a history of 
osteoporosis and/or fractures, or who are at increased risk of osteoporosis.  DXA measurement of both the hip and lumbar spine is suggested.  When either the 
hip or lumbar spine is not a valid skeletal site for BMD measurement, then the 33% (one-third) radius should be measured. In some patients, measurement of 
the hip alone could be sufficient. 
p Pretreatment sample for plasma protein biomarkers should be obtained prior to dosing.  This sample will also be collected prior to dosing at Week 9, Week 16, 
and at the 4-week post-surgical visits.  Refer to laboratory manual for more information. 
q Pretreatment sample for ctDNA may be obtained on Day 1 prior to dosing.  This sample will also be collected prior to dosing at Week 9 and at Week 16, and at 
the 4-week post-surgical visits.  Refer to laboratory manual for more information. 
r Blood for NGS will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1.   
s Blood for pharmacogenomics will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1. 
t Record all medications used by the patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and supplements). 
u All of the study’s inclusion criteria and none of the exclusion criteria should be met prior to study entry. 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
127/Protocol GO28888, Version 4 
v Surgery will take place after at least 16 weeks of combination treatment (i.e., from Week 17 to Week 18), and generally no more than 4 days after the last dose 
of study medication. 
w The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) will be completed by the patients at the investigational site.  All PRO questionnaires must be 
administered prior to any other study assessment(s) and prior to administration of study drug.  
x The assessments at Weeks 7 and 11 may be by telephone contact from the site to the patient, with interview assessment of adverse events and determination 
if intervention is needed. 
 
 


 
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128/Protocol GO28888, Version 4 
Appendix 2  
Schedule of Pharmacokinetic Assessments 
Visit 
Timepoint 
PK Assessments 
Letrozole PK 
Day 1 
3 hours post (± 60 min) letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
0 − 4 hours prior to letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
Day 15 
(+ 2 days) 
3 hours (± 60 min) post letrozole and 
GDC-0032/placebo administration 
ECG before PK 
GDC-0032 PK 
Day 57 
(+ / − 2 days) 
3 hours post (± 60 min) letrozole and 
GDC-0032/placebo administration 
Letrozole PK 
GDC-0032 PK 
ECG = electrocardiogram; min = minutes; PK = pharmacokinetics.  
Record exact time of dose administration and sample collection. 
 


 
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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 
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 
therapy in early breast cancer.  Ultrasound, mammography, and clinical exam are all 
                                            
 
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.) 
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130/Protocol GO28888, Version 4 
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.  Per this protocol, target 
lesion #1 must be ≥ 2 cm and, if selected, target lesion #2 must be ≥ 10 mm.  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 timepoint, 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 
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 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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 
 
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.  


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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132/Protocol GO28888, Version 4 
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  
 
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 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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.  
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.  


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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134/Protocol GO28888, Version 4 
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. 


 
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Appendix 4  
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures   
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
____________________ 
Your birthdate (Day, Month, Year): 
____________________ 
Today's date (Day, Month, Year):  
 
____________________ 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to 
which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
31. Did you have a dry mouth? 
1 
2 
3 
4 
 
32. Did food and drink taste different than usual? 
1 
2 
3 
4 
 
33. Were your eyes painful, irritated or watery? 
1 
2 
3 
4 
 
34. Have you lost any hair? 
1 
2 
3 
4 
 
35. Answer this question only if you had any hair loss: 
Were you upset by the loss of your hair? 
1 
2 
3 
4 
 
36. Did you feel ill or unwell? 
1 
2 
3 
4 
 
37. Did you have hot flushes? 
1 
2 
3 
4 
 
38. Did you have headaches? 
1 
2 
3 
4 
 
39. Have you felt physically less attractive 
as a result of your disease or treatment? 
1 
2 
3 
4 
 
40. Have you been feeling less feminine as a 
result of your disease or treatment? 
1 
2 
3 
4 
 
41. Did you find it difficult to look at yourself naked? 
1 
2 
3 
4 
 
42. Have you been dissatisfied with your body? 
1 
2 
3 
4 
 
43. Were you worried about your health in the future? 
1 
2 
3 
4 
 
 
44. Have you had skin problems (e.g. itchy, dry)?  
1 
2 
3 
4 
 
45. Did itching of your skin bother you? 
1 
2 
3 
4 
  46. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
47. Have you had trouble swallowing? 
1 
2 
3 
4 
 
 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past four weeks: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
48. To what extent were you interested in sex? 
1 
2 
3 
4 
 
49. To what extent were you sexually active? 
(with or without intercourse) 
1 
2 
3 
4 
 
50. Answer this question only if you have been sexually 
active: To what extent was sex enjoyable for you? 
1 
2 
3 
4 
 


 
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Appendix 5  
New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients 
NYHA 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation or dyspnea. 
No objective evidence 
of cardiovascular 
disease. 
II 
Mild 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or 
dyspnea 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or 
dyspnea. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical 
activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 


 
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Appendix 6  
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
DCIS 
Tis (LCIS) 
LCIS 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the 
underlying breast parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on 
the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. 
T1 
Tumor ≤ 20 mm in greatest dimension 
T1mi 
Tumor ≤ 1 mm in greatest dimension 
T1a 
Tumor > 1 mm but ≤ 5 mm in greatest dimension 
T1b 
Tumor > 5 mm but ≤ 10 mm in greatest dimension 
T1c 
Tumor > 10 mm but ≤ 20 mm in greatest dimension 
 
 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Tumor (T) 
T2 
Tumor > 20 mm but ≤ 50 mm in greatest dimension 
T3 
Tumor > 50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)a 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for 
inflammatory carcinoma 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp 347−76. 
DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. 
Note: The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both.  Size should 
be measured to the nearest millimeter.  If the tumor size is slightly less than or greater than a cut-off for a given T classification, it is recommended 
that the size be rounded to the millimeter reading that is closest to the cut-off.  For example, a reported size of 1.1 mm is reported as 1 mm, or a 
size of 2.01 cm is reported as 2 cm.  Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was 
determined by clinical (physical examination or radiologic) or pathologic measurements, respectively.  In general, pathologic determination should 
take precedence over clinical determination of T size. 
a Invasion of the dermis alone does not qualify as T4.  


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Regional Lymph Nodes (N) 
Clinical   
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted 
OR 
N2 
Metastases in clinically detected a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures 
N2b Metastases only in clinically detected a ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph 
node metastases 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement 
OR 
Metastases in clinically detected a ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node 
metastases 
OR 
N3 
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Regional Lymph Nodes (N) 
Clinical 
N3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
a Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics 
highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination.  
Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, for 
example, cN3a(f).  Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a 
clinical N, for example, cN1.  Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine 
needle aspiration, core biopsy, or sentinel lymph node biopsy.  Pathologic classification (pN) is used for excision or sentinel lymph node biopsy 
only in conjunction with a pathologic T assignment. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
Note: ITCs are defined as small clusters of cells ≤ 0.2 mm, or single tumor cells, or a cluster of < 200 cells in a single histologic cross-section.  
ITCs may be detected by routine histology or by IHC methods.  Nodes containing only ITCs are excluded from the total positive node count for 
purposes of N classification but should be included in the total number of nodes evaluated. 
pN0(i–) 
No regional lymph node metastases histologically, negative IHC 
pN0(i +) 
Malignant cells in regional lymph node(s) ≤ 0.2 mm (detected by H&E or IHC including ITC) 
pN0(mol–) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0(mol +) 
Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC 
Micrometastases 
OR 
Metastases in 1–3 axillary lymph nodes 
AND/OR 
pN1 
Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected a 
pN1mi 
Micrometastases (> 0.2 mm and/or > 200 cells but none > 2 mm) 
pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis > 2 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but 
not clinically detected a 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected 
Metastases in 4–9 axillary lymph nodes 
OR 
pN2 
Metastases in clinically detected a internal mammary lymph nodes in the absence of axillary lymph node metastases 
pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit > 2 mm) 
pN2b Metastases in clinically detected d internal mammary lymph nodes in the absence of axillary lymph node metastases 
Metastases in ≥ 10 axillary lymph nodes 
OR 
Metastases in infraclavicular (level III axillary) lymph nodes 
OR 
Metastases in clinically detected c ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary 
lymph nodes 
OR 
Metastases in > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
OR 
pN3 
Metastases in ipsilateral supraclavicular lymph nodes 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit > 2 mm) 
OR 
pN3a 
Metastases to the infraclavicular (level III axillary lymph) nodes. 
Metastases in clinically detected b ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph 
nodes; 
OR 
pN3b 
Metastases in > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
Post-treatment ypN  
Post-treatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above.  The modifier "SN" is used only if a sentinel node 
evaluation was performed after treatment.  If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND. 
The X classification will be used (ypNX) if no yp post-treatment SN or AND was performed 
N categories are the same as those used for pN 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse 
transcriptase/polymerase chain reaction. 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
1 Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  Classification based solely on sentinel lymph 
node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).   
a "Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.   
b "Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having 
characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic 
examination.   
 
Distant Metastases (M) 
 
M0 
No clinical or radiographic evidence of distant metastases 
cM0(i +) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in 
circulating blood, bone marrow, or other non-regional nodal tissue that are ≤ 0.2 mm in a patient without symptoms or signs of 
metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven > 0.2 mm 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
 
Post-treatment yp M classification.  The M category for patients treated with neoadjuvant therapy is the category assigned in the 
clinical stage, prior to initiation of neoadjuvant therapy.  Identification of distant metastases after the start of therapy in cases where 
pre-therapy evaluation showed no metastases is considered progression of disease.  If a patient was designated to have detectable 
distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Anatomic Stage/Prognostic Groupsa  
Stage 
T 
N 
Mc 
0 
Tis 
N0 
M0 
IA 
T1c 
N0 
M0 
IB 
T0 
N1mi 
M0 
 
T1c 
N1mi 
M0 
IIA 
T0 
N1b 
M0 
 
T1c 
N1b 
M0 
 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
 
T1c 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Stage 
T 
N 
Mc 
 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
Note: Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are 
carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.  
Post-neoadjuvant therapy is designated with "yc" or "yp" prefix.  Of note, no stage group is assigned if there is a complete pathologic response (CR) 
to neoadjuvant therapy, for example, ypT0cM0.   
a T1 includes T1mi.   
b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.   
c M0 includes M0(i+); The designation pM0 is not valid; any M0 should be clinical.  If a patient presents with M1 prior to NAST, the stage is 
considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.   
 


 
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Appendix 7  
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume 
All DLCO measurements will be obtained as per the American Thoracic Society and 
European Respiratory Society (ATS/ERS) guidelines (MacIntyre et al. 2005).  
The predicted DLCO value should be corrected for both hemoglobin (Hb) and alveolar 
volume (va).   
Pulmonary function test laboratories that follow the ATS/ERS guidelines should be able 
to provide the value for DLCO, corrected for va.  A single breath va may be used to obtain 
DLCO, corrected for va.  Use the following equation to determine the predicted DLCO, 
corrected for Hb and va: 
Predicted DLCO, corrected for Hb and va = [DLCO, corrected for va] × [1.7 × Hb / 
(9.38 + Hb)] 
Use the formula below to determine the percentage of predicted DLCO value (now 
corrected both for Hb and va):  
% of predicted DLCO (corrected for Hb and va) = [actual DLCO / (predicted DLCO 
corrected for Hb and va)] × 100  
 
 
 
 




GDC-0032—Genentech, Inc. 
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PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol GO28888 has been amended to include the following major changes: 
• 
GDC-0032 two-mg tablet formulation information has been added.  
• 
Information regarding the relative bioavailability of GDC-0032 capsules and tablets 
has been included.  In summary, the GDC-0032 tablet had a 1.5-fold higher drug 
exposure (area under the curve; AUC) in healthy volunteers as compared to the 
GDC-0032 capsule.  In this trial, 2-mg tablets instead of the 3-mg tablets originally 
proposed, will be provided and are expected to have very similar drug exposure as 
the 3-mg capsules used in previous clinical trials with GDC-0032.     
• 
The requirement for taking GDC-0032 on an empty stomach has been removed.  
The drug exposure (AUC) for GDC-0032 in a healthy volunteer study was not 
affected by the consumption of a high-fat meal.   
• 
Management guidelines for adverse events of special interest have been updated. 
More detailed information on the dosage of recommended corticosteroids for 
diarrhea and colitis has been included.  In addition, extra language regarding 
caution with using steroids has been added.   
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The list of abbreviations has been updated to reflect changes to the protocol. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  BACKGROUND ON THE PHOSPHATIDYLINOSITOL-3-
KINASE PATHWAY 
In addition, the PI3K-AKT pathway is activated in numerous types of cancer by receptor 
tyrosine kinase signaling…and Inositol Polyphosphate 4-phosphatase type II (INPP4B), 
or RAS mutations…. 
SECTION 1.4:  BACKGROUND ON REVERSING HORMONAL RESISTANCE 
BY INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, PI3K seems to play an important role in mediating 
hormonal resistance and may be is a viable therapeutic target. 
SECTION 1.5:  BACKGROUND ON NEOADJUVANT THERAPY IN BREAST 
CANCER 
A meta-analysis of nine randomized studies… showed no difference in … distant 
disease recurrence based upon the timing of the systemic therapy (Mauri et al. 2005). 
…meta-analysis was recently conducted evaluating over 12,000 patients treated with 
neoadjuvant chemotherapy as part of clinical trials (Cortazar et al. 20142). 
SECTION 1.6:  BACKGROUND ON GDC-0032 
Enhanced efficacy was demonstrated in combination with tamoxifen, another endocrine 
therapy used in the treatment of hormone receptor-positive advanced breast cancer.   
SECTION 1.7.1:  Clinical Safety Data with GDC-0032 
As of 5 July 2013, a total of 144 patients have been treated with GDC-0032 capsules, in 
the Phase I/II PMT4979g study, either as single agent (n = 90, 63%) or in combination 
with endocrine therapy (n = 54, 37%). 
GDC 0032 is currently in Phase I (Study PMT4979g).  Study PMT4979g is an open label, 
dose escalation trial using a 3 + 3 design to assess the safety, tolerability, and 
pharmacokinetics of GDC 0032 administered orally daily for 28 days to patients with 
locally advanced or metastatic solid tumors and in combination with endocrine therapy in 
ER+ breast cancers.  As of 5 July 2013, enrollment into the dose-escalation stage of 
Study PMT4979g had been completed with 34 patients enrolled at GDC-0032 doses 
with a range of ranging from 3  to 16 mg daily…. As of the cutoff date, a total of 
53 patients have had been enrolled in the 9-mg daily dosing expansion cohorts. 


 
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As of 5 July 2013, adverse events of any grade that occurred in ≥ 10% of the 87 patients 
treated with daily single-agent GDC-0032 capsules and were investigator-assessed as 
related to GDC-0032 were as follows: …fatigue (34.5 35%), decreased appetite (31%), 
rash (25%), stomatitis (13%), vomiting (13%), and mucosal inflammation (11.5 12%).  
Study−drug related Grade 3 and 4 adverse events assessed by the investigator as 
GDC-0032 related included hyperglycemia (9.4 12%), colitis (7. 6%), rash (5%), 
diarrhea (3%), fatigue (3%), pneumonitis (3.8%), rash (including maculopapular rash 
with or without itching, redness, and peeling) 5.7%, asymptomatic, pruritus (2%), 
stomatitis (2%), increased alanine aminotransferase levels in the blood (1.9%), anemia 
(1.9%), increase in blood creatinine (1.9%), diarrhea%), exfoliative rash (1.9%), fatigue 
(1.9%), hypokalemia (1.9%), hypophosphatemia (1.9%), lung infection (1%), 
pneumonia (1.9%), erythematous rash (1%), generalized rash (1%), maculopapular 
rash (1%) and skin exfoliation (1%) and stomatitis acute renal failure (1.9%). 
 … Adverse events of any grade and assessed by the investigator as drug related that 
occurred in ≥ 10% of the 27 safety-evaluable patients assessed as related to GDC-0032 
were …rash (30%),… mucosal inflammation (18.5%), rash (18.5 19%)… and dry mouth 
(11%). dry skin (11%) and muscle spasms (11%). Study − drug related. Grade 3 and 4 
adverse events included assessed by the investigator as GDC-0032 related include 
diarrhea (11%), mucosal inflammation (7.4%), increased amylase in the blood (3.7 4%), 
hyperglycemia (4%), increased aspartate aminotransferase (AST) in the blood (4%), 
stomatitis (3.7%), increased blood alkaline phosphate in the blood (3.7 4%), fatigue (3.7 
4%), increased gamma-glutamyltransferase in the blood (3.7%), hyperglycemia (3.7 4%), 
hypokalemia (3.7 4%), increased lipase in the blood (3.7 4%), and papilloedema (3.7%) 
and stomatitis (3.7 4%). 
…Adverse events assessed by the investigator as GDC-0032 related and of any grade 
that occurred in ≥ 10% of the 27 patients and were assessed as related to GDC-0032 
were diarrhea (46 48%), hyperglycemia (32 33%), nausea (32 33%), decreased appetite 
(25 26%), fatigue (25 26%), rash (21 26%), stomatitis (21 22%), asthenia (18 19%), 
muscle spasms (14 15%), vomiting (14 15%), dysgeusia (11%), gastroesophageal reflux 
disease (11%) and mucosal inflammation (11%).  Study− drug related Grade 3 and 4 
adverse events assessed by the investigator as related to GDC-0032 included 
hyperglycemia (14 15%)... 
SECTION 1.7.1.1:  Preliminary Pharmacokinetics 
Preliminary data from a healthy volunteer study showed that the 3-mg GDC-0032 
tablet produces an estimated geometric mean ratio (90% CI) of 196% (177.1 − 217.0) for 
Cmax and 152.2% (141.9 − 163.2) for AUC time 0 to infinity (AUC0-inf) when compared 
with the 3-mg Phase I capsule.   For this reason, a new 2-mg tablet has been formulated 
to deliver GDC-0032 exposure similar to the 3-mg capsule formulation.   


 
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The drug exposure (AUC) for GDC-0032 in a healthy volunteer study was minimally 
affected by the consumption of a high-fat meal.  Therefore, GDC-0032 may be taken 
without regard to the timing of the administration of food. 
SECTION 1.8:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Nonclinical data support… endocrine therapy in patients with hormone receptor-positive, 
advanced breast cancer. 
As of 5 July 2013, efficacy data are available for 24 patients treated with GDC-0032 
capsules in combination with letrozole… 
SECTION 2.1:  EFFICACY OBJECTIVES 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR as measured by modified RECIST criteria (Appendix 3) using the 
following methods… 
• 
Compare the centrally assessed derived, preoperative endocrine prognostic index 
(PEPI) score upon treatment with letrozole plus GDC-0032 versus letrozole plus 
placebo. 
SECTION 3.1:  DESCRIPTION OF STUDY 
Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 6 4 mg (two 2-mg 
tablets) or placebo on a 5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see 
Figure 5). 
Blood sample for exploratory endpoint analysis will be collected on Day 1 prior to 
dosing, at screening, at Week 3 9, and prior to surgery. 
FIGURE 5:  Study Schema 
Figure 5 has been revised to reflect changes to the protocol.  
SECTION 3.1.1:  Surgery 
The patient should be evaluated at baseline and after Week 13 of treatment for planning 
the surgical procedure (BCS or mastectomy), and both physician recommendation and 
final patient decision the planned and actual surgical treatment and final patient 
decision should be documented in the electronic Case Report Form (eCRF). 
SECTION 3.1.2:  Independent Data Monitoring Committee 
The IDMC will convene for an interim review the unblinded safety analysis to evaluate 
safety and pharmacokinetics data after the first 20 patients have completed surgery and 
have had either 1) finished the 30-days  of follow-up visit after the surgery, or 2) been 
on study for 20 weeks after the randomization date (for those who do not receive the 
surgery), whichever occurs first.  The IDMC will create and review unblinded, 
pooled summaries of the safety and available PK summaries (all interim analyses)…. 


 
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The IDMC will share results from interim safety analyses with the study team.  The study 
team will share interim safety results with study investigators as needed for the conduct 
of the study and the safety of the patients.  Specific potential safety issues anticipated in 
this trial, as well as measures intended to avoid, minimize, and manage such toxicities, 
are outlined in the following sections. 
SECTION 3.3.1:  Rationale for Conducting the Study in the Neoadjuvant 
Setting 
Over the past 10 years, four major classes of breast cancer (Luminal A, Luminal B, 
HER2-enriched, and basal-like) and a Normal Breast like group have been identified and 
intensively studied… 
SECTION 3.3.2:  Rationale for Patient Population 
Important findings in trials with drugs targeting mTOR, like everolimus, produce confirm 
a previously identified pharmacodynamic paradox:  while inhibiting mTOR, they lead to 
an upregulation of the pAKT, resulting in feedback PI3K/AKT/mTOR pathway activation 
through an insulin-like growth factor-1 receptor (IGF-1R) mediated feedback loop 
(Tabernero et al. 2009). 
SECTION 3.3.4.3:  Rationale for Using the Preoperative Endocrine 
Prognostic Index Score 
In this trial, the PEPI score will be assessed derived centrally. 
SECTION 3.3.7:  Rationale for GDC-0032 Dosage 
All patients received GDC-0032 in capsules. Five dose-escalation cohorts (i.e., 3, 5, 8, 
12, and 16 mg daily) were tested (see Section 1.7.1). 
In Study PMT4979g, as of the 5 July 2013 data cutoff date, there were 87 safety 
evaluable patients treated with single agent GDC 0032 capsules (3 − 16 mg daily).  A 
total of 97% of patients experienced at least one adverse event per the National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4 (NCI CTCAE v4.0).  
The most frequently reported adverse events of any grade, occurring in ≥ 10% safety
evaluable patients regardless of causality, were diarrhea (55%), fatigue (49%), 
nausea (47%), decreased appetite (39%), hyperglycemia (38%), vomiting (28%), 
dizziness (22%), rash (22%), dyspnea (18%), hypokalemia (18%), pyrexia (17%), cough 
(16%), anemia (13%), dehydration (13%), headache (13%), stomatitis (13%), AST 
increased (12%), mucosal inflammation (12%) and pruritis (10%).   
As of 5 July 2013, 54 patients have been treated with GDC 0032 capsules in 
combination with endocrine therapy with either letrozole (Cohort E) or fulvestrant 
(Cohort F) at either 6 mg or 9 mg dose levels.  No DLTs were observed during dose 
escalation in either Cohorts E or F.  Expansion cohorts at the 6 mg dose level were 
enrolled to obtain more safety data on long term tolerability.  Fifty (93%) of the 54 safety
evaluable patients experienced at least one adverse event that was assessed as related 
to GDC 0032.  


 
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Of the 54 patients, 17 patients were treated with GDC 0032 capsules plus letrozole. 
Adverse events of any grade that occurred in ≥ 10% of patients that were assessed as 
related to GDC 0032 (6mg and 9mg) were diarrhea (67%), nausea (33%), fatigue (30%), 
rash (30%), hyperglycemia (26%), decreased appetite (26%), stomatitis (26%), 
dysgeusia (22%), mucosal inflammation (19%), asthenia (15%), vomiting (15%), pruritis 
(15%), muscle spasms (11%), dry skin (11%), and dry mouth (11%). 
SECTION 3.3.8:  Rationale for Biomarker Assessments 
Pharmacodynamic biomarkers will be assessed evaluated to assess the biologic activity 
of the addition of GDC-0032 to letrozole. 
SECTION 3.4.1.2:  Secondary Efficacy Outcome Measures 
• 
Compare the centrally assessed derived PEPI score upon treatment with letrozole 
plus GDC-0032 with letrozole plus placebo 
SECTION 4.1.2:  Exclusion Criteria 
• 
Clinically significant (i.e., active) cardiovascular disease, like uncontrolled 
hypertension… 
SECTION 4.3.1.1:  GDC-0032 and Placebo 
GDC-0032 is provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 3 2 mg strength.  The tablet formulation consists 
of GDC 0032 active, lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, and Opadry 2 white film coating.  All excipients used in the 
formulation are compendial (USP/NF/Ph. Eur/JP) grade with the exception of the film
coating.  The film coating consists of polyvinyl alcohol part hydrolyzed, titanium dioxide, 
polyethylene glycol 3350, and talc, and these ingredients are compendial. 
Placebo tablets will be identical in shape and color to the 3 2-mg tablets of GDC-0032 
and will be indistinguishable from the 3 2-mg tablets of GDC-0032.  The ingredients in 
the placebo tablets are identical to those in the 3 2-mg tablets of GDC-0032, except for 
the absence of GDC-0032 active. 
SECTION 4.3.2.1:  GDC-0032 and Placebo 
Patients will receive an oral, daily dose of 46 mg (two 2-mg tablets) GDC-0032 or 
placebo on a schedule of 5 days on/2 days off for a maximum of 16 weeks.  Patients will 
take GDC-0032 or placebo at the same time of day ± 2 hours… 
Unless otherwise instructed, GDC 0032 or placebo should be taken on an empty 
stomach (i.e., approximately 1 hour before or 2 hours after a meal). 
SECTION 4.3.2.2:  Letrozole 
Both GDC-0032 or placebo and letrozole should be taken together (in no particular 
order) at the same time each day ±  2 hours, unless otherwise instructed. 


 
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SECTION 4.5.2:  Medical History and Demographic Data 
Medical history includes clinically significant diseases…and all medications… used by 
the patient within 15 7 days prior to the screening visit. 
SECTION 4.5.3:  Physical Examination 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions Vital Signs eCRF. 
SECTION 4.5.4:  Vital Signs 
Oxygen saturation is obtained by pulse oximetry after the patient has been in a seated 
position for  ≥ 5 minutes.  Obtain vital signs predose. 
SECTION 4.5.11.14:  Osteoporosis Assessment and Monitoring 
Treatment with aromatase inhibitors results in bone loss due to estrogen deficiency 
(Gaillard and Stearns 2011). 
Clinical risk factors for fracture include… and conditions predisposing to secondary 
osteoporosis…. 
SECTION 5.1.1:  Management of Specific Adverse Events of GDC-0032 
TABLE 1:  Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events 
Table 1 has been revised to reflect changes to the protocol. 
SECTION 5.1.1.1:  Management of Hyperglycemia 
Hyperglycemia has been observed in patients who received GDC 0032 in the single
agent Phase I study.   
Patients with diabetes requiring daily anti hyperglycemic medication or who have a 
fasting blood glucose level > 125 mg/dL will be excluded from the study.  HbA1c and 
fasting glucose levels will be monitored at baseline, and additional monitoring of fasting 
glucose levels during the study will be implemented, as outlined in the schedule of 
assessments.  Patients should be instructed to report symptoms associated with 
hyperglycemia such as thirst, frequent urination, and blurred vision. 
TABLE 3:  Dose Modification and Management Guidelines for Pneumonitis 
Table 3 has been revised to reflect changes to the protocol. 
SECTION 5.1.1.2:  Management of Pneumonitis 
TABLE 4:  Dose Modification and Management Guidelines for Pneumonitis 
Table 4 has been revised to reflect changes to the protocol. 
SECTION 5.1.1.3:  Management of Rash 
TABLE 5:  GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Table 5 has been revised to reflect changes to the protocol. 


 
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SECTION 5.1.1.4.1  Management of Diarrhea and Colitis 
Because of the approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032 for Grade ≥ 2 diarrhea until it improves to Grade ≤ 1.    
Steroid-responsive diarrhea and colitis have been difficult to distinguish in patients 
treated with GDC-0032.  All cases of colitis have been reversible with corticosteroid 
treatment.  Prompt initiation of corticosteroids for persistent diarrhea despite 
antidiarrheal treatment can decrease the severity of the diarrhea and prevent the need 
for hospitalizations.  Patients who develop severe steroid-responsive diarrhea usually 
have been on GDC-0032 treatment for at least 2 months, with an average onset between 
4 − 6 months of treatment.  A stool culture is helpful in identifying concurrent 
infections, and patients have been successfully treated with concurrent steroids and 
appropriate antibiotics if needed.  
If a patient is being treated with corticosteroids, total parenteral nutrition is 
discouraged as this increases the risk for severe hyperglycemia.  Discontinuation of 
nonsteroidal inflammatory medications or other medications that exacerbate colitis are 
also recommended during colitis episodes.   
Perforated duodenal ulcer has been observed in 2 patients (one patient at 6 mg in 
combination with letrozole; another patient at 6mg in combination with fulvestrant).  
Appropriate caution should be taken with the administration of medications such as 
aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids, which can increase 
the risk of gastritis, peptic ulcers, or gastrointestinal perforation. 
Specific dose modification and management guidelines for diarrhea and colitis are 
provided in Table 5. 
TABLE 6:  GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis 
Table 6 has been revised to reflect changes to the protocol. 
SECTION 5.1.1.4.2:  Management of Colitis 
Data as of October 2013 show an incidence rate for colitis of 6.2% (10/160) (1 at 16 mg; 
8 at 9 mg; 1 at 6 mg + fulvestrant) with onset at approximately 100 days or longer after 
initiation of treatment with daily GDC 0032 dosing.  Some patients have developed 
Grade 2 or Grade 3 diarrhea, which is non responsive to anti diarrheal medication.  In 
some of these patients, a CT scan or colonoscopy has revealed colitis, which has 
resolved upon treatment with systemic corticosteroids. 
For persistent Grade 2 diarrhea that does not resolve or for Grade ≥ 3 diarrhea, further 
evaluation should include colitis in the differential diagnosis with the appropriate work up 
(e.g., abdominal/ pelvis CT scan, endoscopy with biopsy, stool cultures for 
cytomegalovirus, Clostridium difficile, and parasites).  Grade ≥ 2 colitis should be 
managed by interruption of study treatment.  In addition, discontinuation of nonsteroidal 


 
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anti inflammatory medications or any other medications known to exacerbate colitis 
symptoms should be considered.  If noninfectious colitis is suspected, treatment with 
corticosteroids per institutional standard of care should be considered.  It is suggested 
that prednisone (for oral administration) or solumedrol (for IV administration) are the 
corticosteroids of choice in the treatment of colitis.  For severe symptoms, prednisone 
60 mg or equivalent may be required to control initial symptoms, and the dose should be 
gradually tapered.  Lower doses of prednisone, oral budesonide, or mesalamine 
(or other 5 aminosalicyclic acid derivatives) may be considered for less severe cases of 
colitis. 
Specific dose modification and management guidelines for colitis are provided in Table 7. 
Table 7:  GDC 0032 Dose Modification and Management Guidelines 
for Colitis 
Table 7 has been deleted.  Subsequent tables have been renumbered accordingly. 
SECTION 5.1.1.4.3:  Management of Stomatitis and Oral Mucositis 
TABLE 8:  GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Table 8 has been revised to reflect changes to the protocol. 
SECTION 5.1.2:  Management of Abnormal Liver Function Tests 
Some patients have experienced elevations of liver function tests (e.g., AST or ALT). 
Patients will be monitored throughout the study treatment for changes in liver function 
tests.  Given the potential for hepatic toxicity, all patients must have adequate liver 
function as manifested by measurements of serum bilirubin, hepatic transaminases, and 
alkaline phosphatase for initial and continued dosing.  Separate criteria for eligibility, 
continued dosing, and DLT are given for patients with hepatic metastases and Grade 2 
hepatic transaminase and/or alkaline phosphatase levels at baseline to allow safety 
testing to be adequately assessed in this patient group.   
For new abnormal liver function tests (e.g., elevated AST or ALT), a standard clinical 
work-up to understand the etiology of the abnormality should take place per local 
guidelines.  In many cases, elevated liver function tests may be a result of liver 
metastases, concomitant medications, or biliary obstruction.  Dose modifications for 
elevated liver function tests are described in Table 7. 
SECTION 5.1.3:  Management of Asymptomatic Lipase and/or Amylase 
Elevations 
Some patients treated with GDC-0032 have experienced asymptomatic lipase and/or 
amylase elevations in blood tests without any clinical or radiographic symptoms of 
pancreatitis or another clear etiology for the abnormal laboratory values.  Upon 
discussion with the Medical Monitor and after a risk-benefit assessment, investigators 
can consider continuing GDC-0032 therapy in such patients at the same dose or one 


 
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dose level lower.  Investigators should have a low threshold for interrupting GDC-0032 
for any concerning clinical gastrointestinal toxicities. 
SECTION 5.3.5.5:  Reporting of Abnormal Liver Function Tests as Hy’s 
Law 
SECTION 5.3.5.7:  Preexisting Medical Conditions 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (30 days after the last dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non-serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of 
causality.  The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient exposed to study drug or the female partner of a male 
patient exposed to study drug. 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators”). 
The investigator should report these events directly to Genentech Safety Risk 
Management via telephone at 1 888 835 2555. 
SECTION 6.4.1:  Primary Efficacy Endpoint 
The co-primary efficacy endpoints are (1) tumor ORR, assessed by modified RECIST 
criteria by breast MRI (centrally assessed)… 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST 
criteria by breast MRI (centrally assessed) in PIK3CA WT patients. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status (centrally assessed): 
• 
ORR using modified RECIST criteria by the following methods:  clinical breast 
examination, mammography, and breast ultrasound… 
• 
PEPI score (centrally assessed derived)... 


 
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SECTION 6.10:  INTERIM ANALYSES 
The IDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day, follow-up visit after the surgery, or 2) been 
on study for 20 weeks after the randomization date (for those who do not receive the 
surgery), whichever occurs first.   
SECTION 8.2:  INFORMED CONSENT 
The ICF will contain a separate section that addresses the consent for optional donation 
of remaining samples for the clinical repository. use of remaining mandatory samples 
for optional exploratory research.  Samples stored in the clinical repository may be used 
for future exploratory research. 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 donate their remaining samples to the clinical repository.  If patients 
choose to donate remaining samples, they participate and may withdraw their specimens 
at any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient's agreement to allow any remaining specimens to 
be stored in the clinical repository. used for exploratory research. Patients who decline 
to participate will not provide a separate signature. 
SECTION 9.5:  ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech in 
collaboration with the Breast International Group (BIG), ABCSG, and the SOLTI Spanish 
Breast Cancer Research Group (SOLTI). 
SECTION 10:  REFERENCES 
The following references have been added:   
Cortazar P, Zhang L, Untch M et al.  Pathologic complete response and long-term 
clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;13: 
62422−8. 
Gaillard S and Stearns V. Aromatase inhibitor-associated bone and musculoskeletal 
effects: new evidence defining etiology and strategies for management. Breast Cancer 
Res 2011;13:205. 
APPENDIX 1:  Schedule of Assessments  
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 3:  Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early Breast Cancer 
Appendix 3 has been revised to reflect changes to the protocol. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 21 
PROTOCOL SYNOPSIS .................................................................................... 23 
1. 
BACKGROUND .......................................................................................... 37 
1.1 
Background on the Phosphatidylinositol-3-Kinase 
Pathway................................................................................. 37 
1.2 
Background on Estrogen Receptor-Positive, 
HER2-Negative Breast Cancer.............................................. 37 
1.3 
Background on the PI3K/AKT/MTOR Pathway 
and Breast Cancer................................................................. 38 
1.4 
Background on Reversing Hormonal Resistance 
by Inhibiting the PI3K/MTOR/AKT Pathway........................... 38 
1.5 
Background on Neoadjuvant Therapy in Breast 
Cancer................................................................................... 39 
1.6 
Background on GDC-0032 .................................................... 40 
1.6.1 
Toxicology ............................................................................. 42 
1.7 
Summary of Clinical Data for GDC-0032............................... 43 
1.7.1 
Clinical Safety Data with GDC-0032...................................... 43 
1.7.1.1 
Preliminary Pharmacokinetics ............................................... 44 
1.7.1.2 
Preliminary Pharmacodynamics ............................................ 45 
1.8 
Study Rationale and Benefit-Risk Assessment...................... 46 
2. 
OBJECTIVES.............................................................................................. 48 
2.1 
Efficacy Objectives ................................................................ 48 
2.2 
Safety Objectives................................................................... 48 
2.3 
Patient-Reported Outcome Objectives .................................. 49 
2.4 
Exploratory Objectives........................................................... 49 
3. 
STUDY DESIGN ......................................................................................... 49 
3.1 
Description of Study .............................................................. 49 
3.1.1 
Surgery.................................................................................. 53 
3.1.2 
Independent Data Monitoring Committee .............................. 54 
3.2 
End of Study.......................................................................... 54 
3.3 
Rationale for Study Design.................................................... 55 


 
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3.3.1 
Rationale for Conducting the Study in the 
Neoadjuvant Setting .............................................................. 55 
3.3.2 
Rationale for Patient Population ............................................ 55 
3.3.3 
Rationale for Control Group................................................... 56 
3.3.4 
Rationale for the Efficacy Outcome Measure of 
Response Rate Assessed by Magnetic 
Resonance Imaging............................................................... 57 
3.3.4.1 
Rationale for Efficacy Outcome Measure of 
Pathologic Complete Response ............................................ 58 
3.3.4.2 
Rationale for Ki67 Measurements ......................................... 58 
3.3.4.3 
Rationale for Using the Preoperative Endocrine 
Prognostic Index Score.......................................................... 59 
3.3.4.4 
Rationale for Assessing ORR by Clinical Breast 
Exam (Palpation), Mammography, and Breast 
Ultrasound ............................................................................. 60 
3.3.4.5 
Rationale for Assessing Enhancing Tumor 
Volume by Breast Magnetic Resonance Imaging.................. 60 
3.3.5 
Rationale for Independent Review Facility............................. 60 
3.3.6 
Rationale for Interim Safety Review ...................................... 60 
3.3.7 
Rationale for GDC-0032 Dosage........................................... 60 
3.3.8 
Rationale for Biomarker Assessments................................... 61 
3.3.9 
Rationale for Day 15 Biopsy .................................................. 62 
3.3.10 
Rationale for Collection of Blood Sample for the 
Detection of Plasma Protein Biomarkers ............................... 63 
3.3.11 
Rationale for Collection of Blood Sample for DNA 
Sequencing to Identify Mutations in Plasma.......................... 63 
3.3.12 
Rationale for Collection of Blood Sample for Next 
Generation Sequencing......................................................... 63 
3.3.13 
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 63 
3.3.14 
Rationale for the Collection of DNA for 
Exploratory Pharmacogenetic Polymorphisms ...................... 63 
3.3.15 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 64 
3.4 
Outcome Measures ............................................................... 65 
3.4.1 
Efficacy Outcome Measures.................................................. 65 
3.4.1.1 
Co-Primary Efficacy Outcome Measures............................... 65 


 
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3.4.1.2 
Secondary Efficacy Outcome Measures................................ 65 
3.4.2 
Safety Outcome Measures .................................................... 66 
3.4.3 
Patient-Reported Outcome Measures ................................... 66 
3.4.4 
Exploratory Outcome Measures ............................................ 67 
4. 
MATERIALS AND METHODS .................................................................... 67 
4.1 
Patients.................................................................................. 67 
4.1.1 
Inclusion Criteria.................................................................... 68 
4.1.2 
Exclusion Criteria................................................................... 69 
4.2 
Method of Treatment Assignment and Blinding..................... 70 
4.2.1 
Patient Randomization........................................................... 70 
4.2.2 
Stratification........................................................................... 71 
4.2.3 
Blinding.................................................................................. 71 
4.3 
Study Treatment.................................................................... 71 
4.3.1 
Formulation, Packaging, and Handling.................................. 71 
4.3.1.1 
GDC-0032 and Placebo......................................................... 71 
4.3.1.2 
Letrozole................................................................................ 72 
4.3.2 
Dosage, Administration, and Compliance.............................. 72 
4.3.2.1 
GDC-0032 and Placebo......................................................... 72 
4.3.2.2 
Letrozole................................................................................ 72 
4.3.3 
Investigational Medicinal Product Accountability ................... 73 
4.3.4 
Post-Trial Access to GDC-0032............................................. 73 
4.4 
Concomitant Therapy ............................................................ 74 
4.4.1 
Permitted Therapy ................................................................. 74 
4.4.2 
Prohibited Therapy ................................................................ 75 
4.5 
Study Assessments ............................................................... 75 
4.5.1 
Informed Consent Forms and Screening Log........................ 75 
4.5.2 
Medical History and Demographic Data ................................ 76 
4.5.3 
Physical Examination ............................................................ 76 
4.5.4 
Vital Signs.............................................................................. 76 
4.5.5 
Electrocardiograms................................................................ 76 
4.5.6 
Distant Sites Tumor Assessment........................................... 76 
4.5.7 
Tumor and Response Evaluations......................................... 77 
4.5.8 
Surgical Treatment Plan ........................................................ 78 


 
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4.5.9 
Surgical Specimen – Pathology............................................. 78 
4.5.10 
Laboratory Assessments ....................................................... 78 
4.5.11 
Assay Methods...................................................................... 80 
4.5.11.1 
Mutational Analysis for PIK3CA............................................. 80 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor 
Tissues .................................................................................. 80 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog 
Expression............................................................................. 80 
4.5.11.4 
Confirmation of Estrogen Receptor, 
Progesterone Receptor, and HER2 Status............................ 81 
4.5.11.5 
Circulating Tumor DNA Analysis ........................................... 81 
4.5.11.6 
Messenger RNA Expression Profiling.................................... 81 
4.5.11.7 
Next Generation Sequencing................................................. 81 
4.5.11.8 
Copy Number Analysis .......................................................... 81 
4.5.11.9 
Plasma Biomarker Analyses.................................................. 81 
4.5.11.10 
Plasma Pharmacokinetic Samples ........................................ 81 
4.5.11.11 
Pharmacogenetic Polymorphism Assay ................................ 82 
4.5.11.12 
Electrocardiograms................................................................ 82 
4.5.11.13 
DLCO Testing........................................................................ 82 
4.5.11.14 
Osteoporosis Assessment and Monitoring ............................ 82 
4.5.12 
Patient-Reported Outcomes .................................................. 83 
4.5.13 
Samples for Clinical Repository............................................. 84 
4.5.13.1 
Confidentiality........................................................................ 84 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 85 
4.6.1 
Patient Discontinuation.......................................................... 85 
4.6.2 
Study Treatment Discontinuation........................................... 85 
4.6.3 
Conditions for Terminating the Study .................................... 85 
5. 
ASSESSMENT OF SAFETY....................................................................... 85 
5.1 
Safety Plan ............................................................................ 85 
5.1.1 
Management of Specific Adverse Events of 
GDC-0032 ............................................................................. 86 
5.1.1.1 
Management of Hyperglycemia............................................. 87 
5.1.1.2 
Management of Pneumonitis................................................. 88 


 
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5.1.1.3 
Management of Rash ............................................................ 89 
5.1.1.4 
Management of Gastrointestinal Toxicity............................... 90 
5.1.1.4.1 
Management of Diarrhea and Colitis ..................................... 90 
5.1.1.4.2 
Management of Stomatitis and Oral Mucositis ...................... 92 
5.1.2 
Management of Abnormal Liver Function Tests .................... 93 
5.1.3 
Management of Asymptomatic Lipase and/or 
Amylase Elevations ............................................................... 93 
5.1.4 
Management of Other Clinically Significant 
Adverse Events ..................................................................... 94 
5.1.5 
General Guidance for Dose Modifications and 
Delays for Letrozole............................................................... 94 
5.1.6 
Management of Increases in QT Interval............................... 94 
5.1.7 
Safety Monitoring for Letrozole.............................................. 95 
5.2 
Safety Parameters and Definitions ........................................ 95 
5.2.1 
Adverse Events ..................................................................... 96 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to ABCSG)............................................................................. 96 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to ABCSG)..................................... 97 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 97 
5.3.1 
Adverse Event Reporting Period ........................................... 97 
5.3.2 
Eliciting Adverse Event Information ....................................... 98 
5.3.3 
Assessment of Severity of Adverse Events ........................... 98 
5.3.4 
Assessment of Causality of Adverse Events ......................... 99 
5.3.5 
Procedures for Recording Adverse Events............................ 99 
5.3.5.1 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 100 
5.3.5.2 
Persistent or Recurrent Adverse Events.............................. 100 
5.3.5.3 
Abnormal Laboratory Values ............................................... 101 
5.3.5.4 
Abnormal Vital Sign Values ................................................. 101 
5.3.5.5 
Reporting of Abnormal Liver Function Tests as 
Hy’s Law.............................................................................. 102 
5.3.5.6 
Deaths ................................................................................. 102 
5.3.5.7 
Preexisting Medical Conditions............................................ 103 


 
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5.3.5.8 
Hospitalization or Prolonged Hospitalization........................ 103 
5.3.5.9 
Adverse Events Associated with an Overdose .................... 103 
5.3.5.10 
Patient-Reported Outcome Data ......................................... 104 
5.4 
Immediate Reporting Requirements from 
Investigator to ABCSG......................................................... 104 
5.4.1 
Emergency Medical Contacts.............................................. 104 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 105 
5.5 
Follow-Up of Patients after Adverse Events ........................ 105 
5.5.1 
Investigator Follow-Up......................................................... 105 
5.5.2 
Sponsor Follow-Up .............................................................. 105 
5.6 
Post-Study Adverse Events................................................. 106 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 106 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 107 
6.1 
Determination of Sample Size ............................................. 107 
6.2 
Summaries of Conduct of Study.......................................... 108 
6.3 
Summaries of Treatment Group Comparability ................... 108 
6.4 
Efficacy Analyses ................................................................ 108 
6.4.1 
Primary Efficacy Endpoint.................................................... 108 
6.4.2 
Secondary Efficacy Endpoints............................................. 108 
6.5 
Safety Analyses................................................................... 109 
6.6 
Pharmacodynamic Analyses ............................................... 110 
6.7 
Pharmacokinetic Analyses................................................... 110 
6.8 
Patient-Reported Outcome Analyses .................................. 110 
6.9 
Exploratory Analyses........................................................... 111 
6.10 
Interim Analyses.................................................................. 111 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 111 
7.1 
Data Quality Assurance....................................................... 111 
7.2 
Data(Base) Management..................................................... 111 
7.3 
Electronic Case Report Forms............................................. 112 
7.4 
Source Data Documentation................................................ 113 


 
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7.5 
Use of Computerized Systems ............................................ 113 
7.6 
Retention of Records........................................................... 113 
8. 
ETHICAL CONSIDERATIONS.................................................................. 114 
8.1 
Compliance with Laws and Regulations .............................. 114 
8.2 
Informed Consent ................................................................ 114 
8.3 
Institutional Review Board or Ethics Committee.................. 115 
8.4 
Data Privacy ........................................................................ 116 
8.5 
Financial Disclosure ............................................................ 116 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 117 
9.1 
Study Documentation .......................................................... 117 
9.2 
On Site Quality Control (Monitoring).................................... 117 
9.3 
Protocol Deviations.............................................................. 117 
9.4 
Site Inspections ................................................................... 117 
9.5 
Administrative Structure....................................................... 117 
9.6 
Protocol Amendments ......................................................... 118 
10. REFERENCES ......................................................................................... 119 
 
 
LIST OF TABLES 
Table 1 
Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events........................................................................... 87 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose)..................... 87 
Table 3 
Dose Modification and Management Guidelines for 
Pneumonitis ................................................................................ 88 
Table 4 
GDC-0032 Dose Modification and Management Guidelines 
for Rash ...................................................................................... 90 
Table 5 
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis ............................................................... 91 
Table 6 
GDC-0032 Dose Delay and Modification Guidelines for 
Stomatitis and Oral Mucositis...................................................... 93 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events .......................................... 94 
Table 8 
Adverse Event Severity Grading Scale ....................................... 98 
Table 9 
Causal Attribution Guidance ....................................................... 99 
 


 
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LIST OF FIGURES 
Figure 1 
GDC-0032 Potency in Non-PIK3CA Mutant Breast Cancer 
Cell Lines .................................................................................... 41 
Figure 2 
Combination Effects between Letrozole and GDC-0032 in 
the Aromatase-Expressing MCF7.2x3 Breast Cancer Cell 
Line ............................................................................................. 41 
Figure 3 
Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse 
Xenografts................................................................................... 42 
Figure 4 
Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT 
and WT Tumors .......................................................................... 45 
Figure 5 
Study Schema............................................................................. 51 
Figure 6 
Schematic Representing Confirmation of Progression................ 53 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 125 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 129 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 130 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 
Measures .................................................................................. 136 
Appendix 5 
New York Heart Association Classifications.............................. 140 
Appendix 6 
American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ..................................................................... 141 
Appendix 7 
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume...................................................................................... 151 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY 
OF NEOADJUVANT LETROZOLE PLUS GDC-0032 
VERSUS LETROZOLE PLUS PLACEBO IN 
POSTMENOPAUSAL WOMEN WITH 
ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE 
BREAST CANCER 
PROTOCOL NUMBER: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
MEDICAL MONITOR: 
, M.D., Ph.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 return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 


 
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Principal Investigators: 
 
Author(s): 
Affiliation 
 
, USA 
 
, Belgium 
, SOLTI Breast Cancer Research Group, Diputació 
256 4º1ª 08007 Barcelona, Spain 
, Genentech, South San Francisco, CA, 
USA 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Austria 
, Genentech, South San Francisco, CA, USA 
, Genentech, South San Francisco, CA, USA 
 
 Spain 
 
 Spain 
, Genentech, South San Francisco, 
USA 
 
, 
Belgium 
 
 Belgium 
 
, Spain 
, SOLTI Breast Cancer Research Group, Diputació 
256 4º1ª 08007 Barcelona, Spain 
 
 
, Spain 
  
 
 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY OF 
NEOADJUVANT LETROZOLE PLUS GDC-0032 VERSUS 
LETROZOLE PLUS PLACEBO IN POSTMENOPAUSAL WOMEN 
WITH ER-POSITIVE/HER2- NEGATIVE, EARLY STAGE BREAST 
CANCER 
PROTOCOL NUMBER: 
GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
PHASE: 
II 
INDICATION: 
Early stage breast cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Efficacy Objectives 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus 
letrozole plus placebo in women with estrogen receptor-positive/human epidermal growth factor 
receptor 2-negative (ER+/HER2-) early stage breast cancer, as measured by the following co-
primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA mutant (MT) patients 
• 
Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local 
evaluation in all enrolled patients and PIK3CA MT patients 
The secondary efficacy objectives of this study are the following: 
• 
Tumor objective response rate (ORR), assessed by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA 
wildtype (WT) patients  
The following secondary objectives will be performed in all enrolled patients and separated by 
PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally assessed 
ORR as measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery.  


 
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• 
Compare the centrally derived, preoperative endocrine prognostic index (PEPI) score upon 
treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, 
ypNX (breast pCR). 
Safety Objective 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
Patient-Reported Outcome Objectives  
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL) between treatment arms as measured by the 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23) 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited to 
somatic cancer associated mutations, PTEN expression, pro-survival pathways (such as 
PI3K/AKT, MAPK etc.), apoptotic markers, and levels of RNA and DNA expression are 
predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream 
markers in tumor tissue and to examine the relationship to anti-tumor activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline biopsy 
and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole and 
GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or letrozole 
on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in letrozole 
plus GDC-0032 versus letrozole plus placebo. 
Study Design 
Description of Study 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the 
effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal 
women with ER+/HER2- untreated, Stage I-III operable breast cancer whose primary tumors 
are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  Standard of care 
assessments/procedures (e.g., bilateral mammogram) performed within 28 days of Day 1 
dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal cutting 
temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]). Two pretreatment 
FFPE core biopsies and one freshly frozen core biopsy must be obtained for all patients prior to 
beginning study drug treatment.  Prior diagnostic FFPE core biopsies may be used for 
enrollment eligibility purposes.  For the purpose of enrollment, ER, progesterone receptor (PR), 
and HER2 will be locally determined prior to beginning of study treatment. ER, PR, HER2, and 


 
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the percentage of Ki67-positive cells will also be centrally assessed, but the results do not have 
to be available prior to enrollment in the study.  Remaining tissue will be retained for future 
translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not allowed. 
Patients will be randomized into one of the two treatment arms with a 1:1 randomization ratio.  
Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 4 mg (two 2-mg tablets) 
placebo on a 5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see Figure 5).  A 
maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be continued up to 
surgery per the investigator’s discretion. 
After confirmation of all the eligibility criteria, patients will be randomized to one of the treatment 
arms.  A second biopsy will be performed on Day 15 (Week 3) for biomarker analyses. Biopsies 
should be performed at least 2 hours after GDC-0032 dose administration. 
Randomization will be stratified according to 2 factors: 
1. 
Tumor size (T1-T2 vs. T3) 
2. 
Nodal status (cytologically positive vs. radiologically or cytologically negative) 
The study will enroll approximately 330 patients at approximately 110 global sites. 
At Weeks 1, 5, 9, 13, and 16 the primary breast tumor and axillary lymph nodes will be 
assessed by clinical breast examination (palpation and caliper measurement).  Suspicion of 
progression based on clinical exam at any time should be further evaluated (Figure 6).  
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive disease 
and for the purpose of surgery planning. Suspicion of progressive disease on breast ultrasound 
should be confirmed by investigator-assessed breast MRI.  Patients with primary disease not 
evaluable by ultrasound at baseline should be assessed by MRI at Week 9.  Suspected 
progression in nodes should also be confirmed by fine needle aspiration (FNA) if these nodes 
had not been previously shown to be cytologically positive for cancer.  Patients with progressive 
disease (as defined by modified RECIST, Appendix 3), can either proceed directly to surgery or 
be taken off of the study, according to the investigator’s decision. If the patient goes off-study, 
every reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. Clinical 
breast exam, breast ultrasound, and mammography will also be conducted prior to surgery for 
the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected on Day 1 prior to dosing, at 
Week 9, and prior to surgery. 
Surgery 
Surgery will take place after at least 16 weeks of treatment, during Weeks 17 − 18.  Surgery 
should be performed within 4 days after the last dose of GDC-0032, if possible, to best observe 
pharmacodynamic knockdown with GDC-0032 in the surgical specimen.  Surgery may be 
delayed due to toxicity or other safety issues, upon discussion with the Medical Monitor (see 
Section 5.4.1) or recommendations from the Independent Data Monitoring Committee (IDMC; 
see below).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be 
continued up to surgery per the investigator’s discretion.   
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. Surgery specimens will be 
collected for histological examination to assess for pCR and for other endpoint analyses. 
Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the end of 
the study. Assessment of adverse events and general safety will be collected at this visit and 
the plan for future treatment will be recorded. 


 
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The patient should be evaluated at baseline and after Week 13 of treatment for planning the 
surgical procedure (BCS or mastectomy), and both the planned and actual surgical treatment 
should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pathological complete response (pCR–ypT0/is, ypN0) will be 
established via a local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and directions 
for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  IRF 
procedures are detailed in the IRF charter. 
Number of Patients 
The study will enroll approximately 330 patients at approximately 110 global sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age ≥ 18 years. Postmenopausal status is defined as follows: 
– 
Age ≥ 60 years or 
– 
Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) 
and plasma estradiol levels within postmenopausal range by local laboratory 
assessment or 
– 
Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated as the “target” lesion for 
all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as determined by 
institutional practice (in patients where there may be a reasonable suspicion of 
advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and 
symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable 
for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5  ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be 
enrolled 


 
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• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase 
≤ 1.5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the 
basis of the Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × ULN and activated partial thromboplastin time 
(aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is 
required.  If anticoagulation is required for a prosthetic heart valve, then INR should be 
between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply with the 
protocol, in the investigator’s judgment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as optimal 
neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric absorption 
• 
History of prior or currently active small or large intestine inflammation (such as Crohn’s 
disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
> 470 msec 
• 
DLCO < 60% of the predicted values (see Appendix 7 for calculations) 
• 
Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II-IV (New York Heart 
Association, Appendix 5), or any other that in the judgment of the investigator could 
jeopardize patient safety or study outcomes 
• 
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 


 
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– 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, that may affect 
the interpretation of the results, or renders the patients at high risk from treatment 
complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer 
Concomitant 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 7 days prior to 
screening to the study completion/discontinuation visit.   
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak time 
dependent inhibitor of CYP3A4.  Although in vitro induction studies in human hepatocytes 
suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, preliminary data 
from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 daily for 2 weeks in 
patients had no apparent effect on the pharmacokinetics of midazolam (a sensitive CYP3A4 
substrate).  Therefore, GDC 0032 may be administered concomitantly with CYP3A4 substrates 
without the risk of a pharmacokinetic drug-drug interaction (DDI).  
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy (other than letrozole permitted in this protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is receiving 
these at the moment of registration, treatment should be discontinued prior to 
randomization.  
• 
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.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an alternate 
medication with no or minimal potential to inhibit CYP3A4.  If a strong CYP3A4 inhibitor is 
co-administered with GDC-0032, patients should be closely monitored for adverse reactions. 


 
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• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, rifampin, phenobarbital) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to induce CYP3A4.  If a strong CYP3A4 
inducer is co-administered with GDC-0032, patients should be closely monitored for 
adverse reactions. 
Length of Study 
The total duration of the study is expected to be approximately 24 months for enrollment, plus 
5.5 months after last patient in. 
End of Study 
The end of the study is defined as the date when the last patient has her postsurgery visit.  
Outcome Measures 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR via centrally assessed breast MRI (centrally assessed) via modified RECIST 
(Appendix 3) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the American Joint 
Committee on Cancer staging system (Appendix 6) by local evaluation in all enrolled 
patients and PIK3CA MT patients 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST (Appendix 3) 
in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients 
The following secondary outcome measures will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery 
• 
Compare the centrally derived PEPI score upon treatment with letrozole plus GDC-0032 
with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) yoT0/is, 
ypNX (breast pCR) 
Safety Outcome Measures 
The safety and tolerability of GDC-0032 will be assessed using the following primary safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during the 
adverse event reporting period (see Section 5.3.1) 


 
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Patient-Reported Outcome Measures  
The PRO outcome measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty swallowing, 
diarrhea, skin problems), and patient functioning as measured using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ–C30) and the modified breast cancer module QLQ–BR23 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are not 
limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
Circulating tumor DNA (ctDNA) 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 versus 
letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug safety 
response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing enzymes and 
transporters and other patient-specific covariates with PK of GDC-0032 or letrozole and/or 
drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a marker of 
tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, diffusion 
metrics], ultrasound, mammography) in measuring tumor response 
Investigational Medicinal Products 
Study treatment is neoadjuvant (pre-operative) therapy.   
Test Product 
The test product for this study is GDC-0032.  Patients will receive an oral, daily dose of 4 mg 
(two 2-mg tablets) GDC-0032 or placebo on a schedule of 5 days on/2 days off for a maximum 
of 16 weeks.  Patients will take GDC-0032 at the same time of day ± 2 hours, unless otherwise 
instructed.  Patients will be instructed as to the number of tablets to take.  
Information on the formulation, packaging, handling, and administration of GDC-0032 are 
provided in the GDC-0032 Investigator’s Brochure. 
Non-Investigational Medicinal Products 
Letrozole 
Letrozole is a marketed product that is approved in the European Union and the United States 
for the treatment of hormone receptor-positive breast cancer.  Based upon the different 
mechanisms of action of GDC-0032 and the well-established safety profile of letrozole, there 
are no expected overlapping, significant toxicities between letrozole and GDC-0032.   
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of surgery 
at the investigator’s discretion).   


 
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Statistical Methods 
Primary Analysis 
This study is designed for testing the effect of GDC-0032 on the two co-primary endpoints in all 
enrolled patients and in the PIK3CA MT patients and plans to enroll 330 patients in total. 
Assuming the PIK3CA mutation status will not be available (unknown) for approximately 10% of 
the patients and the prevalence of PIK3CA mutant is 40%, there will be approximately 
120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, there 
might be a possible imbalance between treatment arms within the PIK3CA MT cohort, which 
may reduce the statistical power in this cohort. To ensure the study provides sufficient statistical 
power even when the treatment assignment is imbalanced, the sample size was calculated 
based on a conservative scenario by assuming that the treatment assignment imbalance in 
PIK3CA MT is 40% vs. 60%. The sample size was calculated based on a chi²-test using 
continuity correction (Ury and Fleiss 1980). 
To control an overall two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 enrolled 
patients and 108 patients in the PIK3CA MT cohort will be evaluable for analyses. This sample 
size allows us to detect an absolute percentage increase of 24% in MRI ORR rate in the 
GDC-0032 plus letrozole arm (64%) versus the letrozole-only arm (40%; Smith et al. 2005; 
Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power and 16% two-sided significance 
level.  The minimal detectable difference for ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled patients and 
120 in the PIK3CA MT cohort), this sample size provides 80% power to detect an absolute 
percentage increase of 18% in pCR in the GDC-0032 plus letrozole arm (19%) versus the 
letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at the 
4% two-sided significance level.  The minimal detectable difference for pCR rate is 
approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more substantial 
treatment assignment imbalance in the PIK3CA MT cohort than assumed, or there is an 
increased number of unevaluable patients for the MRI ORR, the sample size may be increased 
to obtain the level of power at 80%, and the enrollment may be limited to patients with PIK3CA 
MT.   
Secondary Analysis 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by 
breast MRI (centrally assessed) in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT 
patients.  
These endpoint measures will be summarized by treatment arm and will be analyzed analogue 
to the primary efficacy endpoint. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status (centrally assessed): 
• 
ORR using modified RECIST criteria by the following methods: by clinical breast 
examination, mammography and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery 
(centrally assessed) 
• 
PEPI score (centrally derived) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 


 
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These endpoint measures will be summarized by treatment arm and will be compared between 
the two treatment arms within each population based on appropriate statistical analyses: ORR 
will be compared using a Cochrane Mantel-Haenszel test, stratified by tumor size and nodal 
status; PEPI, Ki67, and tumor volume change will be compared by regression analyses, 
adjusted for tumor size and nodal status. All secondary endpoints will be tested at a two-sided 
type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
Determination of Sample Size   
 Please refer to the primary analysis in the Statistical Methods section. 
 Interim Analyses 
An Independent Data Monitoring Committee (IDMC) will monitor accumulating patient safety 
data at a minimum of once every 6 months until the last patient has completed study treatment.  
Additional details (e.g., IDMC members, communication, affiliations) will be provided in the 
IDMC charter.   
The IDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day follow-up visit after the surgery, or 2) been on 
study for 20 weeks after the randomization date (for those who do not receive the surgery).  The 
IDMC will create and review unblinded, pooled summaries of the safety and available PK 
summaries (all interim analyses).  While this review is being conducted, patient accrual into the 
study will continue.  The Medical Monitor may also request additional safety analysis and may 
call for additional meetings of the IDMC to review ongoing safety data.  
The IDMC will share results from interim safety analyses with the study team.  The study team 
will share interim safety results with study investigators as needed for the conduct of the study 
and the safety of the patients.  Specific potential safety issues anticipated in this trial, as well as 
measures intended to avoid, minimize, and manage such toxicities, are outlined in the following 
sections.  All available information of all enrolled patients with all available assessments at the 
respective timepoint will be included in the interim analyses. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABCSG 
Austrian Breast and Colorectal Cancer Study Group 
ADC 
apparent diffusion coefficient 
AE 
adverse events 
AI 
aromatase inhibitors 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ASCO-CAP 
American Society of Clinical Oncology-College of 
American Pathologists 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-24 
area under the concentration–time curve from 0 to 24 
hours 
AUC0-inf 
area under the concentration–time curve from 0 to 
infinity 
BCS 
breast conserving surgery 
BIG 
Breast International Group 
BUN 
blood urea nitrogen 
CD 
compact disc 
CI 
confidence interval 
Cmax 
maximum plasma concentration observed  
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
cPR 
confirmed partial responses 
CRA 
clinical research associate 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTNeoBC 
Collaborative Trials in Neoadjuvant Breast Cancer 
DCR 
data clarification request 
DDI 
drug-drug interaction 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DMP 
data management plan 
DXA 
dual-energy X-ray absorptiometry 
DVD 
digital video disk 
EC 
Ethics Committee 


 
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Abbreviation 
Definition 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER+ 
estrogen receptor-positive 
E.U. 
European Union 
FFPE 
formalin-fixed paraffin-embedded 
FDA 
Food and Drug Administration 
FNA 
fine needle aspiration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HLM 
human liver microsomes 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IGF-1R 
insulin-like growth factor-1 receptor 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
ISH 
in situ hybridization 


 
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Abbreviation 
Definition 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LDL 
low-density lipoprotein 
LPLV 
last patient, last visit 
MAPK 
mitogen-activated protein kinase 
MDD 
minimum detected difference 
MP 
monitoring plan 
MRI 
magnetic resonance imaging 
MT 
mutant 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSCLC 
non − small-cell lung cancer 
nu/nu 
immunocompromised nune (mice) 
OCT 
Optimal cutting temperature 
ORR 
objective response rate 
pAKT 
phosphorylated form of AKT 
pCR 
pathologic complete response 
PD 
progressive disease 
PEPI 
preoperative endocrine prognostic index 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PI3K 
phosphatidylinositol-3-kinase 
PIP2 
phosphatidylinositol-4,5-bisphosphate 
PIP3 
phosphatidylinositol 3,4,5 trisphosphate 
PO 
oral 
PR 
progesterone receptor 
PRO 
patient-reported outcome 
PTEN 
phosphatase tensin homolog 
QD 
once daily 
QLQ-BR23 
Quality of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 


 
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Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
relapse-free survival 
RPPA 
reverse phase protein array 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
source data verification 
SLNB 
sentinel lymph node biopsy 
SOLTI 
Spanish Breast Cancer Research Group 
SOP 
standard operating procedure 
SmPC 
summary of product characteristics 
t1/2 
terminal half-life 
TGI 
tumor growth inhibition 
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
WT 
wildtype 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON THE PHOSPHATIDYLINOSITOL-3-KINASE 
PATHWAY 
Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase involved in tumor cell proliferation, 
survival, and migration upon activation by growth factor receptors and integrins.  
PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) 
to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Cantley 2002), 
a second messenger involved in the phosphorylation of AKT and associated proteins in 
the AKT-mammalian target of rapamycin (mTOR) pathway (Guertin and Sabatini 2007).  
Activating and transforming mutations, as well as amplification, in the p110α subunit of 
PI3K are commonly found in solid and hematological tumors (Li et al. 1997).  In addition, 
the PI3K-AKT pathway is activated in numerous types of cancer by receptor tyrosine 
kinase signaling, the loss of the phosphatase tensin homolog (PTEN) and Inositol 
Polyphosphate 4-phosphatase type II (INPP4B), or RAS mutations 
(Shayesteh et al. 1999; Cantley 2002; Massion et al. 2004; Wu et al. 2005). 
1.2 
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE, 
HER2-NEGATIVE BREAST CANCER 
Breast cancer is the most frequently diagnosed cancer worldwide and the leading cause 
of cancer death among females, accounting for 23% of the total cancer cases and 14% 
of total cancer deaths (Jemal et al. 2011).  As a large proportion of breast cancer cases, 
especially in developed countries, are now diagnosed in early stages, they are amenable 
to cure with a stage-appropriate combination of surgery, systemic therapy 
(chemotherapy and/or hormonal therapy), and radiotherapy. 
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative 
(HER2-) breast cancer accounts for about 60% − 70% of all breast cancers.  However, 
not all ER+ breast cancers respond optimally to endocrine therapy (Davies et al. 2011).  
There are several mechanisms that can lead to primary and/or secondary hormonal 
resistance in ER+ breast cancer:  decrease of ER expression, loss of ER expression, or 
upregulation of growth factor signaling pathways, such as the epidermal growth factor 
receptor (EGFR)/HER2, the mitogen-activated protein kinase (MAPK), or the 
PI3K/AKT/mTOR pathways (Johnston 2009). 
In the setting of ER + /HER2-negative breast cancer, the PI3K/AKT/mTOR pathway plays 
an important role in mediating hormonal resistance and is a viable therapeutic target to 
explore (Miller et al. 2010). 


 
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1.3 
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Genes in the PI3K/AKT/mTOR signaling pathway are frequently mutated or amplified in 
breast cancer, especially in the ER+ subtype (Cancer Genome Atlas Network 2012).  
Molecular alterations of the PI3K/AKT/mTOR pathway include the following: 
(1) Mutations or amplifications in PIK3CA, the gene encoding the alpha catalytic subunit 
of PI3K (p110α) (Saal et al. 2005; Wu et al. 2005); (2) Alterations in the tumor 
suppressor gene PTEN, either by loss of protein expression (PTEN null), inactivation 
mutations and/or epigenetic deregulation through promoter hypermethylation (García et 
al. 2004); (3) PDKP1 amplification and/or overexpression (Brugge et al. 2007); (4) AKT1 
somatic gain of function mutations (Stemke-Hale et al. 2008) and AKT2 amplifications 
(Bellacosa et al. 1995). Overall, it is estimated that up to 70% of breast cancers can 
have some form of molecular aberration of the PI3K/AKT/mTOR pathway (CGAN 2012).   
1.4 
BACKGROUND ON REVERSING HORMONAL RESISTANCE BY 
INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, PI3K seems to play an important role in mediating 
hormonal resistance and is a viable therapeutic target. Hyperactivation of this signaling 
pathway was proved to promote both de novo and acquired resistance to hormone 
therapy in ER+ breast cancer cell lines and xenograft models (Sabnis et al. 2007), and 
simultaneous blocking of the PI3K/AKT/mTOR pathway with everolimus and the ER 
pathway with letrozole enhances antitumor activity of either agent alone (Boulay et al. 
2005). Importantly, a baseline protein signature of PI3K activation was found to be 
predictive of a poor prognosis after adjuvant endocrine therapy (Miller et al. 2010). 
In the clinical setting, impressive results of the combination of exemestane and 
everolimus, an mTOR inhibitor, were reported in the BOLERO-2 trial (Baselga et al. 
2009). This trial compared everolimus and exemestane with placebo and exemestane in 
724 postmenopausal patients with ER+ advanced breast cancer who had experienced 
recurrence or progression while receiving previous therapy with a nonsteroidal 
aromatase inhibitor in the adjuvant setting and/or in advanced disease. Median 
progression-free survival (PFS) in the everolimus group was 6.9 months, as compared to 
2.8 months in the placebo group.  Hazard ratio (HR) for progression or death was 0.43, 
with a 95% confidence interval (CI) of 0.35 − 0.54 (p < 0.001), as per the investigator’s 
assessment, and the magnitude of the effect was even greater as per central 
assessment (HR, 0.36, 95% CI, 0.27 − 0.47; p < 0.001).  In the open-label Phase II 
TAMRAD trial, patients with aromatase inhibitors (AI) resistant metastatic breast cancer 
received tamoxifen plus everolimus or tamoxifen alone (Bachelot et al. 2012). The 
6-month clinical benefit rate was 61% (95% CI, 47% − 74%) with tamoxifen plus 
everolimus and 42% (95% CI, 29% − 56%) with tamoxifen alone. Time to progression 
increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus 
everolimus, corresponding to a 46% reduction in risk of progression with the combination 


 
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(HR, 0.54; 95% CI, 0.36 − 0.81).  Risk of death was reduced by 55% with tamoxifen plus 
everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 − 0.81). 
In the neoadjuvant setting, combination of letrozole and everolimus also resulted in 
improved responses over letrozole alone in patients with ER+ breast cancer 
(Baselga et al. 2009).  In this study, 270 postmenopausal patients with operable ER+ 
breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment 
with letrozole and either everolimus or placebo. The primary endpoint of the trial, clinical 
response by palpation, was higher in the everolimus arm than in the control arm (68.1% 
vs. 59.1%, p = 0.062), a statistically significant result (one-sided, α = 0.1 level). 
An important finding in trials with mTOR-targeting drugs like everolimus is that they 
produce a pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the phosphorylated form of AKT (pAKT), resulting in feedback 
PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009). This finding suggests that 
alternative pharmacologic strategies to effectively shut down the pathway upstream of 
AKT should be pursued.  One of these strategies is inhibiting the PI3K/AKT/mTOR 
pathway at the level of PI3K. 
1.5 
BACKGROUND ON NEOADJUVANT THERAPY IN 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 and Smith 2003; Scholl et al. 1994; Semiglazov et al. 2004; 
Fisher et al. 2012; Wolff and Davidson 2000).  The randomized studies evaluating 
neoadjuvant therapy as well as meta-analyses of these studies have shown that 
neoadjuvant therapy can improve breast conservation rates, decreasing the number of 
women obligated to undergo mastectomy (Mieog et al. 2007; Fisher et al. 2012).  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 distant disease recurrence based upon the timing of the systemic 
therapy (Mauri et al. 2005).  The concept of neoadjuvant therapy is now well established 
and a standard treatment option for patients with early breast cancer.  The Collaborative 
Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis was recently conducted 
evaluating over 12,000 patients treated with neoadjuvant chemotherapy as part of 
clinical trials (Cortazar et al. 2014).  The results of this meta-analysis confirmed an 
association of pathologic complete response [pCR] with favorable long-term outcomes in 
high-risk populations (i.e., HER2-positive, high-grade hormone receptor positive and 
triple negative subtypes), although the magnitude of pCR improvement predictive of the 
long-term survival benefits could not be determined.  In September 2013, the Food and 
Drug Administration (FDA) granted accelerated approval of Perjeta as part of a complete 
treatment regimen for patients with HER2-positive, locally advanced, inflammatory, or 
early stage breast cancer in the neoadjuvant setting. 


 
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1.6 
BACKGROUND ON GDC-0032 
GDC-0032 is a potent selective inhibitor of Class I PI3K alpha, delta, and gamma 
isoforms, with 30-fold less potent inhibition of the beta isoform that is being developed as 
a therapy for human cancers.  Nonclinical studies with GDC-0032 demonstrate that 
GDC-0032 inhibits proliferation of p110α-mutant breast cell lines, inhibits tumor growth 
in human breast xenograft models harboring PIK3CA mutations, and results in a 
substantial reduction of PI3K pathway markers, including pAkt, pPRAS40, and pS6.   
GDC-0032 has demonstrated activity in nonclinical models of PIK3CA-mutant breast 
tumors in vivo as a single agent and in combination with standard of care (e.g., paclitaxel 
or docetaxel) or endocrine therapies (e.g., letrozole or fulvestrant).  GDC-0032 has a 
favorable in vitro and nonclinical in vivo absorption, distribution, metabolism, and 
elimination profile that has characteristics consistent with a compound that can be 
delivered orally to achieve clinical exposure similar to the nonclinical efficacy findings 
described herein.  Additional studies, including 16-week toxicity studies in rats and dogs, 
phototoxicity studies, and an embryo-fetal development study, support the Phase II 
neoadjuvant trial with GDC-0032 in combination with endocrine therapy.   
In vitro, single-agent GDC-0032 potency is also observed in cell lines that do not harbor 
PIK3CA mutations (Figure 1).  In in vitro combination studies, the aromatase-expressing 
breast cancer cell line (MCF7X2.3.ARO) showed positive combination effects between 
GDC-0032 and endocrine therapies (see Figure 2).  In this cell line, GDC-0032 alone 
caused growth inhibition (50% effective concentration [EC50]  = 95 nM). Effects on growth 
were also observed with letrozole and fulvestrant.  Combined treatment of cells with 
GDC-0032 and letrozole caused dose-dependent inhibition of cell viability at lower 
concentrations of either GDC-0032 or letrozole resulting in enhanced activity for the 
combination. In addition, combination activity was demonstrated in the PIK3CA wild-type 
(WT) cell line ZR75-1 when GDC-0032 was added to either fulvestrant or tamoxifen 
endocrine therapies (combination with letrozole not available in this cell line).  However, 
in vivo data in a PIK3CA WT model are not available, because these cell lines do not 
grow as xenografts. 




 
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Figure 3 Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse Xenografts 
 
 
QD = once daily; PO = oral gavage. 
Vehicle was MCT (0.5% methycellulose/0.2% Tween-80). 
Tamoxifen pellets (5 mg/pellet, 60-day release) were implanted on Day 0 of dosing (8 days post 
tumor implantation).  Tumor volumes after QD oral administration of GDC-0032 for 21 days are 
depicted by dose group. 
 
Please refer to the GDC-0032 Investigator’s Brochure for additional nonclinical data for 
GDC-0032 supporting this clinical trial.    
 
1.6.1 
Toxicology 
Please refer to the GDC-0032 Investigator’s Brochure for details on the toxicology 
program to support this clinical trial.   
 


 
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1.7 
SUMMARY OF CLINICAL DATA FOR GDC-0032  
1.7.1 
Clinical Safety Data with GDC-0032 
As of 5 July 2013, a total of 144 patients have been treated with GDC-0032 capsules, in 
the Phase I/II PMT4979g study, either as single agent (n = 90, 63%) or in combination 
with endocrine therapy (n = 54, 37%). 
As of 5 July 2013, enrollment into the dose-escalation stage of Study PMT4979g had 
been completed with 34 patients enrolled at GDC-0032 doses ranging from 3  to 16 mg 
daily.  GDC-0032 was well tolerated in the first three cohorts (3, 5, and 8 mg), with no 
patients experiencing a dose-limiting toxicity (DLT).  At the 16-mg dose level, 2 of the 
11 safety-evaluable patients experienced a DLT (Grade 4 hyperglycemia and Grade 3 
fatigue).  At the 12-mg dose level, 1 of the 10 safety-evaluable patients experienced a 
DLT of Grade 3 acute renal failure.  Although the single-agent GDC-0032 maximum 
tolerated dose (MTD) was not exceeded at the 16-mg dose level, the recommended 
GDC-0032 dose and schedule for the single-agent expansion cohorts is 9 mg daily on 
the basis of long-term safety data through multiple treatment cycles.  As of the cutoff 
date, a total of 53 patients had been enrolled in the 9-mg daily dosing expansion cohorts. 
As of 5 July 2013, adverse events of any grade that occurred in ≥ 10% of the 87 patients 
treated with daily single-agent GDC-0032 capsules and were investigator-assessed as 
related to GDC-0032 were as follows:  diarrhea (47%), hyperglycemia (38%), nausea 
(36%), fatigue (35%), decreased appetite (31%), rash (25%), stomatitis (13%), vomiting 
(13%), and mucosal inflammation (12%). Grade 3 and 4 adverse events assessed by the 
investigator as GDC-0032 related included hyperglycemia (12%), colitis (6%), rash (5%), 
diarrhea (3%), fatigue (3%), pneumonitis (3%), pruritus (2%), stomatitis (2%), 
increased alanine aminotransferase levels (1%), anemia (1%), increase in blood 
creatinine (1%), exfoliative rash (1%), hypokalemia (1%), hypophosphatemia (1%), lung 
infection (1%), pneumonia (1%), erythematous rash (1%), generalized rash (1%), 
maculopapular rash (1%) and skin exfoliation (1%), and acute renal failure (1%).    
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (19 patients at 6 mg, and 8 patients at 
9 mg) daily in combination with letrozole (Cohort E).  No DLTs were observed at either 
dose level.  Adverse events of any grade and assessed by the investigator as drug 
related that occurred in ≥ 10% of the 27 safety-evaluable patients assessed as related to 
GDC-0032 were diarrhea (67%), fatigue (30%), nausea (30%), rash (30%), decreased 
appetite (26%), hyperglycemia (26%), stomatitis (26%), dysgeusia (22%), mucosal 
inflammation (19%), asthenia (15%), pruritis (15%), vomiting (15%), and dry mouth 
(11%). Grade 3 and 4 adverse events assessed by the investigator as GDC-0032 related 
include diarrhea (11%), mucosal inflammation (7%), increased amylase (4%), 
hyperglycemia (4%), increased aspartate aminotransferase (AST) (4%), stomatitis 
(3.7%), increased blood alkaline phosphate (4%), fatigue (4%), increased 


 
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gamma-glutamyltransferase in the blood (4%), hypokalemia (4%), increased lipase in 
the blood, (4%), and papilloedema (4%). 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (21 patients at 6 mg and 6 patients at 9 mg) 
in combination with fulvestrant (Cohort F).  No DLTs were observed at either dose level.  
One patient has been enrolled in the Phase II part of the study with 6 mg GDC-0032 in 
combination with fulvestrant.  Adverse events assessed by the investigator as GDC-0032 
related and of any grade that occurred in ≥ 10% of the 27 patients and were assessed as 
related to GDC-0032 were diarrhea (48%), hyperglycemia (33%), nausea (33%), 
decreased appetite (26%), fatigue (26%), rash (26%), stomatitis (22%), asthenia (19%), 
muscle spasms (15%), vomiting (15%), dysgeusia (11%), gastroesophageal reflux 
disease (11%) and mucosal inflammation (11%).  Grade 3 and 4 adverse events 
assessed by the investigator as related to GDC-0032 included hyperglycemia (15%), 
diarrhea (7%), dyspnea (4%), flank pain (4%), hyponatremia (4%), neutropenia (4%), 
rash (4%) and vomiting (4%). 
Please refer to the GDC-0032 Investigator’s Brochure for additional information. 
1.7.1.1 
Preliminary Pharmacokinetics 
Pharmacokinetic (PK) data are available from 34 patients treated with GDC-0032 at 3, 5, 
8, 12, and 16 mg in the ongoing Phase I/II clinical trial (Study PMT4979g).  The cohort 
mean apparent clearance and the terminal half-life (t1/2) following a single, oral dose of 
GDC-0032 had a range of 4.77−9.17 L/hour and 36.7−43.8 hours, respectively.  
Following daily oral dosing for 8 days, there was a 2- to 4-fold accumulation of 
GDC-0032.  The pharmacokinetics of GDC-0032 appears to be dose linear and 
time-independent.  Preliminary PK data from Cohort E suggest there is no drug-drug 
interaction (DDI) between letrozole plus GDC-0032.  Mean plasma exposure of letrozole 
when given in combination with GDC-0032 (maximum concentration observed 
[Cmax] = 0.407 μM and area under the concentration–time curve from 0 to 24 hours 
[AUC0-24 ] = 8.01 μM*hr) was comparable with the historical single-agent exposure 
(Cmax = 0.495 μM and AUC0-24  = 10.1 μM*hr) (Awada et al. 2008). Similarly, plasma 
concentrations of GDC-0032, when given in combination with letrozole, were within the 
range predicted by the population PK model. Therefore, letrozole plus GDC-0032 can be 
co-administered without the risk of a DDI.  
GDC-0032 was metabolized primarily by CYP3A4 in human liver microsomes (HLMs) 
and appeared to be a weak time-dependent inhibitor of CYP3A4.  Although in vitro 
induction studies in human hepatocytes suggested that GDC-0032 has low to moderate 
potential to induce CYP3A4, preliminary data from the Phase I/II study (PMT4979g) 
indicate that 9 mg of GDC-0032 daily for 2 weeks in patients had no apparent effect on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate).  Therefore, 
GDC-0032 may be administered concomitantly with CYP3A4 substrates without the risk 
of a PK DDI.  


 
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Preliminary data from a healthy volunteer study showed that the 3-mg GDC-0032 
tablet produces an estimated geometric mean ratio (90% CI) of 196% (177.1 − 217.0) for 
Cmax and 152.2% (141.9 − 163.2) for AUC time 0 to infinity (AUC0-inf) when compared 
with the 3-mg Phase I capsule.   For this reason, a new 2-mg tablet has been formulated 
to deliver GDC-0032 exposure similar to the 3-mg capsule formulation.   
The drug exposure (AUC) for GDC-0032 in a healthy volunteer study was minimally 
affected by the consumption of a high-fat meal.  Therefore, GDC-0032 may be taken 
without regard to the timing of the administration of food.     
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.7.1.2 
Preliminary Pharmacodynamics 
Paired tumor biopsies were obtained from both PIK3CA MT and PIK3CA WT non-small 
cell lung cancer (NSCLC) patients treated at either the 3-mg or 16-mg GDC-0032 dose 
level, respectively, at screening (pretreatment biopsy) and during Cycle 1 in 
Study PMT4979g (on-treatment biopsy).  Inhibition of PI3K pathway markers, including 
decreases of > 60% in pAKT and pS6 (compared with baseline), were demonstrated in 
these patients’ paired tumor biopsies (see Figure 4).  
Figure 4 Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT and WT 
Tumors 
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
(16mg): NSCLC adeno 
PIK3CA wt, EGFR (exon 19 del) 
 (3mg): NSCLC (squam) 
PIK3CA (H1047R) 
 
 
MT = mutant; NSCLC = non − small-cell lung cancer; WT = wild type. 
 
As of 5 July 2013, metabolic partial responses via FDG-PET ( ≥ 20% decrease in 
maximum standardized uptake value) were observed in 23 out of 38 patients assessed 
(61%) and included patients from the lowest dose tested (3 mg).  Thirteen of these 23 
were breast-cancer patients.  Of the 13 response-evaluable patients treated with 


 
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GDC-0032 plus letrozole, 10 patients (77%) had a partial metabolic response.  Of the 
15 response-evaluable patients treated with GDC-0032 plus fulvestrant, 11 (73%) had a 
partial metabolic response.  
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.8 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Cancer is one of the leading causes of death worldwide, with solid tumors accounting for 
the majority of these deaths.  An estimated 1.38 million women across the world were 
diagnosed with breast cancer in 2008, accounting for 23% of all cancers diagnosed in 
women.  Breast cancer is the most common cause of death from cancer in women 
worldwide, estimated to be responsible for almost 460,000 deaths in 2008 (Ferlay et al. 
2010). 
A neoadjuvant study in a similar patient population with the combination of letrozole and 
the mTOR inhibitor everolimus has already been completed (Baselga et al. 2009).  
Please refer to Sections 1.4, 1.5, and 3.3 for further rationale supporting the proposed 
trial design of combining GDC-0032 with letrozole in the neoadjuvant setting for this 
patient population.  In postmenopausal women with hormone receptor-positive 
metastatic breast cancer, it is hypothesized that the combination of decreasing estrogen 
levels with letrozole and inhibition of the PI3K pathway with GDC-0032 may have 
improved anti-tumor activity as compared to endocrine therapy alone.  This is supported 
by the nonclinical and clinical data outlined below. 
GDC-0032 is a potent, selective small molecule inhibitor of Class 1 PI3K that is being 
developed by Roche/Genentech as an anti-cancer therapeutic agent.  Activating and 
transforming mutations in the p110 alpha subunit of PI3K are commonly found in tumors.  
GDC-0032 has been shown to be a potent inhibitor of growth in various human cancer 
cell lines, and especially in nonclinical models of PIK3CA MT tumors.  In addition, 
combination activity was demonstrated in the PIK3CA WT cell line ZR75-1 when 
GDC-0032 was added to either fulvestrant or tamoxifen endocrine therapies 
(combination with letrozole not available in this cell line).   
GDC-0032 has also shown additive efficacy in combination with endocrine therapy in a 
hormone receptor-positive breast cancer xenograft model as outlined in Section 1.6. 
Nonclinical data support the investigation of GDC-0032 as a single-agent in solid tumors 
and in combination with endocrine therapy in patients with hormone receptor-positive 
breast cancer.  
Available clinical data with single-agent GDC-0032 suggest that GDC-0032 has 
dose-linear pharmacokinetics with a half-life of approximately 37− 44 hours.  
Pharmacodynamic markers of PI3K pathway inhibition upon treatment with GDC-0032 
have been observed.  These include decreases in phospho-S6 in platelet-rich plasma 
and decreases in F- flurodeoxyglucose-positron emission tomography uptake.  Available 


 
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clinical data also include multiple confirmed partial responses in patients treated with 
GDC-0032.  These include a patient with PIK3CA MT lung adenocarcinoma treated at 
the 3 mg daily dose and another patient with PIK3CA MT, hormone receptor-positive, 
HER2-positive metastatic breast cancer treated at the 5 mg daily dose.  In addition, a 
patient with PIK3CA WT lung cancer treated at the 3 mg daily dose has had prolonged 
stable disease and remained on study for over 11 months.  These data show that 
single-agent GDC-0032 doses below 6 mg have been shown to have anti-tumor activity.  
These aggregate data support the use of 6 mg in combination with letrozole.   
Letrozole is a marketed product that is approved in the European Union (E.U.) and the 
United States (U.S.) for the treatment of hormone receptor-positive breast cancer.  
Based upon the different mechanisms of action of GDC-0032 and the well-established 
safety profile of letrozole, there are no expected overlapping, significant toxicities 
between letrozole and GDC-0032.  
As of 5 July 2013, efficacy data are available for 24 patients treated with GDC-0032 
capsules in combination with letrozole; 3 patients (12.5%) had a partial response as best 
overall response, 2 of which were confirmed partial responses (cPRs) (1 cPR at 6 mg; 
1 cPR at 9 mg).  Of the 25 efficacy-evaluable patients treated with GDC-0032 in 
combination with fulvestrant, 7 patients (28%) had a partial response as best overall 
response, of which 3 were cPRs (1 cPR at 6 mg; 1 partial response at 9 mg).  cPRs 
have been observed in both PIK3CA mutant and PIK3CA WT breast cancer patients.  
Maintenance of cPR has been observed in a patient who had a dose reduction from 
6 mg to 3 mg for an adverse event.  In addition, no additional safety concerns have been 
observed with GDC-0032 in combination with letrozole in the ongoing Phase I study 
compared to GDC-0032 given as single agent. 
A number of clinically appropriate strategies to minimize risk to patients have been built 
into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, 
protocol design, and management guidelines.  These will also be clearly highlighted and 
discussed in detail at investigator meetings and site visits.  In addition, please refer to 
the GDC-0032 Investigator’s Brochure for details regarding potential risks, associated 
precautions, and other relevant nonclinical and clinical safety information. 
Due to the need to develop improved therapies to reverse or delay resistance to current 
endocrine therapy in HER2-negative, hormone receptor-positive breast cancer and on 
the basis of the clinical and nonclinical data available for GDC-0032, Genentech/Roche 
feels that the risk-benefit profile of GDC-0032 in combination with letrozole in 
postmenopausal patients with HER2-negative, hormone receptor-positive early stage 
breast cancer is favorable for proceeding with the proposed randomized Phase II clinical 
trial. 


 
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2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 
versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as 
measured by the following co-primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled 
patients and PIK3CA MT patients  
The secondary efficacy objectives of this study are the following: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified Response 
Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in 
PIK3CA WT patients  
 
The following secondary objectives will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR as measured by modified RECIST criteria (Appendix 3) using the 
following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally derived, preoperative endocrine prognostic index (PEPI) 
score upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
 


 
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2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, 
and health-related quality of life (HRQoL) between treatment arms as measured by 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module 
(QLQ-BR23) 
2.4 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by 
diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited 
to somatic cancer associated mutations, PTEN expression, pro-survival pathways 
(such as PI3K/AKT, MAPK etc.), apoptotic markers, hormone receptor expression 
levels, and levels of RNA and DNA expression are predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to anti-tumor 
activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline 
biopsy and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, 
enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor 
response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole 
and GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or 
letrozole on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in 
letrozole plus GDC-0032 versus letrozole plus placebo. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate 
the effect of combining letrozole and GDC-0032 versus letrozole and placebo in 
postmenopausal women with ER+/HER2- untreated, Stage I-III operable breast cancer 
whose primary tumors are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  


 
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Standard of care assessments/procedures (e.g., bilateral mammogram) performed 
within 28 days of Day 1 dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal 
cutting temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]).  Two 
pretreatment FFPE core biopsies and one freshly frozen core biopsy must be obtained 
for all patients prior to beginning study drug treatment.  Tumor tissue from prior 
diagnostic FFPE core biopsies may be used for enrollment eligibility purposes. For the 
purpose of enrollment, ER, progesterone receptor (PR), and HER2 will be locally 
determined prior to beginning of study treatment. Remaining tissue will be retained for 
future translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not 
allowed.   
Patients will be randomized into one of the two treatment arms with a 1:1 randomization 
ratio.  Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 4 mg (two 
2-mg tablets) or placebo on a 5 − days-on/ 2 − days-off schedule for a total of 16 weeks 
(see Figure 5).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole 
can be continued up to surgery per the investigator’s discretion. 




 
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At Week 9, a breast ultrasound will be performed to ensure that there is no progressive 
disease and for the purpose of surgery planning. Suspicion of progressive disease on 
breast ultrasound should be confirmed by investigator-assessed breast MRI.  Patients 
with primary disease not evaluable by ultrasound at baseline should be assessed by 
MRI at Week 9.  Suspected progression in nodes should also be confirmed by fine 
needle aspiration (FNA) if these nodes had not been previously shown to be 
cytologically positive for cancer.  Patients with progressive disease (as defined by 
modified RECIST, Appendix 3), can either proceed directly to surgery or be taken off of 
the study, according to the investigator’s decision. If the patient goes off-study, every 
reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. 
Clinical breast exam, breast ultrasound, and mammography will also be conducted prior 
to surgery for the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected on Day 1 prior to 
dosing, at Week 9, and prior to surgery. 




 
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Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the 
end of the study. Assessment of adverse events and general safety will be collected at 
this visit and the plan for future treatment will be recorded. 
The patient should be evaluated at baseline and after Week 13 of treatment for planning 
the surgical procedure (BCS or mastectomy), and both the planned and actual surgical 
treatment should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pCR (pCR–ypT0/is, ypN0) will be established via a 
local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and 
directions for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  
IRF procedures are detailed in the IRF charter. 
3.1.2 
Independent Data Monitoring Committee  
An IDMC will monitor accumulating patient safety data at a minimum of once every 
6 months until the last patient has completed study treatment.  Additional details 
(e.g., IDMC members, communication, affiliations) will be provided in the IDMC charter.   
The IDMC will review the unblinded safety data after the first 20 patients have either 1) 
finished the 30-day follow-up visit after the surgery, or 2) been on study for 20 weeks 
after the randomization date (for those who do not receive the surgery), whichever 
occurs first.  While this review is being conducted, patient accrual into the study will 
continue.  The Medical Monitor may also request additional safety analysis and may call 
for additional meetings of the IDMC to review ongoing safety data.   
3.2 
END OF STUDY  
The end of the study is defined as the date when the last patient has her postsurgery 
visit. The total duration of the study is expected to be approximately 24 months for 
enrollment, plus 5.5 months after last patient in.   


 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Conducting the Study in the Neoadjuvant Setting 
Breast cancer is a heterogeneous disease, and not every breast tumor responds equally 
to a specific agent.  Studies based on global gene expression analyses have provided 
additional insights into this complex scenario.  Over the past 10 years, four major 
classes of breast cancer (Luminal A, Luminal B, HER2-enriched, and basal-like) have 
been identified and intensively studied (Perou et al. 2000; Sørlie et al. 2001). Known as 
the intrinsic subtypes of breast cancer, these groups of tumors have revealed critical 
differences in incidence, survival, and response to treatment. As genomic studies evolve, 
further sub-classifications of breast tumors are expected to emerge. Thus, a major 
challenge in breast cancer management is how to prospectively select patients who will 
derive the maximum benefit from a given drug regimen, minimizing unnecessary 
toxicities for patients with non-responsive disease. 
Neoadjuvant therapy, a systemic therapy administered prior to breast cancer surgery, is 
now widely used in the 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, 
especially those with larger tumors. The tumor may shrink prior to surgery, thus 
increasing the rate of BCS (Coudert et al. 2006), and since the response to therapy can 
be monitored, the patient might be also spared further treatment with inactive 
medications.  
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 treatment response at a biological level. Finally, the surgical 
specimen, if pCR is not reached, can be utilized as well. 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 (von Minckwitz and Fontanella 
2013; Cortazar et al. 2012). 
3.3.2 
Rationale for Patient Population 
Postmenopausal patients with HER2-negative, ER+, early stage breast cancer will be 
enrolled in this study.  This patient population is usually treated with a combination of 
surgery, anti-hormonal therapy and/or chemotherapy, according to staging and biological 
features.  
Recently, everolimus was approved by the FDA and European Medicines Agency in 
combination with exemestane for the treatment of advanced or metastatic breast cancer 
in patients after recurrence or progression following treatment with nonsteroidal AIs.  In 


 
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the neoadjuvant setting, a combination of letrozole and everolimus resulted in improved 
responses over letrozole alone in patients with ER+ breast cancer (Baselga et al. 2009). 
Important findings in trials with drugs targeting mTOR, like everolimus, confirm a 
previously identified pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the pAKT, resulting in feedback PI3K/AKT/mTOR pathway activation 
through an insulin-like growth factor-1 receptor (IGF-1R) mediated feedback loop 
(Tabernero et al. 2009). This finding suggests that alternative pharmacologic strategies 
to shut down the pathway upstream of AKT should be pursued. One of these strategies 
is to inhibit the PI3K/AKT/mTOR pathway at the PI3K level. PI3K-inhibitors are central 
regulators of the mTOR signaling pathway, and nonclinical findings show that 
PI3K-inhibitors and dual PI3K-mTOR inhibitors induce a greater amount of apoptosis 
than everolimus in estrogen-deprived in vitro models (Sanchez et al. 2011); therefore, it 
is hypothesized that PI3K-inhibitors may be active and demonstrate greater anti-tumor 
activity as compared to AIs alone in the neoadjuvant setting. 
3.3.3 
Rationale for Control Group  
Aromatase inhibitors (AIs) have been found to be more effective than tamoxifen as a 
neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer. 
Several trials have assessed the efficacy and safety of neoadjuvant endocrine therapy 
using AIs in patients with postmenopausal breast cancer (Eiermann et al. 2001; Smith 
et al. 2005; Ellis et al. 2011). 
The P024 trial was a worldwide, prospective, randomized, multicenter trial that 
randomized 337 postmenopausal patients with ER +  breast cancer to receive either 
4 months of neoadjuvant letrozole or tamoxifen (Eiermann et al. 2001). The primary 
endpoint of P024 was the percentage of patients in each treatment arm with objective 
response as determined by clinical palpation. Secondary endpoints included ORR 
determined by mammogram and ultrasound, and included the percentage of patients in 
each arm who had become eligible for BCS. The trial demonstrated a significantly higher 
clinical response rate for letrozole when compared to tamoxifen (55% vs. 36%; p < 0.001) 
in the intent-to-treat (ITT) population. An improved ORR for letrozole was also observed 
with ultrasound (35% vs. 25%; p < 0.042) and mammogram (34% vs. 16%; p < 0.001). 
The higher response rate assessed by clinical palpation translated into a significantly 
higher rate of women undergoing BCS in tumors that had initially been considered 
unsuitable for this procedure (45% vs. 35%; p = 0.022). Median time-to-response was 
66 days in the letrozole group and 70 days in the tamoxifen group, and both treatments 
were well tolerated. 
The IMPACT trial was a randomized, Phase II, double-blind, double-dummy, multicenter 
trial that randomly assigned 330 postmenopausal women with ER+ operable or locally 
advanced, potentially operable breast cancer in a 1:1:1 ratio to receive a daily dose of 
anastrozole 1 mg and tamoxifen placebo, tamoxifen 20 mg and anastrozole placebo, or 


 
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a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks before surgery. 
The tumor ORR was assessed by both caliper and ultrasound. No significant differences 
in ORR in the ITT population between patients receiving tamoxifen, anastrozole, or the 
combination were seen. However, in a predefined analysis, there was a nonsignificant 
trend towards more patients requiring mastectomy at baseline actually receiving BCS 
with anastrozole than with tamoxifen (44% vs. 31%, respectively; p = 0.23); this 
difference became significant for patients deemed by their surgeon to be eligible for BCS 
after treatment (46% vs. 22%, respectively; p = 0.03). All treatments were well tolerated. 
The ACOSOG Z1031 trial compared three AIs in a randomized, Phase II, neoadjuvant 
trial designed to select agents for Phase III investigations. Three hundred seventy-seven 
postmenopausal women with clinical Stage II to III ER+ breast cancer were randomly 
assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary 
endpoint was clinical response. No formal comparison between arms was pre-specified 
in the statistical plan. ORR was 62.9%, 74.8%, and 69.1% for the exemestane, letrozole 
and anastrozole arms, respectively. On the basis of clinical response rates, letrozole and 
anastrozole were selected for further investigation; however, no other differences in 
surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for 
mastectomy-only patients at presentation was 51%. 
Results from these trials suggest that neoadjuvant endocrine therapy can be beneficial 
in postmenopausal patients with hormone-sensitive breast cancer, and that it offers an 
alternative to neoadjuvant chemotherapy. 
3.3.4 
Rationale for the Efficacy Outcome Measure of Response Rate 
Assessed by Magnetic Resonance Imaging  
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, non-registrational, neoadjuvant trials in combination with endocrine therapy 
(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 computed tomography (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 (Akazawa et al. 
2006; Balu-Maestro et al. 2002; Yeh et al. 2005), including the I-SPY trial (Hylton et al. 
2012).  For these reasons, ORR as assessed by breast MRI has been chosen as a 
co-primary endpoint for this trial.  


 
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3.3.4.1 
Rationale for Efficacy Outcome Measure of Pathologic 
Complete Response 
pCR is a recognized efficacy endpoint of neoadjuvant trials, especially those with 
neoadjuvant chemotherapy, as it has been correlated with long-term outcomes, such as 
event-free survival (von Minckwitz and Fontanella 2013).  
In trials of neoadjuvant hormonal therapy, pCR is an unlikely event.  For instance, in the 
neoadjuvant trial comparing everolimus plus letrozole to letrozole, pCR rates were 1.4% 
and 0.8%, respectively (Baselga et al. 2009). 
In the ongoing Phase I/II trial that combines letrozole with GDC-0032, tumor shrinkage 
has been observed, and some patients presented sustained partial responses. As pCR 
is a recognized indicator of activity to a given regimen, it would be useful to assess it as 
a co-primary efficacy endpoint of this trial. Furthermore, for the same trial size, this 
would represent a minimal increase in the minimum detected difference (MDD) of the 
co-primary endpoint for pCR ORR (from MDD of 12% to MDD of 13%). 
In September of 2013, the FDA granted accelerated approval of Perjeta as part of a 
complete treatment regimen for patients with HER2-positive, locally advanced, 
inflammatory or early stage breast cancer in the neoadjuvant setting.   
3.3.4.2 
Rationale for Ki67 Measurements 
Ki67 is a well-established proliferation biomarker with prognostic value in ER+ breast 
cancer (Dowsett et al. 2011). Efficacy of endocrine therapy relies on induction of 
cell-cycle arrest, and during neoadjuvant treatment, Ki67 levels reflect the ability of 
endocrine agents to suppress proliferation (Smith et al. 2005; Ellis et al. 2011).  In the 
neoadjuvant trial of letrozole with everolimus, by using the definition that patients with 
natural log (Ki67) < 1 at Day 15 have an antiproliferative response, 57% of 
everolimus-treated patients were responders vs. 30% in the placebo arm, with a 
significant p value of < 0.01 (Baselga et al. 2009). Furthermore, the mean reduction in 
the percentage of Ki67-positive tumor cells at Day 15 relative to baseline was greater in 
the everolimus-treated patients (90.7% ± 3.2%) than in the placebo group (74.8% ± 6.8%; 
p = 0.0002). In the IMPACT trial, Ki67 was assessed at baseline, on Day 15, and at 
surgery (Smith et al. 2005). For each treatment arm, the reduction in geometric mean 
Ki67 levels was significantly higher for anastrozole than for tamoxifen at both time points 
(p = 0.004, p = 0.001, respectively), but no differences were found between tamoxifen and 
the combination. In the ASCOSOG Z1031 trial (Ellis et al. 2011), although no data on 
Ki67 at Day 15 were available, no differences were found between treatments at 
baseline and at surgery (after 16 − 18 weeks of therapy). The geometric mean 
percentage change in Ki67 for each treatment was similar between the arms 
(anastrozole 78%, exemestane 81.2%, and letrozole 87.1%). 
The issue of whether Ki67 decrease at surgery or at any timepoint during treatment 
correlates with long-term efficacy outcomes has been addressed in the P024 trial 


 
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(Eiermann et al. 2001). Treatment with letrozole led to higher, treatment-induced 
reduction of Ki67 levels in the tumor at surgery (87% reduction in the letrozole arm vs. 
75% in the tamoxifen arm; analysis of covariance p = 0.0009) based on the 185 
specimens with available data on Ki67 (Ellis et al. 2003). With a median follow-up of 
61.2 months, low levels of Ki67 in the biopsy at the end of treatment were significantly 
associated with better relapse-free survival (RFS; HR 1.4 per natural log increase in the 
Ki67 value, 95% CI 1.2 − 1.6, p < 0.001), and breast cancer specific survival (HR 1.4, 
95% CI 1.1 − 1.7, p =  0.009).  Finally, in the IMPACT trial, higher Ki67 expression after 
2 weeks of endocrine therapy was statistically significantly associated with lower RFS 
(p = 0.004), whereas higher Ki67 expression at baseline was not (Smith et al. 2005). 
Importantly, the Ki67 suppression in these hormonal neoadjuvant trials mirrored efficacy 
outcomes in large adjuvant trials: adjuvant BIG1-98 trial (n = 8,010) showed the superior 
efficacy of letrozole over tamoxifen (Regan et al. 2011), similar to the neoadjuvant P024 
trial (n = 185); the adjuvant ATAC trial (n = 9,366) showed that anastrozole was better 
than tamoxifen and the combination of anastrozole plus tamoxifen (Cuzick et al. 2010), 
similar to neoadjuvant IMPACT (n = 259); and the adjuvant MA27 trial (n = 7,576) showed 
similar efficacy of anastrozole and exemestane (Goss et al. 2013), mirroring neoadjuvant 
ACOSOG Z1031 (n = 266). These results suggest that a biological superiority hypothesis 
generated by a neoadjuvant study may help the design of future adjuvant hormonal 
therapy trials. 
In summary, reduction in Ki67 after neoadjuvant treatment with AIs is a good marker of 
suppression of cellular proliferation, correlates with long term efficacy outcomes, and 
mirrors results of large adjuvant endocrine trials, which make it an attractive endpoint to 
assess in the present trial. 
3.3.4.3 
Rationale for Using the Preoperative Endocrine Prognostic 
Index Score 
In addition to Ki67, pathologic tumor size (T1 or T2 versus T3 or T4), node status 
(positive or negative), and the ER status (positive Allred score 3–8 versus negative 
Allred score 0–2) of the surgery specimen were also determined to have independent 
prognostic value for relapse and death after relapse in the P024 trial (Ellis et al. 2008).  
A PEPI score, prognostic for RFS, which weighs each of these factors according to their 
associated hazard ratios, was developed and subsequently validated in an independent 
data set from the IMPACT trial (Ellis et al. 2008). No relapses were recorded in either 
trial in patients with tumors classified as T1N0 and with a PEPI score of 0 (residual 
tumor with a Ki67 level  ≤ 2.7%, and with maintained ER expression) or in the rare patient 
with a pCR. 
In this trial, the PEPI score will be derived centrally.  


 
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3.3.4.4 
Rationale for Assessing ORR by Clinical Breast Exam 
(Palpation), Mammography, and Breast Ultrasound 
Objective overall response rate will also be assessed by clinical breast exam, 
mammography, and breast ultrasound during screening and prior to surgery. These data 
will allow for more direct comparison of results to other neoadjuvant trials with endocrine 
therapy as described in Section 3.3.3. The concurrent acquisition of ORR data with 
these techniques, in addition to MRI-based measures, will also provide valuable 
comparative information on these methods, which will be important for both future 
neoadjuvant studies and GDC-0032 clinical development.  
3.3.4.5 
Rationale for Assessing Enhancing Tumor Volume by Breast 
Magnetic Resonance Imaging  
As shown in the I-SPY trial, tumor volume measurements based on the percent of tumor 
with enhancing signal after contrast agent administration may be a more sensitive 
measure of response during neoadjuvant treatment than longest dimension measures 
(Hylton et al. 2012). However, there are no established response criteria for volumetric 
data, and the extrapolation of current one- and two-dimensional criteria to volumetric 
data based on a spherical model may not be appropriate given the range of tumor 
morphologies expected in this population of patients (Loo et al. 2011).  Additionally, 
there are only very limited data on the clinical relevance of any particular range in 
change in tumor volume during the course of neoadjuvant treatment. For these reasons, 
changes in enhancing tumor volume as measured by breast MRI will be a secondary 
endpoint in the trial.     
3.3.5 
Rationale for Independent Review Facility 
Due to the relatively novel nature of using MRI as an imaging endpoint, a central 
assessment by an IRF for the co-primary endpoint of response rate via MRI will be 
performed to ensure consistency across all sites participating in the study.  
3.3.6 
Rationale for Interim Safety Review 
The first 20 patients will be assessed for safety following surgery and 30 days beyond. 
This will allow the IDMC to review all safety data during the treatment period and to 
evaluate any surgery complications that may be attributed to GDC-0032. 
3.3.7 
Rationale for GDC-0032 Dosage 
As of 5 July 2013, 34 patients have been enrolled into the dose-escalation stage of 
Study PMT4979g, and 56 patients have been enrolled into the single-agent expansion 
cohorts at 9 mg in Stage 2 (Cohorts A-D and G).  All patients received GDC-0032 in 
capsules.  Five dose-escalation cohorts (i.e., 3, 5, 8, 12, and 16 mg daily) were tested 
(see Section 1.7.1).  The maximal administered dose was 16 mg.  To obtain more safety 
data on long-term tolerability, the recommended single-agent dose and schedule for the 
single-agent GDC-0032 expansion stage is 9 mg daily. 


 
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Of the 19 efficacy-evaluable patients treated with GDC-0032 in combination with 
letrozole, one patient at 6 mg had a cPR. The PIK3CA mutation status of this patient is 
unknown. Since efficacy has been observed at 6 mg, and the long-term safety suggests 
that 6 mg is better tolerated, the neoadjuvant study will utilize 6 mg GDC-0032 in 
combination with letrozole.  
Of the 27 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 2 confirmed partial responses were observed at 6 mg and 1 confirmed partial 
response at 9 mg. 
Colitis has been observed with an incidence rate of 6.2% (10/160 patients).  The time 
(from the first dose of study treatment) to onset of colitis ranged from approximately 
82 − 248 days as either a single agent or in combination with letrozole or fulvestrant.  
Most of the colitis cases have been observed at the 9-mg dose level or higher.  Most of 
the colitis cases have been observed at the 9-mg dose level or higher.  To mitigate the 
late-onset adverse events, such as colitis, an intermittent dosing schedule will be applied. 
With the 40-hour half-life, a limited impact on efficacy is anticipated.  PK modeling has 
shown that a schedule of 5 days on/2 days off will maintain GDC-0032 drug exposure 
levels within an efficacious range as assessed by various breast cancer cell lines.  There 
has also been data presented for another PI3K inhibitor BKM120 with a similar half-life in 
combination with letrozole in a Phase Ib study that demonstrated improved tolerability 
with similar efficacy for a schedule of 5 days on/2 days off as compared to daily 
continuous dosing of the PI3K inhibitor (Mayer et al. 2012). 
3.3.8 
Rationale for Biomarker Assessments  
Breast cancer is a heterogeneous disease, and PIK3CA mutations have been shown to 
vary among patients (CGAN 2012).  Therefore, all patients may not equally likely benefit 
from treatment with GDC-0032.  Predictive biomarker samples collected prior to dosing 
will be assessed in an effort to identify those patients with PIK3CA-driven pathogenesis 
who are most likely to respond to GDC-0032.  Pharmacodynamic biomarkers will be 
evaluated to assess the biologic activity of the addition of GDC-0032 to letrozole.  
It has been suggested that not all molecular alterations in the PI3K/AKT/mTOR pathway 
result in pathway activation.  In a comprehensive analysis of tumors from 850 breast 
cancer patients, protein markers of PI3K/AKT/mTOR pathway activation (pAKT, pS6, 
and p4EBP1) correlated strongly with INPP4B and PTEN loss, to a degree with PIK3CA 
amplification, but were not elevated in PIK3CA- MT luminal A cancers (CGAN 2012).  
This apparent disconnect between the presence of PIK3CA mutations and biomarkers of 
pathway activation had been previously noted (Loi et al. 2010), and stress the need to 
find innovative and robust predictive biomarkers to PI3K/AKT/mTOR pathway inhibiting 
agents (Saini et al. 2013). 
Next generation sequencing (NGS) techniques, like deep genome sequencing, may offer 
a unique opportunity to identify such biomarkers of response.  For example, using whole 


 
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genome sequencing, a two base-pair deletion in the TSC1 gene was found in a 
metastatic bladder cancer patient with a prolonged response (> 2 years) to everolimus as 
single agent (Iyer et al. 2012).  Among 13 additional bladder cancer patients treated with 
everolimus in the same trial, those with TSC1 mutant tumors remained on therapy longer 
than those with WT tumors (7.7 vs. 2.0 months, p = 0.004), suggesting that mTORC-1 
directed therapies may be most effective in cancer patients whose tumors harbor TSC1 
somatic mutations.  Similar approaches could be of great value when analyzing 
responses to agents targeting the PI3K/AKT/mTOR pathway, especially in the 
neoadjuvant setting. 
In addition to mutational activation of proteins, levels of RNA and DNA can also activate 
the PI3K pathway.  For example, increases in DNA copy number in receptor tyrosine 
kinases such as FGFR1/2 and IGF-1R, which occur at some frequency in breast cancer, 
can activate downstream PI3K pathway.  Hormone receptor positive breast cancer can 
be divided into luminal A and luminal B subtype, with the luminal B subtype displaying a 
higher proliferative index.  Therefore, profiling the RNA and DNA expression of tumors 
will allow intrinsic subtyping of patients enrolled onto study.  In addition, PI3K 
transcription activation signatures may identify additional patients who could respond to 
PI3K inhibitors outside of PIK3CA mutations.  
The use of circulating tumor DNA (ctDNA) to monitor response to treatment is an area of 
great interest.  It could allow for an early, non-invasive, and quantifiable method for use 
in the clinical setting to identify candidates for specific therapies and monitoring of 
disease mutation status over time (Higgins et al. 2012).  The neoadjuvant setting is ideal 
to prospectively test these approaches. 
3.3.9 
Rationale for Day 15 Biopsy 
On-study biopsies can provide valuable information regarding target engagement and 
downstream pathway suppression. Assessing how GDC-0032 interacts with letrozole in 
this previously untreated patient population provides a unique opportunity to understand 
the interaction between two anti-cancer molecules.  When available, FFPE tumor 
samples will be assessed for pathway modulation using immunohistochemistry (IHC) 
methodologies, and fresh frozen OCT samples will be assessed using reverse phase 
protein array (RPPA) technologies, or equivalent.  Measurement of Ki67 after 2 weeks of 
continuous letrozole and GDC-0032 combination treatment versus letrozole and placebo 
will give a good benchmark to prior neoadjuvant studies that demonstrated a larger 
decrease in Ki67 at this 2-week timepoint for a combination of letrozole and everolimus 
as compared to letrozole and placebo (Baselga et al. 2009).  This Day 15 biopsy will 
also be useful in identifying potential biomarkers that may help predict a tumor response 
for patients treated with GDC-0032.   


 
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3.3.10 
Rationale for Collection of Blood Sample for the Detection 
of Plasma Protein Biomarkers 
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate response 
to drugs, particularly targeted agents such as GDC-0032 (Wilson et al. 2012).  Assays 
to assess the expression of soluble, systemic cytokines and chemokines from the 
plasma of patients will be carried out using ELISA-based mass spectrometry or 
equivalent methodologies.   
3.3.11 
Rationale for Collection of Blood Sample for DNA Sequencing 
to Identify Mutations in Plasma 
There is increasing evidence that circulating DNA obtained from blood specimens of 
cancer patients is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008; Maheswaran et al. 2008).  Assays are available that can detect the 
major PI3K mutations (and other cancer-related genes) in plasma, and results from this 
analysis will be correlated with tumor specimens. 
3.3.12 
Rationale for Collection of Blood Sample for Next Generation 
Sequencing 
Next generation sequencing (NGS) technologies generate a large quantity of 
sequencing data.  Tumor DNA can contain both reported and unreported chromosomal 
alterations due to tumorigenesis process.  To help control for sequencing calls in 
previously unreported genomic alterations, a normal blood sample will be taken during 
pre-screening to determine whether the alteration is somatic or germline.  
3.3.13 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected from early breast cancer patients in this study to assess the 
pharmacokinetics of GDC-0032 and possible DDI between letrozole and GDC-0032 in 
this population.  Considering the lack of DDI between GDC-0032 and letrozole upon 
concomitant administration in the 24 metastatic breast cancer patients in the Phase I 
study (preliminary data), this drug interaction in early breast cancer patients is unlikely.  
Hence, extensive PK sample collection is not needed; sparse PK sampling from patients 
enrolled in this study is adequate.  The proposed PK sample collection schedule will also 
enable assessment of a concentration and response relationship to better understand 
the following:  pharmacokinetics/pharmacodynamics (efficacy), PK/safety correlation, 
and population pharmacokinetics.  Additional PK samples may be collected for safety 
concerns (e.g., severe adverse event) in order to better characterize drug levels in these 
patients at the time of the adverse event.   
3.3.14 
Rationale for the Collection of DNA for Exploratory 
Pharmacogenetic Polymorphisms 
One sample (approximately 3 mL of whole blood) will be collected from all patients using 
K3-EDTA collection tubes. Samples will be used for the evaluation of genetic 


 
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polymorphisms of drug metabolic enzymes including, but not limited to, CYP2C9, 
CYP3A4/5, and UGT1A1, and transporters (e.g., OATP1B1) and for genetic variants 
which could contribute to potentially drug-related rash and/or colitis safety assessments 
(including but not limited to human leukocyte antigen [HLA]).  For sample handling 
procedures, storage conditions, and shipment instructions, see the laboratory manual. 
Only in circumstances where there is concern for collection of this genetic material for 
above evaluations, can this assessment be considered not mandatory as part of study 
assessments in this study.  Results of any analyses from these samples will be reported 
outside the clinical study report. 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affects their safety and efficacy.  For 
example, patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN 38 
(the active metabolite of irinotecan), are at higher risk for adverse effects associated with 
the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  Preliminary 
results from in vitro metabolism studies with GDC-0032 suggest that they are partially 
metabolized by multiple Phase I cytochrome P450 enzymes, including CYP3A4.  
Although in vitro studies can help elucidate the roles of enzymes in the metabolism of 
the drug, these results are not always predictive of in vivo metabolism for a number of 
reasons, such as differences in drug concentrations that the enzymes encounter in vitro 
and in vivo.  For this reason, a blood sample for DNA isolation is proposed to be 
collected from all patients in this study for potential pharmacogenetic analysis of genes 
or biomarkers that may affect the pharmacokinetics or response to GDC-0032.  The 
decision to analyze the samples will be based on a review of the pharmacokinetics and 
response data.  Most recently, the role of HLA has been demonstrated to play an 
important role in the development of drug-induced rash for some drugs (carbamazepine, 
abacavir, and allopurinol).  Therefore, evaluation of genetic variants of genes that may 
regulate the immune response (including but not limited to HLA) may also be 
investigated to characterize unusual safety responses that are not predicted by 
GDC-0032 pharmacokinetics. 
The analysis will be performed on identifiable DNA samples, because it is necessary to 
link a patient’s PK data with genotype.  This analysis would be restricted to the 
evaluation of genes that may be involved in the pharmacokinetics of GDC-0032, drug 
metabolism, disposition, or elimination and/or response of patients who develop severe 
adverse reactions such as colitis or rash.  Samples may be stored and analyzed up to 
15 years after the completion of the study, at which time all DNA samples collected for 
this analysis will be destroyed. 
3.3.15 
Rationale for Patient-Reported Outcome Assessments  
A PRO is “any report on the status of a patient’s health condition that comes directly 
from the patient, without any interpretation of the patient’s response by a clinician or 


 
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anyone else” (FDA Guidance for Industry 2007).  PRO measures are able to 
contextualize a patient’s experience on trial, elucidating symptom and treatment burden.  
Since early breast cancer is often asymptomatic, the PRO objective is to evaluate and 
compare PROs of treatment-related symptoms, patient functioning, and the health-
related quality of life between treatment arms (Lemieux et al. 2011).  
The EORTC QLQ-C30 and associated breast cancer module, QLQ-BR23, were selected 
because they were specifically developed to assess the most salient constructs and 
experiences with breast cancer and its treatment.  The EORTC QLQ-C30 is a widely and 
frequently used PRO measure in oncology trials that contains a global health status 
scale, functional scales (physical, role, emotional, cognitive, and social), and general 
cancer symptom scales/items with a recall period of ‘the past week.’  
The second measure, the QLQ-BR23, is a breast cancer specific modular supplement to 
the EORTC QLQ-C30, and includes additional functioning scales and symptom 
scales/items relating to breast cancer.  
These instruments demonstrate strong psychometric properties, of both reliability and 
validity, and meet the requirements for this study (EORTC QLQ-C30 Scoring Manual, 
1999).  Therefore, PRO data will be collected from patients using the EORTC QLQ-C30 
and modified QLQ-BR23 (Quinten et al. 2009). 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR, via centrally assessed breast MRI via modified RECIST (Appendix 3) 
in all enrolled patients and PIK3CA MT patients. 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the 
American Joint Committee on Cancer staging system (Appendix 6) by local 
evaluation in all enrolled patients and PIK3CA MT patients.  
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST 
(Appendix 3) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients. 


 
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The following secondary outcome measures will be performed in all enrolled patients 
and separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally derived PEPI score upon treatment with letrozole plus 
GDC-0032 with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
yoT0/is, ypNX (breast pCR) 
 
3.4.2 
Safety Outcome Measures  
The safety and tolerability of GDC-0032 will be assessed using the following primary 
safety outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE, v4.0  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, 
or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during 
the adverse event reporting period (see Section 5.3.1) 
  
3.4.3 
Patient-Reported Outcome Measures   
The PRO measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty 
swallowing, diarrhea, skin problems), and patient functioning as measured using the 
EORTC QLQ–C30 and the modified breast cancer module QLQ–BR23 
 


 
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3.4.4 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are 
not limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Hormone receptor expression levels 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
ctDNA 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 
versus letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug 
safety response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing 
enzymes and transporters and other patient-specific covariates with PK of 
GDC-0032 or letrozole and/or drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a 
marker of tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response  
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients for this study include postmenopausal patients with ER+/HER2- untreated, 
Stage I-III operable breast cancer.  The size of the primary tumor should be  ≥ 2 cm by 
MRI.   


 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age  ≥ 18 years. Postmenopausal status is defined as 
follows: 
– 
Age  ≥  60 years or 
– 
Age  <  60 years and 12 months of amenorrhea plus follicle stimulating hormone 
(FSH) and plasma estradiol levels within postmenopausal range by local 
laboratory assessment or 
– 
Prior bilateral oophorectomy ( ≥  28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following 
characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated 
as the “target” lesion for all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as 
determined by institutional practice (in patients where there may be a 
reasonable suspicion of advanced disease e.g., large tumors, clinically positive 
axillary lymph nodes, signs and symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional 
definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as 
evaluable for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose  ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5 ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may 
be enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline 
phosphatase ≤ 1.5 ×  ULN  


 
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• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the basis of 
the Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × upper limit of normal (ULN) and activated 
partial thromboplastin time (aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 
2−3 is required.  If anticoagulation is required for a prosthetic heart valve, then INR 
should be between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply 
with the protocol, in the investigator’s judgment 
4.1.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as optimal 
neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric 
absorption 
• 
History of prior or currently active small or large intestine inflammation (such as 
Crohn’s disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula 
(QTcF) >  470 msec 
• 
DLCO <  60% of the predicted values (see Appendix 7 for calculations)  
• 
Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II-IV (New 


 
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York Heart Association, Appendix 5), or any other that in the judgment of the 
investigator could jeopardize patient safety or study outcomes 
• 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, 
current alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic 
dysfunction, physical examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug, that may affect the interpretation of the results, or renders the 
patients at high risk from treatment complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Patient Randomization 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain a patient’s identification number and treatment assignment 
using a permuted block randomization algorithm via an interactive voice or web-based 
response system (IxRS).  


 
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4.2.2 
Stratification 
Patients will be randomized into one of the two treatment arms in a 1:1 ratio based on 
the following stratification factors: 
• 
Tumor size (T1-2 vs. T3) 
• 
Nodal status (cytologically positive vs. radiologically or cytologically negative). If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then fine needle aspiration (FNA) or core biopsy is required to 
confirm nodal status. 
 
4.2.3 
Blinding 
Investigators and patients will be blinded to treatment assignment of GDC-0032 or 
placebo. 
For emergency situations, the investigator will be able to break the treatment code by 
contacting the IxRS.  The responsibility to break the treatment code in emergency 
situations resides solely with the investigator.   For non-emergency situations, the 
investigator needs to obtain approval from the Medical Monitor to break the treatment 
code.  Unblinding during the study will result in the withdrawal of a patient from the study.  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected, suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  The PK 
assay group will be unblinded to patients’ treatment assignments to identify appropriate 
PK samples to be analyzed and bioanalytical methodology to employ.  However, the PK 
scientist does not have access to the PK assay results and therefore stays blinded until 
the PK assay results need to be interpreted and reported.  Samples from patients 
assigned to the comparator arm will be analyzed for letrozole.  However, GDC-0032 
assay will be analyzed by request (i.e., to evaluate a possible error in dosing). 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0032 and Placebo  
GDC-0032 Drug Substance and Drug Product are manufactured according to current 
Good Manufacturing Practice guidelines for use in the clinical studies.  Each lot of 
GDC-0032 for clinical studies is subjected to a series of quality control tests to confirm 
its identity, purity, potency, and quality. 
GDC-0032 is provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 2 mg strength. 


 
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Placebo tablets will be identical in shape and color to the 2-mg tablets of GDC-0032 and 
will be indistinguishable from the 2-mg tablets of GDC-0032.  The ingredients in the 
placebo tablets are identical to those in the 2-mg tablets of GDC-0032, except for the 
absence of GDC-0032 active. 
The GDC-0032 active and placebo tablets are packaged in high-density polyethylene 
bottles, are labeled for clinical use, and should not be stored above 25°C. 
For further details, see the GDC-0032 Investigator’s Brochure. 
4.3.1.2 
Letrozole 
Letrozole will be labeled according to regulatory requirements in each country, as well as 
in accordance with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and will be labeled for investigational use only.  The Sponsor will provide 
letrozole free of charge to all study sites. 
Refer to the letrozole (e.g., Femara®) Package Insert or summary of product 
characteristics (SmPC) for details on the formulation and storage of letrozole. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0032 and Placebo 
Patients will receive an oral, daily dose of 4 mg (two 2-mg tablets) GDC-0032 or 
placebo on a schedule of 5 days on/2 days off for a maximum of 16 weeks.  Patients will 
take GDC-0032 or placebo at the same time of day ± 2 hours, unless otherwise instructed.  
Patients will be instructed as to the number of tablets to take.  Patients will be asked to 
record the time and date that they take each dose in a medication diary. 
If a patient misses a GDC-0032 or placebo dose or vomits up a tablet, she should be 
instructed to skip that dose and to resume dosing with the next scheduled dose.  Missed 
doses will not be made up.  Patients will be instructed to bring their medication diary to 
each study visit for assessment of compliance.  Patients will also be instructed to bring 
all unused tablets to each study visit for GDC-0032 or placebo accountability. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
4.3.2.2 
Letrozole 
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of 
surgery at the investigator’s discretion).  No dose modifications of letrozole are permitted.  
Any overdose or incorrect administration of letrozole should be noted on the letrozole 


 
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Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of letrozole should be recorded on the Adverse Event eCRF.  
Both GDC-0032 or placebo and letrozole should be taken together (in no particular 
order) at the same time each day ±  2 hours, unless otherwise instructed.   
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(letrozole and GDC-0032) will be provided by the Sponsor where required by local health 
authority regulations.  The investigational site will acknowledge receipt of IMPs, using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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 GDC-0032 
The Sponsor will offer post-trial access to the study drug (GDC-0032, letrozole, or other 
study interventions) 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 would not 
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 untreated, postmenopausal ER + /HER2 −, early 
stage, operable breast cancer 


 
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• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for untreated, postmenopausal postmenopausal ER + /HER2 −, early stage, operable 
breast cancer 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at 
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 
7 days prior to screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak 
time-dependent inhibitor of CYP3A4.  Although in vitro induction studies in human 
hepatocytes suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, 
preliminary data from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 
daily for 2 weeks in patients had no apparent effect on the pharmacokinetics of 
midazolam (a sensitive CYP3A4 substrate).  Therefore, GDC-0032 may be administered 
concomitantly with CYP3A4 substrates without the risk of a pharmacokinetic DDI.  
Letrozole is mainly metabolized to a pharmacologically inactive carbinol metabolite by 
CYP2A6 and CYP3A4 in vivo. GDC-0032, which has the potential to induce CYP3A4 
based on in vitro induction studies, was administered in combination with letrozole in the 
expansion phase of Study PMT4979g to assess their DDI potential. Preliminary data 
from 10 patients in this cohort indicated that steady state plasma concentrations of both 
letrozole and GDC-0032, following once daily administration of the combination (2.5 mg 
letrozole plus 6 or 9 mg GDC-0032), were similar to historical, single-agent data 
suggesting lack of DDI between GDC-0032 and letrozole. These preliminary results 
suggest that GDC-0032 and letrozole combination may be administered without the risk 
of a pharmacokinetic DDI.  
In vitro CYP inhibition studies in HLMs and induction studies in human hepatocytes 
suggested a low to moderate potential of GDC-0032 to perpetrate DDIs.  A clinical DDI 
study with rifampin (CYP3A4 inducer) and itraconazole (CYP3A4 inhibitor), to 
understand the effect of CYP inhibitors or inducers on the pharmacokinetics of 
GDC-0032, is currently ongoing (Study GP28617). 


 
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4.4.2 
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer 
agents such as chemotherapy, immunotherapy, targeted therapy, biological 
response modifiers, or endocrine therapy (other than letrozole permitted in this 
protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is 
receiving these at the moment of registration, treatment should be discontinued prior 
to randomization.  
• 
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.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to inhibit CYP3A4.  If a strong 
CYP3A4 inhibitor is co-administered with GDC-0032, patients should be closely 
monitored for adverse reactions. 
• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., 
phenytoin, carbamazepine, rifampin, phenobarbital) with GDC-0032 should be 
avoided.  Consider an alternate medication with no or minimal potential to induce 
CYP3A4.  If a strong CYP3A4 inducer is co-administered with GDC-0032, patients 
should be closely monitored for adverse reactions. 
4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments to be performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  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. 


 
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4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases that are currently active or that 
were active within the previous 5 years, surgeries, cancer history (including prior cancer 
therapies and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to the screening visit.   
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examination 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems as well as weight and height 
(height is measured at the screening visit 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), limited, symptom-directed physical 
examination may be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressure while the patient is in a seated position, and temperature.  Oxygen 
saturation is obtained by pulse oximetry after the patient has been in a seated position 
for  ≥ 5 minutes.  Obtain vital signs predose. 
4.5.5 
Electrocardiograms 
Triplicate electrocardiogram (ECG) recordings will be obtained at each specified 
timepoint (see the schedule of assessments in Appendix 1).  
4.5.6 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to randomization.   
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage:  
• 
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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• 
For Stage IIIB and Stage IIIC: bone scan and CT of chest, abdomen, and pelvis 
should be conducted for all patients. 
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.   
4.5.7 
Tumor and Response Evaluations 
All measurable disease must be documented at screening and reassessed at 
subsequent timepoints as outlined in Appendix 1. Responses based on clinical breast 
exam, breast ultrasound, and mammography will be investigator-assessed.  Whenever 
possible, assessments should be performed by the same evaluator to ensure internal 
consistency across visits. Response via breast MRI will be centrally assessed, and all 
assessments will be based on modified RECIST criteria (see Appendix 3).  
Clinical Breast Examination:  Assessment of primary breast tumor and regional lymph 
nodes must be done by physical examination (palpation) during baseline evaluation, 
Weeks 1, 5, 9, 13 and 16 during the treatment phase, and prior to surgery. Breast tumor 
measurement by caliper (preferred) or rule 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.  
Mammogram:  Bilateral mammograms must be obtained at baseline within 28 days 
prior to enrollment and again prior to surgery. Mammographic tumor measurements are 
to be recorded in the eCRF.  
Breast Ultrasound:  Bilateral breast ultrasounds must be obtained at baseline within 
28 days prior to enrollment.  Investigator decision whether to perform unilateral or 
bilateral ultrasounds performed at Week 9 and prior to surgery (Week 16) may be 
unilateral or bilateral and per investigator discretion.  If on ultrasound examination there 
is evidence of suspicious axillary lymph nodes at the baseline examination, then FNA or 
core biopsy is required.  Sonographic tumor measurements are to be recorded in the 
eCRF. The tumor site may be marked with a radiopaque clip or marker via radiographic 
guidance (e.g., ultrasound) prior to initiation of neoadjuvant therapy.  
Breast MRI:  Contrast-enhanced breast MRI scans will be mandatory for all study 
patients at baseline (within 28 days prior to enrollment) and prior to surgery (Week 16).  
MRI is optional at Week 9, but will be mandatory if a primary breast lesion is not 
evaluable by ultrasound, or if there are signs of disease progression on the Week 9 
ultrasound (see Figure 6).   


 
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Breast MRI scans should not be acquired within 48 hours after biopsy, and the 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 as 
assessed by the central reading facility, the scan may be repeated, at least 48 hours 
after the first scan before the start of study treatment. Other MRI acquisition sequences, 
such as diffusion-weighted imaging, may be acquired during this study during the MRI 
scan visits for each patient.  Additional MRI-derived metrics such as ADC value may 
provide additional insight into changes in tumor cellular composition.  
For information about patient preparation, scanner requirements and settings, and image 
acquisition, refer to the Study Imaging Manual. Standard site practice may be followed 
regarding the use of mild sedatives or anti-anxiolytics for claustrophobic patients prior to 
MRI. 
4.5.8 
Surgical Treatment Plan 
The planned and actual surgical treatment (BCS or mastectomy) performed should be 
documented and reported in the eCRF.  Patients should be reassessed after completion 
of neoadjuvant therapy and prior to surgery.  
4.5.9 
Surgical Specimen – Pathology 
The co-primary endpoint of the study (pCR) will be as identified by local pathology 
review. Guidelines regarding pathology specimen preparation, labeling and review are 
outlined in the pathology manual. 
4.5.10 
Laboratory Assessments 
The following assessments will be performed at the local laboratory.  The frequency of 
assessments is provided in Appendix 1. 
• 
Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, and other cells]), and platelet 
count.   
• 
Coagulation (INR and aPTT/PTT) 
• 
Fasting serum chemistry (blood urea nitrogen [BUN], creatinine, sodium, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, serum 
bilirubin, alkaline phosphatase, glucose, AST, ALT), performed following  ≥ 10-hour 
fast 
• 
Fasting lipid profile and amylase (total cholesterol, high-density lipoprotein [HDL], 
low-density lipoprotein [LDL], triglycerides, amylase, and lipase) performed following 
a  ≥ 10 hour fast 
• 
Fasting insulin and glucose  
• 
Glycosylated hemoglobin (HbA1c) 


 
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• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
The following assessments will be performed at a central laboratory.  Instruction 
manuals outlining sampling procedures, storage conditions, and shipment instructions 
and supply kits will be provided for all central laboratory assessments: 
• 
Mandatory tumor tissue 
• 
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 PIK3CA mutation testing as well as 
for other protocol-mandated exploratory assessments at baseline, Day 15, and at 
surgery. 
• 
Tumor tissue should be of good quality based on total and viable tumor content.  
Evaluation of the patient’s tumor sample for adequate tumor tissue content by a 
central laboratory must occur prior to initiation of study treatment.  A minimum of ten 
unstained slides from a prior diagnostic FFPE core biopsy would be required for 
enrollment eligibility purposes. 
Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen 
OCT core needle biopsy are required at baseline and Day 15 (Week 3).    
A formalin-fixed, paraffin-embedded tumor block from surgical resection 
(Weeks 17 − 18) is required.  If a tumor block cannot be obtained for various reasons 
(e.g., the tumor tissue is not sufficient at surgical resection), the site should discuss 
with the central study team.  In such cases, paraffin-embedded, unstained slides (a 
minimum of 20 and up to 40 unstained slides) from a surgical specimen are required 
at surgery (Weeks 17 − 18). 
The specimens will be used for confirmatory central laboratory assessment of 
PIK3CA mutation status, Ki67, PTEN, ER/PgR and HER2 expression.  In addition, 
other exploratory assessments, including but not limited to, PI3K signaling pathways 
may be evaluated, including protein expression and molecular profiling studies such 
as NGS and gene-expression. 
• 
Plasma samples for exploratory research on candidate biomarkers include, but are 
not limited, to the following:  ctDNA and plasma protein biomarkers 
• 
Blood for NGS (if approved by local regulatory authorities) 
• 
Blood for pharmacogenomics (if approved by local regulatory authorities) 
• 
PK assessment  
 
Plasma samples will be collected to measure letrozole and GDC-0032 
concentrations (see 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. 
 


 
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4.5.11 
Assay Methods 
4.5.11.1 
Mutational Analysis for PIK3CA 
The PIK3CA mutation assay will be performed by a central laboratory. 
Somatic mutations in the PIK3CA gene are found in approximately 35% − 40% of 
ER-positive breast cancers and occur most commonly in Exons 9 and 20 in the codons 
encoding amino acids E542, E545, and H1047 (Saal et al. 2005).  Real-time polymerase 
chain reaction (RT-PCR) assays that amplify exons that are commonly mutated in 
PIK3CA offer a sensitive and quantitative method to detect mutations from a tumor 
specimen.  DNA will be extracted from tumor samples and subjected to allele-specific 
PCR assays that detect the WT allele, as well as to assays for nucleotide substitutions 
that include, but are not limited to, the following amino acid changes:  R88Q, N345K, 
C420R, E542K, E545K/A/G/D, E546K/E/R/L, M1043I, H1047R/L/Y, H1049R.  Following 
histopathological review, samples with  < 10% tumor content may not be evaluable for 
the PIK3CA assay. Samples will be run on cobas z480 analyzer, and PIK3CA mutation 
status (mutant or WT) will be made using appropriate cutoffs and automated software.   
A designation of PIK3CA status unknown will be assigned to a sample wherein any one 
of the predefined mutations was not conclusively assessed. 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor Tissues 
Ki67 antigen is an important cell cycle-related nuclear protein that is expressed by 
proliferating cells in all phases of the active cell cycle (G1, S, G2, and M phase).  As 
such, it is a useful marker of the proliferative state of a tumor.  Ki67 protein levels will be 
determined by IHC through the use of standard techniques.   
PI3K pathway, and other pro-survival, biomarkers will be tested in the fresh tumor 
biopsies by IHC, including, but not limited to, phospho-S6, phospho-AKT, 
phospho-4EBP1, and phospho-ERK.  If tissue quantity permits, change in expression of 
pathway biomarkers will be measured by the RPPA using OCT fixed tissue.  The basis 
of the technology is to immobilize small amounts of lysate from a tumor biopsy sample in 
serial dilution on a microarray slide.  Multiple samples are thus arrayed on a slide and 
can be probed with antibodies that detect a particular phospho-epitope.  Using this 
technology, we will profile approximately 80 key signaling nodes representing a number 
of pathways known to be dysregulated in cancer, including receptors in the HER family, 
multiple components of PI3K/mTor signaling, as well as key members of the RAS/MAP 
kinase pathway. 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog Expression 
PTEN status will be examined by IHC using a protocol that has been validated for 
specificity using several available cell line controls at a central laboratory.  Tumor 
specimen will be scored only if appropriate staining is observed in internal control 
stromal or normal (non-tumor) tissue elements.  


 
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4.5.11.4 
Confirmation of Estrogen Receptor, Progesterone Receptor, 
and HER2 Status 
ER, PR, and HER2 status will be determined at a central laboratory according to the 
American Society of Clinical Oncology-College of American Pathologists 
(ASCO-CAP) guidelines. 
4.5.11.5 
Circulating Tumor DNA Analysis 
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations using appropriate technologies.  The prevalence of 
the mutations measured at baseline and post-treatment may provide information on 
response or resistance to therapy. 
4.5.11.6 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression will be 
performed using gene expression assays conducted on the NanoString platform or 
equivalent.  Analysis may include, but is not limited to, a panel of genes important for 
intrinsic subtyping, breast cancer biology and PI3K signaling.  The goal will be to 
generate a database of expression status to examine whether there are gene expression 
patterns that are associated with clinical response to GDC-0032. 
4.5.11.7 
Next Generation Sequencing 
In cases where there is sufficient material to isolate DNA, NGS will be performed using 
NGS platforms, such as Illumina or equivalent. The goal will be to determine whether the 
percentage of genetic mutations are associated with clinical response to GDC-0032. 
4.5.11.8 
Copy Number Analysis  
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically using chromosomal in situ hybridization 
(ISH), using next-generation sequencing platforms or by RT-PCR-based or equivalent 
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(fluorescence in situ hybridization assay) or chromogenic-based (chromogenic in situ 
hybridization).  Increased copy number of PI3K pathways activating genes may provide 
information on response or resistance to therapy.  
4.5.11.9 
Plasma Biomarker Analyses 
Assays to assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be carried out using appropriate methodologies, such as 
enzyme-linked immunosorbent assay (ELISA)-based or mass spectrometry-based or 
equivalent technologies.   
4.5.11.10 
Plasma Pharmacokinetic Samples 
Plasma GDC-0032 and letrozole samples will be analyzed using a validated liquid 
chromatography tandem mass spectrometry. 


 
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After the plasma samples are analyzed, any remaining samples may be used for 
exploratory metabolite profiling and identification, ex vivo protein binding, and PK, or 
pharmacodynamic assay development purposes. 
4.5.11.11 
Pharmacogenetic Polymorphism Assay 
If approved by the local regulatory authority, gene mutations will be assayed using 
multiplex PCR, allele-specific PCR, direct sequencing, or other acceptable methods.  
Results may be correlated to population PK parameters or other clinical measures in order 
to better understand the impact of genetic variants on drug metabolism, exposure, adverse 
events, and/or response.   
A sample will also be utilized as a source of normal DNA to determine whether sequence 
variants in the PIK3CA gene and in other relevant oncogenes in the tumor DNA are 
somatic mutations or single nucleotide polymorphisms. 
4.5.11.12 
Electrocardiograms 
Triplicate ECG recordings will be obtained at each specified timepoint (see the schedule 
of assessments in Appendix 1).  
4.5.11.13 
DLCO Testing 
A diffusion capacity of the lung for carbon monoxide (DLCO) test will be required at 
baseline and at the end of study-drug treatment (prior to surgery) for all patients.  The 
DLCO test should be repeated if there is clinical suspicion of pneumonitis.  Further 
guidance regarding DLCO testing is contained in Appendix 7 and in the management 
guidelines for pneumonitis (Section 5.1.1.2).   
4.5.11.14 
Osteoporosis Assessment and Monitoring 
Treatment with aromatase inhibitors results in bone loss due to estrogen deficiency 
(Gaillard and Stearns 2011).  For patients who have a history of osteoporosis and/or 
fractures, or who are at increased risk of osteoporosis, a bone mineral density 
assessment will be required at baseline prior to initiating study treatment.  Baseline bone 
mineral density will be measured via dual-energy X-ray absorptiometry (DXA).  DXA 
measurement of both the hip and lumbar spine is suggested.  When either the hip or 
lumbar spine is not a valid skeletal site for a bone mineral density measurement, then 
the 33% (one-third) radius should be measured.  In some patients, measurement of the 
hip alone could be sufficient. 
Appropriate monitoring in these patients will occur per institutional guidelines.  
Assessment for fractures is already included as part of the scheduled physical 
examinations.  Determination of patients who are at increased risk for osteoporosis will 
be per institutional guidelines.  Clinical risk factors for fracture include advancing age, 
previous fracture, glucocorticoid therapy, parental history of hip fracture, low body weight, 
current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, and 
conditions predisposing to secondary osteoporosis (e.g., hypogonadism or premature 


 
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menopause, malabsorption, chronic liver disease, inflammatory bowel disease) 
(Kanis et al. 2005).   
4.5.12 
Patient-Reported Outcomes  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of GDC-0032.  The PRO questionnaires, translated as required in the local 
language, will be distributed by the investigator staff and completed in their entirety by 
the patient.  To ensure instrument validity and that data standards meet health authority 
requirements, PRO questionnaires should be self-administered at the investigational site 
prior to the completion of other study assessments and the administration of study 
treatment.  
The EORTC QLQ-C30 and the Modified Breast Cancer module QLQ-BR23 
questionnaires will be used to assess HRQoL, including side-effects of systemic therapy 
(e.g., sore mouth/tongue, difficulty swallowing, diarrhea, skin problems) and patient 
functioning during the neoadjuvant period (refer to schedule of assessments in 
Appendix 1 for a detailed description of timepoints) and post-surgery follow-up.  
The EORTC QLQ-C30 is a widely used HRQoL measure in oncology trials with excellent 
psychometric properties demonstrating both reliability and validity. The measure consists 
of “five functional scales (physical, role, cognitive, emotional, and social); three symptom 
scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life 
scale” with a recall period of “the past week” (Aaronson et al. 1993). Scale scores can be 
obtained for each of the multi-item scales, global health status/QoL scale, and six single 
items by using a liner transformation for standardization of the calculated raw score.   
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of “the past week,” and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment).  As this 
trial will include patients in the neo-adjuvant setting, the last seven items of the original 
BR23 questionnaire, items numbered 47 − 53 that deal with symptoms and side effects 
not relevant to the population under study, will be removed.  These seven items 
addressed symptoms experienced by metastatic breast cancer patients and those 
undergoing radiation.  Therefore, in consultation with the EORTC, these items were 
deleted, as the validity of the measure would not be compromised by their removal.  In 
addition, as “oral mucositis” and “skin problems” are key symptoms of this therapy not 
assessed by currently available tools, validated items from the EORTC item bank were 
added to assess the presence and bothersomeness of oral mucositis (2 items:  sore 
mouth/tongue, difficulty swallowing) and skin problems (2 items).  Data analysis will be 
performed on the final modified BR23 data set in parallel with the final data analysis to 
assess the psychometric properties of the modified instrument and will be reported along 
with the clinical trial results.  Scale scores can be obtained for each of the multi-item and 
single-item scales by using a linear transformation for standardization of the calculated 
raw score. 


 
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The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient.  Patients must 
complete these instruments in the clinic (cannot be taken home) prior to any healthcare 
provider interactions (i.e., prior to administration of study drug and prior to any other 
study assessment) to ensure that the validity of the instruments are not compromised 
and to ensure that data quality meet regulatory requirements. 
Refer to Appendix 4 for the EORTC QLQ-C30 and the modified QLQ-BR23. 
4.5.13 
Samples for Clinical Repository 
All residual samples (or leftover biologic samples after protocol-defined studies are 
completed) obtained during the study (FFPE, fresh-frozen, plasma, etc.) will be stored in 
an academic central repository.  The specimens in the study repository will be made 
available for future biomarker research towards further understanding of treatment with 
GDC-0032, of breast cancer, related diseases, and adverse events, and for the 
development of potential, associated diagnostic assays.  The implementation of study 
repository specimens is governed by the Study Steering Committee, with guidance from 
a dedicated Translational Research Committee to ensure the appropriate use of the 
study specimens. 
All biomarker specimens will be retained for new research related to this study and/or 
disease in accordance with the recommendations and approval of the Study Steering 
Committee.  Samples will be only destroyed if required by local laws relating to the 
collection, storage, and destruction of biological specimens. 
Specimens will be stored up to 15 years or until they are exhausted.  The storage period 
will be in accordance with the institutional review board/ethics committee 
(IRB/EC)-approved ICF and applicable laws (e.g., health authority requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.13.1 
Confidentiality 
Patient medical information associated with biologic specimens is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Data derived from biologic specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using biologic specimens will be available 
in accordance with the effective Translational Reseach Committee policy on study data 
publication. 


 
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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 
 
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. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Disease progression 
• 
Unacceptable toxicity 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Conditions for Terminating the Study 
Both the Sponsor and the investigator reserve the right to terminate their participation in 
the study under the circumstances agreed upon in the site agreement.  Should this be 
necessary, both parties will arrange the procedures on an individual basis after review 
and consultation.  In terminating the study, the Sponsor and investigator will assure that 
adequate consideration is given to the protection of the patients’ interest. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
GDC-0032 is not approved and is currently in early clinical development.  Thus, the 
entire safety profile is not known at this time.  Human experience is currently limited.  
The following information is based on results from ongoing clinical studies.  The safety 
plan for this study is designed to ensure patient safety and will include specific eligibility 
criteria and monitoring assessments as detailed below.  


 
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Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events, and laboratory abnormalities (see Section 5.3.5.3), defined 
and graded according to NCI CTCAE v4.0.  General safety assessments will include 
serial interval histories, physical examinations, and specific laboratory studies, including 
serum chemistry and blood counts.  All serious adverse events and non-serious adverse 
events of special interest will be reported in an expedited fashion, via fax to Austrian 
Breast and Colorectal Cancer Study Group (ABCSG) safety department and also 
captured in the electronic data capture (EDC) system.  In addition, the Sponsor and the 
investigators will review and evaluate observed adverse events on a regular basis. 
All adverse events will be recorded during the trial and for 30 days after the last dose of 
study treatment or until the end of study visit, whichever occurs later.  Patients who have 
an ongoing study treatment-related adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the adverse event. 
All adverse events should be attributed by the investigator to study drug or to another 
clearly identified etiology by the investigator (see Table 9).  
Specific potential safety issues anticipated in this trial, as well as measures intended to 
avoid, minimize, and manage such toxicities, are outlined in the following sections. 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
5.1.1 
Management of Specific Adverse Events of GDC-0032  
Guidelines for management of specific adverse events are outlined in Table 1.  
Additional guidelines are provided in the subsections below.  
Due to the approximately 40-hour half-life for GDC-0032, investigators should consider 
holding GDC-0032 for certain Grade 2 toxicities until the adverse event resolves to 
Grade ≤ 1 as discussed below (e.g., stomatitis/mucositis, colitis, rash, diarrhea, 
pneumonitis).  Certain toxicities can occur within 1−2 weeks of holding or discontinuing 
GDC-0032 drug (e.g., pneumonitis, colitis, rash).  In these cases, the adverse event 
eventually resolves.  Investigators should follow management guidelines and dose 
modifications for toxicities as described below, including administration of topical or 
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Table 1 Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events 
 
GDC-0032 
Starting dose 
4 mg at 5 days on / 2 days off 
First reduction 
2 mg at 5 days on / 2 days off  
Second reduction  
2 mg at 3 days on / 4 days off a 
 a If the patient continues to experience specified drug-related adverse 
events after the second dose reduction, the treatment should be 
discontinued. 
  
5.1.1.1 
Management of Hyperglycemia 
Metformin is the first antihyperglycemic medication of choice because of the lower risk of 
hypoglycemia with this agent.  Because metformin in some patients may also cause 
diarrhea and not be well tolerated, other antihyperglycemic medications such as 
sulfonylureas (e.g., glimepiride, glipizide) can be used.  Extra caution should be used 
with other drugs such as sulfonylureas because of the increased risk for hypoglycemia 
with these agents.  Consultation with an endocrinologist can be helpful in managing 
hyperglycemia.   
Specific dose modification and management guidelines for hyperglycemia are provided 
in Table 2. 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) 
Grade 
Dose Modification and Management Guidelines for Hyperglycemia 
(based on fasting blood glucose) 
Grade 2 
Initiation of an anti-hyperglycemic agent (e.g., metformin) and 
additional glucose monitoring will be implemented.   
Dosing with GDC-0032 may either be held or continued per 
investigator evaluation. 
Grade 3  
(asymptomatic) 
GDC-0032 dosing will be suspended and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of an anti-hyperglycemic therapy (e.g., metformin).   
If the hyperglycemic event does not improve to Grade ≤  1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 


 
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Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) (cont.)  
Grade 3  
(symptomatic) a, 
Grade 3 
(requiring 
hospitalization),  
or Grade 4 
GDC-0032 dosing will be suspended, and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of anti-hyperglycemic therapy.   
If the hyperglycemic event does not improve to Grade ≤ 1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 
a For example, blurred vision, frequent urination, excessive thirst. 
  
5.1.1.2 
Management of Pneumonitis 
Patients who require any daily supplemental oxygen are not eligible for the study.  
Patients who have DLCO values < 60% will be excluded from the study.  Patients will be 
assessed for pulmonary signs and symptoms throughout the study.  The DLCO test 
should be repeated if there is clinical suspicion of pneumonitis.  The DLCO test will also 
be repeated presurgery after completion of study treatment.  Management guidelines for 
patients with possible pneumonitis are listed in Table 3. 
Table 3 
Dose Modification and Management Guidelines for Pneumonitis 
Grade
Intervention 
Investigations 
GDC-0032 a  
Dose Adjustment 
1 
No specific therapy 
required. 
CT scan.  Consider DLCO. b 
Repeat CT scan every 
8 weeks until return to 
baseline. 
No change. 
2 
Symptomatic only.  
Prescribe 
corticosteroids if 
cough is troublesome. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline.  
Consider bronchoscopy. 
Interrupt GDC-0032 treatment 
until improvement to Grade ≤ 1. 
Interrupt treatment as long as 
corticosteroids are being given. 
Restart GDC-0032 at the same 
dose if clinical benefit evident.  
Consider restarting at reduced 
dose if recurrent event or per 
discussion with Medical Monitor. 
Discontinue treatment if recovery 
to Grade ≤ 1 is not evident within 
28 days. 
 


 
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Table 3 
Dose Modification and Management Guidelines for Pneumonitis 
(cont.) 
 
3 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline. c 
Bronchoscopy is 
recommended. 
Interrupt treatment until 
improvement to Grade ≤ 1. 
Restart therapy within 28 days at 
a reduced dose if clinical benefit 
is evident. 
Interrupt treatment as long as 
corticosteroids are being given. 
4 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline. 
Bronchoscopy is 
recommended. 
Permanently discontinue 
GDC-0032. 
Table modified from White et al. 2010.  
CT = computed tomography; DLCO = diffusion capacity of the lung for carbon monoxide.  
a Dose reductions per Section 5.1.1. 
b DLCO may be useful to monitor the effect of interventions such as dose 
reduction/discontinuation and corticosteroids, in conjunction with imaging (White et al. 2010). 
c Follow-up imaging and investigation should be coordinated with the local pulmonologist if 
no baseline scans are available.     
 
 
5.1.1.3 
Management of Rash 
Rash and other dermatological events should be closely monitored, and patients with 
severe rash should be monitored for associated signs and symptoms such as fever and 
hypotension that may be suggestive of a systemic hypersensitivity reaction.  For severe 
rash, dosing of GDC-0032 should be interrupted, and patients should be treated with 
supportive therapy per standard of care.  Use of antihistamines, as well as topical or 
systemic corticosteroids, may be considered (see Table 4).   


 
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Table 4 
GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Grade of Rash 
GDC-0032  
Grade 1 
Continue dosing at current dose and monitor for change in severity.  
Consider prescribing topical corticosteroids a 
Grade 2 
Consider holding GDC-0032 or reducing to the next lower dose if 
rash is troublesome.   
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b). 
Grade 3 
Hold GDC-0032 until Grade ≤ 1. 
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b).  
Consider dermatological consultation.  
Consider obtaining photographs of rash if permitted by local 
regulations. 
After rash improves to Grade ≤ 1, restart GDC-0032 at the next 
lower dose upon discussion with Medical Monitor, or permanently 
discontinue. 
Grade 4  
Permanently discontinue GDC-0032. 
AE = adverse event. 
AE grading is based on NCI CTCAE, Version 4.0. 
a Suggested topical steroids include hydrocortisone 2.5% to face twice daily, 
triamcinolone 0.1%, or fluocinonide 0.1% cream to body twice daily. 
b Suggested oral steroids include a methylprednisolone dose pack or prednisone 
60 mg daily followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, 
etc.). 
 
 
5.1.1.4 
Management of Gastrointestinal Toxicity 
5.1.1.4.1 
Management of Diarrhea and Colitis 
Patients should be closely monitored for gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea, abdominal pain, stomatitis, and changes in stool, including checking 
for blood in stool if clinically indicated).  Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is mild.  Gastrointestinal symptoms should 
be managed per protocol guidelines and institutional standard of care.  For example, 
prompt management of diarrhea with antidiarrheal medications should be implemented.  
Because of the approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032 for Grade ≥ 2 diarrhea.     
Steroid-responsive diarrhea and colitis have been difficult to distinguish in patients 
treated with GDC-0032.  All cases of colitis have been reversible with corticosteroid 
treatment.  Prompt initiation of corticosteroids for persistent diarrhea despite 
antidiarrheal treatment can decrease the severity of the diarrhea and prevent the need 
for hospitalizations.  Patients who develop severe steroid-responsive diarrhea usually 
have been on GDC-0032 treatment for at least 2 months, with an average onset between 
4 − 6 months of treatment.  A stool culture is helpful in identifying concurrent 


 
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infections, and patients have been successfully treated with concurrent steroids and 
appropriate antibiotics if needed.  
If a patient is being treated with corticosteroids, total parenteral nutrition is 
discouraged as this increases the risk for severe hyperglycemia.  Discontinuation of 
nonsteroidal inflammatory medications or other medications that exacerbate colitis are 
also recommended during colitis episodes.   
Perforated duodenal ulcer has been observed in 2 patients (one patient at 6 mg in 
combination with letrozole; another patient at 6mg in combination with fulvestrant).  
Appropriate caution should be taken with the administration of medications such as 
aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids, which can increase 
the risk of gastritis, peptic ulcers, or gastrointestinal perforation. 
Specific dose modification and management guidelines for diarrhea and colitis are 
provided in Table 5.  
Table 5 GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis 
Grade of Diarrhea 
Dose Modification and Management Guidelines  
Grade 1 
• Manage per institutional standard of care that includes 
antidiarrheals.a 
• 
For persistent Grade 1 diarrhea occurring after Cycle 2, 
recommend evaluation for infectious causes via stool culture.b  
For noninfectious diarrhea, consider colonoscopy to evaluate for 
colitis.   
Grade 2 
• Hold GDC-0032 and initially manage with antidiarrheals.a 
• Obtain stool culture for infectious workup. b  Infections (e.g., 
Clostridium difficile, enteric bacteria, CMV) should be treated 
with the appropriate antibiotic. 
• For persistent Grade 2 non-infectious diarrhea lasting longer 
than 48 hours despite treatment with antidiarrheals, treat with 
oral corticosteroids (20 − 40 mg prednisone QD starting dose 
with taper) or budesonide 9 mg PO QD. 
• If Grade 2 diarrhea occurred after Cycle 2, was a recurrent 
episode, or improved with corticosteroid treatment, resume 
GDC-0032 treatment at one dose level lower upon improvement 
to Grade ≤ 1 and after completion of corticosteroid treatment.  
• If Grade 2 diarrhea occurred before Cycle 2, did not require 
corticosteroid treatment, and was an initial episode, resume 
GDC-0032 treatment at the same dose upon improvement to 
Grade ≤ 1.  
• For Grade 2 colitis, resume GDC-0032 treatment at one dose 
level lower upon improvement to Grade ≤ 1 and after 
completion of corticosteroid treatment. 
  


 
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Grade of Diarrhea 
Dose Modification and Management Guidelines  
• If Grade 2 diarrhea does not improve after 48 hours of 
corticosteroid treatment, a colonoscopy is recommended to 
evaluate for other causes of diarrhea (e.g., CMV colitis). 
Grade 3 (first 
episode)  
• Hold GDC-0032 and initially with antidiarrheals. a   
• Obtain stool culture for infectious workup. b 
• For G3 diarrhea or colitis, treat with systemic corticosteroids 
(prednisone 60 − 80 mg QD equivalent or solumedrol 16 − 20 
mg IV q8hr to start).  Can increase steroid dosage if diarrhea 
does not improve. 
• Concurrent infections (e.g., Clostridium difficile, enteric 
bacteria, CMV) should be treated with the appropriate 
antibiotic. 
• For patients who do not improve upon 48 hours of 
corticosteroid treatment, a colonoscopy is recommended to 
evaluate for other causes of diarrhea (e.g., CMV colitis).  
• If diarrhea or colitis improves to Grade ≤ 1 and upon 
completion of any steroid taper or antibiotic treatment, resume 
GDC-0032 treatment at one dose level lower. 
Grade 3 (recurrent) 
or Grade 4 
• Permanently discontinue GDC-0032.   
• Workup and treatment algorithm as for Grade 3 (first episode). 
• If patient receiving endocrine therapy, upon recovery to 
Grade  ≤ 1, can resume endocrine therapy alone.   
CMV = cytomegalovirus; IV = intravenous; PO = oral; QD = once daily; q8hr = every eight 
hours; SOC = standard of care. 
a Suggested antidiarrheals include the following: loperamide (initial: 4 mg, followed by 
2 mg after each loose stool, up to 16 mg/day); diphenoxylate and atropine 
(Diphenoxylate 5 mg 4 times/day until control achieved [maximum:  20 mg/day], then 
reduce dose as needed; some patients may be controlled on doses of 5 mg/day; tincture 
of opium (6 mg of undiluted opium tincture [10 mg/mL]) 4 times daily. 
b Non-infectious diarrhea can be diagnosed by stool culture with workup for various 
enteric bacteria and C. difficile. Fecal calprotectin is a possible marker for bowel 
inflammation.  Blood-based CMV PCR test can also be used to detect CMV infection. 
  
5.1.1.4.2 
Management of Stomatitis and Oral Mucositis 
Aggressive mouth care for oral mucositis and stomatitis with mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal 
and/or antibiotics) may also be helpful in managing symptoms, and it is recommended 
that these are implemented with early signs of dry mouth, Grade 1 mucositis, or Grade 1 
stomatitis (see Table 6).  Avoidance of spicy foods may also be helpful.   


 
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Table 6 GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Grade of 
Stomatitis/Mucositis 
GDC-0032  
All grades 
• 
Aggressive mouth care that includes mouthwash 
formulations (e.g., combinations of local anesthetic, 
antihistamine, corticosteroid, antacid, antifungal and/or 
antibiotics)  
• 
Diet management (e.g., avoidance of spicy foods) 
Grade 1 
• 
Monitor symptoms and initiate management (see above). 
Re-evaluate within 48 − 72 hours.   
Grade 2 
• 
Hold GDC-0032 and manage until Grade ≤ 1.   
• 
Restart GDC-0032 at the same dose.   
• 
If Grade 2 stomatitis/oral mucositis recurs, hold GDC-0032 
until Grade ≤ 1.  Restart GDC-0032 at the next lower dose. 
Grade 3 
• 
Hold GDC-0032 and manage until Grade ≤ 1.  Restart 
GDC-0032 at the next lower dose.  
For Grade 3 event that was not adequately managed upon 
initial presentation, consider restarting at same dose upon 
discussion with Medical Monitor.   
Grade 4 
• 
Permanently discontinue GDC-0032. 
  
5.1.2 
Management of Abnormal Liver Function Tests 
Some patients have experienced elevations of liver function tests (e.g., AST or ALT). 
Patients will be monitored throughout the study treatment for changes in liver function 
tests.  Given the potential for hepatic toxicity, all patients must have adequate liver 
function as manifested by measurements of serum bilirubin, hepatic transaminases, and 
alkaline phosphatase for initial and continued dosing.  Separate criteria for eligibility, 
continued dosing, and DLT are given for patients with hepatic metastases and Grade 2 
hepatic transaminase and/or alkaline phosphatase levels at baseline to allow safety 
testing to be adequately assessed in this patient group.   
For new abnormal liver function tests (e.g., elevated AST or ALT), a standard clinical 
work-up to understand the etiology of the abnormality should take place per local 
guidelines.  In many cases, elevated liver function tests may be a result of liver 
metastases, concomitant medications, or biliary obstruction.  Dose modifications for 
elevated liver function tests are described in Table 7.  
5.1.3 
Management of Asymptomatic Lipase and/or Amylase 
Elevations 
Some patients treated with GDC-0032 have experienced asymptomatic lipase and/or 
amylase elevations in blood tests without any clinical or radiographic symptoms of 
pancreatitis or another clear etiology for the abnormal laboratory values.  Upon 
discussion with the Medical Monitor and after a risk-benefit assessment, investigators 


 
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can consider continuing GDC-0032 therapy in such patients at the same dose or one 
dose level lower.  Investigators should have a low threshold for interrupting GDC-0032 
for any concerning clinical gastrointestinal toxicities. 
5.1.4 
Management of Other Clinically Significant Adverse Events 
See Table 7 for the dose modifications for other clinically significant adverse events. 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events 
Grade 
GDC-0032  
Grade 3:  first event 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Consider restarting at next lower dose. 
Grade 3:  recurrent 
Grade 4:  non-life-threatening 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Restart at next lower dose. 
Grade 4:  life-threatening 
• 
Permanently discontinue GDC-0032.  
  
5.1.5 
General Guidance for Dose Modifications and Delays for 
Letrozole 
The letrozole dose level cannot be modified.  In general, the investigator can consider 
continuing letrozole if it is not thought to be letrozole-related.   
All dose modifications should be based on the adverse event requiring the greatest 
modification and should be properly documented in the source documents. 
5.1.6 
Management of Increases in QT Interval  
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
1. 
Sustained (at least two ECG measurements  > 30 minutes apart) QTcF that 
is  > 500 msec and  > 60 msec longer than the baseline value 
2. 
Sustained absolute QTcF that is  > 515 msec  
3. 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, as this represents an increase in 
QTcF unrelated to alterations in repolarization.  Also of note, it is not uncommon to 
record arrhythmias such as non-sustained ventricular tachycardia, supraventricular 
tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving placebo during 
periods of extended ECG monitoring.  Therefore, it is critical that expert 
electrophysiologic advice be sought to confirm any ECG changes and to ascertain the 
likelihood of a drug-induced arrhythmia versus the background occurrence of this 
arrhythmia.  In such a situation, saving all available ECG data is highly suggested. 


 
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Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients. 
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied. 
5.1.7 
Safety Monitoring for Letrozole 
Letrozole is a nonsteroidal AI indicated for first line treatment of hormone receptor 
positive, locally advanced, or metastatic breast cancer in postmenopausal women.  
Letrozole is also indicated for adjuvant treatment in postmenopausal hormone-receptor 
positive patients and for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following anti-estrogen therapy. 
The most frequently reported adverse events in a first line, breast cancer clinical trial 
with letrozole were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea.  
Clinically significant adverse events also include bone effects (osteoporosis and bone 
fractures) and hypercholesterolemia.  Discontinuations for adverse events other than 
progression of tumor occurred in 2% of patients on letrozole.  Refer to the U.S. letrozole 
Package Insert or SmPC for additional information.   
There are no expected significant overlapping toxicities between letrozole and 
GDC-0032. Routine safety monitoring and periodic laboratory tests for the letrozole and 
GDC-0032 combination will occur throughout the study. 
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; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 


 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), 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 
procedures such as biopsies) 
5.2.2 
Serious Adverse Events (Immediately Reportable to ABCSG) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (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). 


 
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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 ABCSG safety 
department 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 ABCSG)  
Non-serious adverse events of special interest are required to be reported by the 
investigator to ABCSG safety department 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: 
• 
Grade 4 hyperglycemia 
• 
Grade  ≥  3 symptomatic hyperglycemia 
• 
Grade  ≥  2 colitis or enterocolitis  
• 
Grade ≥ 3 diarrhea 
• 
Grade  ≥  3 rash 
• 
Grade  ≥  2 pneumonitis  
• 
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 5.3.5.5) 
• 
Suspected transmission of an infectious agent by the study drug  
 
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 additionally reported to ABCSG 
safety department in case they fulfill the criteria for expedited reported in accordance 
with instructions provided in this section and in Section 5.4 −Section 5.6. 
For each adverse event recorded on the Adverse Event CRF, 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 
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 until the end of 
study visit, whichever occurs later.  After this period, investigators should report any 
deaths, serious adverse events, or other adverse events of concern deemed related to 
prior study drug treatment or study procedures (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 (v 4.0) will be used for 
assessing adverse event severity.  Table 8 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 8 
Adverse Event Severity Grading Scale 
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 (v 4.0), 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 one's self, 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. 


 
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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 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 9): 
• 
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 (where 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 9 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 
Adverse events will be considered related, unless they fulfill the criteria as 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. 


 
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If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.1 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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. 
5.3.5.2 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The progression (increase and decrease) of an adverse 
event must be documented in the Adverse Event eCRF.   
The initial severity of the event should be recorded, and the severity should be updated 
to reflect the most extreme severity any time the event worsens. If the event becomes 
serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 


 
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5.3.5.3 
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: 
• 
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 
• 
Clinically significant in the investigator’s judgment 
 
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 times the 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.4 
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: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 


 
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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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.5 
Reporting of Abnormal Liver Function Tests as Hy’s Law 
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 ABCSG safety department immediately (i.e., no more than 24 hours 
after learning of the event), either as serious adverse event or a non-serious adverse 
event of special interest (see Section 5.4.2). 
5.3.5.6 
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 ABCSG safety department 
(see Section 5.4.2). This includes death attributed to progression of breast cancer. 
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 only be used 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 of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, 
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death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
5.3.5.7 
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 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”). 
5.3.5.8 
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: 
• 
Perform an efficacy measurement for the study 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol for breast cancer surgery  
• 
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 suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
• 
Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care 
• 
Hospitalization for protocol mandated biopsies 
 
5.3.5.9 
Adverse Events Associated with an Overdose 
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 serious 
criteria, the event should be reported to the ABCSG safety department immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 


 
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5.3.5.10 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO ABCSG 
Certain events require immediate reporting to allow ABCSG safety department to take 
appropriate measures to address potential new risks in a clinical trial.  The investigator 
must report such events to ABCSG safety department 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 
ABCSG safety department 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 
ABCSG safety department immediately (i.e., no more than 24 hours after becoming 
aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
U.S. Medical Monitor Contact Information  
Genentech’s Medical Monitor Contact Information: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No. 
Alternate Telephone No.: 
 


 
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Medical Monitor Contact Information for Sites outside the United States:  
Please refer to the country/region-specific phone numbers provided in the study binder. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the paper Serious Adverse Event reporting form and transmit to ABCSG 
safety department via fax. In addition the serious adverse event and non-serious 
adverse event of special interest information will be captured in the EDC system.   
Worldwide Sites: 
ABCSG safety department  
Fax No.: 
+43 1 409 09 90 
Relevant follow-up information should be submitted to ABCSG safety department as 
soon as it becomes available and/or upon request. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification (SDV).  For follow-up reports of serious adverse events and non-serious 
adverse events of special interest, investigators should record all follow up information 
immediately (i.e., within 24 hours) on the paper Serious Adverse Event reporting form 
and transmit to ABCSG safety department via fax. In addition the serious adverse event 
and non-serious adverse event of special interest follow-up information will be captured 
in the EDC system. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and paper 
Serious Adverse Event form, if applicable.   
All pregnancies reported during the study should be followed until pregnancy outcome, 
and they should be reported according to the instructions provided in Section 5.4. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor and/or ABCSG safety department 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, 


 
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consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (30 days after the last dose of study 
drug).  However, the Sponsor should be notified if the investigator becomes aware of 
any death, other serious adverse event, or non-serious adverse event of special interest 
occurring after the end of the adverse event reporting period, regardless of 
causality.  The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient exposed to study drug or the female partner of a male 
patient exposed to study drug. 
The investigator should report these events by completing and faxing a paper Serious 
Adverse Event Reporting Form and fax cover sheet to Safety Risk Management using 
the fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of 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: 
• 
GDC-0032 Investigator's Brochure  
• 
Local prescribing information for letrozole SmPC 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


 
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An IDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
Primary and secondary efficacy analyses will include all patients who were included 
in the randomization. Final analysis will be performed after last patient, last visit (LPLV) 
and subsequent data cleaning, with patients allocated to the treatment arm associated 
by randomization. 
Safety analyses will include all patients who were included in the randomization and 
received at least one dose of study treatment, with patients allocated to the treatment 
arm associated with the regimen actually received.  
6.1 
DETERMINATION OF SAMPLE SIZE  
This study is designed for testing the effect of GDC-0032 on the two co-primary 
endpoints in all enrolled patients and in the PIK3CA MT patients and plans to enroll 
330 patients in total. Assuming the PIK3CA mutation status will not be available 
(unknown) for approximately 10% of the patients and the prevalence of PIK3CA mutant 
is 40%, there will be approximately 120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, 
there might be a possible imbalance between treatment arms within the PIK3CA MT 
cohort, which may reduce the statistical power in this cohort. To ensure the study 
provides sufficient statistical power even when the treatment assignment is imbalanced, 
the sample size was calculated based on a conservative scenario by assuming that the 
treatment assignment imbalance in PIK3CA MT is 40% vs. 60%. The sample size was 
calculated based on a chi²-test using continuity correction (Ury and Fleiss 1980). 
To control an overall, two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, 
respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 
300 enrolled patients and 108 patients in the PIK3CA MT cohort will be evaluable for 
analyses. This sample size allows us to detect an absolute percentage increase of 24% 
in MRI ORR rate in the GDC-0032 plus letrozole arm (64%) versus the letrozole-only 
arm (40%; Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power 
and 16% two-sided significance level.  The minimal detectable difference for ORR is 
approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled 
patients and 120 in the PIK3CA MT cohort), this sample size provides 80% power to 


 
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detect an absolute percentage increase of 18% in pCR in the GDC-0032 plus letrozole 
arm (19%) versus the letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in 
the PIK3CA MT cohort at the 4% two-sided significance level.  The minimal detectable 
difference for pCR rate is approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more 
substantial treatment assignment imbalance in the PIK3CA MT cohort than assumed, or 
there is an increased number of unevaluable patients for the MRI ORR, the sample size 
may be increased to obtain the level of power at 80%, and the enrollment may be limited 
to patients with PIK3CA MT.   
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 incidence of study treatment 
discontinuation for reasons other than disease progression will be tabulated. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized by treatment arm. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the ITT population; that is, all 
randomized patients will be included in the analyses, with patients grouped according to 
the treatment assigned at randomization.  
6.4.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are (1) tumor ORR, assessed by modified RECIST 
criteria by breast MRI (centrally assessed) and (2) the rate of pCR in breast and axilla 
(total pCR) after completion of study drug. 
The tumor ORR will be calculated by treatment arm in all enrolled population and in 
PIK3CA MT population. Within each population, the ORR for the two treatment arms will 
be compared at a two-sided alpha of 16% using a Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status. The pCR rate will also be calculated and 
compared at a two-sided alpha of 4% based on the same analytical approach as ORR. 
The two alpha values account for a family-wise type I error rate of 20%. Patients with 
early study termination and hence missing efficacy outcome will be considered as non-
responders. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST 
criteria by breast MRI (centrally assessed) in PIK3CA WT patients. 


 
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• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in 
PIK3CA WT patients.  
These endpoint measures will be summarized by treatment arm and will be 
analyzed analogue to the primary efficacy endpoint. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status (centrally assessed): 
• 
ORR using modified RECIST criteria by the following methods:  clinical breast 
examination, mammography, and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to 
surgery (centrally assessed) 
• 
PEPI score (centrally derived) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast 
MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and 
b) ypT0/is, ypNX (breast pCR) 
These endpoint measures will be summarized by treatment arm and will be compared 
between the two treatment arms within each population based on appropriate statistical 
analyses:  ORR will be compared using a Cochrane Mantel-Haenszel test, stratified by 
tumor size and nodal status; PEPI, Ki67, and tumor volume change will be compared by 
regression analyses, adjusted for tumor size and nodal status. All secondary endpoints 
will be tested at a two-sided type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study 
treatment, with patients allocated to the treatment arm associated with the regimen 
actually received.  
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and letrozole and GDC-0032 exposure. 
Verbatim descriptions of adverse events will be mapped to thesaurus terms.  Adverse 
event data will be listed by study site, treatment arm, patient number, and study day, 
severity, relationship to study drug, outcome, and action taken with the study treatments.  
Events occurring on or after treatment on Day 1 of Week 1 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.  


 
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Relevant laboratory and vital sign (heart rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE v4.0 Grade 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized in tables by 
NCI CTCAE v4.0 grade. 
6.6 
PHARMACODYNAMIC ANALYSES  
Ki67 biomarker analyses will include patients with at least one predose and one 
postdose biomarker assessment, with patients grouped according to the treatment 
actually received.  
6.7 
PHARMACOKINETIC ANALYSES  
Individual Cmax and trough plasma concentrations (Cmin) of GDC-0032 and letrozole from 
all patients enrolled will be reported. Mean of trough plasma concentrations of 
GDC-0032 and letrozole will be tabulated. The population pharmacokinetics of letrozole 
and GDC-0032 in this study will be compared with historical single-agent 
pharmacokinetics to assess the potential DDI between GDC-0032 and letrozole in this 
population.   
Additional PK analyses on metabolites of GDC-0032, letrozole, and/or other concomitant 
medications may be conducted as appropriate. 
6.8 
PATIENT-REPORTED OUTCOME ANALYSES 
Patient-reported outcomes of breast cancer symptoms, patient functioning, and HRQoL 
will be assessed by the EORTC QLQ-C30 and the modified Breast Cancer module 
(QLQ-BR23)  
Summary statistics (mean, standard deviation, median and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the modified QLQ-BR23 according to the EORTC scoring manual 
guidelines for each assessment time point. The mean change of the linear transformed 
scores from baseline (and 95% CI using the normal approximation) will also be 
assessed. Line charts depicting the mean changes (and standard errors) of items and 
subscales over time will be provided for each treatment arm from the baseline 
assessment. 
Data analysis will be performed on the final modified BR23 data set in parallel with the 
final data analysis to assess the psychometric properties of the modified instrument and 
will be reported along with the clinical trial results.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data. Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses. The number and 
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symptom and functional domains, global QoL, and single items of the EORTC QLQ-C30 
and QLQ-BR23 will be summarized. 
6.9 
EXPLORATORY ANALYSES  
Additional details on analyses will be specified in the SAP. 
6.10 
INTERIM ANALYSES  
The IDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day, follow-up visit after the surgery, or 2) been 
on study for 20 weeks after the randomization date (for those who do not receive the 
surgery), whichever occurs first.  All available information of all enrolled patients with all 
available assessments at the respective timepoint will be included in the interim 
analyses.  In addition, the IDMC or the Medical Monitor may request additional ad hoc 
meetings of the IDMC at any time during the study to review safety data. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
ABCSG will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, ABCSG 
and/or all involved clinical research associates (CRAs) will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
ABCSG will produce a Data Management Plan that describes the quality checking to be 
performed on the data. The Sponsor will perform oversight of the data management of 
this study, including review of the ABCSG’s data management plan and corresponding 
specifications.  Data will be transferred electronically from ABCSG to the Sponsor at the 
end of the study and whenever otherwise contractually agreed, and the Sponsor’s 
standard procedures will be used 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 at ABCSG and records retention for the study data will 
be consistent with the ABCSG’s standard procedures. 
Data from paper PRO questionnaires will be entered into the EDC system by site staff. 
Original PRO questionnaires will be kept in the patient’s medical record as source 
documentation. 
7.2 
DATA(BASE) MANAGEMENT 
ABCSG Clinical Data Management will check all e-forms for plausibility and consistency 
by automatic edit checks and manual data review according to study-specific data 
management plan (DMP).  If necessary, web-based data queries (data clarification 


 
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requests [DCRs]) will be generated and subsequently visible for the investigators, 
dedicated site staff, responsible CRAs, and responsible ABCSG staff.  For those eCRFs 
which pass all verification procedures and are regarded as correct and complete, they 
will be frozen subsequently by ABCSG clinical data management.  Consequently, no 
further data entries or changes on frozen eCRFs are possible. The status of frozen 
eCRFs is flagged by the specific icon. 
Clinical Data Management ensures that the database is corrected for the following eCRF 
issues without immediate notification to site staff (self-evident corrections).  Notification 
of site staff is provided via a specific report after final data cleaning procedures and 
before final data confirmation by the investigator or a designee: 
• 
misspellings/typing errors that do not change the meaning of the word 
• 
location of data recorded at an incorrect variable field or eForm (e.g., moving lab 
data from general comments to the appropriate lab table) 
• 
standard time to 24-hour clock 
• 
correction of date format, if required (dd/mm/yyyy) 
• 
if equivalent units of terms are recorded instead of the acceptable ABCSG standard 
• 
data changes due to plausibility checks and eCRF content (e.g., combination of 
several variables and/or eCRFs) 
All data management workflows are described in detail in the relevant SOPs and 
working instructions of ABCSG. 
7.3 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using the Clinical Data Management System “MACRO,” a 
web-interface DATAPORT.  Sites will receive training by the responsible CRAs and have 
access to a manual for appropriate eCRF completion (web data entry).   
All eCRFs should be completed by designated, trained site staff in a timely manner, 
usually within 2 weeks after the patient visit.  Electronic CRFs should be reviewed and 
respective data confirmation eCRF should be electronically signed and dated by the 
investigator or a designee at the end of the study.  
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a storage medium (compact disc [CD], digital video disk [DVD] etc.) 
that must be kept with the study records.  Acknowledgement of receipt of the storage 
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7.4 
SOURCE DATA DOCUMENTATION 
Study monitors (CRAs) will perform ongoing SDV 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 7.6. 
To facilitate SDV, the investigators and institutions must provide the Sponsor/CRAs 
direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review. The investigational site must also allow inspection 
by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), ICFs, 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 


 
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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 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 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/European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs) 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 ICFs 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. 
The ICF will contain a separate section that addresses the consent for optional donation 
of remaining samples for the clinical repository.  Samples stored in the clinical 
repository may be used for future exploratory research.  Patients will be told that they 
are free to refuse to donate their remaining samples to the clinical repository.  If 
patients choose to donate remaining samples, they may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to allow any remaining specimens to be 
stored in the clinical repository. 
The ICFs must be signed and dated by the patient or the patient’s legally 
authorized representative before 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 eCRF contains a section to document whether the patient has signed the ICF or not. 


 
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The ICFs 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. 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion. After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood. The investigator or designee must also explain that the patients are 
completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason. 
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated ICFs 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 ICF 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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the sponsor, the affiliated 
groups, or contract research organizations (CROs) according to the applicable local laws 
and regulations, if applicable 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 Sponsor, affiliated groups, or CROs are responsible for providing written summaries 
of the status of the study to the IRB/EC annually or more frequently in accordance with 


 
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the requirements, policies, and procedures established by the local IRB/EC. The 
Sponsor, affiliated groups, or CROs 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 local 
health authority requirements and the policies and procedures established by their 
IRB/EC, and archived in the site’s study file.  
8.4 
DATA PRIVACY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique 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 only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or 
required by local 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, provided 
the patient has given consent. 
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. The patient will have to consent to such access by signing the informed 
consent form. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 


 
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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, ICFs, and documentation of IRB/EC and governmental (health authorities) 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
which includes an audit trail containing a complete record of all changes to data. 
9.2 
ON SITE QUALITY CONTROL (MONITORING) 
During the study, CRAs will visit their respective sites on a regular basis as outlined in 
the study specific monitoring plan (MP) and all other relevant specifications, in order to 
guarantee adherence to the protocol and to the principles of GCP and to check for the 
progress of enrolment, adequate storage conditions of IMP and adequate drug 
dispensing and accounting records.  
CRAs will review documented data in the eCRFs for completeness and accuracy 
according to the study-specific MP, subsequently flag all reviewed pages with a specific 
mark (“SDV done”) within the EDC system “MACRO,” web-interface DATAPORT, 
developed by 
.  The CRAs will raise data queries (“DCRs”) in cases of 
missing source data or incorrect data entries. Immediately after electronic issue of the 
queries, they become visible to the investigator, the clinical data managers, and the 
ABCSG clinical safety officers (“raised DCRs”).  CRAs and/or clinical data managers 
and/or ABCSG clinical safety officers will follow up with trial site personnel until final data 
query resolution. 
9.3 
PROTOCOL DEVIATIONS 
The investigator should document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with 
established IRB/EC policies and procedures. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit international and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech in 
collaboration with the Breast International Group (BIG), ABCSG, and the SOLTI Breast 
Cancer Research Group. Genentech in collaboration with BIG, ABCSG, and SOLTI will 


 
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provide clinical operations management, data management, and medical monitoring.  
Approximately 110 U.S. and international sites will participate to enroll approximately 
330 patients. 
An IDMC will be in place throughout the study and will provide oversight of safety and 
efficacy analyses (see Section 3.1.2). 
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the IxRS system. Once eligibility has been established, the 
patient will be enrolled, and the study site will obtain the patient’s identification number 
from the IxRS. Once results of the tissue analysis are made available, the patient will be 
randomized, and the site will obtain the blinded treatment assignment from the IxRS.  
The IxRS will manage GDC-0032/placebo drug inventory at all sites and letrozole drug 
inventory at all study sites outside the United States.  IxRS will be required to randomize 
patients, to monitor enrollment and patient status, and to manage study treatment 
requests and shipments.  
Patient data will be recorded via an electronic data capture (EDC) system from 
 
(
, United Kingdom), which will be managed by ABCSG using eCRFs 
(see Section 7.2).   
Central laboratories, including Genentech and Genentech collaborators, will be used for 
PIK3CA mutation detection, Ki67, and PTEN status and/or will provide kits for PK, 
pharmacogenomic, tissue, whole blood, and plasma sample analyses to be conducted at 
central laboratories, Genentech, or Genentech collaborators. 
An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans throughout the trial. The review facility will retain 
copies of scans for centralized assessments of MRI-related endpoints.   
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). 


 
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10. 
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  125 
Appendix 1  
Schedule of Assessments 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
Informed consent a 
x 
 
 
 
 
 
 
 
 
Medical history and  
demographic data b 
x 
 
 
 
 
 
 
 
 
Physical examination c 
x 
 
 
x 
x 
x 
x 
 
x 
Clinical breast and regional lymph 
node examination  
x 
x 
 
x 
x 
x 
x 
 
 
Vital signs d 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
x 
12-Lead ECG e 
x 
 
x 
 
 
 
 
 
 
Mammography  
x 
 
 
 
 
 
x 
 
 
Breast ultrasound and axillary lymph 
node status f 
x 
 
 
 
x 
 
x 
 
 
Breast MRI g 
x 
 
 
 
 
 
x 
 
 
Collection of tumor samples h  
x 
 
x 
 
 
 
 
x 
 
Confirmation of receipt of adequate 
tissue for PIK3CA assessment 
x 
 
 
 
 
 
 
 
 
CBC with differential and  
platelet count i 
x 
x 
 
x 
x 
x 
x 
 
x 
Fasting serum chemistry j 
x 
x 
 
x 
x 
x 
x 
 
x 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
 
 
 
 
 
 
 
 
 
  126 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
Glycosylated hemoglobin (HbA1c) 
x 
 
 
 
 
 
 
 
 
Fasting insulin and glucose k 
x 
x 
 
x 
x 
x 
x 
 
x 
Fasting lipid profile and amylase l 
x 
 
 
x 
 
x 
x 
 
x 
Coagulation (INR and aPTT)  
x 
 
 
x 
x 
x 
x 
 
x 
Urinalysis (laboratory) m 
x 
 
 
x 
x 
 
x 
 
x 
DLCO n 
x 
 
 
 
 
 
x 
 
 
Bone mineral density test o 
x 
 
 
 
 
 
 
 
 
Blood sample for plasma protein 
biomarkers p 
 
x 
 
 
x 
 
x 
 
 
Blood sample for ctDNA q 
 
x 
 
 
x 
 
x 
 
 
Blood sample for NGS r 
 
x 
 
 
 
 
 
 
 
Pharmacogenomic sample s  
 
x 
 
 
 
 
 
 
 
Concomitant medication t 
x 
x 
x 
x 
x 
x 
x 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
 
x 
Inclusion/exclusion criteria u 
x 
 
 
 
 
 
 
 
 
Visit with breast surgeon (may occur 
from Week 13) 
 
 
 
 
 
x 
 
 
 
Surgery v 
 
 
 
 
 
 
 
x 
 
Randomization  
x 
 
 
 
 
 
 
 
 
Letrozole accountability/dispensation 
 
x 
x 
x 
x 
x 
x 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
 
 
 
 
 
 
 
 
 
  127 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
GDC-0032/placebo accountability/ 
dispensation  
 
x 
x 
x 
x 
x 
x 
 
 
Patient-reported outcomes w 
 
x 
 
x 
x 
x 
x 
 
x 
Pharmacokinetic sample (see 
Appendix 2) 
 
x 
x 
 
x 
 
 
 
 
aPTT = activated partial thromboplastin time; CA-125 = cancer antigen 125; CTCs = circulating tumor cells; ctDNA = circulating tumor DNA; 
DLCO = diffusion capacity of the lung for carbon monoxide; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INR = international 
normalized ratio; MRI = magnetic resonance imaging; NGS = next-generation sequencing. 
Note:  All assessments should be performed before dosing, unless otherwise stated.  Some assessments may be performed outside the window indicated 
to accommodate holidays, unforeseen scheduling issues, or ongoing safety issues with the trial and the patient, after approval by the Medical Monitor. 
a Perform within 28 days prior to Day 1 of Cycle 1.  Signed informed consent must be provided prior to any study-specific evaluations.  Assessments 
performed as standard of care within the timeframe may be used. 
b Medical history includes clinically significant diseases that are currently active or that were active within the last 5 years, surgeries, cancer history 
(including date of diagnosis, primary tumor histology, grade, staging, prior cancer therapies, and procedures), reproductive status, smoking history, use 
of alcohol and drugs of abuse. Demographic data include age, sex, and self-reported race/ethnicity. 
c A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; 
height is measured at the screening visit only).  Perform symptom-directed physical examination after baseline assessment. 
d Vital signs include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated position and 
temperature. Oxygen saturation is obtained by pulse oximetry after the patient has been in a seated position for ≥ 5 minutes. Obtain vital signs predose. 
e Triplicate ECG recordings will be obtained at each specified timepoint.  A window of  ± 30 minutes is acceptable for all timepoints.  Submit all ECGs to 
the diagnostic facility for central review. 
f Baseline evaluation of axillary lymph nodes assessed with ultrasound. 
g MRI evaluation is optional at Week 9.  MRI is mandatory at Week 9 in the event that disease progression is suspected, or if the primary lesion is not 
evaluable by ultrasound at baseline.  Send all scans to the central reading facility for evaluation. 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
 
 
 
 
 
 
 
 
 
  128 
h Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen OCT core needle biopsy are required prior to initiation of treatment 
(pretreatment) and also on Day 15.  A formalin-fixed, paraffin-embedded tumor block from a surgical resection is required at surgery (Weeks 17 − 18). 
i Complete blood count includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils, bands, eosinophils, 
basophils, lymphocytes, monocytes, and other cells), and platelet count. Screening results may be valid for Week 1, Day 1 if performed within 7 days 
prior to Week 1, Day 1. 
j Fasting ( ≥ 10-hour fast) serum chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, 
serum bilirubin, alkaline phosphatase, glucose, AST, and ALT. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to 
Week 1, Day 1. 
k Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, Day 1. 
l Fasting lipid profile includes total cholesterol, HDL, LDL, triglycerides, amylase, and lipase. Screening results may be valid for Week 1, Day 1 if 
performed within 7 days prior to Week 1, Day 1. 
m Includes specific gravity, pH, glucose, protein, ketones, and blood. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to 
Week 1, Day 1. 
n   DLCO is obtained at screening and prior to surgery.  The DLCO test should be repeated if there is clinical suspicion of pneumonitis.  DLCO calculations 
are described in Appendix 7.  The hemoglobin value used for correcting DLCO should represent the patient’s actual hemoglobin level and should be 
obtained within 7 days of the DLCO test. 
o Baseline bone mineral density will be measured via dual-energy X-ray absorptiometry (DXA) and will need to be obtained in women with a history of 
osteoporosis and/or fractures, or who are at increased risk of osteoporosis.  DXA measurement of both the hip and lumbar spine is suggested.  When 
either the hip or lumbar spine is not a valid skeletal site for BMD measurement, then the 33% (one-third) radius should be measured. In some patients, 
measurement of the hip alone could be sufficient. 
p Pretreatment sample for plasma protein biomarkers should be obtained prior to dosing.  Refer to laboratory manual for more information. 
q Pretreatment sample for ctDNA may be obtained on Day 1 prior to dosing.  This sample will also be collected prior to dosing at Week 9 and at 
Week 16.  Refer to laboratory manual for more information. 
r Blood for NGS will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1.   
s Blood for pharmacogenomics will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1. 
t Record all medications used by the patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements). 
u All of the study’s inclusion criteria and none of the exclusion criteria should be met prior to study entry. 
v Surgery will take place after at least 16 weeks of combination treatment (i.e., from Week 17 to Week 18), and generally no more than 4 days after the 
last dose of study medication. 
w The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) will be completed by the patients at the investigational site.  All PRO questionnaires 
must be administered prior to any other study assessment(s) and prior to administration of study drug.  
 


 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
129 
Appendix 2  
Schedule of Pharmacokinetic Assessments 
Visit 
Timepoint 
PK Assessments 
Letrozole PK 
Day 1 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
0 − 4 hours prior to letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
Day 15 
( + 2 days) 
3 hours ( ± 60 min) post letrozole and 
GDC -0032/placebo administration 
ECG before PK 
GDC-0032 PK 
Day 57 
( + / − 2 days) 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
Letrozole PK 
GDC-0032 PK 
ECG = electrocardiogram; min = minutes; PK = pharmacokinetics.  
Record exact time of dose administration and sample collection. 
 


 
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130 
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 
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 
therapy in early breast cancer.  Ultrasound, mammography, and clinical exam are all 
                                            
 
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.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  131 
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 
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.   


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  132 
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 
 
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. 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  133 
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 
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. 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  134 
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.  
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.  


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  135 
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. 


 
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Protocol GO28888, Version 3 
136 
Appendix 4  
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures   
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
____________________ 
Your birthdate (Day, Month, Year): 
____________________ 
Today's date (Day, Month, Year):  
 
____________________ 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


 
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Protocol GO28888, Version 3 
  137 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
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Protocol GO28888, Version 3 
  138 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to 
which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
31. Did you have a dry mouth? 
1 
2 
3 
4 
 
32. Did food and drink taste different than usual? 
1 
2 
3 
4 
 
33. Were your eyes painful, irritated or watery? 
1 
2 
3 
4 
 
34. Have you lost any hair? 
1 
2 
3 
4 
 
35. Answer this question only if you had any hair loss: 
Were you upset by the loss of your hair? 
1 
2 
3 
4 
 
36. Did you feel ill or unwell? 
1 
2 
3 
4 
 
37. Did you have hot flushes? 
1 
2 
3 
4 
 
38. Did you have headaches? 
1 
2 
3 
4 
 
39. Have you felt physically less attractive 
as a result of your disease or treatment? 
1 
2 
3 
4 
 
40. Have you been feeling less feminine as a 
result of your disease or treatment? 
1 
2 
3 
4 
 
41. Did you find it difficult to look at yourself naked? 
1 
2 
3 
4 
 
42. Have you been dissatisfied with your body? 
1 
2 
3 
4 
 
43. Were you worried about your health in the future? 
1 
2 
3 
4 
 
 
44. Have you had skin problems (e.g. itchy, dry)?  
1 
2 
3 
4 
 
45. Did itching of your skin bother you? 
1 
2 
3 
4 
  46. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
47. Have you had trouble swallowing? 
1 
2 
3 
4 
 
 
 
 
Please go on to the next page 
 


 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 3 
  139 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past four weeks: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
48. To what extent were you interested in sex? 
1 
2 
3 
4 
 
49. To what extent were you sexually active? 
(with or without intercourse) 
1 
2 
3 
4 
 
50. Answer this question only if you have been sexually 
active: To what extent was sex enjoyable for you? 
1 
2 
3 
4 
 


 
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  140 
Appendix 5  
New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients 
NYHA 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation or dyspnea. 
No objective evidence 
of cardiovascular 
disease. 
II 
Mild 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or 
dyspnea 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or 
dyspnea. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical 
activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 


 
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  141 
Appendix 6  
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
DCIS 
Tis (LCIS) 
LCIS 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the 
underlying breast parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on 
the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. 
T1 
Tumor  ≤20 mm in greatest dimension 
T1mi 
Tumor  ≤1 mm in greatest dimension 
T1a 
Tumor  >1 mm but  ≤5 mm in greatest dimension 
T1b 
Tumor  >5 mm but  ≤10 mm in greatest dimension 
T1c 
Tumor  >10 mm but  ≤20 mm in greatest dimension 
 
 


 
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  142 
Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Tumor (T) 
T2 
Tumor  >20 mm but  ≤50 mm in greatest dimension 
T3 
Tumor  >50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)a 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for 
inflammatory carcinoma 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp 347−76. 
DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. 
Note: The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both.  Size should 
be measured to the nearest millimeter.  If the tumor size is slightly less than or greater than a cut-off for a given T classification, it is recommended 
that the size be rounded to the millimeter reading that is closest to the cut-off.  For example, a reported size of 1.1 mm is reported as 1 mm, or a 
size of 2.01 cm is reported as 2 cm.  Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was 
determined by clinical (physical examination or radiologic) or pathologic measurements, respectively.  In general, pathologic determination should 
take precedence over clinical determination of T size. 
a Invasion of the dermis alone does not qualify as T4.  


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Regional Lymph Nodes (N) 
Clinical   
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted 
OR 
N2 
Metastases in clinically detected a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures 
N2b Metastases only in clinically detected a ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph 
node metastases 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement 
OR 
Metastases in clinically detected a ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node 
metastases 
OR 
N3 
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Regional Lymph Nodes (N) 
Clinical 
N3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 34776.   
a Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics 
highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination.  
Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, for 
example, cN3a(f).  Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a 
clinical N, for example, cN1.  Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine 
needle aspiration, core biopsy, or sentinel lymph node biopsy.  Pathologic classification (pN) is used for excision or sentinel lymph node biopsy 
only in conjunction with a pathologic T assignment. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
Note: ITCs are defined as small clusters of cells  ≤ 0.2 mm, or single tumor cells, or a cluster of  < 200 cells in a single histologic cross-section.  
ITCs may be detected by routine histology or by IHC methods.  Nodes containing only ITCs are excluded from the total positive node count for 
purposes of N classification but should be included in the total number of nodes evaluated. 
pN0(i–) 
No regional lymph node metastases histologically, negative IHC 
pN0(i + ) 
Malignant cells in regional lymph node(s)  ≤ 0.2 mm (detected by H&E or IHC including ITC) 
pN0(mol–) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0(mol + ) 
Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC 
Micrometastases 
OR 
Metastases in 1–3 axillary lymph nodes 
AND/OR 
pN1 
Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected a 
pN1mi 
Micrometastases ( >0.2 mm and/or >200 cells but none  > 2 mm) 
pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis  > 2 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but 
not clinically detected a 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected 
Metastases in 4–9 axillary lymph nodes 
OR 
pN2 
Metastases in clinically detected a internal mammary lymph nodes in the absence of axillary lymph node metastases 
pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit  > 2 mm) 
pN2b Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases 
Metastases in  ≥ 10 axillary lymph nodes 
OR 
Metastases in infraclavicular (level III axillary) lymph nodes 
OR 
Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary 
lymph nodes 
OR 
Metastases in  > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
OR 
pN3 
Metastases in ipsilateral supraclavicular lymph nodes 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit >2 mm) 
OR 
pN3a 
Metastases to the infraclavicular (level III axillary lymph) nodes. 
Metastases in clinically detected b ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph 
nodes; 
OR 
pN3b 
Metastases in > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
Post-treatment ypN  
Post-treatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above.  The modifier "SN" is used only if a sentinel node 
evaluation was performed after treatment.  If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND. 
The X classification will be used (ypNX) if no yp post-treatment SN or AND was performed 
N categories are the same as those used for pN 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse 
transcriptase/polymerase chain reaction. 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
1 Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  Classification based solely on sentinel lymph 
node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).   
a "Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.   
b "Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having 
characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic 
examination.   
 
Distant Metastases (M) 
 
M0 
No clinical or radiographic evidence of distant metastases 
cM0(i + ) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in 
circulating blood, bone marrow, or other non-regional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of 
metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
 
Post-treatment yp M classification.  The M category for patients treated with neoadjuvant therapy is the category assigned in the 
clinical stage, prior to initiation of neoadjuvant therapy.  Identification of distant metastases after the start of therapy in cases where 
pre-therapy evaluation showed no metastases is considered progression of disease.  If a patient was designated to have detectable 
distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Anatomic Stage/Prognostic Groupsa  
Stage 
T 
N 
Mc 
0 
Tis 
N0 
M0 
IA 
T1c 
N0 
M0 
IB 
T0 
N1mi 
M0 
 
T1c 
N1mi 
M0 
IIA 
T0 
N1b 
M0 
 
T1c 
N1b 
M0 
 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
 
T1c 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Stage 
T 
N 
Mc 
 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
Note: Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are 
carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.  
Post-neoadjuvant therapy is designated with "yc" or "yp" prefix.  Of note, no stage group is assigned if there is a complete pathologic response (CR) 
to neoadjuvant therapy, for example, ypT0cM0.   
a T1 includes T1mi.   
b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.   
c M0 includes M0(i+); The designation pM0 is not valid; any M0 should be clinical.  If a patient presents with M1 prior to NAST, the stage is 
considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.   
 


 
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Appendix 7  
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume 
All DLCO measurements will be obtained as per the American Thoracic Society and 
European Respiratory Society (ATS/ERS) guidelines (MacIntyre et al. 2005).  
The predicted DLCO value should be corrected for both hemoglobin (Hb) and alveolar 
volume (va).   
Pulmonary function test laboratories that follow the ATS/ERS guidelines should be able 
to provide the value for DLCO, corrected for va.  A single breath va may be used to obtain 
DLCO, corrected for va.  Use the following equation to determine the predicted DLCO, 
corrected for Hb and va: 
Predicted DLCO, corrected for Hb and va = [DLCO, corrected for va] × [1.7 × Hb / 
(9.38 + Hb)] 
Use the formula below to determine the percentage of predicted DLCO value (now 
corrected both for Hb and va):  
% of predicted DLCO (corrected for Hb and va) = [actual DLCO / (predicted DLCO 
corrected for Hb and va)] × 100  
 
 
 
 




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PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol GO28888 has been amended to include the following major changes: 
• 
Language has been amended to clarify that the investigator has the sole 
responsibility to break the treatment code in emergency situations.  These changes 
have been incorporated into Section 4.2.3 of the study protocol.  
• 
Because pneumonitis is a known GDC-0032 toxicity, additional screening and 
management of pulmonary function is an important safety consideration for this trial.  
Exclusion criteria have been updated to exclude patients with diffusion capacity of 
the lung for carbon monoxide (DLCO) values < 60% of predicted (Section 4.1.2).  
Calculations for DLCO have been included in Appendix 7.  Management guidelines 
for pneumonitis (Section 5.1.1.2) have been updated to repeat the DLCO test if 
there is clinical suspicion of pneumonitis.  The schedule of assessments has been 
updated to include DLCO testing at baseline and at the end of study treatment 
(Appendix 1, footnote n).  Additional language describing DLCO testing has been 
added to the study assessments in Section 4.5.11.13. 
• 
To ensure that the appropriate patients are enrolled into this study, exclusion criteria 
have been updated (Section 4.1.2) as follows:   
– 
Patients for whom upfront chemotherapy is clinically judged appropriate as 
optimal neoadjuvant treatment will be excluded from this study.  
– 
Patients for whom immediate surgery is indicated will be excluded from this 
study. 
• 
Because letrozole is a potent estrogen-lowering agent, it can cause bone loss and 
may increase the risk of fractures.  Section 4.5.11.14 has been amended to include 
a baseline bone mineral density assessment and adequate monitoring of women 
with a history of osteoporosis and/or fractures, or who are at increased risk of 
osteoporosis.  The schedule of assessments (Appendix 1, footnote o) has been 
updated to reflect these changes.  In addition, protocol language has been added to 
ensure appropriate monitoring.   
• 
Section 4.4.2 has been amended to clarify that bisphosphonates can be used for the 
treatment of osteoporosis.   
• 
The list of prohibited therapies in Section 4.4.2 has been updated to include potent 
CYP3A4 inducers. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
A Protocol Amendment Acceptance Form has been added.   
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The list of abbreviations has been updated to reflect changes to the protocol. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 4.1.2:  Exclusion Criteria 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as 
optimal neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
DLCO< 60% of the predicted values (see Appendix 7 for calculations) 
SECTION 4.2.3:  Blinding 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), For emergency situations, the investigator will be able to break the 
treatment code by contacting the IxRS following approval from.  The responsibility to 
break the treatment code in emergency situations resides solely with the Medical 
Monitor.  Treatment codes should not be broken except in emergency situations where 
unblinding is needed for treatment decisions.  Effort should be made investigator.  For 
non-emergency situations, the investigator needs to obtain approval from the Medical 
Monitor before unblinding.  Patient treatment assignment may be unblinded at the to 
break the patient discontinues from the blinded treatment phase at the request of the 
treating physician by contacting the IxRS following approval from the Medical Monitor 
and stating the reason for unblinding. treatment code. 
SECTION 4.4.2:  Prohibited Therapy 
• 
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.  Patients who develop osteopenia 
or osteoporosis in the follow up period may receive bone targeted therapy as per the 
clinician’s discretion.  Primary use of bisphosphonates as a prevention of bone 
metastasis or as a prevention of bone loss is prohibited. … 


 
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• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., 
phenytoin, carbamazepine, rifampin, phenobarbital) with GDC-0032 should be 
avoided.  Consider an alternate medication with no or minimal potential to induce 
CYP3A4.  If a strong CYP3A4 inducer is co-administered with GDC-0032, patients 
should be closely monitored for adverse reactions. 
SECTION 4.5.11.13:  DLCO Testing 
A diffusion capacity of the lung for carbon monoxide (DLCO) test will be required at 
baseline and at the end of study-drug treatment (prior to surgery) for all patients.  The 
DLCO test should be repeated if there is clinical suspicion of pneumonitis.  Further 
guidance regarding DLCO testing is contained in Appendix 7 and in the management 
guidelines for pneumonitis (Section 5.1.1.2). 
SECTION 4.5.11.14:  Osteoporosis Assessment and Monitoring 
Treatment with aromatase inhibitors results in bone loss due to estrogen deficiency.  
For patients who have a history of osteoporosis and/or fractures, or who are at increased 
risk of osteoporosis, a bone mineral density assessment will be required at baseline prior 
to initiating study treatment.  Baseline bone mineral density will be measured via 
dual-energy X-ray absorptiometry (DXA).  DXA measurement of both the hip and 
lumbar spine is suggested.  When either the hip or lumbar spine is not a valid skeletal 
site for a bone mineral density measurement, then the 33% (one-third) radius should be 
measured.  In some patients, measurement of the hip alone could be sufficient. 
Appropriate monitoring in these patients will occur per institutional guidelines.  
Assessment for fractures is already included as part of the scheduled physical 
examinations.  Determination of patients who are at increased risk for osteoporosis will 
be per institutional guidelines.  Clinical risk factors for fracture include advancing age, 
previous fracture, glucocorticoid therapy, parental history of hip fracture, low body 
weight, current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, 
and secondary osteoporosis (e.g., hypogonadism or premature menopause, 
malabsorption, chronic liver disease, inflammatory bowel disease) (Kanis et al., 2005).   
SECTION 5.1.1.2:  Management of Pneumonitis 
Patients who have DLCO values < 60% will be excluded from the study.  … The DLCO 
test should be repeated if there is clinical suspicion of pneumonitis.  The DLCO test 
will also be repeated presurgery after completion of study treatment. 
TABLE 3:  Dose Modification and Management Guidelines for Pneumonitis  
Table 3 has been revised to include diffusion capacity of the lung for carbon monoxide 
(DLCO) testing for managing pneumonitis. 
 


 
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REFERENCES:   
The following references have been added: 
Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteopors 
Int 2005;16:581− 9.  
MacIntyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur Resp J 
2005;26:720−35. 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 7:  Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume  
Appendix 7 has been added to provide DLCO calculations. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 16 
1. 
BACKGROUND .......................................................................................... 30 
1.1 
Background on the Phosphatidylinositol-3-Kinase 
Pathway................................................................................. 30 
1.2 
Background on Estrogen Receptor-Positive, 
HER2-Negative Breast Cancer.............................................. 30 
1.3 
Background on the PI3K/AKT/MTOR Pathway 
and Breast Cancer................................................................. 31 
1.4 
Background on Reversing Hormonal Resistance 
by Inhibiting the PI3K/MTOR/AKT Pathway........................... 31 
1.5 
Background on Neoadjuvant Therapy in Breast 
Cancer................................................................................... 32 
1.6 
Background on GDC-0032 .................................................... 33 
1.6.1 
Toxicology ............................................................................. 35 
1.7 
Summary of Clinical Data for GDC-0032............................... 36 
1.7.1 
Clinical Safety Data with GDC-0032...................................... 36 
1.7.1.1 
Preliminary Pharmacokinetics ............................................... 37 
1.7.1.2 
Preliminary Pharmacodynamics ............................................ 38 
1.8 
Study Rationale and Benefit-Risk Assessment...................... 39 
2. 
OBJECTIVES.............................................................................................. 41 
2.1 
Efficacy Objectives ................................................................ 41 
2.2 
Safety Objectives................................................................... 41 
2.3 
Patient-Reported Outcome Objectives .................................. 42 
2.4 
Exploratory Objectives........................................................... 42 
3. 
STUDY DESIGN ......................................................................................... 42 
3.1 
Description of Study .............................................................. 42 
3.1.1 
Surgery.................................................................................. 46 
3.1.2 
Independent Data Monitoring Committee .............................. 47 
3.2 
End of Study.......................................................................... 48 
3.3 
Rationale for Study Design.................................................... 48 


 
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3.3.1 
Rationale for Conducting the Study in the 
Neoadjuvant Setting .............................................................. 48 
3.3.2 
Rationale for Patient Population ............................................ 48 
3.3.3 
Rationale for Control Group................................................... 49 
3.3.4 
Rationale for the Efficacy Outcome Measure of 
Response Rate Assessed by Magnetic 
Resonance Imaging............................................................... 50 
3.3.4.1 
Rationale for Efficacy Outcome Measure of 
Pathologic Complete Response ............................................ 51 
3.3.4.2 
Rationale for Ki67 Measurements ......................................... 51 
3.3.4.3 
Rationale for Using the Preoperative Endocrine 
Prognostic Index Score.......................................................... 52 
3.3.4.4 
Rationale for Assessing ORR by Clinical Breast 
Exam (Palpation), Mammography, and Breast 
Ultrasound ............................................................................. 53 
3.3.4.5 
Rationale for Assessing Enhancing Tumor 
Volume by Breast Magnetic Resonance Imaging.................. 53 
3.3.5 
Rationale for Independent Review Facility............................. 53 
3.3.6 
Rationale for Interim Safety Review ...................................... 53 
3.3.7 
Rationale for GDC-0032 Dosage........................................... 53 
3.3.8 
Rationale for Biomarker Assessments................................... 55 
3.3.9 
Rationale for Day 15 Biopsy .................................................. 56 
3.3.10 
Rationale for Collection of Blood Sample for the 
Detection of Plasma Protein Biomarkers ............................... 56 
3.3.11 
Rationale for Collection of Blood Sample for DNA 
Sequencing to Identify Mutations in Plasma.......................... 56 
3.3.12 
Rationale for Collection of Blood Sample for Next 
Generation Sequencing......................................................... 56 
3.3.13 
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 57 
3.3.14 
Rationale for the Collection of DNA for 
Exploratory Pharmacogenetic Polymorphisms ...................... 57 
3.3.15 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 58 
3.4 
Outcome Measures ............................................................... 59 
3.4.1 
Efficacy Outcome Measures.................................................. 59 
3.4.1.1 
Co-Primary Efficacy Outcome Measures............................... 59 


 
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3.4.1.2 
Secondary Efficacy Outcome Measures................................ 59 
3.4.2 
Safety Outcome Measures .................................................... 59 
3.4.3 
Patient-Reported Outcome Measures ................................... 60 
3.4.4 
Exploratory Outcome Measures ............................................ 60 
4. 
MATERIALS AND METHODS .................................................................... 61 
4.1 
Patients.................................................................................. 61 
4.1.1 
Inclusion Criteria.................................................................... 61 
4.1.2 
Exclusion Criteria................................................................... 62 
4.2 
Method of Treatment Assignment and Blinding..................... 64 
4.2.1 
Patient Randomization........................................................... 64 
4.2.2 
Stratification........................................................................... 64 
4.2.3 
Blinding.................................................................................. 64 
4.3 
Study Treatment.................................................................... 65 
4.3.1 
Formulation, Packaging, and Handling.................................. 65 
4.3.1.1 
GDC-0032 and Placebo......................................................... 65 
4.3.1.2 
Letrozole................................................................................ 65 
4.3.2 
Dosage, Administration, and Compliance.............................. 65 
4.3.2.1 
GDC-0032 and Placebo......................................................... 65 
4.3.2.2 
Letrozole................................................................................ 66 
4.3.3 
Investigational Medicinal Product Accountability ................... 66 
4.3.4 
Post-Trial Access to GDC-0032............................................. 66 
4.4 
Concomitant Therapy ............................................................ 67 
4.4.1 
Permitted Therapy ................................................................. 67 
4.4.2 
Prohibited Therapy ................................................................ 68 
4.5 
Study Assessments ............................................................... 69 
4.5.1 
Informed Consent Forms and Screening Log........................ 69 
4.5.2 
Medical History and Demographic Data ................................ 69 
4.5.3 
Physical Examination ............................................................ 69 
4.5.4 
Vital Signs.............................................................................. 69 
4.5.5 
Electrocardiograms................................................................ 69 
4.5.6 
Distant Sites Tumor Assessment........................................... 70 
4.5.7 
Tumor and Response Evaluations......................................... 70 
4.5.8 
Surgical Treatment Plan ........................................................ 71 


 
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4.5.9 
Surgical Specimen – Pathology............................................. 71 
4.5.10 
Laboratory Assessments ....................................................... 71 
4.5.11 
Assay Methods...................................................................... 73 
4.5.11.1 
Mutational Analysis for PIK3CA............................................. 73 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor 
Tissues .................................................................................. 73 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog 
Expression............................................................................. 74 
4.5.11.4 
Confirmation of Estrogen Receptor, 
Progesterone Receptor, and HER2 Status............................ 74 
4.5.11.5 
Circulating Tumor DNA Analysis ........................................... 74 
4.5.11.6 
Messenger RNA Expression Profiling.................................... 74 
4.5.11.7 
Next Generation Sequencing................................................. 74 
4.5.11.8 
Copy Number Analysis .......................................................... 74 
4.5.11.9 
Plasma Biomarker Analyses.................................................. 75 
4.5.11.10 
Plasma Pharmacokinetic Samples ........................................ 75 
4.5.11.11 
Pharmacogenetic Polymorphism Assay ................................ 75 
4.5.11.12 
Electrocardiograms................................................................ 75 
4.5.11.13 
DLCO Testing........................................................................ 75 
4.5.11.14 
Osteoporosis Assessment and Monitoring ............................ 75 
4.5.12 
Patient-Reported Outcomes .................................................. 76 
4.5.13 
Samples for Clinical Repository............................................. 77 
4.5.13.1 
Confidentiality........................................................................ 77 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 78 
4.6.1 
Patient Discontinuation.......................................................... 78 
4.6.2 
Study Treatment Discontinuation........................................... 78 
4.6.3 
Conditions for Terminating the Study .................................... 78 
5. 
ASSESSMENT OF SAFETY....................................................................... 79 
5.1 
Safety Plan ............................................................................ 79 
5.1.1 
Management of Specific Adverse Events of 
GDC-0032 ............................................................................. 79 
5.1.1.1 
Management of Hyperglycemia............................................. 80 
5.1.1.2 
Management of Pneumonitis................................................. 81 


 
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5.1.1.3 
Management of Rash ............................................................ 82 
5.1.1.4 
Management of Gastrointestinal Toxicity............................... 83 
5.1.2 
Management of Other Clinically Significant 
Adverse Events ..................................................................... 87 
5.1.3 
General Guidance for Dose Modifications and 
Delays for Letrozole............................................................... 87 
5.1.4 
Management of Increases in QT Interval............................... 88 
5.1.5 
Safety Monitoring for Letrozole.............................................. 88 
5.2 
Safety Parameters and Definitions ........................................ 89 
5.2.1 
Adverse Events ..................................................................... 89 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to ABCSG)............................................................................. 90 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to ABCSG)..................................... 90 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91 
5.3.1 
Adverse Event Reporting Period ........................................... 91 
5.3.2 
Eliciting Adverse Event Information ....................................... 91 
5.3.3 
Assessment of Severity of Adverse Events ........................... 91 
5.3.4 
Assessment of Causality of Adverse Events ......................... 92 
5.3.5 
Procedures for Recording Adverse Events............................ 93 
5.3.5.1 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 94 
5.3.5.2 
Persistent or Recurrent Adverse Events................................ 94 
5.3.5.3 
Abnormal Laboratory Values ................................................. 94 
5.3.5.4 
Abnormal Vital Sign Values ................................................... 95 
5.3.5.5 
Abnormal Liver Function Tests.............................................. 96 
5.3.5.6 
Deaths ................................................................................... 96 
5.3.5.7 
Preexisting Medical Conditions.............................................. 96 
5.3.5.8 
Hospitalization or Prolonged Hospitalization.......................... 97 
5.3.5.9 
Adverse Events Associated with an Overdose ...................... 97 
5.3.5.10 
Patient-Reported Outcome Data ........................................... 97 
5.4 
Immediate Reporting Requirements from 
Investigator to ABCSG........................................................... 98 
5.4.1 
Emergency Medical Contacts................................................ 98 


 
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5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 99 
5.5 
Follow-Up of Patients after Adverse Events .......................... 99 
5.5.1 
Investigator Follow-Up........................................................... 99 
5.5.2 
Sponsor Follow-Up ................................................................ 99 
5.6 
Post-Study Adverse Events................................................. 100 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 100 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 100 
6.1 
Determination of Sample Size ............................................. 101 
6.2 
Summaries of Conduct of Study.......................................... 101 
6.3 
Summaries of Treatment Group Comparability ................... 102 
6.4 
Efficacy Analyses ................................................................ 102 
6.4.1 
Primary Efficacy Endpoint.................................................... 102 
6.4.2 
Secondary Efficacy Endpoints............................................. 102 
6.5 
Safety Analyses................................................................... 103 
6.6 
Pharmacodynamic Analyses ............................................... 103 
6.7 
Pharmacokinetic Analyses................................................... 103 
6.8 
Patient-Reported Outcome Analyses .................................. 104 
6.9 
Exploratory Analyses........................................................... 104 
6.10 
Interim Analyses.................................................................. 104 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 105 
7.1 
Data Quality Assurance....................................................... 105 
7.2 
Data(Base) Management..................................................... 105 
7.3 
Electronic Case Report Forms............................................. 106 
7.4 
Source Data Documentation................................................ 106 
7.5 
Use of Computerized Systems ............................................ 107 
7.6 
Retention of Records........................................................... 107 
8. 
ETHICAL CONSIDERATIONS.................................................................. 107 
8.1 
Compliance with Laws and Regulations .............................. 107 
8.2 
Informed Consent ................................................................ 108 


 
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8.3 
Institutional Review Board or Ethics Committee.................. 109 
8.4 
Data Privacy ........................................................................ 109 
8.5 
Financial Disclosure ............................................................ 110 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 110 
9.1 
Study Documentation .......................................................... 110 
9.2 
On Site Quality Control (Monitoring).................................... 110 
9.3 
Protocol Deviations.............................................................. 111 
9.4 
Site Inspections ................................................................... 111 
9.5 
Administrative Structure....................................................... 111 
9.6 
Protocol Amendments ......................................................... 112 
10. REFERENCES ......................................................................................... 113 
 
 
LIST OF TABLES 
Table 1 
Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events........................................................................... 80 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose)..................... 81 
Table 3 
Dose Modification and Management Guidelines for 
Pneumonitis ................................................................................ 82 
Table 4 
GDC-0032 Dose Modification and Management Guidelines 
for Rash ...................................................................................... 83 
Table 5 
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea................................................................................. 84 
Table 6 
GDC-0032 Dose Modification and Management Guidelines 
for Colitis..................................................................................... 86 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for 
Stomatitis and Oral Mucositis...................................................... 87 
Table 8 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events .......................................... 87 
Table 9 
Adverse Event Severity Grading Scale ....................................... 92 
Table 10 
Causal Attribution Guidance ....................................................... 93 
 
 
LIST OF FIGURES 
Figure 1 
GDC-0032 Potency in Non-PIK3CA Mutant Breast Cancer 
Cell Lines .................................................................................... 34 


 
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Figure 2 
Combination Effects between Letrozole and GDC-0032 in 
the Aromatase-Expressing MCF7.2x3 Breast Cancer Cell 
Line ............................................................................................. 34 
Figure 3 
Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse 
Xenografts................................................................................... 35 
Figure 4 
Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT 
and WT Tumors .......................................................................... 38 
Figure 5 
Study Schema............................................................................. 44 
Figure 6 
Schematic Representing Confirmation of Progression................ 46 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 119 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 123 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 124 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 
Measures .................................................................................. 130 
Appendix 5 
New York Heart Association Classifications.............................. 134 
Appendix 6 
American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ..................................................................... 135 
Appendix 7 
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume...................................................................................... 145 


GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 2 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY 
OF NEOADJUVANT LETROZOLE PLUS GDC-0032 
VERSUS LETROZOLE PLUS PLACEBO IN 
POSTMENOPAUSAL WOMEN WITH 
ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE 
BREAST CANCER 
PROTOCOL NUMBER: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
MEDICAL MONITOR: 
, M.D., Ph.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 return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 


 
GDC-0032—Genentech, Inc. 
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Principal Investigators: 
 
Author(s): 
Affiliation 
 
, USA 
 
, Belgium 
, Diputació 256 4º1ª 08007 Barcelona, Spain 
, Genentech, South San Francisco, CA, 
USA 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Austria 
, Genentech, South San Francisco, CA, USA 
, Genentech, South San Francisco, CA, USA 
 
 Spain 
 
 Spain 
, Genentech, South San Francisco, USA 
 
, 
Belgium 
 
 Belgium 
 
, Spain 
, Diputació 256 4º1ª 08007 Barcelona, Spain 
 
 
, Spain 
  
 
 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY OF 
NEOADJUVANT LETROZOLE PLUS GDC-0032 VERSUS 
LETROZOLE PLUS PLACEBO IN POSTMENOPAUSAL WOMEN 
WITH ER-POSITIVE/HER2- NEGATIVE, EARLY STAGE BREAST 
CANCER 
PROTOCOL NUMBER: 
GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
PHASE: 
II 
INDICATION: 
Early stage breast cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Efficacy Objectives 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus 
letrozole plus placebo in women with estrogen receptor-positive/human epidermal growth factor 
receptor 2-negative (ER+/HER2-) early stage breast cancer, as measured by the following co-
primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA mutant (MT) patients 
• 
Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local 
evaluation in all enrolled patients and PIK3CA MT patients 
The secondary efficacy objectives of this study are the following: 
• 
Tumor objective response rate (ORR), assessed by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA 
wildtype (WT) patients  
The following secondary objectives will be performed in all enrolled patients and separated by 
PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally assessed 
ORR using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery.  


 
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• 
Compare the centrally assessed, preoperative endocrine prognostic index (PEPI) score 
upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, 
ypNX (breast pCR). 
Safety Objective 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
Patient-Reported Outcome Objectives  
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL) between treatment arms as measured by the 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23) 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited to 
somatic cancer associated mutations, PTEN expression, pro-survival pathways (such as 
PI3K/AKT, MAPK etc.), apoptotic markers, and levels of RNA and DNA expression are 
predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream 
markers in tumor tissue and to examine the relationship to anti-tumor activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline biopsy 
and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole and GDC-
0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or letrozole 
on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in letrozole 
plus GDC-0032 versus letrozole plus placebo. 
Study Design 
Description of Study 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the 
effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal 
women with ER+/HER2- untreated, Stage I-III operable breast cancer whose primary tumors 
are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  Standard of care 
assessments/procedures (e.g., bilateral mammogram) performed within 28 days of Day 1 
dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal cutting 
temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]). Two pretreatment 
FFPE core biopsies and one freshly frozen core biopsy must be obtained for all patients prior to 
beginning study drug treatment.  Prior diagnostic FFPE core biopsies may be used for 
enrollment eligibility purposes.  For the purpose of enrollment, ER, progesterone receptor (PR), 
and HER2 will be locally determined prior to beginning of study treatment. ER, PR, HER2, and 


 
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the percentage of Ki67-positive cells will also be centrally assessed, but the results do not have 
to be available prior to enrollment in the study.  Remaining tissue will be retained for future 
translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not allowed. 
Patients will be randomized into one of the two treatment arms with a 1:1 randomization ratio.  
Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 6 mg or placebo on a 
5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see Figure 5).  A maximum of 
16 weeks of GDC-0032 can be administered.  Letrozole can be continued up to surgery per the 
investigator’s discretion. 
After confirmation of all the eligibility criteria, patients will be randomized to one of the treatment 
arms.  A second biopsy will be performed on Day 15 (Week 3) for biomarker analyses. Biopsies 
should be performed at least 2 hours after GDC-0032 dose administration. 
Randomization will be stratified according to 2 factors: 
1. 
Tumor size (T1-T2 vs. T3) 
2. 
Nodal status (cytologically positive vs. radiologically or cytologically negative) 
The study will enroll approximately 330 patients at approximately 110 global sites. 
At Weeks 1, 5, 9, 13, and 16 the primary breast tumor and axillary lymph nodes will be 
assessed by clinical breast examination (palpation and caliper measurement).  Suspicion of 
progression based on clinical exam at any time should be further evaluated (Figure 6).  
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive disease 
and for the purpose of surgery planning. Suspicion of progressive disease on breast ultrasound 
should be confirmed by investigator-assessed breast MRI.  Patients with primary disease not 
evaluable by ultrasound at baseline should be assessed by MRI at Week 9.  Suspected 
progression in nodes should also be confirmed by fine needle aspiration (FNA) if these nodes 
had not been previously shown to be cytologically positive for cancer.  Patients with progressive 
disease (as defined by modified RECIST, Appendix 3), can either proceed directly to surgery or 
be taken off of the study, according to the investigator’s decision. If the patient goes off-study, 
every reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. Clinical 
breast exam, breast ultrasound, and mammography will also be conducted prior to surgery for 
the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected at screening, at Week 3, and 
prior to surgery. 
Surgery 
Surgery will take place after at least 16 weeks of treatment, during Weeks 17 − 18.  Surgery 
should be performed within 4 days after the last dose of GDC-0032, if possible, to best observe 
pharmacodynamic knockdown with GDC-0032 in the surgical specimen.  Surgery may be 
delayed due to toxicity or other safety issues, upon discussion with the Medical Monitor (see 
Section 5.4.1) or recommendations from the Independent Data Monitoring Committee (IDMC; 
see below).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be 
continued up to surgery per the investigator’s discretion.   
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. Surgery specimens will be 
collected for histological examination to assess for pCR and for other endpoint analyses. 
Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the end of 
the study. Assessment of adverse events and general safety will be collected at this visit and 
the plan for future treatment will be recorded. 


 
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The patient should be evaluated at baseline and after Week 13 of treatment for planning of the 
surgical procedure (BCS or mastectomy), and both physician recommendation and final patient 
decision should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pathological complete response (pCR–ypT0/is, ypN0) will be 
established via a local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and directions 
for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  IRF 
procedures are detailed in the IRF charter. 
Number of Patients 
The study will enroll approximately 330 patients at approximately 110 global sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age ≥ 18 years. Postmenopausal status is defined as follows: 
– 
Age ≥ 60 years or 
– 
Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) 
and plasma estradiol levels within postmenopausal range by local laboratory 
assessment or 
– 
Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated as the “target” lesion for 
all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as determined by 
institutional practice (in patients where there may be a reasonable suspicion of 
advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and 
symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable 
for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5  ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be 
enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase 
≤ 1.5 × ULN  


 
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• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the basis of the 
Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × ULN and activated partial thromboplastin time 
(aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is 
required.  If anticoagulation is required for a prosthetic heart valve, then INR should be 
between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply with the 
protocol, in the investigator’s judgment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as optimal neoadjuvant 
treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric absorption 
• 
History of prior or currently active small or large intestine inflammation (such as Crohn’s 
disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
> 470 msec 
• 
DLCO <  60% of the predicted values (see Appendix 7 for calculations) 
• 
Clinically significant (i.e., active) cardiovascular disease, like uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II-IV (New York Heart 
Association, Appendix 5), or any other that in the judgment of the investigator could 
jeopardize patient safety or study outcomes 
• 
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 


 
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– 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, that may affect 
the interpretation of the results, or renders the patients at high risk from treatment 
complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer 
Concomitant 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 7 days prior to 
screening to the study completion/discontinuation visit.   
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak time 
dependent inhibitor of CYP3A4.  Although in vitro induction studies in human hepatocytes 
suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, preliminary data 
from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 daily for 2 weeks in 
patients had no apparent effect on the pharmacokinetics of midazolam (a sensitive CYP3A4 
substrate).  Therefore, GDC 0032 may be administered concomitantly with CYP3A4 substrates 
without the risk of a pharmacokinetic drug-drug interaction (DDI).  
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy (other than letrozole permitted in this protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is receiving 
these at the moment of registration, treatment should be discontinued prior to 
randomization.  
• 
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.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an alternate 
medication with no or minimal potential to inhibit CYP3A4.  If a strong CYP3A4 inhibitor is 
co-administered with GDC-0032, patients should be closely monitored for adverse reactions. 


 
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• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., 
phenytoin, carbamazepine, rifampin, phenobarbital) with GDC-0032 should be avoided.  
Consider an alternate medication with no or minimal potential to induce CYP3A4.  If a 
strong CYP3A4 inducer is co-administered with GDC-0032, patients should be closely 
monitored for adverse reactions. 
Length of Study 
The total duration of the study is expected to be approximately 24 months for enrollment, plus 
5.5 months after last patient in. 
End of Study 
The end of the study is defined as the date when the last patient has her postsurgery visit.  
Outcome Measures 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR via centrally assessed breast MRI via modified RECIST (Appendix 3) in all 
enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the American Joint 
Committee on Cancer staging system (Appendix 6) by local evaluation in all enrolled 
patients and PIK3CA MT patients 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST (Appendix 3) 
in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients 
The following secondary outcome measures will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery 
• 
Compare the centrally assessed PEPI score upon treatment with letrozole plus GDC-0032 
with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) yoT0/is, 
ypNX (breast pCR) 
Safety Outcome Measures 
The safety and tolerability of GDC-0032 will be assessed using the following primary safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during the 
adverse event reporting period (see Section 5.3.1) 


 
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Patient-Reported Outcome Measures  
The PRO outcome measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty swallowing, 
diarrhea, skin problems), and patient functioning as measured using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ–C30) and the modified breast cancer module QLQ–BR23 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are not 
limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
Circulating tumor DNA (ctDNA) 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 versus 
letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug safety 
response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing enzymes and 
transporters and other patient-specific covariates with PK of GDC-0032 or letrozole and/or 
drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a marker of 
tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, diffusion 
metrics], ultrasound, mammography) in measuring tumor response 
Investigational Medicinal Products 
Study treatment is neoadjuvant (pre-operative) therapy.   
Test Product 
The test product for this study is GDC-0032.  Patients will receive an oral, daily dose of 6 mg 
GDC-0032 or placebo on a schedule of 5 days on/2 days off for a maximum of 16 weeks.  
Patients will take GDC-0032 at the same time of day ± 2 hours, unless otherwise instructed.  
Patients will be instructed as to the number of tablets to take.  
Information on the formulation, packaging, handling, and administration of GDC-0032 are 
provided in the GDC-0032 Investigator’s Brochure. 
Non-Investigational Medicinal Products 
Letrozole 
Letrozole is a marketed product that is approved in the European Union and the United States 
for the treatment of hormone receptor-positive breast cancer.  Based upon the different 
mechanisms of action of GDC-0032 and the well-established safety profile of letrozole, there 
are no expected overlapping, significant toxicities between letrozole and GDC-0032.   
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of surgery 
at the investigator’s discretion).   


 
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Statistical Methods 
Primary Analysis 
This study is designed for testing the effect of GDC-0032 on the two co-primary endpoints in all 
enrolled patients and in the PIK3CA MT patients and plans to enroll 330 patients in total. 
Assuming the PIK3CA mutation status will not be available (unknown) for approximately 10% of 
the patients and the prevalence of PIK3CA mutant is 40%, there will be approximately 120 
patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, there 
might be a possible imbalance between treatment arms within the PIK3CA MT cohort, which 
may reduce the statistical power in this cohort. To ensure the study provides sufficient statistical 
power even when the treatment assignment is imbalanced, the sample size was calculated 
based on a conservative scenario by assuming that the treatment assignment imbalance in 
PIK3CA MT is 40% vs. 60%. The sample size was calculated based on a chi²-test using 
continuity correction (Ury and Fleiss 1980). 
To control an overall two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 enrolled 
patients and 108 patients in the PIK3CA MT cohort will be evaluable for analyses. This sample 
size allows us to detect an absolute percentage increase of 24% in MRI ORR rate in the GDC-
0032 plus letrozole arm (64%) versus the letrozole-only arm (40%; Smith et al. 2005; Ellis and 
Ma 2007) in the PIK3CA MT cohort at 80% power and 16% two-sided significance level.  The 
minimal detectable difference for ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled patients and 
120 in the PIK3CA MT cohort), this sample size provides 80% power to detect an absolute 
percentage increase of 18% in pCR in the GDC-0032 plus letrozole arm (19%) versus the 
letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at the 
4% two-sided significance level.  The minimal detectable difference for pCR rate is 
approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more substantial 
treatment assignment imbalance in the PIK3CA MT cohort than assumed, or there is an 
increased number of unevaluable patients for the MRI ORR, the sample size may be increased 
to obtain the level of power at 80%, and the enrollment may be limited to patients with PIK3CA 
MT.   
Secondary Analysis 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by 
breast MRI in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT 
patients.  
These endpoint measures will be summarized by treatment arm and will be analyzed analogue 
to the primary efficacy endpoint. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
ORR by clinical breast examination, mammography and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery 
(centrally assessed) 
• 
PEPI score (centrally assessed) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
These endpoint measures will be summarized by treatment arm and will be compared between 
the two treatment arms within each population based on appropriate statistical analyses: ORR 


 
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will be compared using a Cochrane Mantel-Haenszel test, stratified by tumor size and nodal 
status; PEPI, Ki67, and tumor volume change will be compared by regression analyses, 
adjusted for tumor size and nodal status. All secondary endpoints will be tested at a two-sided 
type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
Determination of Sample Size   
 Please refer to the primary analysis in the Statistical Methods section. 
 Interim Analyses 
An Independent Data Monitoring Committee (IDMC) will monitor accumulating patient safety 
data at a minimum of once every 6 months until the last patient has completed study treatment.  
Additional details (e.g., IDMC members, communication, affiliations) will be provided in the 
IDMC charter.   
The IDMC will conduct interim analyses to review the unblinded safety data after the first 20 
patients have either 1) finished the 30-day follow-up visit after the surgery, or 2) been on study 
for 20 weeks after the randomization date (for those who do not receive the surgery).  The 
IDMC will create and review unblinded, pooled summaries of the safety and available PK 
summaries (all interim analyses).  While this review is being conducted, patient accrual into the 
study will continue.  The Medical Monitor may also request additional safety analysis and may 
call for additional meetings of the IDMC to review ongoing safety data.  
The IDMC will share results from interim safety analyses with the study team.  The study team 
will share interim safety results with study investigators as needed for the conduct of the study 
and the safety of the patients.  Specific potential safety issues anticipated in this trial, as well as 
measures intended to avoid, minimize, and manage such toxicities, are outlined in the following 
sections.  All available information of all enrolled patients with all available assessments at the 
respective timepoint will be included in the interim analyses. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABCSG 
Austrian Breast and Colorectal Cancer Study Group 
ADC 
apparent diffusion coefficient 
AE 
adverse events 
AI 
aromatase inhibitors 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ASCO-CAP 
American Society of Clinical Oncology-College of 
American Pathologists 
AST 
aspartate aminotransferase 
AUC0-24 
area under the concentration–time curve from 0 to 24 
hours 
BCS 
breast conserving surgery 
BIG 
Breast International Group 
BUN 
blood urea nitrogen 
CD 
compact disc 
CI 
confidence interval 
Cmax 
maximum plasma concentration observed  
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
cPR 
confirmed partial responses 
CRA 
clinical research associate 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTNeoBC 
Collaborative Trials in Neoadjuvant Breast Cancer 
DCR 
data clarification request 
DDI 
drug-drug interaction 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DMP 
data management plan 
DXA 
dual-energy X-ray absorptiometry 
DVD 
digital video disk 
EC 
Ethics Committee 
EC50 
50% effective concentration 
ECG 
electrocardiogram 


 
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Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER+ 
estrogen receptor-positive 
E.U. 
European Union 
FFPE 
formalin-fixed paraffin-embedded 
FDA 
Food and Drug Administration 
FNA 
fine needle aspiration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HLM 
human liver microsomes 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
ISH 
in situ hybridization 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 


 
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Abbreviation 
Definition 
LDL 
low-density lipoprotein 
LPLV 
last patient, last visit 
MAPK 
mitogen-activated protein kinase 
MDD 
minimum detected difference 
MP 
monitoring plan 
MRI 
magnetic resonance imaging 
MT 
mutant 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSCLC 
non − small-cell lung cancer 
nu/nu 
immunocompromised nune (mice) 
OCT 
Optimal cutting temperature 
ORR 
objective response rate 
pAKT 
phosphorylated form of AKT 
pCR 
pathologic complete response 
PD 
progressive disease 
PEPI 
preoperative endocrine prognostic index 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PI3K 
phosphatidylinositol-3-kinase 
PIP2 
phosphatidylinositol-4,5-bisphosphate 
PIP3 
phosphatidylinositol 3,4,5 trisphosphate 
PO 
oral 
PR 
progesterone receptor 
PRO 
patient-reported outcome 
PTEN 
phosphatase tensin homolog 
QD 
once daily 
QLQ-BR23 
Quality of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
relapse-free survival 
RPPA 
reverse phase protein array 


 
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Abbreviation 
Definition 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
source data verification 
SLNB 
sentinel lymph node biopsy 
SOLTI 
Spanish Breast Cancer Research Group 
SOP 
standard operating procedure 
SmPC 
summary of product characteristics 
t1/2 
terminal half-life 
TGI 
tumor growth inhibition 
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
WT 
wildtype 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON THE PHOSPHATIDYLINOSITOL-3-KINASE 
PATHWAY 
Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase involved in tumor cell proliferation, 
survival, and migration upon activation by growth factor receptors and integrins.  
PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) 
to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Cantley 2002), 
a second messenger involved in the phosphorylation of AKT and associated proteins in 
the AKT-mammalian target of rapamycin (mTOR) pathway (Guertin and Sabatini 2007).  
Activating and transforming mutations, as well as amplification, in the p110α subunit of 
PI3K are commonly found in solid and hematological tumors (Li et al. 1997).  In addition, 
the PI3K-AKT pathway is activated in numerous types of cancer by receptor tyrosine 
kinase signaling, the loss of the phosphatase tensin homolog (PTEN), or RAS mutations 
(Shayesteh et al. 1999 ; Cantley 2002; Massion et al. 2004; Wu et al. 2005). 
1.2 
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE, 
HER2-NEGATIVE BREAST CANCER 
Breast cancer is the most frequently diagnosed cancer worldwide and the leading cause 
of cancer death among females, accounting for 23% of the total cancer cases and 14% 
of total cancer deaths (Jemal et al. 2011).  As a large proportion of breast cancer cases, 
especially in developed countries, are now diagnosed in early stages, they are amenable 
to cure with a stage-appropriate combination of surgery, systemic therapy 
(chemotherapy and/or hormonal therapy), and radiotherapy. 
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative 
(HER2-) breast cancer accounts for about 60% − 70% of all breast cancers.  However, 
not all ER+ breast cancers respond optimally to endocrine therapy (Davies et al. 2011).  
There are several mechanisms that can lead to primary and/or secondary hormonal 
resistance in ER+ breast cancer:  decrease of ER expression, loss of ER expression, or 
upregulation of growth factor signaling pathways, like the epidermal growth factor 
receptor (EGFR)/HER2, the mitogen-activated protein kinase (MAPK), or the 
PI3K/AKT/mTOR pathways (Johnston 2009). 
In the setting of ER + /HER2-negative breast cancer, the PI3K/AKT/mTOR pathway plays 
an important role in mediating hormonal resistance and is a viable therapeutic target to 
explore (Miller et al. 2010). 


 
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1.3 
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Genes in the PI3K/AKT/mTOR signaling pathway are frequently mutated or amplified in 
breast cancer, especially in the ER+ subtype (Cancer Genome Atlas Network 2012).  
Molecular alterations of the PI3K/AKT/mTOR pathway include the following: (1) 
Mutations or amplifications in PIK3CA, the gene encoding the alpha catalytic subunit of 
PI3K (p110α) (Saal et al. 2005; Wu et al. 2005); (2) Alterations in the tumor suppressor 
gene PTEN, either by loss of protein expression (PTEN null), inactivation mutations 
and/or epigenetic deregulation through promoter hypermethylation (García et al. 2004); 
(3) PDKP1 amplification and/or overexpression (Brugge et al. 2007); (4) AKT1 somatic 
gain of function mutations (Stemke-Hale et al. 2008) and AKT2 amplifications (Bellacosa 
et al. 1995). Overall, it is estimated that up to 70% of breast cancers can have some 
form of molecular aberration of the PI3K/AKT/mTOR pathway (CGAN 2012).   
1.4 
BACKGROUND ON REVERSING HORMONAL RESISTANCE BY 
INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, PI3K seems to play an important role in mediating 
hormonal resistance and may be a viable therapeutic target. Hyperactivation of this 
signaling pathway was proved to promote both de novo and acquired resistance to 
hormone therapy in ER+ breast cancer cell lines and xenograft models (Sabnis et al. 
2007), and simultaneous blocking of the PI3K/AKT/mTOR pathway with everolimus and 
the ER pathway with letrozole enhances antitumor activity of either agent alone (Boulay 
et al. 2005). Importantly, a baseline protein signature of PI3K activation was found to be 
predictive of a poor prognosis after adjuvant endocrine therapy (Miller et al. 2010). 
In the clinical setting, impressive results of the combination of exemestane and 
everolimus, an mTOR inhibitor, were reported in the BOLERO-2 trial (Baselga et al. 
2009). This trial compared everolimus and exemestane with placebo and exemestane in 
724 postmenopausal patients with ER+ advanced breast cancer who had experienced 
recurrence or progression while receiving previous therapy with a nonsteroidal 
aromatase inhibitor in the adjuvant setting and/or in advanced disease. Median 
progression-free survival (PFS) in the everolimus group was 6.9 months, as compared to 
2.8 months in the placebo group.  Hazard ratio (HR) for progression or death was 0.43, 
with a 95% confidence interval (CI) of 0.35 − 0.54 (p < 0.001), as per the investigator’s 
assessment, and the magnitude of the effect was even greater as per central 
assessment (HR, 0.36, 95% CI, 0.27 − 0.47; p < 0.001).  In the open-label Phase II 
TAMRAD trial, patients with aromatase inhibitors (AI) resistant metastatic breast cancer 
received tamoxifen plus everolimus or tamoxifen alone (Bachelot et al. 2012). The 
6-month clinical benefit rate was 61% (95% CI, 47% − 74%) with tamoxifen plus 
everolimus and 42% (95% CI, 29% − 56%) with tamoxifen alone. Time to progression 
increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus 
everolimus, corresponding to a 46% reduction in risk of progression with the combination 


 
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(HR, 0.54; 95% CI, 0.36 − 0.81).  Risk of death was reduced by 55% with tamoxifen plus 
everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 − 0.81). 
In the neoadjuvant setting, combination of letrozole and everolimus also resulted in 
improved responses over letrozole alone in patients with ER+ breast cancer (Baselga et 
al. 2009).  In this study, 270 postmenopausal patients with operable ER+ breast cancer 
were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole and 
either everolimus or placebo. The primary endpoint of the trial, clinical response by 
palpation, was higher in the everolimus arm than in the control arm (68.1% vs. 59.1%, 
p = 0.062), a statistically significant result (one-sided, α = 0.1 level). 
An important finding in trials with mTOR-targeting drugs like everolimus is that they 
produce a pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the phosphorylated form of AKT (pAKT), resulting in feedback 
PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009). This finding suggests that 
alternative pharmacologic strategies to effectively shut down the pathway upstream of 
AKT should be pursued.  One of these strategies is inhibiting the PI3K/AKT/mTOR 
pathway at the level of PI3K. 
1.5 
BACKGROUND ON NEOADJUVANT THERAPY IN 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 and Smith 2003; Scholl et al. 1994; Semiglazov et al. 2004; 
Fisher et al. 2012; Wolff and Davidson 2000).  The randomized studies evaluating 
neoadjuvant therapy as well as meta-analyses of these studies have shown that 
neoadjuvant therapy can improve breast conservation rates, decreasing the number of 
women obligated to undergo mastectomy (Mieog et al. 2007; Fisher et al. 2012).  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).  The concept of neoadjuvant therapy is now well established and a standard 
treatment option for patients with early breast cancer.  The Collaborative Trials in 
Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis was recently conducted 
evaluating over 12,000 patients treated with neoadjuvant chemotherapy as part of 
clinical trials (Cortazar et al. 2012).  The results of this meta-analysis confirmed an 
association of pathologic complete response [pCR] with favorable long-term outcomes in 
high-risk populations (i.e., HER2-positive, high-grade hormone receptor positive and 
triple negative subtypes), although the magnitude of pCR improvement predictive of the 
long-term survival benefits could not be determined.  In September 2013, the Food and 
Drug Administration (FDA) granted accelerated approval of Perjeta as part of a complete 
treatment regimen for patients with HER2-positive, locally advanced, inflammatory, or 
early stage breast cancer in the neoadjuvant setting. 


 
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1.6 
BACKGROUND ON GDC-0032 
GDC-0032 is a potent selective inhibitor of Class I PI3K alpha, delta, and gamma 
isoforms, with 30-fold less potent inhibition of the beta isoform that is being developed as 
a therapy for human cancers.  Nonclinical studies with GDC-0032 demonstrate that 
GDC-0032 inhibits proliferation of p110α-mutant breast cell lines, inhibits tumor growth 
in human breast xenograft models harboring PIK3CA mutations, and results in a 
substantial reduction of PI3K pathway markers, including pAkt, pPRAS40, and pS6.   
GDC-0032 has demonstrated activity in nonclinical models of PIK3CA-mutant breast 
tumors in vivo as a single agent and in combination with standard of care (e.g., paclitaxel 
or docetaxel) or endocrine therapies (e.g., letrozole or fulvestrant).  GDC-0032 has a 
favorable in vitro and nonclinical in vivo absorption, distribution, metabolism, and 
elimination profile that has characteristics consistent with a compound that can be 
delivered orally to achieve clinical exposure similar to the nonclinical efficacy findings 
described herein.  Additional studies, including 16-week toxicity studies in rats and dogs, 
phototoxicity studies, and an embryo-fetal development study, support the Phase II 
neoadjuvant trial with GDC-0032 in combination with endocrine therapy.   
In vitro, single-agent GDC-0032 potency is also observed in cell lines that do not harbor 
PIK3CA mutations (Figure 1).  In in vitro combination studies, the aromatase-expressing 
breast cancer cell line (MCF7X2.3.ARO) showed positive combination effects between 
GDC-0032 and endocrine therapies (see Figure 2).  In this cell line, GDC-0032 alone 
caused growth inhibition (50% effective concentration [EC50]  = 95 nM). Effects on growth 
were also observed with letrozole and fulvestrant.  Combined treatment of cells with 
GDC-0032 and letrozole caused dose-dependent inhibition of cell viability at lower 
concentrations of either GDC-0032 or letrozole resulting in enhanced activity for the 
combination. In addition, combination activity was demonstrated in the PIK3CA wild-type 
(WT) cell line ZR75-1 when GDC-0032 was added to either fulvestrant or tamoxifen 
endocrine therapies (combination with letrozole not available in this cell line).  However, 
in vivo data in a PIK3CA WT model are not available, because these cell lines do not 
grow as xenografts. 




 
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Figure 3 Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse Xenografts 
 
 
QD = once daily; PO = oral gavage. 
Vehicle was MCT (0.5% methycellulose/0.2% Tween-80). 
Tamoxifen pellets (5 mg/pellet, 60-day release) were implanted on Day 0 of dosing (8 days post 
tumor implantation).  Tumor volumes after QD oral administration of GDC-0032 for 21 days are 
depicted by dose group. 
 
Please refer to the GDC-0032 Investigator’s Brochure for additional nonclinical data for 
GDC-0032 supporting this clinical trial.    
 
1.6.1 
Toxicology 
Please refer to the GDC-0032 Investigator’s Brochure for details on the toxicology 
program to support this clinical trial.   
 


 
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1.7 
SUMMARY OF CLINICAL DATA FOR GDC-0032  
1.7.1 
Clinical Safety Data with GDC-0032 
As of 5 July 2013, a total of 144 patients have been treated with GDC-0032 either as 
single agent (90, 63%) or in combination with endocrine therapy (54, 37%). 
GDC-0032 is currently in Phase I (Study PMT4979g).  Study PMT4979g is an open-label, 
dose-escalation trial using a 3 + 3 design to assess the safety, tolerability, and 
pharmacokinetics of GDC-0032 administered orally daily for 28 days to patients with 
locally advanced or metastatic solid tumors and in combination with endocrine therapy in 
ER+ breast cancers.  As of 5 July 2013, enrollment into the dose-escalation stage of 
Study PMT4979g had been completed with 34 patients enrolled at doses with a range of 
3  to 16 mg daily.  GDC-0032 was well tolerated in the first three cohorts (3, 5, and 8 mg), 
with no patients experiencing a dose-limiting toxicity (DLT).  At the 16-mg dose level, 
2 of the 11 safety-evaluable patients experienced a DLT (Grade 4 hyperglycemia and 
Grade 3 fatigue).  At the 12-mg dose level, 1 of the 10 safety-evaluable patients 
experienced a DLT of Grade 3 acute renal failure.  Although the single-agent GDC-0032 
maximum tolerated dose (MTD) was not exceeded at the 16-mg dose level, the 
recommended GDC-0032 dose and schedule for the single-agent expansion cohorts is 
9 mg daily on the basis of long-term safety data through multiple treatment cycles.  As of 
the cutoff date, a total of 53 patients have been enrolled in the 9-mg daily dosing 
expansion cohorts.  
As of 5 July 2013, adverse events that occurred in ≥ 10% of the 87 patients treated with 
daily single-agent GDC-0032 and were assessed as related to GDC-0032 were as 
follows:  diarrhea (47%), hyperglycemia (38%), nausea (36%), fatigue (34.5%), 
decreased appetite (31%), rash (16%), stomatitis (13%), vomiting (13%), and mucosal 
inflammation (11.5%).  Study−drug-related Grade 3 and 4 adverse events included 
hyperglycemia (9.4%), colitis (7.5%), pneumonitis (3.8%), rash (including maculopapular 
rash with or without itching, redness, and peeling) 5.7%, asymptomatic increased 
aminotransferase levels in the blood (1.9%), anemia (1.9%), increase in blood creatinine 
(1.9%), diarrhea (1.9%), fatigue (1.9%), hypokalemia (1.9%), hypophosphatemia (1.9%), 
pneumonia (1.9%) and stomatitis (1.9%).    
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (19 patients at 6 mg, and 8 patients at 
9 mg) daily in combination with letrozole (Cohort E).  No DLTs were observed at either 
dose level.  Adverse events that occurred in ≥ 10% of the 27 safety-evaluable patients 
assessed as related to GDC-0032 were diarrhea (67%), fatigue (30%), nausea (30%), 
decreased appetite (26%), hyperglycemia (26%), stomatitis (26%), dysgeusia (22%), 
mucosal inflammation (18.5%), rash (18.5%), asthenia (15%), pruritis (15%), vomiting 
(15%), dry mouth (11%), dry skin (11%) and muscle spasms (11%). Study − drug-related 
Grade 3 and 4 adverse events included diarrhea (11%), mucosal inflammation (7.4%), 
increased amylase in the blood (3.7%), increased aspartate aminotransferase (AST) in 


 
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the blood (3.7%), increased alkaline phosphate in the blood (3.7%), fatigue (3.7%), 
increased gamma-glutamyltransferase in the blood (3.7%), hyperglycemia (3.7%), 
hypokalemia (3.7%), increased lipase in the blood (3.7%), papilloedema (3.7%) and 
stomatitis (3.7%). 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (21 patients at 6 mg and 6 patients at 9 mg) 
in combination with fulvestrant (Cohort F).  No DLTs were observed at either dose level.  
One patient has been enrolled in the Phase II part of the study with 6 mg GDC-0032 in 
combination with fulvestrant.  Adverse events that occurred in ≥ 10% of the 27 patients 
and were assessed as related to GDC-0032 were diarrhea (46%), hyperglycemia (32%), 
nausea (32%), decreased appetite (25%), fatigue (25%), rash (21%), stomatitis (21%), 
asthenia (18%), muscle spasms (14%), vomiting (14%), dysgeusia (11%), 
gastroesophageal reflux disease (11%) and mucosal inflammation (11%).  Study− drug-
related Grade 3 and 4 adverse events included hyperglycemia (14%), diarrhea (7%), 
dyspnea (4%), flank pain (4%), hyponatremia (4%), neutropenia (4%), rash (4%) and 
vomiting (4%). 
Please refer to the GDC-0032 Investigator’s Brochure for additional information. 
1.7.1.1 
Preliminary Pharmacokinetics 
Pharmacokinetic (PK) data are available from 34 patients treated with GDC-0032 at 3, 5, 
8, 12, and 16 mg in the ongoing Phase I/II clinical trial (Study PMT4979g).  The cohort 
mean apparent clearance and the terminal half-life (t1/2) following a single, oral dose of 
GDC-0032 had a range of 4.77−9.17 L/hour and 36.7−43.8 hours, respectively.  
Following daily oral dosing for 8 days, there was a 2- to 4-fold accumulation of 
GDC-0032.  The pharmacokinetics of GDC-0032 appears to be dose linear and time-
independent.  Preliminary PK data from Cohort E suggest there is no drug-drug 
interaction (DDI) between letrozole plus GDC-0032.  Mean plasma exposure of letrozole 
when given in combination with GDC-0032 (maximum concentration observed 
[Cmax] = 0.407 μM and area under the concentration–time curve from 0 to 24 hours 
[AUC0-24 ] = 8.01 μM*hr) was comparable with the historical single-agent exposure 
(Cmax = 0.495 μM and AUC0-24  = 10.1 μM*hr) (Awada et al. 2008). Similarly, plasma 
concentrations of GDC-0032, when given in combination with letrozole, were within the 
range predicted by the population PK model. Therefore, letrozole plus GDC-0032 can be 
co-administered without the risk of a DDI.  
GDC-0032 was metabolized primarily by CYP3A4 in human liver microsomes (HLMs) 
and appeared to be a weak time-dependent inhibitor of CYP3A4.  Although in vitro 
induction studies in human hepatocytes suggested that GDC-0032 has low to moderate 
potential to induce CYP3A4, preliminary data from the Phase I/II study (PMT4979g) 
indicate that 9 mg of GDC-0032 daily for 2 weeks in patients had no apparent effect on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate).  Therefore, 


 
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GDC-0032 may be administered concomitantly with CYP3A4 substrates without the risk 
of a PK DDI.  
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.7.1.2 
Preliminary Pharmacodynamics 
Paired tumor biopsies were obtained from both PIK3CA MT and PIK3CA WT non-small 
cell lung cancer (NSCLC) patients treated at either the 3-mg or 16-mg GDC-0032 dose 
level, respectively, at screening (pretreatment biopsy) and during Cycle 1 in 
Study PMT4979g (on-treatment biopsy).  Inhibition of PI3K pathway markers, including 
decreases of > 60% in pAKT and pS6 (compared with baseline), were demonstrated in 
these patients’ paired tumor biopsies (see Figure 4).  
Figure 4 Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT and WT 
Tumors 
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
(16mg): NSCLC adeno 
PIK3CA wt, EGFR (exon 19 del) 
 (3mg): NSCLC (squam) 
PIK3CA (H1047R) 
 
 
MT = mutant; NSCLC = non − small-cell lung cancer; WT = wild type. 
 
As of 5 July 2013, metabolic partial responses via FDG-PET ( ≥ 20% decrease in 
maximum standardized uptake value) were observed in 23 out of 38 patients assessed 
(61%) and included patients from the lowest dose tested (3 mg).  Thirteen of these 23 
were breast cancer patients.  Of the 13 response-evaluable patients treated with 
GDC-0032 plus letrozole, 10 patients (77%) had a partial metabolic response.  Of the 15 
response-evaluable patients treated with GDC-0032 plus fulvestrant, 11 (73%) had a 
partial metabolic response.  


 
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For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.8 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Cancer is one of the leading causes of death worldwide, with solid tumors accounting for 
the majority of these deaths.  An estimated 1.38 million women across the world were 
diagnosed with breast cancer in 2008, accounting for 23% of all cancers diagnosed in 
women.  Breast cancer is the most common cause of death from cancer in women 
worldwide, estimated to be responsible for almost 460,000 deaths in 2008 (Ferlay et al. 
2010). 
A neoadjuvant study in a similar patient population with the combination of letrozole and 
the mTOR inhibitor everolimus has already been completed (Baselga et al. 2009).  
Please refer to Sections 1.4, 1.5, and 3.3 for further rationale supporting the proposed 
trial design of combining GDC-0032 with letrozole in the neoadjuvant setting for this 
patient population.  In postmenopausal women with hormone receptor-positive 
metastatic breast cancer, it is hypothesized that the combination of decreasing estrogen 
levels with letrozole and inhibition of the PI3K pathway with GDC-0032 may have 
improved anti-tumor activity as compared to endocrine therapy alone.  This is supported 
by the nonclinical and clinical data outlined below. 
GDC-0032 is a potent, selective small molecule inhibitor of Class 1 PI3K that is being 
developed by Roche/Genentech as an anti-cancer therapeutic agent.  Activating and 
transforming mutations in the p110 alpha subunit of PI3K are commonly found in tumors.  
GDC-0032 has been shown to be a potent inhibitor of growth in various human cancer 
cell lines, and especially in nonclinical models of PIK3CA MT tumors.  In addition, 
combination activity was demonstrated in the PIK3CA WT cell line ZR75-1 when 
GDC-0032 was added to either fulvestrant or tamoxifen endocrine therapies 
(combination with letrozole not available in this cell line).   
GDC-0032 has also shown additive efficacy in combination with endocrine therapy in a 
hormone receptor-positive breast cancer xenograft model as outlined in Section 1.6. 
Nonclinical data support the investigation of GDC-0032 as a single-agent in solid tumors 
and in combination with endocrine therapy in patients with hormone receptor-positive, 
advanced breast cancer.  
Available clinical data with single-agent GDC-0032 suggest that GDC-0032 has 
dose-linear pharmacokinetics with a half-life of approximately 37− 44 hours.  
Pharmacodynamic markers of PI3K pathway inhibition upon treatment with GDC-0032 
have been observed.  These include decreases in phospho-S6 in platelet-rich plasma 
and decreases in F- flurodeoxyglucose-positron emission tomography uptake.  Available 
clinical data also include multiple confirmed partial responses in patients treated with 
GDC-0032.  These include a patient with PIK3CA MT lung adenocarcinoma treated at 
the 3 mg daily dose and another patient with PIK3CA MT, hormone receptor-positive, 
HER2-positive metastatic breast cancer treated at the 5 mg daily dose.  In addition, a 


 
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patient with PIK3CA WT lung cancer treated at the 3 mg daily dose has had prolonged 
stable disease and remained on study for over 11 months.  These data show that single-
agent GDC-0032 doses below 6 mg have been shown to have anti-tumor activity.  
These aggregate data support the use of 6 mg in combination with letrozole.   
Letrozole is a marketed product that is approved in the European Union (E.U.) and the 
United States (U.S.) for the treatment of hormone receptor-positive breast cancer.  
Based upon the different mechanisms of action of GDC-0032 and the well-established 
safety profile of letrozole, there are no expected overlapping, significant toxicities 
between letrozole and GDC-0032.  
As of 5 July 2013, efficacy data are available for 24 patients treated with GDC-0032 in 
combination with letrozole; 3 patients (12.5%) had a partial response as best overall 
response, 2 of which were confirmed partial responses (cPRs) (1 cPR at 6 mg; 1 cPR at 
9 mg).  Of the 25 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 7 patients (28%) had a partial response as best overall response, of which 3 
were cPRs (1 cPR at 6 mg; 1 partial response at 9 mg).  cPRs have been observed in 
both PIK3CA mutant and PIK3CA WT breast cancer patients.  Maintenance of cPR has 
been observed in a patient who had a dose reduction from 6 mg to 3 mg for an adverse 
event.  In addition, no additional safety concerns have been observed with GDC-0032 in 
combination with letrozole in the ongoing Phase I study compared to GDC-0032 given 
as single agent. 
A number of clinically appropriate strategies to minimize risk to patients have been built 
into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, 
protocol design, and management guidelines.  These will also be clearly highlighted and 
discussed in detail at investigator meetings and site visits.  In addition, please refer to 
the GDC-0032 Investigator’s Brochure for details regarding potential risks, associated 
precautions, and other relevant nonclinical and clinical safety information. 
Due to the need to develop improved therapies to reverse or delay resistance to current 
endocrine therapy in HER2-negative, hormone receptor-positive breast cancer and on 
the basis of the clinical and nonclinical data available for GDC-0032, Genentech/Roche 
feels that the risk-benefit profile of GDC-0032 in combination with letrozole in 
postmenopausal patients with HER2-negative, hormone receptor-positive early stage 
breast cancer is favorable for proceeding with the proposed randomized Phase II clinical 
trial. 


 
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2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 
versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as 
measured by the following co-primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled 
patients and PIK3CA MT patients  
The secondary efficacy objectives of this study are the following: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified Response 
Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in 
PIK3CA WT patients  
 
• 
The following secondary objectives will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally assessed, preoperative endocrine prognostic index (PEPI) 
score upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
 
2.2 
SAFETY OBJECTIVES 
• 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
 


 
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2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, 
and health-related quality of life (HRQoL) between treatment arms as measured by 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module 
(QLQ-BR23) 
2.4 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-
weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited 
to somatic cancer associated mutations, PTEN expression, pro-survival pathways 
(such as PI3K/AKT, MAPK etc.), apoptotic markers, hormone receptor expression 
levels, and levels of RNA and DNA expression are predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to anti-tumor 
activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline 
biopsy and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, 
enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor 
response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole 
and GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or 
letrozole on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in 
letrozole plus GDC-0032 versus letrozole plus placebo. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate 
the effect of combining letrozole and GDC-0032 versus letrozole and placebo in 
postmenopausal women with ER+/HER2- untreated, Stage I-III operable breast cancer 
whose primary tumors are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  


 
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Standard of care assessments/procedures (e.g., bilateral mammogram) performed 
within 28 days of Day 1 dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal 
cutting temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]).  Two 
pretreatment FFPE core biopsies and one freshly frozen core biopsy must be obtained 
for all patients prior to beginning study drug treatment.  Tumor tissue from prior 
diagnostic FFPE core biopsies may be used for enrollment eligibility purposes. For the 
purpose of enrollment, ER, progesterone receptor (PR), and HER2 will be locally 
determined prior to beginning of study treatment. Remaining tissue will be retained for 
future translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not 
allowed.   
Patients will be randomized into one of the two treatment arms with a 1:1 randomization 
ratio.  Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 6 mg or 
placebo on a 5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see Figure 5).  A 
maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be continued 
up to surgery per the investigator’s discretion. 




 
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At Week 9, a breast ultrasound will be performed to ensure that there is no progressive 
disease and for the purpose of surgery planning. Suspicion of progressive disease on 
breast ultrasound should be confirmed by investigator-assessed breast MRI.  Patients 
with primary disease not evaluable by ultrasound at baseline should be assessed by 
MRI at Week 9.  Suspected progression in nodes should also be confirmed by fine 
needle aspiration (FNA) if these nodes had not been previously shown to be 
cytologically positive for cancer.  Patients with progressive disease (as defined by 
modified RECIST, Appendix 3), can either proceed directly to surgery or be taken off of 
the study, according to the investigator’s decision. If the patient goes off-study, every 
reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. 
Clinical breast exam, breast ultrasound, and mammography will also be conducted prior 
to surgery for the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected at screening, at Week 3, 
and prior to surgery. 




 
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Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the 
end of the study. Assessment of adverse events and general safety will be collected at 
this visit and the plan for future treatment will be recorded. 
The patient should be evaluated at baseline and after Week 13 of treatment for planning 
of the surgical procedure (BCS or mastectomy), and both physician recommendation 
and final patient decision should be documented in the electronic Case Report Form 
(eCRF).  
The co-primary efficacy endpoint, pCR (pCR–ypT0/is, ypN0) will be established via a 
local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and 
directions for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  
IRF procedures are detailed in the IRF charter. 
3.1.2 
Independent Data Monitoring Committee  
An IDMC will monitor accumulating patient safety data at a minimum of once every 
6 months until the last patient has completed study treatment.  Additional details 
(e.g., IDMC members, communication, affiliations) will be provided in the IDMC charter.   
The IDMC will convene for an interim safety analysis to evaluate safety and 
pharmacokinetics after the first 20 patients have completed surgery and have had 
30 days of follow-up.  The IDMC will create and review unblinded, pooled summaries of 
the safety and available PK summaries (all interim analyses).  While this review is being 
conducted, patient accrual into the study will continue.  The Medical Monitor may also 
request additional safety analysis and may call for additional meetings of the IDMC to 
review ongoing safety data.  
The IDMC will share results from interim safety analyses with the study team.  The study 
team will share interim safety results with study investigators as needed for the conduct 
of the study and the safety of the patients.  Specific potential safety issues anticipated in 
this trial, as well as measures intended to avoid, minimize, and manage such toxicities, 
are outlined in the following sections. 


 
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3.2 
END OF STUDY  
The end of the study is defined as the date when the last patient has her postsurgery 
visit. The total duration of the study is expected to be approximately 24 months for 
enrollment, plus 5.5 months after last patient in.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Conducting the Study in the Neoadjuvant Setting 
Breast cancer is a heterogeneous disease, and not every breast tumor responds equally 
to a specific agent.  Studies based on global gene expression analyses have provided 
additional insights into this complex scenario.  Over the past 10 years, four major 
classes of breast cancer (Luminal A, Luminal B, HER2-enriched, and Basal-like) and a 
Normal Breast-like group have been identified and intensively studied (Perou et al. 2000; 
Sørlie et al. 2001). Known as the intrinsic subtypes of breast cancer, these groups of 
tumors have revealed critical differences in incidence, survival, and response to 
treatment. As genomic studies evolve, further sub-classifications of breast tumors are 
expected to emerge. Thus, a major challenge in breast cancer management is how to 
prospectively select patients who will derive the maximum benefit from a given drug 
regimen, minimizing unnecessary toxicities for patients with non-responsive disease. 
Neoadjuvant therapy, a systemic therapy administered prior to breast cancer surgery, is 
now widely used in the 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, 
especially those with larger tumors. The tumor may shrink prior to surgery, thus 
increasing the rate of BCS (Coudert et al. 2006), and since the response to therapy can 
be monitored, the patient might be also spared further treatment with inactive 
medications.  
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 treatment response at a biological level. Finally, the surgical 
specimen, if pCR is not reached, can be utilized as well. 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 (von Minckwitz and Fontanella 
2013; Cortazar et al. 2012). 
3.3.2 
Rationale for Patient Population 
Postmenopausal patients with HER2-negative, ER+, early stage breast cancer will be 
enrolled in this study.  This patient population is usually treated with a combination of 
surgery, anti-hormonal therapy and/or chemotherapy, according to staging and biological 
features.  


 
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Recently, everolimus was approved by the FDA and European Medicines Agency in 
combination with exemestane for the treatment of advanced or metastatic breast cancer 
in patients after recurrence or progression following treatment with nonsteroidal AIs. In 
the neoadjuvant setting, a combination of letrozole and everolimus resulted in improved 
responses over letrozole alone in patients with ER+ breast cancer (Baselga et al. 2009). 
Important findings in trials with drugs targeting mTOR, like everolimus, produce a 
pharmacodynamic paradox:  while inhibiting mTOR, they lead to an upregulation of the 
pAKT, resulting in feedback PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009). 
This finding suggests that alternative pharmacologic strategies to shut down the pathway 
upstream of AKT should be pursued. One of these strategies is to inhibit the 
PI3K/AKT/mTOR pathway at the PI3K level. PI3K-inhibitors are central regulators of the 
mTOR signaling pathway, and nonclinical findings show that PI3K-inhibitors and dual 
PI3K-mTOR inhibitors induce a greater amount of apoptosis than everolimus in 
estrogen-deprived in vitro models (Sanchez et al. 2011); therefore, it is hypothesized 
that PI3K-inhibitors may be active and demonstrate greater anti-tumor activity as 
compared to AIs alone in the neoadjuvant setting. 
3.3.3 
Rationale for Control Group  
Aromatase inhibitors (AIs) have been found to be more effective than tamoxifen as a 
neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer. 
Several trials have assessed the efficacy and safety of neoadjuvant endocrine therapy 
using AIs in patients with postmenopausal breast cancer (Eiermann et al. 2001; Smith et 
al. 2005; Ellis et al. 2011). 
The P024 trial was a worldwide, prospective, randomized, multicenter trial that 
randomized 337 postmenopausal patients with ER +  breast cancer to receive either 
4 months of neoadjuvant letrozole or tamoxifen (Eiermann et al. 2001). The primary 
endpoint of P024 was the percentage of patients in each treatment arm with objective 
response as determined by clinical palpation. Secondary endpoints included ORR 
determined by mammogram and ultrasound, and included the percentage of patients in 
each arm who had become eligible for BCS. The trial demonstrated a significantly higher 
clinical response rate for letrozole when compared to tamoxifen (55% vs. 36%; p < 0.001) 
in the intent-to-treat (ITT) population. An improved ORR for letrozole was also observed 
with ultrasound (35% vs. 25%; p < 0.042) and mammogram (34% vs. 16%; p < 0.001). 
The higher response rate assessed by clinical palpation translated into a significantly 
higher rate of women undergoing BCS in tumors that had initially been considered 
unsuitable for this procedure (45% vs. 35%; p = 0.022). Median time-to-response was 66 
days in the letrozole group and 70 days in the tamoxifen group, and both treatments 
were well tolerated. 
The IMPACT trial was a randomized, Phase II, double-blind, double-dummy, multicenter 
trial that randomly assigned 330 postmenopausal women with ER+ operable or locally 


 
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advanced, potentially operable breast cancer in a 1:1:1 ratio to receive a daily dose of 
anastrozole 1 mg and tamoxifen placebo, tamoxifen 20 mg and anastrozole placebo, or 
a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks before surgery. 
The tumor ORR was assessed by both caliper and ultrasound. No significant differences 
in ORR in the ITT population between patients receiving tamoxifen, anastrozole, or the 
combination were seen. However, in a predefined analysis, there was a nonsignificant 
trend towards more patients requiring mastectomy at baseline actually receiving BCS 
with anastrozole than with tamoxifen (44% vs. 31%, respectively; p = 0.23); this 
difference became significant for patients deemed by their surgeon to be eligible for BCS 
after treatment (46% vs. 22%, respectively; p = 0.03). All treatments were well tolerated. 
The ACOSOG Z1031 trial compared three AIs in a randomized, Phase II, neoadjuvant 
trial designed to select agents for Phase III investigations. Three hundred seventy-seven 
postmenopausal women with clinical Stage II to III ER+ breast cancer were randomly 
assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary 
endpoint was clinical response. No formal comparison between arms was pre-specified 
in the statistical plan. ORR was 62.9%, 74.8%, and 69.1% for the exemestane, letrozole 
and anastrozole arms, respectively. On the basis of clinical response rates, letrozole and 
anastrozole were selected for further investigation; however, no other differences in 
surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for 
mastectomy-only patients at presentation was 51%. 
Results from these trials suggest that neoadjuvant endocrine therapy can be beneficial 
in postmenopausal patients with hormone-sensitive breast cancer, and that it offers an 
alternative to neoadjuvant chemotherapy. 
3.3.4 
Rationale for the Efficacy Outcome Measure of Response Rate 
Assessed by Magnetic Resonance Imaging  
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, non-registrational, neoadjuvant trials in combination with endocrine therapy 
(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 computed tomography (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 (Akazawa et al. 
2006; Balu-Maestro et al. 2002; Yeh et al. 2005), including the I-SPY trial (Hylton et al. 
2012).  For these reasons, ORR as assessed by breast MRI has been chosen as a co-
primary endpoint for this trial.  


 
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3.3.4.1 
Rationale for Efficacy Outcome Measure of Pathologic 
Complete Response 
pCR is a recognized efficacy endpoint of neoadjuvant trials, especially those with 
neoadjuvant chemotherapy, as it has been correlated with long-term outcomes, such as 
event-free survival (von Minckwitz and Fontanella 2013).  
In trials of neoadjuvant hormonal therapy, pCR is an unlikely event.  For instance, in the 
neoadjuvant trial comparing everolimus plus letrozole to letrozole, pCR rates were 1.4% 
and 0.8%, respectively (Baselga et al. 2009). 
In the ongoing Phase I/II trial that combines letrozole with GDC-0032, tumor shrinkage 
has been observed, and some patients presented sustained partial responses. As pCR 
is a recognized indicator of activity to a given regimen, it would be useful to assess it as 
a co-primary efficacy endpoint of this trial. Furthermore, for the same trial size, this 
would represent a minimal increase in the minimum detected difference (MDD) of the 
co-primary endpoint for pCR ORR (from MDD of 12% to MDD of 13%). 
In September of 2013, the FDA granted accelerated approval of Perjeta as part of a 
complete treatment regimen for patients with HER2-positive, locally advanced, 
inflammatory or early stage breast cancer in the neoadjuvant setting.   
3.3.4.2 
Rationale for Ki67 Measurements 
Ki67 is a well-established proliferation biomarker with prognostic value in ER+ breast 
cancer (Dowsett et al. 2011). Efficacy of endocrine therapy relies on induction of cell-
cycle arrest, and during neoadjuvant treatment, Ki67 levels reflect the ability of 
endocrine agents to suppress proliferation (Smith et al. 2005; Ellis et al. 2011).  In the 
neoadjuvant trial of letrozole with everolimus, by using the definition that patients with 
natural log (Ki67) < 1 at Day 15 have an antiproliferative response, 57% of everolimus-
treated patients were responders vs. 30% in the placebo arm, with a significant p value 
of < 0.01 (Baselga et al. 2009). Furthermore, the mean reduction in the percentage of 
Ki67-positive tumor cells at Day 15 relative to baseline was greater in the everolimus-
treated patients (90.7% ± 3.2%) than in the placebo group (74.8% ± 6.8%; p = 0.0002). In 
the IMPACT trial, Ki67 was assessed at baseline, on Day 15, and at surgery (Smith et al. 
2005). For each treatment arm, the reduction in geometric mean Ki67 levels was 
significantly higher for anastrozole than for tamoxifen at both time points (p = 0.004, 
p = 0.001, respectively), but no differences were found between tamoxifen and the 
combination. In the ASCOSOG Z1031 trial (Ellis et al. 2011), although no data on Ki67 
at Day 15 were available, no differences were found between treatments at baseline and 
at surgery (after 16 − 18 weeks of therapy). The geometric mean percentage change in 
Ki67 for each treatment was similar between the arms (anastrozole 78%, exemestane 
81.2%, and letrozole 87.1%). 
The issue of whether Ki67 decrease at surgery or at any timepoint during treatment 
correlates with long-term efficacy outcomes has been addressed in the P024 trial 


 
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(Eiermann et al. 2001). Treatment with letrozole led to higher, treatment-induced 
reduction of Ki67 levels in the tumor at surgery (87% reduction in the letrozole arm vs. 
75% in the tamoxifen arm; analysis of covariance p = 0.0009) based on the 185 
specimens with available data on Ki67 (Ellis et al. 2003). With a median follow-up of 61.2 
months, low levels of Ki67 in the biopsy at the end of treatment were significantly 
associated with better relapse-free survival (RFS; HR 1.4 per natural log increase in the 
Ki67 value, 95% CI 1.2 − 1.6, p < 0.001), and breast cancer specific survival (HR 1.4, 
95% CI 1.1 − 1.7, p =  0.009).  Finally, in the IMPACT trial, higher Ki67 expression after 2 
weeks of endocrine therapy was statistically significantly associated with lower RFS 
(p = 0.004), whereas higher Ki67 expression at baseline was not (Smith et al. 2005). 
Importantly, the Ki67 suppression in these hormonal neoadjuvant trials mirrored efficacy 
outcomes in large adjuvant trials: adjuvant BIG1-98 trial (n = 8,010) showed the superior 
efficacy of letrozole over tamoxifen (Regan et al. 2011), similar to the neoadjuvant P024 
trial (n = 185); the adjuvant ATAC trial (n = 9,366) showed that anastrozole was better 
than tamoxifen and the combination of anastrozole plus tamoxifen (Cuzick et al. 2010), 
similar to neoadjuvant IMPACT (n = 259); and the adjuvant MA27 trial (n = 7,576) showed 
similar efficacy of anastrozole and exemestane (Goss et al. 2013), mirroring neoadjuvant 
ACOSOG Z1031 (n = 266). These results suggest that a biological superiority hypothesis 
generated by a neoadjuvant study may help the design of future adjuvant hormonal 
therapy trials. 
In summary, reduction in Ki67 after neoadjuvant treatment with AIs is a good marker of 
suppression of cellular proliferation, correlates with long term efficacy outcomes, and 
mirrors results of large adjuvant endocrine trials, which make it an attractive endpoint to 
assess in the present trial. 
3.3.4.3 
Rationale for Using the Preoperative Endocrine Prognostic 
Index Score 
In addition to Ki67, pathologic tumor size (T1 or T2 versus T3 or T4), node status 
(positive or negative), and the ER status (positive Allred score 3–8 versus negative 
Allred score 0–2) of the surgery specimen were also determined to have independent 
prognostic value for relapse and death after relapse in the P024 trial (Ellis et al. 2008).  
A PEPI score, prognostic for RFS, which weighs each of these factors according to their 
associated hazard ratios, was developed and subsequently validated in an independent 
data set from the IMPACT trial (Ellis et al. 2008). No relapses were recorded in either 
trial in patients with tumors classified as T1N0 and with a PEPI score of 0 (residual 
tumor with a Ki67 level  ≤ 2.7%, and with maintained ER expression) or in the rare patient 
with a pCR. 
In this trial, the PEPI score will be assessed centrally.  


 
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3.3.4.4 
Rationale for Assessing ORR by Clinical Breast Exam 
(Palpation), Mammography, and Breast Ultrasound 
Objective overall response rate will also be assessed by clinical breast exam, 
mammography, and breast ultrasound during screening and prior to surgery. These data 
will allow for more direct comparison of results to other neoadjuvant trials with endocrine 
therapy as described in Section 3.3.3. The concurrent acquisition of ORR data with 
these techniques, in addition to MRI-based measures, will also provide valuable 
comparative information on these methods, which will be important for both future 
neoadjuvant studies and GDC-0032 clinical development.  
3.3.4.5 
Rationale for Assessing Enhancing Tumor Volume by Breast 
Magnetic Resonance Imaging  
As shown in the I-SPY trial, tumor volume measurements based on the percent of tumor 
with enhancing signal after contrast agent administration may be a more sensitive 
measure of response during neoadjuvant treatment than longest dimension measures 
(Hylton et al. 2012). However, there are no established response criteria for volumetric 
data, and the extrapolation of current one- and two-dimensional criteria to volumetric 
data based on a spherical model may not be appropriate given the range of tumor 
morphologies expected in this population of patients (Loo et al. 2011).  Additionally, 
there are only very limited data on the clinical relevance of any particular range in 
change in tumor volume during the course of neoadjuvant treatment. For these reasons, 
changes in enhancing tumor volume as measured by breast MRI will be a secondary 
endpoint in the trial.     
3.3.5 
Rationale for Independent Review Facility 
Due to the relatively novel nature of using MRI as an imaging endpoint, a central 
assessment by an IRF for the co-primary endpoint of response rate via MRI will be 
performed to ensure consistency across all sites participating in the study.  
3.3.6 
Rationale for Interim Safety Review 
The first 20 patients will be assessed for safety following surgery and 30 days beyond. 
This will allow the IDMC to review all safety data during the treatment period and to 
evaluate any surgery complications that may be attributed to GDC-0032. 
3.3.7 
Rationale for GDC-0032 Dosage 
As of 5 July 2013, 34 patients have been enrolled into the dose-escalation stage of 
Study PMT4979g, and 56 patients have been enrolled into the single-agent expansion 
cohorts at 9 mg in Stage 2 (Cohorts A-D and G).  Five dose-escalation cohorts (i.e., 3, 5, 
8, 12, and 16 mg daily) were tested.  The maximal administered dose was 16 mg.  To 
obtain more safety data on long-term tolerability, the recommended single-agent dose 
and schedule for the single-agent GDC-0032 expansion stage is 9 mg daily. 
In Study PMT4979g, as of the 5 July 2013 data cutoff date, there were 87 safety 
evaluable patients treated with single-agent GDC-0032 (3 − 16 mg daily).  A total of 97% 


 
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of patients experienced at least one adverse event per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4 (NCI CTCAE v4.0).  The 
most frequently reported adverse events, occurring in ≥ 10% safety-evaluable patients 
regardless of causality, were diarrhea (55%), fatigue (49%), nausea (47%), 
decreased appetite (39%), hyperglycemia (38%), vomiting (28%), dizziness (22%), 
rash (22%), dyspnea (18%), hypokalemia (18%), pyrexia (17%), cough (16%), anemia 
(13%), dehydration (13%), headache (13%), stomatitis (13%), AST increased (12%), 
mucosal inflammation (12%) and pruritis (10%).   
As of 5 July 2013, 54 patients have been treated with GDC-0032 in combination with 
endocrine therapy with either letrozole (Cohort E) or fulvestrant (Cohort F) at either 6 mg 
or 9 mg dose levels.  No DLTs were observed during dose escalation in either Cohorts E 
or F.  Expansion cohorts at the 6-mg dose level were enrolled to obtain more safety data 
on long-term tolerability.  Fifty (93%) of the 54 safety-evaluable patients experienced at 
least one adverse event that was assessed as related to GDC-0032.  
Of the 54 patients, 17 patients were treated with GDC-0032 plus letrozole. Adverse 
events that occurred in ≥ 10% of patients that were assessed as related to GDC-0032 
(6mg and 9mg) were diarrhea (67%), nausea (33%), fatigue (30%), rash (30%), 
hyperglycemia (26%), decreased appetite (26%), stomatitis (26%), dysgeusia (22%), 
mucosal inflammation (19%), asthenia (15%), vomiting (15%), pruritis (15%), muscle 
spasms (11%), dry skin (11%), and dry mouth (11%). 
Of the 19 efficacy-evaluable patients treated with GDC-0032 in combination with 
letrozole, one patient at 6 mg had a cPR. The PIK3CA mutation status of this patient is 
unknown. Since efficacy has been observed at 6 mg, and the long-term safety suggests 
that 6 mg is better tolerated, the neoadjuvant study will utilize 6 mg GDC-0032 in 
combination with letrozole.  
Of the 27 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 2 confirmed partial responses were observed at 6 mg and 1 confirmed partial 
response at 9 mg. 
Colitis has been observed with an incidence rate of 6.2% (10/160 patients).  The time 
(from the first dose of study treatment) to onset of colitis ranged from approximately 
82 − 248 days as either a single agent or in combination with letrozole or fulvestrant.  
Most of the colitis cases have been observed at the 9-mg dose level or higher.  Most of 
the colitis cases have been observed at the 9-mg dose level or higher.  To mitigate the 
late-onset adverse events, such as colitis, an intermittent dosing schedule will be applied. 
With the 40-hour half-life, a limited impact on efficacy is anticipated.  PK modeling has 
shown that a schedule of 5 days on/2 days off will maintain GDC-0032 drug exposure 
levels within an efficacious range as assessed by various breast cancer cell lines.  There 
has also been data presented for another PI3K inhibitor BKM120 with a similar half-life in 
combination with letrozole in a Phase Ib study that demonstrated improved tolerability 


 
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with similar efficacy for a schedule of 5 days on/2 days off as compared to daily 
continuous dosing of the PI3K inhibitor (Mayer et al. 2012). 
3.3.8 
Rationale for Biomarker Assessments  
Breast cancer is a heterogeneous disease, and PIK3CA mutations have been shown to 
vary among patients (CGAN 2012).  Therefore, all patients may not equally likely benefit 
from treatment with GDC-0032.  Predictive biomarker samples collected prior to dosing 
will be assessed in an effort to identify those patients with PIK3CA-driven pathogenesis 
who are most likely to respond to GDC-0032.  Pharmacodynamic biomarkers will be 
assessed to assess the biologic activity of the addition of GDC-0032 to letrozole.  
It has been suggested that not all molecular alterations in the PI3K/AKT/mTOR pathway 
result in pathway activation.  In a comprehensive analysis of tumors from 850 breast 
cancer patients, protein markers of PI3K/AKT/mTOR pathway activation (pAKT, pS6, 
and p4EBP1) correlated strongly with INPP4B and PTEN loss, to a degree with PIK3CA 
amplification, but were not elevated in PIK3CA- MT luminal A cancers (CGAN 2012).  
This apparent disconnect between the presence of PIK3CA mutations and biomarkers of 
pathway activation had been previously noted (Loi et al. 2010), and stress the need to 
find innovative and robust predictive biomarkers to PI3K/AKT/mTOR pathway inhibiting 
agents (Saini et al. 2013). 
Next generation sequencing (NGS) techniques, like deep genome sequencing, may offer 
a unique opportunity to identify such biomarkers of response.  For example, using whole 
genome sequencing, a two base-pair deletion in the TSC1 gene was found in a 
metastatic bladder cancer patient with a prolonged response (> 2 years) to everolimus as 
single agent (Iyer et al. 2012).  Among 13 additional bladder cancer patients treated with 
everolimus in the same trial, those with TSC1 mutant tumors remained on therapy longer 
than those with WT tumors (7.7 vs. 2.0 months, p = 0.004), suggesting that mTORC-1 
directed therapies may be most effective in cancer patients whose tumors harbor TSC1 
somatic mutations.  Similar approaches could be of great value when analyzing 
responses to agents targeting the PI3K/AKT/mTOR pathway, especially in the 
neoadjuvant setting. 
In addition to mutational activation of proteins, levels of RNA and DNA can also activate 
the PI3K pathway.  For example, increases in DNA copy number in receptor tyrosine 
kinases such as FGFR1/2 and IGF-1R, which occur at some frequency in breast cancer, 
can activate downstream PI3K pathway.  Hormone receptor positive breast cancer can 
be divided into luminal A and luminal B subtype, with the luminal B subtype displaying a 
higher proliferative index.  Therefore, profiling the RNA and DNA expression of tumors 
will allow intrinsic subtyping of patients enrolled onto study.  In addition, PI3K 
transcription activation signatures may identify additional patients who could respond to 
PI3K inhibitors outside of PIK3CA mutations.  


 
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The use of circulating tumor DNA (ctDNA) to monitor response to treatment is an area of 
great interest.  It could allow for an early, non-invasive, and quantifiable method for use 
in the clinical setting to identify candidates for specific therapies and monitoring of 
disease mutation status over time (Higgins et al. 2012).  The neoadjuvant setting is ideal 
to prospectively test these approaches. 
3.3.9 
Rationale for Day 15 Biopsy 
On-study biopsies can provide valuable information regarding target engagement and 
downstream pathway suppression. Assessing how GDC-0032 interacts with letrozole in 
this previously untreated patient population provides a unique opportunity to understand 
the interaction between two anti-cancer molecules.  When available, FFPE tumor 
samples will be assessed for pathway modulation using immunohistochemistry (IHC) 
methodologies, and fresh frozen OCT samples will be assessed using reverse phase 
protein array (RPPA) technologies, or equivalent.  Measurement of Ki67 after 2 weeks of 
continuous letrozole and GDC-0032 combination treatment versus letrozole and placebo 
will give a good benchmark to prior neoadjuvant studies that demonstrated a larger 
decrease in Ki67 at this 2-week timepoint for a combination of letrozole and everolimus 
as compared to letrozole and placebo (Baselga et al. 2009).  This Day 15 biopsy will 
also be useful in identifying potential biomarkers that may help predict a tumor response 
for patients treated with GDC-0032.   
3.3.10 
Rationale for Collection of Blood Sample for the Detection 
of Plasma Protein Biomarkers 
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate response 
to drugs, particularly targeted agents such as GDC-0032 (Wilson et al. 2012).  Assays 
to assess the expression of soluble, systemic cytokines and chemokines from the 
plasma of patients will be carried out using ELISA-based mass spectrometry or 
equivalent methodologies.   
3.3.11 
Rationale for Collection of Blood Sample for DNA Sequencing 
to Identify Mutations in Plasma 
There is increasing evidence that circulating DNA obtained from blood specimens of 
cancer patients is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008; Maheswaran et al. 2008).  Assays are available that can detect the 
major PI3K mutations (and other cancer-related genes) in plasma, and results from this 
analysis will be correlated with tumor specimens. 
3.3.12 
Rationale for Collection of Blood Sample for Next Generation 
Sequencing 
Next generation sequencing (NGS) technologies generate a large quantity of 
sequencing data.  Tumor DNA can contain both reported and unreported chromosomal 
alterations due to tumorigenesis process.  To help control for sequencing calls in 


 
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previously unreported genomic alterations, a normal blood sample will be taken during 
pre-screening to determine whether the alteration is somatic or germline.  
3.3.13 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected from early breast cancer patients in this study to assess the 
pharmacokinetics of GDC-0032 and possible DDI between letrozole and GDC-0032 in 
this population.  Considering the lack of DDI between GDC-0032 and letrozole upon 
concomitant administration in the 24 metastatic breast cancer patients in the Phase I 
study (preliminary data), this drug interaction in early breast cancer patients is unlikely.  
Hence, extensive PK sample collection is not needed; sparse PK sampling from patients 
enrolled in this study is adequate.  The proposed PK sample collection schedule will also 
enable assessment of a concentration and response relationship to better understand 
the following:  pharmacokinetics/pharmacodynamics (efficacy), PK/safety correlation, 
and population pharmacokinetics.  Additional PK samples may be collected for safety 
concerns (e.g., severe adverse event) in order to better characterize drug levels in these 
patients at the time of the adverse event.   
3.3.14 
Rationale for the Collection of DNA for Exploratory 
Pharmacogenetic Polymorphisms 
One sample (approximately 3 mL of whole blood) will be collected from all patients using 
K3-EDTA collection tubes. Samples  will be used for the evaluation of genetic 
polymorphisms of drug metabolic enzymes including, but not limited to, CYP2C9, 
CYP3A4/5, and UGT1A1, and transporters (e.g., OATP1B1) and for genetic variants 
which could contribute to potentially drug-related rash and/or colitis safety assessments 
(including but not limited to human leukocyte antigen [HLA]).  For sample handling 
procedures, storage conditions, and shipment instructions, see the laboratory manual. 
Only in circumstances where there is concern for collection of this genetic material for 
above evaluations, can this assessment be considered not mandatory as part of study 
assessments in this study.  Results of any analyses from these samples will be reported 
outside the clinical study report. 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affects their safety and efficacy.  For 
example, patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN 38 
(the active metabolite of irinotecan), are at higher risk for adverse effects associated with 
the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  Preliminary 
results from in vitro metabolism studies with GDC-0032 suggest that they are partially 
metabolized by multiple Phase I cytochrome P450 enzymes, including CYP3A4.  
Although in vitro studies can help elucidate the roles of enzymes in the metabolism of 
the drug, these results are not always predictive of in vivo metabolism for a number of 
reasons, such as differences in drug concentrations that the enzymes encounter in vitro 
and in vivo.  For this reason, a blood sample for DNA isolation is proposed to be 


 
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collected from all patients in this study for potential pharmacogenetic analysis of genes 
or biomarkers that may affect the pharmacokinetics or response to GDC-0032.  The 
decision to analyze the samples will be based on a review of the pharmacokinetics and 
response data.  Most recently, the role of HLA has been demonstrated to play an 
important role in the development of drug-induced rash for some drugs (carbamazepine, 
abacavir, and allopurinol).  Therefore, evaluation of genetic variants of genes that may 
regulate the immune response (including but not limited to HLA) may also be 
investigated to characterize unusual safety responses that are not predicted by GDC-
0032 pharmacokinetics. 
The analysis will be performed on identifiable DNA samples, because it is necessary to 
link a patient’s PK data with genotype.  This analysis would be restricted to the 
evaluation of genes that may be involved in the pharmacokinetics of GDC-0032, drug 
metabolism, disposition, or elimination and/or response of patients who develop severe 
adverse reactions such as colitis or rash.  Samples may be stored and analyzed up to 
15 years after the completion of the study, at which time all DNA samples collected for 
this analysis will be destroyed. 
3.3.15 
Rationale for Patient-Reported Outcome Assessments  
A PRO is “any report on the status of a patient’s health condition that comes directly 
from the patient, without any interpretation of the patient’s response by a clinician or 
anyone else” (FDA Guidance for Industry 2007).  PRO measures are able to 
contextualize a patient’s experience on trial, elucidating symptom and treatment burden.  
Since early breast cancer is often asymptomatic, the PRO objective is to evaluate and 
compare PROs of treatment-related symptoms, patient functioning, and the health-
related quality of life between treatment arms (Lemieux et al. 2011).  
The EORTC QLQ-C30 and associated breast cancer module, QLQ-BR23, were selected 
because they were specifically developed to assess the most salient constructs and 
experiences with breast cancer and its treatment.  The EORTC QLQ-C30 is a widely and 
frequently used PRO measure in oncology trials that contains a global health status 
scale, functional scales (physical, role, emotional, cognitive, and social), and general 
cancer symptom scales/items with a recall period of ‘the past week.’  
The second measure, the QLQ-BR23, is a breast cancer specific modular supplement to 
the EORTC QLQ-C30, and includes additional functioning scales and symptom 
scales/items relating to breast cancer.  
These instruments demonstrate strong psychometric properties, of both reliability and 
validity, and meet the requirements for this study (EORTC QLQ-C30 Scoring Manual, 
1999).  Therefore, PRO data will be collected from patients using the EORTC QLQ-C30 
and modified QLQ-BR23 (Quinten et al. 2009). 


 
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3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR, via centrally assessed breast MRI via modified RECIST (Appendix 3) 
in all enrolled patients and PIK3CA MT patients. 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the 
American Joint Committee on Cancer staging system (Appendix 6) by local 
evaluation in all enrolled patients and PIK3CA MT patients.  
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST 
(Appendix 3) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients. 
The following secondary outcome measures will be performed in all enrolled patients 
and separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally assessed PEPI score upon treatment with letrozole plus 
GDC-0032 with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
yoT0/is, ypNX (breast pCR) 
 
3.4.2 
Safety Outcome Measures  
The safety and tolerability of GDC-0032 will be assessed using the following primary 
safety outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE, v4.0  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, 
or delay 
• 
Serious adverse events 


 
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• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during 
the adverse event reporting period (see Section 5.3.1) 
  
3.4.3 
Patient-Reported Outcome Measures   
The PRO measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty 
swallowing, diarrhea, skin problems), and patient functioning as measured using the 
EORTC QLQ–C30 and the modified breast cancer module QLQ–BR23 
 
3.4.4 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are 
not limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Hormone receptor expression levels 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
ctDNA 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 
versus letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug 
safety response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing 
enzymes and transporters and other patient-specific covariates with PK of GDC-
0032 or letrozole and/or drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a 
marker of tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response  
 


 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients for this study include postmenopausal patients with ER+/HER2- untreated, 
Stage I-III operable breast cancer.  The size of the primary tumor should be  ≥ 2 cm by 
MRI.   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age  ≥ 18 years. Postmenopausal status is defined as 
follows: 
– 
Age  ≥  60 years or 
– 
Age  <  60 years and 12 months of amenorrhea plus follicle stimulating hormone 
(FSH) and plasma estradiol levels within postmenopausal range by local 
laboratory assessment or 
– 
Prior bilateral oophorectomy ( ≥  28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following 
characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated 
as the “target” lesion for all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as 
determined by institutional practice (in patients where there may be a 
reasonable suspicion of advanced disease e.g., large tumors, clinically positive 
axillary lymph nodes, signs and symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional 
definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as 
evaluable for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose  ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 


 
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– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5 ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may 
be enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline 
phosphatase ≤ 1.5 ×  ULN  
• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the basis of 
the Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × upper limit of normal (ULN) and activated 
partial thromboplastin time (aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 
2−3 is required.  If anticoagulation is required for a prosthetic heart valve, then INR 
should be between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply 
with the protocol, in the investigator’s judgment 
4.1.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Patients for whom upfront chemotherapy is clinically judged appropriate as 
optimal neoadjuvant treatment 
• 
Patients for whom immediate surgery is indicated 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric 
absorption 


 
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• 
History of prior or currently active small or large intestine inflammation (such as 
Crohn’s disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula 
(QTcF) >  470 msec 
• 
DLCO <  60% of the predicted values (see Appendix 7 for calculations)  
• 
Clinically significant (i.e., active) cardiovascular disease, like uncontrolled 
hypertension, unstable angina, history of myocardial infarction, cardiac failure class 
II-IV (New York Heart Association, Appendix 5), or any other that in the judgment of 
the investigator could jeopardize patient safety or study outcomes 
• 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, 
current alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic 
dysfunction, physical examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug, that may affect the interpretation of the results, or renders the 
patients at high risk from treatment complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Patient Randomization 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain a patient’s identification number and treatment assignment 
using a permuted block randomization algorithm via an interactive voice or web-based 
response system (IxRS).  
4.2.2 
Stratification 
Patients will be randomized into one of the two treatment arms in a 1:1 ratio based on 
the following stratification factors: 
• 
Tumor size (T1-2 vs. T3) 
• 
Nodal status (cytologically positive vs. radiologically or cytologically negative). If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then fine needle aspiration (FNA) or core biopsy is required to 
confirm nodal status. 
 
4.2.3 
Blinding 
Investigators and patients will be blinded to treatment assignment of GDC-0032 or 
placebo. 
For emergency situations, the investigator will be able to break the treatment code by 
contacting the IxRS.  The responsibility to break the treatment code in emergency 
situations resides solely with the investigator.   For non-emergency situations, the 
investigator needs to obtain approval from the Medical Monitor to break the treatment 
code.  Unblinding during the study will result in the withdrawal of a patient from the study.  
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected, suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  The PK 
assay group will be unblinded to patients’ treatment assignments to identify appropriate 
PK samples to be analyzed and bioanalytical methodology to employ.  However, the PK 
scientist does not have access to the PK assay results and therefore stays blinded until 
the PK assay results need to be interpreted and reported.  Samples from patients 
assigned to the comparator arm will be analyzed for letrozole.  However, GDC-0032 
assay will be analyzed by request (i.e., to evaluate a possible error in dosing). 


 
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4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0032 and Placebo  
GDC-0032 Drug Substance and Drug Product are manufactured according to current 
Good Manufacturing Practice guidelines for use in the clinical studies.  Each lot of 
GDC-0032 for clinical studies is subjected to a series of quality control tests to confirm 
its identity, purity, potency, and quality. 
GDC-0032 is provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 3 mg strength.  The tablet formulation consists of 
GDC-0032 active, lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, and Opadry 2 white film coating.  All excipients used in the 
formulation are compendial (USP/NF/Ph. Eur/JP) grade with the exception of the film-
coating.  The film-coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, 
polyethylene glycol 3350, and talc, and these ingredients are compendial. 
Placebo tablets will be identical in shape and color to the 3-mg tablets of GDC-0032 and 
will be indistinguishable from the 3-mg tablets of GDC-0032.  The ingredients in the 
placebo tablets are identical to those in the 3-mg tablets of GDC-0032, except for the 
absence of GDC-0032 active. 
The GDC-0032 active and placebo tablets are packaged in high-density polyethylene 
bottles, are labeled for clinical use, and should not be stored above 25°C. 
For further details, see the GDC-0032 Investigator’s Brochure. 
4.3.1.2 
Letrozole 
Letrozole will be labeled according to regulatory requirements in each country, as well as 
in accordance with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and will be labeled for investigational use only.  The Sponsor will provide 
letrozole free of charge to all study sites. 
Refer to the letrozole (e.g., Femara®) Package Insert or summary of product 
characteristics (SmPC) for details on the formulation and storage of letrozole. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0032 and Placebo 
Patients will receive an oral, daily dose of 6 mg GDC-0032 or placebo on a schedule of 
5 days on/2 days off for a maximum of 16 weeks.  Patients will take GDC-0032 at the 
same time of day ± 2 hours, unless otherwise instructed.  Patients will be instructed as to 
the number of tablets to take.  Patients will be asked to record the time and date that 
they take each dose in a medication diary. 


 
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Unless otherwise instructed, GDC-0032 or placebo should be taken on an empty 
stomach (i.e., approximately 1 hour before or 2 hours after a meal). 
If a patient misses a GDC-0032 or placebo dose or vomits up a tablet, she should be 
instructed to skip that dose and to resume dosing with the next scheduled dose.  Missed 
doses will not be made up.  Patients will be instructed to bring their medication diary to 
each study visit for assessment of compliance.  Patients will also be instructed to bring 
all unused tablets to each study visit for GDC-0032 or placebo accountability. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
4.3.2.2 
Letrozole 
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of 
surgery at the investigator’s discretion).  No dose modifications of letrozole are permitted.  
Any overdose or incorrect administration of letrozole should be noted on the letrozole 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of letrozole 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 
(letrozole and GDC-0032) will be provided by the Sponsor where required by local health 
authority regulations.  The investigational site will acknowledge receipt of IMPs, using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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 GDC-0032 
The Sponsor will offer post-trial access to the study drug (GDC-0032, letrozole, or other 
study interventions) free of charge to eligible patients in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, as outlined 
below. 


 
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A patient will be eligible to receive 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 would not 
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 untreated, postmenopausal ER + /HER2 −, early 
stage, operable breast cancer 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for untreated, postmenopausal postmenopausal ER + /HER2 −, early stage, operable 
breast cancer 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at 
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 
7 days prior to screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak 
time-dependent inhibitor of CYP3A4.  Although in vitro induction studies in human 
hepatocytes suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, 
preliminary data from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 
daily for 2 weeks in patients had no apparent effect on the pharmacokinetics of 
midazolam (a sensitive CYP3A4 substrate).  Therefore, GDC-0032 may be administered 
concomitantly with CYP3A4 substrates without the risk of a pharmacokinetic DDI.  


 
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Letrozole is mainly metabolized to a pharmacologically inactive carbinol metabolite by 
CYP2A6 and CYP3A4 in vivo. GDC-0032, which has the potential to induce CYP3A4 
based on in vitro induction studies, was administered in combination with letrozole in the 
expansion phase of Study PMT4979g to assess their DDI potential. Preliminary data 
from 10 patients in this cohort indicated that steady state plasma concentrations of both 
letrozole and GDC-0032, following once daily administration of the combination (2.5 mg 
letrozole plus 6 or 9 mg GDC-0032), were similar to historical, single-agent data 
suggesting lack of DDI between GDC-0032 and letrozole. These preliminary results 
suggest that GDC-0032 and letrozole combination may be administered without the risk 
of a pharmacokinetic DDI.  
In vitro CYP inhibition studies in HLMs and induction studies in human hepatocytes 
suggested a low to moderate potential of GDC-0032 to perpetrate DDIs.  A clinical DDI 
study with rifampin (CYP3A4 inducer) and itraconazole (CYP3A4 inhibitor), to 
understand the effect of CYP inhibitors or inducers on the pharmacokinetics of GDC-
0032, is currently ongoing (Study GP28617). 
4.4.2 
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer 
agents such as chemotherapy, immunotherapy, targeted therapy, biological 
response modifiers, or endocrine therapy (other than letrozole permitted in this 
protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is 
receiving these at the moment of registration, treatment should be discontinued prior 
to randomization.  
• 
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.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to inhibit CYP3A4.  If a strong 
CYP3A4 inhibitor is co-administered with GDC-0032, patients should be closely 
monitored for adverse reactions. 
• 
Potent CYP3A4 inducers:  Concomitant use of strong CYP3A4 inducers (e.g., 
phenytoin, carbamazepine, rifampin, phenobarbital) with GDC-0032 should be 
avoided.  Consider an alternate medication with no or minimal potential to induce 
CYP3A4.  If a strong CYP3A4 inducer is co-administered with GDC-0032, 
patients should be closely monitored for adverse reactions. 


 
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4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments to be performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  ICFs for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases that are currently active or that 
were active within the previous 5 years, surgeries, cancer history (including prior cancer 
therapies and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
15 days prior to the screening visit.   
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examination 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems as well as weight and height 
(height is measured at the screening visit only).  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examination may be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressure while the patient is in a seated position, and temperature.  
4.5.5 
Electrocardiograms 
Triplicate electrocardiogram (ECG) recordings will be obtained at each specified 
timepoint (see the schedule of assessments in Appendix 1).  


 
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4.5.6 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to randomization.   
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage:  
• 
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.   
• 
For Stage IIIB and Stage IIIC: bone scan and CT of chest, abdomen, and pelvis 
should be conducted for all patients. 
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.   
4.5.7 
Tumor and Response Evaluations 
All measurable disease must be documented at screening and reassessed at 
subsequent timepoints as outlined in Appendix 1. Responses based on clinical breast 
exam, breast ultrasound, and mammography will be investigator-assessed.  Whenever 
possible, assessments should be performed by the same evaluator to ensure internal 
consistency across visits. Response via breast MRI will be centrally assessed, and all 
assessments will be based on modified RECIST criteria (see Appendix 3).  
Clinical Breast Examination:  Assessment of primary breast tumor and regional lymph 
nodes must be done by physical examination (palpation) during baseline evaluation, 
Weeks 1, 5, 9, 13 and 16 during the treatment phase, and prior to surgery. Breast tumor 
measurement by caliper (preferred) or rule 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.  
Mammogram:  Bilateral mammograms must be obtained at baseline within 28 days 
prior to enrollment and again prior to surgery. Mammographic tumor measurements are 
to be recorded in the eCRF.  
Breast Ultrasound:  Bilateral breast ultrasounds must be obtained at baseline within 
28 days prior to enrollment.  Investigator decision whether to perform unilateral or 
bilateral ultrasounds performed at Week 9 and prior to surgery (Week 16) may be 
unilateral or bilateral and per investigator discretion.  If on ultrasound examination there 
is evidence of suspicious axillary lymph nodes at the baseline examination, then FNA or 


 
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core biopsy is required.  Sonographic tumor measurements are to be recorded in the 
eCRF. The tumor site may be marked with a radiopaque clip or marker via radiographic 
guidance (e.g., ultrasound) prior to initiation of neoadjuvant therapy.  
Breast MRI:  Contrast-enhanced breast MRI scans will be mandatory for all study 
patients at baseline (within 28 days prior to enrollment) and prior to surgery (Week 16).  
MRI is optional at Week 9, but will be mandatory if a primary breast lesion is not 
evaluable by ultrasound, or if there are signs of disease progression on the Week 9 
ultrasound (see Figure 6).   
Breast MRI scans should not be acquired within 48 hours after biopsy, and the 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 as 
assessed by the central reading facility, the scan may be repeated, at least 48 hours 
after the first scan before the start of study treatment. Other MRI acquisition sequences, 
such as diffusion-weighted imaging, may be acquired during this study during the MRI 
scan visits for each patient.  Additional MRI-derived metrics such as ADC value may 
provide additional insight into changes in tumor cellular composition.  
For information about patient preparation, scanner requirements and settings, and image 
acquisition, refer to the Study Imaging Manual. Standard site practice may be followed 
regarding the use of mild sedatives or anti-anxiolytics for claustrophobic patients prior to 
MRI. 
4.5.8 
Surgical Treatment Plan 
The planned and actual surgical treatment (BCS or mastectomy) performed should be 
documented and reported in the eCRF.  Patients should be reassessed after completion 
of neoadjuvant therapy and prior to surgery.  
4.5.9 
Surgical Specimen – Pathology 
The co-primary endpoint of the study (pCR) will be as identified by local pathology 
review. Guidelines regarding pathology specimen preparation, labeling and review are 
outlined in the pathology manual. 
4.5.10 
Laboratory Assessments 
The following assessments will be performed at the local laboratory.  The frequency of 
assessments is provided in Appendix 1. 
• 
Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, and other cells]), and platelet 
count.   
• 
Coagulation (INR and aPTT/PTT) 


 
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• 
Fasting serum chemistry (blood urea nitrogen [BUN], creatinine, sodium, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, serum 
bilirubin, alkaline phosphatase, glucose, AST, ALT), performed following  ≥ 10-hour 
fast 
• 
Fasting lipid profile and amylase (total cholesterol, high-density lipoprotein [HDL], 
low-density lipoprotein [LDL], triglycerides, amylase, and lipase) performed following 
a  ≥ 10 hour fast 
• 
Fasting insulin and glucose  
• 
Glycosylated hemoglobin (HbA1c) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
The following assessments will be performed at a central laboratory.  Instruction 
manuals outlining sampling procedures, storage conditions, and shipment instructions 
and supply kits will be provided for all central laboratory assessments: 
• 
Mandatory tumor tissue 
• 
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 PIK3CA mutation testing as well as 
for other protocol-mandated exploratory assessments at baseline, Day 15, and at 
surgery. 
• 
Tumor tissue should be of good quality based on total and viable tumor content.  
Evaluation of the patient’s tumor sample for adequate tumor tissue content by a 
central laboratory must occur prior to initiation of study treatment.  A minimum of ten 
unstained slides from a prior diagnostic FFPE core biopsy would be required for 
enrollment eligibility purposes. 
Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen 
OCT core needle biopsy are required at baseline and Day 15 (Week 3).    
A formalin-fixed, paraffin-embedded tumor block from surgical resection 
(Weeks 17 − 18) is required.  If a tumor block cannot be obtained for various reasons 
(e.g., the tumor tissue is not sufficient at surgical resection), the site should discuss 
with the central study team.  In such cases, paraffin-embedded, unstained slides (a 
minimum of 20 and up to 40 unstained slides) from a surgical specimen are required 
at surgery (Weeks 17 − 18). 
The specimens will be used for confirmatory central laboratory assessment of 
PIK3CA mutation status, Ki67, PTEN, ER/PgR and HER2 expression.  In addition, 
other exploratory assessments, including but not limited to, PI3K signaling pathways 
may be evaluated, including protein expression and molecular profiling studies such 
as NGS and gene-expression. 
• 
Plasma samples for exploratory research on candidate biomarkers include, but are 
not limited, to the following:  ctDNA and plasma protein biomarkers 


 
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• 
Blood for NGS (if approved by local regulatory authorities) 
• 
Blood for pharmacogenomics (if approved by local regulatory authorities) 
• 
PK assessment  
 
Plasma samples will be collected to measure letrozole and GDC-0032 
concentrations (see 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. 
 
4.5.11 
Assay Methods 
4.5.11.1 
Mutational Analysis for PIK3CA 
The PIK3CA mutation assay will be performed by a central laboratory. 
Somatic mutations in the PIK3CA gene are found in approximately 35% − 40% of 
ER-positive breast cancers and occur most commonly in Exons 9 and 20 in the codons 
encoding amino acids E542, E545, and H1047 (Saal et al. 2005).  Real-time polymerase 
chain reaction (RT-PCR) assays that amplify exons that are commonly mutated in 
PIK3CA offer a sensitive and quantitative method to detect mutations from a tumor 
specimen.  DNA will be extracted from tumor samples and subjected to allele-specific 
PCR assays that detect the WT allele, as well as to assays for nucleotide substitutions 
that include, but are not limited to, the following amino acid changes:  R88Q, N345K, 
C420R, E542K, E545K/A/G/D, E546K/E/R/L, M1043I, H1047R/L/Y, H1049R.  Following 
histopathological review, samples with  < 10% tumor content may not be evaluable for 
the PIK3CA assay. Samples will be run on cobas z480 analyzer, and PIK3CA mutation 
status (mutant or WT) will be made using appropriate cutoffs and automated software.   
A designation of PIK3CA status unknown will be assigned to a sample wherein any one 
of the predefined mutations was not conclusively assessed. 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor Tissues 
Ki67 antigen is an important cell cycle-related nuclear protein that is expressed by 
proliferating cells in all phases of the active cell cycle (G1, S, G2, and M phase).  As 
such, it is a useful marker of the proliferative state of a tumor.  Ki67 protein levels will be 
determined by IHC through the use of standard techniques.   
PI3K pathway, and other pro-survival, biomarkers will be tested in the fresh tumor 
biopsies by IHC, including, but not limited to, phospho-S6, phospho-AKT, 
phospho-4EBP1, and phospho-ERK.  If tissue quantity permits, change in expression of 
pathway biomarkers will be measured by the RPPA using OCT fixed tissue.  The basis 
of the technology is to immobilize small amounts of lysate from a tumor biopsy sample in 
serial dilution on a microarray slide.  Multiple samples are thus arrayed on a slide and 
can be probed with antibodies that detect a particular phospho-epitope.  Using this 
technology, we will profile approximately 80 key signaling nodes representing a number 


 
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of pathways known to be dysregulated in cancer, including receptors in the HER family, 
multiple components of PI3K/mTor signaling, as well as key members of the RAS/MAP 
kinase pathway. 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog Expression 
PTEN status will be examined by IHC using a protocol that has been validated for 
specificity using several available cell line controls at a central laboratory.  Tumor 
specimen will be scored only if appropriate staining is observed in internal control 
stromal or normal (non-tumor) tissue elements.  
4.5.11.4 
Confirmation of Estrogen Receptor, Progesterone Receptor, 
and HER2 Status 
ER, PR, and HER2 status will be determined at a central laboratory according to the 
American Society of Clinical Oncology-College of American Pathologists (ASCO-
CAP) guidelines. 
4.5.11.5 
Circulating Tumor DNA Analysis 
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations using appropriate technologies.  The prevalence of 
the mutations measured at baseline and post-treatment may provide information on 
response or resistance to therapy. 
4.5.11.6 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression will be 
performed using gene expression assays conducted on the NanoString platform or 
equivalent.  Analysis may include, but is not limited to, a panel of genes important for 
intrinsic subtyping, breast cancer biology and PI3K signaling.  The goal will be to 
generate a database of expression status to examine whether there are gene expression 
patterns that are associated with clinical response to GDC-0032. 
4.5.11.7 
Next Generation Sequencing 
In cases where there is sufficient material to isolate DNA, NGS will be performed using 
NGS platforms, such as Illumina or equivalent. The goal will be to determine whether the 
percentage of genetic mutations are associated with clinical response to GDC-0032. 
4.5.11.8 
Copy Number Analysis  
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically using chromosomal in situ hybridization 
(ISH), using next-generation sequencing platforms or by RT-PCR-based or equivalent 
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(fluorescence in situ hybridization assay) or chromogenic-based (chromogenic in situ 
hybridization).  Increased copy number of PI3K pathways activating genes may provide 
information on response or resistance to therapy.  


 
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4.5.11.9 
Plasma Biomarker Analyses 
Assays to assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be carried out using appropriate methodologies, such as 
enzyme-linked immunosorbent assay (ELISA)-based or mass spectrometry-based or 
equivalent technologies.   
4.5.11.10 
Plasma Pharmacokinetic Samples 
Plasma GDC-0032 and letrozole samples will be analyzed using a validated liquid 
chromatography tandem mass spectrometry. 
After the plasma samples are analyzed, any remaining samples may be used for 
exploratory metabolite profiling and identification, ex vivo protein binding, and PK, or 
pharmacodynamic assay development purposes. 
4.5.11.11 
Pharmacogenetic Polymorphism Assay 
If approved by the local regulatory authority, gene mutations will be assayed using 
multiplex PCR, allele-specific PCR, direct sequencing, or other acceptable methods.  
Results may be correlated to population PK parameters or other clinical measures in order 
to better understand the impact of genetic variants on drug metabolism, exposure, adverse 
events, and/or response.   
A sample will also be utilized as a source of normal DNA to determine whether sequence 
variants in the PIK3CA gene and in other relevant oncogenes in the tumor DNA are 
somatic mutations or single nucleotide polymorphisms. 
4.5.11.12 
Electrocardiograms 
Triplicate ECG recordings will be obtained at each specified timepoint (see the schedule 
of assessments in Appendix 1).  
4.5.11.13 
DLCO Testing 
A diffusion capacity of the lung for carbon monoxide (DLCO) test will be required at 
baseline and at the end of study-drug treatment (prior to surgery) for all patients.  The 
DLCO test should be repeated if there is clinical suspicion of pneumonitis.  Further 
guidance regarding DLCO testing is contained in Appendix 7 and in the management 
guidelines for pneumonitis (Section 5.1.1.2).   
4.5.11.14 
Osteoporosis Assessment and Monitoring 
Treatment with aromatase inhibitors results in bone loss due to estrogen deficiency.  
For patients who have a history of osteoporosis and/or fractures, or who are at increased 
risk of osteoporosis, a bone mineral density assessment will be required at baseline prior 
to initiating study treatment.  Baseline bone mineral density will be measured via 
dual-energy X-ray absorptiometry (DXA).  DXA measurement of both the hip and 
lumbar spine is suggested.  When either the hip or lumbar spine is not a valid skeletal 
site for a bone mineral density measurement, then the 33% (one-third) radius should be 
measured.  In some patients, measurement of the hip alone could be sufficient. 


 
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Appropriate monitoring in these patients will occur per institutional guidelines.  
Assessment for fractures is already included as part of the scheduled physical 
examinations.  Determination of patients who are at increased risk for osteoporosis will 
be per institutional guidelines.  Clinical risk factors for fracture include advancing age, 
previous fracture, glucocorticoid therapy, parental history of hip fracture, low body 
weight, current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, 
and secondary osteoporosis (e.g., hypogonadism or premature menopause, 
malabsorption, chronic liver disease, inflammatory bowel disease) (Kanis et al., 2005).   
4.5.12 
Patient-Reported Outcomes  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of GDC-0032.  The PRO questionnaires, translated as required in the local 
language, will be distributed by the investigator staff and completed in their entirety by 
the patient.  To ensure instrument validity and that data standards meet health authority 
requirements, PRO questionnaires should be self-administered at the investigational site 
prior to the completion of other study assessments and the administration of study 
treatment.  
The EORTC QLQ-C30 and the Modified Breast Cancer module QLQ-BR23 
questionnaires will be used to assess HRQoL, including side-effects of systemic therapy 
(e.g., sore mouth/tongue, difficulty swallowing, diarrhea, skin problems) and patient 
functioning during the neoadjuvant period (refer to schedule of assessments in 
Appendix 1 for a detailed description of timepoints) and post-surgery follow-up.  
The EORTC QLQ-C30 is a widely used HRQoL measure in oncology trials with excellent 
psychometric properties demonstrating both reliability and validity. The measure consists 
of “five functional scales (physical, role, cognitive, emotional, and social); three symptom 
scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life 
scale” with a recall period of “the past week” (Aaronson et al. 1993). Scale scores can be 
obtained for each of the multi-item scales, global health status/QoL scale, and six single 
items by using a liner transformation for standardization of the calculated raw score.   
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of “the past week,” and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment).  As this 
trial will include patients in the neo-adjuvant setting, the last seven items of the original 
BR23 questionnaire, items numbered 47 − 53 that deal with symptoms and side effects 
not relevant to the population under study, will be removed.  These seven items 
addressed symptoms experienced by metastatic breast cancer patients and those 
undergoing radiation.  Therefore, in consultation with the EORTC, these items were 
deleted, as the validity of the measure would not be compromised by their removal.  In 
addition, as “oral mucositis” and “skin problems” are key symptoms of this therapy not 
assessed by currently available tools, validated items from the EORTC item bank were 
added to assess the presence and bothersomeness of oral mucositis (2 items:  sore 


 
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mouth/tongue, difficulty swallowing) and skin problems (2 items).  Data analysis will be 
performed on the final modified BR23 data set in parallel with the final data analysis to 
assess the psychometric properties of the modified instrument and will be reported along 
with the clinical trial results.  Scale scores can be obtained for each of the multi-item and 
single-item scales by using a linear transformation for standardization of the calculated 
raw score. 
The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient.  Patients must 
complete these instruments in the clinic (cannot be taken home) prior to any healthcare 
provider interactions (i.e., prior to administration of study drug and prior to any other 
study assessment) to ensure that the validity of the instruments are not compromised 
and to ensure that data quality meet regulatory requirements. 
Refer to Appendix 4 for the EORTC QLQ-C30 and the modified QLQ-BR23. 
4.5.13 
Samples for Clinical Repository 
All residual samples (or leftover biologic samples after protocol-defined studies are 
completed) obtained during the study (FFPE, fresh-frozen, plasma, etc.) will be stored in 
an academic central repository.  The specimens in the study repository will be made 
available for future biomarker research towards further understanding of treatment with 
GDC-0032, of breast cancer, related diseases, and adverse events, and for the 
development of potential, associated diagnostic assays.  The implementation of study 
repository specimens is governed by the Study Steering Committee, with guidance from 
a dedicated Translational Research Committee to ensure the appropriate use of the 
study specimens. 
All biomarker specimens will be retained for new research related to this study and/or 
disease in accordance with the recommendations and approval of the Study Steering 
Committee.  Samples will be only destroyed if required by local laws relating to the 
collection, storage, and destruction of biological specimens. 
Specimens will be stored up to 15 years or until they are exhausted.  The storage period 
will be in accordance with the institutional review board/ethics committee 
(IRB/EC)-approved ICF and applicable laws (e.g., health authority requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.13.1 
Confidentiality 
Patient medical information associated with biologic specimens is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 


 
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use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Data derived from biologic specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using biologic specimens will be available 
in accordance with the effective Translational Reseach Committee policy on study data 
publication. 
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 
 
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. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Disease progression 
• 
Unacceptable toxicity 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Conditions for Terminating the Study 
Both the Sponsor and the investigator reserve the right to terminate their participation in 
the study under the circumstances agreed upon in the site agreement.  Should this be 
necessary, both parties will arrange the procedures on an individual basis after review 
and consultation.  In terminating the study, the Sponsor and investigator will assure that 
adequate consideration is given to the protection of the patients’ interest. 


 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
GDC-0032 is not approved and is currently in early clinical development.  Thus, the 
entire safety profile is not known at this time.  Human experience is currently limited.  
The following information is based on results from ongoing clinical studies.  The safety 
plan for this study is designed to ensure patient safety and will include specific eligibility 
criteria and monitoring assessments as detailed below.  
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events, and laboratory abnormalities (see Section 5.3.5.3), defined 
and graded according to NCI CTCAE v4.0.  General safety assessments will include 
serial interval histories, physical examinations, and specific laboratory studies, including 
serum chemistry and blood counts.  All serious adverse events and non-serious adverse 
events of special interest will be reported in an expedited fashion, via fax to Austrian 
Breast and Colorectal Cancer Study Group (ABCSG) safety department and also 
captured in the electronic data capture (EDC) system.  In addition, the Sponsor and the 
investigators will review and evaluate observed adverse events on a regular basis. 
All adverse events will be recorded during the trial and for 30 days after the last dose of 
study treatment or until the end of study visit, whichever occurs later.  Patients who have 
an ongoing study treatment-related adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the adverse event. 
All adverse events should be attributed by the investigator to study drug or to another 
clearly identified etiology by the investigator (see Table 10).  
Specific potential safety issues anticipated in this trial, as well as measures intended to 
avoid, minimize, and manage such toxicities, are outlined in the following sections. 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
5.1.1 
Management of Specific Adverse Events of GDC-0032  
Guidelines for management of specific adverse events are outlined in Table 1.  
Additional guidelines are provided in the subsections below.  
Due to the approximately 40-hour half-life for GDC-0032, investigators should consider 
holding GDC-0032 for certain Grade 2 toxicities until the adverse event resolves to 
Grade ≤ 1 as discussed below (e.g., stomatitis/mucositis, colitis, rash, diarrhea, 
pneumonitis).  Certain toxicities can occur within 1−2 weeks of holding or discontinuing 


 
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GDC-0032 drug (e.g., pneumonitis, colitis, rash).  In these cases, the adverse event 
eventually resolves.  Investigators should follow management guidelines and dose 
modifications for toxicities as described below, including administration of topical or 
systemic corticosteroids as appropriate.   
Table 1 Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events 
 
GDC-0032 
Starting dose 
6 mg at 5 days on / 2 days off 
First reduction 
3 mg at 5 days on / 2 days off  
Second reduction  
3 mg at 3 days on / 4 days off a 
 a If the patient continues to experience specified drug-related adverse 
events after the second dose reduction, the treatment should be 
discontinued. 
  
5.1.1.1 
Management of Hyperglycemia 
Hyperglycemia has been observed in patients who received GDC-0032 in the single-
agent Phase I study.   
Patients with diabetes requiring daily anti-hyperglycemic medication or who have a 
fasting blood glucose level > 125 mg/dL will be excluded from the study.  HbA1c and 
fasting glucose levels will be monitored at baseline, and additional monitoring of fasting 
glucose levels during the study will be implemented, as outlined in the schedule of 
assessments.  Patients should be instructed to report symptoms associated with 
hyperglycemia such as thirst, frequent urination, and blurred vision. 
Metformin is the first antihyperglycemic medication of choice because of the lower risk of 
hypoglycemia with this agent.  Because metformin in some patients may also cause 
diarrhea and not be well tolerated, other antihyperglycemic medications such as 
sulfonylureas (e.g., glimepiride, glipizide) can be used.  Extra caution should be used 
with other drugs such as sulfonylureas because of the increased risk for hypoglycemia 
with these agents.  Consultation with an endocrinologist can be helpful in managing 
hyperglycemia.   
Specific dose modification and management guidelines for hyperglycemia are provided 
in Table 2. 


 
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Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) 
Grade 
Dose Modification and Management Guidelines for Hyperglycemia 
(based on fasting blood glucose) 
Grade 2 
Initiation of an anti-hyperglycemic agent (e.g., metformin) and 
additional glucose monitoring will be implemented.   
Dosing with GDC-0032 may either be held or continued per 
investigator evaluation. 
Grade 3  
(asymptomatic) 
GDC-0032 dosing will be suspended and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of an anti-hyperglycemic therapy (e.g., metformin).   
If the hyperglycemic event does not improve to Grade ≤  1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 
Grade 3  
(symptomatic) a, 
Grade 3 
(requiring 
hospitalization),  
or Grade 4 
GDC-0032 dosing will be suspended, and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of anti-hyperglycemic therapy.   
If the hyperglycemic event does not improve to Grade ≤ 1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 
a For example, blurred vision, frequent urination, excessive thirst. 
  
5.1.1.2 
Management of Pneumonitis 
Patients who require any daily supplemental oxygen are not eligible for the study.  
Patients who have DLCO values < 60% will be excluded from the study.  Patients will 
be assessed for pulmonary signs and symptoms throughout the study.  The DLCO test 
should be repeated if there is clinical suspicion of pneumonitis.  The DLCO test will 
also be repeated presurgery after completion of study treatment.  Management 
guidelines for patients with possible pneumonitis are listed in Table 3. 


 
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Table 3 
Dose Modification and Management Guidelines for Pneumonitis 
Grade
Intervention 
Investigations 
GDC-0032 a  
Dose Adjustment 
1 
No specific therapy 
required. 
CT scan.  Consider DLCO. b 
Repeat CT scan every 
8 weeks until return to 
baseline. 
No change. 
2 
Symptomatic only.  
Prescribe 
corticosteroids if 
cough is troublesome. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline.  
Consider bronchoscopy. 
Reduce dose until improvement 
to Grade ≤ 1; consider 
interruption if symptoms are 
troublesome. 
Interrupt treatment as long as 
corticosteroids are being given. 
Restart GDC-0032 at the same 
dose if clinical benefit evident.  
Consider restarting at reduced 
dose if recurrent event or per 
discussion with Medical Monitor. 
Discontinue treatment if recovery 
to Grade ≤ 1 is not evident within 
28 days. 
3 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline. 
Bronchoscopy is 
recommended. 
Interrupt treatment until 
improvement to Grade ≤ 1. 
Restart therapy within 28 days at 
a reduced dose if clinical benefit 
is evident. 
Interrupt treatment as long as 
corticosteroids are being given. 
4 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
and DLCO every 4 weeks 
until return to baseline. 
Bronchoscopy is 
recommended. 
Discontinue treatment. 
Table modified from White et al. 2010.  
CT = computed tomography; DLCO = diffusion capacity of the lung for carbon monoxide.  
a Dose reductions per Section 5.1.1. 
b DLCO may be useful to monitor the effect of interventions such as dose 
reduction/discontinuation and corticosteroids, in conjunction with imaging (White et al. 2010).  
 
 
5.1.1.3 
Management of Rash 
Rash and other dermatological events should be closely monitored, and patients with 
severe rash should be monitored for associated signs and symptoms such as fever and 
hypotension that may be suggestive of a systemic hypersensitivity reaction.  For severe 
rash, dosing of GDC-0032 should be interrupted, and patients should be treated with 
supportive therapy per standard of care.  Use of antihistamines, as well as topical or 
systemic corticosteroids, may be considered (see Table 4).   


 
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Table 4 
GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Grade of Rash 
GDC-0032  
Grade 1 
Continue dosing at current dose and monitor for change in severity.  
Consider prescribing topical corticosteroids a 
Grade 2 
Consider holding GDC-0032 or reducing to the next lower dose if 
rash is troublesome.   
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b). 
Grade 3 or 4 
Hold GDC-0032 until Grade ≤ 1. 
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b).  
Consider dermatological consultation.  
Consider obtaining photographs of rash if permitted by local 
regulations. 
After rash improves to Grade ≤ 1, restart GDC-0032 at the next 
lower dose upon discussion with Medical Monitor, or permanently 
discontinue. 
AE = adverse event. 
AE grading is based on NCI CTCAE, Version 4.0. 
a Suggested topical steroids include hydrocortisone 2.5% to face twice daily, 
triamcinolone 0.1%, or fluocinonide 0.1% cream to body twice daily. 
b Suggested oral steroids include a methylprednisolone dose pack or prednisone 
60 mg daily followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, 
etc.). 
 
 
5.1.1.4 
Management of Gastrointestinal Toxicity 
5.1.1.4.1 
Management of Diarrhea 
Patients should be closely monitored for gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea, abdominal pain, stomatitis, and changes in stool, including checking 
for blood in stool if clinically indicated).  Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is mild.  Gastrointestinal symptoms should 
be managed per protocol guidelines and institutional standard of care.  For example, 
prompt management of diarrhea with antidiarrheal medications should be implemented.  
Because of the approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032 for Grade ≥ 2 diarrhea until it improves to Grade ≤ 1.   
Specific dose modification and management guidelines for diarrhea are provided in 
Table 5.  


 
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Table 5 GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea 
Grade of Diarrhea 
Dose Modification and Management Guidelines  
Grade 1 
• Manage per institutional standard of care that includes 
antidiarrheals. a 
Grade 2 
• Hold GDC-0032 and manage per institutional standard of care 
until Grade  ≤ 1.  These include antidiarrheals. a 
• For persistent Grade 2 non-infectious diarrhea despite treatment 
with antidiarrheals, additional coadministration of corticosteroids 
(e.g., budesonide 9 mg PO QD) are recommended. b  Non-
infectious diarrhea can be diagnosed by stool culture. 
• For persistent Grade 2 diarrhea lasting longer than 1 week with 
an adequate trial of anti-diarrheal medications, or for recurrent 
Grade 2 diarrhea, restarting at the next lower dose level should 
be strongly considered after diarrhea improves to Grade  ≤  1.  
• If Grade 2 diarrhea is persistent despite treatment with SOC, 
consider work-up for colitis (e.g., performing abdominal/pelvis CT 
and/or endoscopy, and stool culture as appropriate).   
Grade 3 or 4 
• Hold GDC-0032 and manage per institutional standard of care 
until Grade  ≤ 1. These include antidiarrheals. a   
• Consider work-up for colitis (e.g., performing abdominal/pelvis 
CT and/or endoscopy, and stool culture as appropriate). 
• Restart GDC-0032 at the next lower dose level upon resolution 
to Grade ≤ 1. 
• For persistent Grade 3 − 4 non-infectious diarrhea despite 
treatment with antidiarrheals, administration of systemic 
corticosteroids should be considered. b 
• For Grade 3 diarrhea, may consider restarting at the same dose 
if event occurred because of lack of optimal medical 
management with antidiarrheal medications, after discussion with 
and approval by the medical monitor.   
• For Grade 4 diarrhea, consider permanent discontinuation of 
GDC-0032. 
CT = computed tomography; PO = oral; QD = once daily; SOC = standard of care. 
a Suggested antidiarrheals include the following: loperamide (initial: 4 mg, followed by 
2 mg after each loose stool, up to 16 mg/day); diphenoxylate and atropine 
(Diphenoxylate 5 mg 4 times/day until control achieved [maximum:  20 mg/day], then 
reduce dose as needed; some patients may be controlled on doses of 5 mg/day; tincture 
of opium (6 mg of undiluted opium tincture [10 mg/mL]) 4 times daily. 
b Examples of corticosteroid regimens include the following:  For the steroid taper, 
suggested steroids include a methylprednisolone dose pack or prednisone 60 mg daily 
followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, etc.).  Can also 
consider budesonide 9 mg PO QD or prednisone 5 mg to 10 mg PO QD. 
 
 


 
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5.1.1.4.2 
Management of Colitis 
Data as of October 2013 show an incidence rate for colitis of 6.2% (10/160) (1 at 16 mg; 
8 at 9 mg; 1 at 6 mg + fulvestrant) with onset at approximately 100 days or longer after 
initiation of treatment with daily GDC-0032 dosing.  Some patients have developed 
Grade 2 or Grade 3 diarrhea, which is non-responsive to anti-diarrheal medication.  In 
some of these patients, a CT scan or colonoscopy has revealed colitis, which has 
resolved upon treatment with systemic corticosteroids. 
For persistent Grade 2 diarrhea that does not resolve or for Grade ≥ 3 diarrhea, further 
evaluation should include colitis in the differential diagnosis with the appropriate work-up 
(e.g., abdominal/ pelvis CT scan, endoscopy with biopsy, stool cultures for 
cytomegalovirus, Clostridium difficile, and parasites).  Grade ≥ 2 colitis should be 
managed by interruption of study treatment.  In addition, discontinuation of nonsteroidal 
anti-inflammatory medications or any other medications known to exacerbate colitis 
symptoms should be considered.  If noninfectious colitis is suspected, treatment with 
corticosteroids per institutional standard of care should be considered.  It is suggested 
that prednisone (for oral administration) or solumedrol (for IV administration) are the 
corticosteroids of choice in the treatment of colitis.  For severe symptoms, prednisone 
60 mg or equivalent may be required to control initial symptoms, and the dose should be 
gradually tapered.  Lower doses of prednisone, oral budesonide, or mesalamine 
(or other 5-aminosalicyclic acid derivatives) may be considered for less severe cases of 
colitis. 
Specific dose modification and management guidelines for colitis are provided in Table 6.  


 
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Table 6 GDC-0032 Dose Modification and Management Guidelines 
for Colitis 
Grade of Colitis 
Dose Modification and Management Guidelines  
Grade 2 or Grade 3 
(first event) 
• 
Hold GDC-0032 and manage per institutional standard of 
care until Grade ≤ 1.   
• 
Initiate corticosteroid therapy for noninfectious colitis. a 
• 
Recommend discontinuation of any nonsteroidal anti-
inflammatory medications or any other medications known 
to exacerbate colitis symptoms. 
• 
Restart GDC-0032 at the next lower dose level upon 
resolution to Grade ≤ 1.  In cases where risk/benefit is 
deemed favorable, may consider restarting at the same 
dose after discussion with and approval by the Medical 
Monitor. 
Grade 3 (first 
recurrence) 
• 
Hold GDC-0032. 
• 
Initiate corticosteroid therapy for noninfectious colitis. a   
• 
Permanently discontinue GDC-0032.  In cases where 
risk/benefit is deemed favorable, may consider restarting at 
the next lower dose level upon resolution to Grade ≤ 1 after 
discussion with and approval by the Medical Monitor.   
Grade 3 (second 
recurrence) or Grade 4 
• 
Permanently discontinue GDC-0032. 
• 
Initiate corticosteroid therapy for noninfectious colitis. a 
a Examples of corticosteroid regimens include the following:  For the steroid taper, suggested 
steroids include methylprednisolone dose pack or prednisone 60 mg daily followed by a taper 
(e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, etc.). 
 
5.1.1.4.3 
Management of Stomatitis and Oral Mucositis 
Aggressive mouth care for oral mucositis and stomatitis with mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal 
and/or antibiotics) may also be helpful in managing symptoms, and it is recommended 
that these are implemented with early signs of dry mouth, Grade 1 mucositis, or Grade 1 
stomatitis (see Table 7).  Avoidance of spicy foods may also be helpful.   


 
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Table 7 GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Grade of 
Stomatitis/Mucositis 
GDC-0032  
All grades 
• 
Aggressive mouth care that includes mouthwash 
formulations (e.g., combinations of local anesthetic, 
antihistamine, corticosteroid, antacid, antifungal and/or 
antibiotics)  
• 
Diet management (e.g., avoidance of spicy foods) 
Grade 1 
• 
Monitor symptoms and initiate management (see above). 
Re-evaluate within 48 − 72 hours.   
Grade 2 
• 
Hold GDC-0032 and manage until Grade ≤ 1.   
• 
Restart GDC-0032 at the same dose.   
• 
If Grade 2 stomatitis/oral mucositis recurs, hold GDC-0032 
until Grade ≤ 1.  Restart GDC-0032 at the next lower dose. 
Grade 3 or 4 
• 
Hold GDC-0032 and manage until Grade ≤ 1.  Restart 
GDC-0032 at the next lower dose.  
• 
For Grade 3 event that was not adequately managed upon 
initial presentation, consider restarting at same dose upon 
discussion with Medical Monitor.   
• 
For Grade 4 event, consider permanent discontinuation of 
GDC-0032. 
  
5.1.2 
Management of Other Clinically Significant Adverse Events 
See Table 8 for the dose modifications for other clinically significant adverse events. 
Table 8 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events 
Grade 
GDC-0032  
Grade 3:  first event 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Consider restarting at next lower dose. 
Grade 3:  recurrent 
Grade 4:  non-life-threatening 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Restart at next lower dose. 
Grade 4:  life-threatening 
• 
Permanently discontinue GDC-0032.  
 
5.1.3 
General Guidance for Dose Modifications and Delays for 
Letrozole 
The letrozole dose level cannot be modified.  In general, the investigator can consider 
continuing letrozole if it is not thought to be letrozole-related.   
All dose modifications should be based on the adverse event requiring the greatest 
modification and should be properly documented in the source documents. 


 
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5.1.4 
Management of Increases in QT Interval  
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
1. 
Sustained (at least two ECG measurements  > 30 minutes apart) QTcF that 
is  > 500 msec and  > 60 msec longer than the baseline value 
2. 
Sustained absolute QTcF that is  > 515 msec  
3. 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, as this represents an increase in 
QTcF unrelated to alterations in repolarization.  Also of note, it is not uncommon to 
record arrhythmias such as non-sustained ventricular tachycardia, supraventricular 
tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving placebo during 
periods of extended ECG monitoring.  Therefore, it is critical that expert 
electrophysiologic advice be sought to confirm any ECG changes and to ascertain the 
likelihood of a drug-induced arrhythmia versus the background occurrence of this 
arrhythmia.  In such a situation, saving all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients. 
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied. 
5.1.5 
Safety Monitoring for Letrozole 
Letrozole is a nonsteroidal AI indicated for first line treatment of hormone receptor 
positive, locally advanced, or metastatic breast cancer in postmenopausal women.  
Letrozole is also indicated for adjuvant treatment in postmenopausal hormone-receptor 
positive patients and for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following anti-estrogen therapy. 
The most frequently reported adverse events in a first line, breast cancer clinical trial 
with letrozole were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea.  
Clinically significant adverse events also include bone effects (osteoporosis and bone 
fractures) and hypercholesterolemia.  Discontinuations for adverse events other than 
progression of tumor occurred in 2% of patients on letrozole.  Refer to the U.S. letrozole 
Package Insert or SmPC for additional information.   


 
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There are no expected significant overlapping toxicities between letrozole and 
GDC-0032. Routine safety monitoring and periodic laboratory tests for the letrozole and 
GDC-0032 combination will occur throughout the study. 
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; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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 ABCSG) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (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 ABCSG safety 
department 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 ABCSG)  
Non-serious adverse events of special interest are required to be reported by the 
investigator to ABCSG safety department 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: 
• 
Grade 4 hyperglycemia 
• 
Grade  ≥  3 symptomatic hyperglycemia 
• 
Grade  ≥  2 colitis or enterocolitis  
• 
Grade ≥ 3 diarrhea 
• 
Grade  ≥  3 rash 
• 
Grade  ≥  2 pneumonitis  


 
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• 
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 5.3.5.5) 
• 
Suspected transmission of an infectious agent by the study drug  
 
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 additionally reported to ABCSG 
safety department in case they fulfill the criteria for expedited reported in accordance 
with instructions provided in this section and in Section 5.4 −Section 5.6. 
For each adverse event recorded on the Adverse Event CRF, 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 
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 until the end of 
study visit, whichever occurs later.  After this period, investigators should report any 
deaths, serious adverse events, or other adverse events of concern deemed related to 
prior study drug treatment or study procedures (Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v 4.0) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 9 
Adverse Event Severity Grading Scale 
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 (v 4.0), 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 one's self, 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 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 10): 
• 
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 (where 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 
 


 
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Table 10 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 
Adverse events will be considered related, unless they fulfill the criteria as 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. 
If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


 
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5.3.5.1 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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. 
5.3.5.2 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The progression (increase and decrease) of an adverse 
event must be documented in the Adverse Event eCRF.   
The initial severity of the event should be recorded, and the severity should be updated 
to reflect the most extreme severity any time the event worsens. If the event becomes 
serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.3 
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: 
• 
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 
• 
Clinically significant in the investigator’s judgment 
 


 
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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 times the 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.4 
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: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 


 
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5.3.5.5 
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 ABCSG safety department immediately (i.e., no more than 24 hours 
after learning of the event), either as serious adverse event or a non-serious adverse 
event of special interest (see Section 5.4.2). 
5.3.5.6 
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 ABCSG safety department 
(see Section 5.4.2). This includes death attributed to progression of breast cancer. 
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 only be used 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 of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive 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. 
5.3.5.7 
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 CRF. 
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”). 


 
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5.3.5.8 
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: 
• 
Perform an efficacy measurement for the study 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol for breast cancer surgery  
• 
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 suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
• 
Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care 
• 
Hospitalization for protocol mandated biopsies 
 
5.3.5.9 
Adverse Events Associated with an Overdose 
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 serious 
criteria, the event should be reported to the ABCSG safety department immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.10 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO ABCSG 
Certain events require immediate reporting to allow ABCSG safety department to take 
appropriate measures to address potential new risks in a clinical trial.  The investigator 
must report such events to ABCSG safety department 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 
ABCSG safety department 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 
ABCSG safety department immediately (i.e., no more than 24 hours after becoming 
aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
U.S. Medical Monitor Contact Information  
Genentech’s Medical Monitor Contact Information: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No. 
Alternate Telephone No.: 
 
Medical Monitor Contact Information for Sites outside the United States:  
Please refer to the country/region-specific phone numbers provided in the study binder. 


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the paper Serious Adverse Event reporting form and transmit to ABCSG 
safety department via fax. In addition the serious adverse event and non-serious 
adverse event of special interest information will be captured in the EDC system.   
Worldwide Sites: 
ABCSG safety department  
Fax No.: 
+43 1 409 09 90 
Relevant follow-up information should be submitted to ABCSG safety department as 
soon as it becomes available and/or upon request. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification (SDV).  For follow-up reports of serious adverse events and non-serious 
adverse events of special interest, investigators should record all follow up information 
immediately (i.e., within 24 hours) on the paper Serious Adverse Event reporting form 
and transmit to ABCSG safety department via fax. In addition the serious adverse event 
and non-serious adverse event of special interest follow-up information will be captured 
in the EDC system. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and paper 
Serious Adverse Event form, if applicable.   
All pregnancies reported during the study should be followed until pregnancy outcome, 
and they should be reported according to the instructions provided in Section 5.4. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor and/or ABCSG safety department 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. 


 
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5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator should report these events directly to Genentech Safety Risk 
Management via telephone at 1-888-835-2555. 
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: 
• 
GDC-0032 Investigator's Brochure  
• 
Local prescribing information for letrozole SmPC 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An IDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
Primary and secondary efficacy analyses will include all patients who were included 
in the randomization. Final analysis will be performed after last patient, last visit (LPLV) 
and subsequent data cleaning, with patients allocated to the treatment arm associated 
by randomization. 
Safety analyses will include all patients who were included in the randomization and 
received at least one dose of study treatment, with patients allocated to the treatment 
arm associated with the regimen actually received.  


 
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6.1 
DETERMINATION OF SAMPLE SIZE  
This study is designed for testing the effect of GDC-0032 on the two co-primary 
endpoints in all enrolled patients and in the PIK3CA MT patients and plans to enroll 330 
patients in total. Assuming the PIK3CA mutation status will not be available (unknown) 
for approximately 10% of the patients and the prevalence of PIK3CA mutant is 40%, 
there will be approximately 120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, 
there might be a possible imbalance between treatment arms within the PIK3CA MT 
cohort, which may reduce the statistical power in this cohort. To ensure the study 
provides sufficient statistical power even when the treatment assignment is imbalanced, 
the sample size was calculated based on a conservative scenario by assuming that the 
treatment assignment imbalance in PIK3CA MT is 40% vs. 60%. The sample size was 
calculated based on a chi²-test using continuity correction (Ury and Fleiss 1980). 
To control an overall, two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, 
respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 
enrolled patients and 108 patients in the PIK3CA MT cohort will be evaluable for 
analyses. This sample size allows us to detect an absolute percentage increase of 24% 
in MRI ORR rate in the GDC-0032 plus letrozole arm (64%) versus the letrozole-only 
arm (40%; Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power 
and 16% two-sided significance level.  The minimal detectable difference for ORR is 
approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled 
patients and 120 in the PIK3CA MT cohort), this sample size provides 80% power to 
detect an absolute percentage increase of 18% in pCR in the GDC-0032 plus letrozole 
arm (19%) versus the letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in 
the PIK3CA MT cohort at the 4% two-sided significance level.  The minimal detectable 
difference for pCR rate is approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more 
substantial treatment assignment imbalance in the PIK3CA MT cohort than assumed, or 
there is an increased number of unevaluable patients for the MRI ORR, the sample size 
may be increased to obtain the level of power at 80%, and the enrollment may be limited 
to patients with PIK3CA MT.   
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 incidence of study treatment 
discontinuation for reasons other than disease progression will be tabulated. 


 
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6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized by treatment arm. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the ITT population; that is, all 
randomized patients will be included in the analyses, with patients grouped according to 
the treatment assigned at randomization.  
6.4.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are (1) tumor ORR, assessed by modified RECIST 
criteria by breast MRI and (2) the rate of pCR in breast and axilla (total pCR) after 
completion of study drug. 
The tumor ORR will be calculated by treatment arm in all enrolled population and in 
PIK3CA MT population. Within each population, the ORR for the two treatment arms will 
be compared at a two-sided alpha of 16% using a Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status. The pCR rate will also be calculated and 
compared at a two-sided alpha of 4% based on the same analytical approach as ORR. 
The two alpha values account for a family-wise type I error rate of 20%. Patients with 
early study termination and hence missing efficacy outcome will be considered as non-
responders. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST 
criteria by breast MRI in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in 
PIK3CA WT patients.  
• 
These endpoint measures will be summarized by treatment arm and will be 
analyzed analogue to the primary efficacy endpoint. 
• 
The following secondary efficacy endpoints will be performed in all enrolled patients 
and separated by PIK3CA mutation status: 
• 
ORR by clinical breast examination, mammography, and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to 
surgery (centrally assessed) 
• 
PEPI score (centrally assessed) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast 
MRI 


 
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• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and 
b) ypT0/is, ypNX (breast pCR) 
These endpoint measures will be summarized by treatment arm and will be compared 
between the two treatment arms within each population based on appropriate statistical 
analyses:  ORR will be compared using a Cochrane Mantel-Haenszel test, stratified by 
tumor size and nodal status; PEPI, Ki67, and tumor volume change will be compared by 
regression analyses, adjusted for tumor size and nodal status. All secondary endpoints 
will be tested at a two-sided type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study 
treatment, with patients allocated to the treatment arm associated with the regimen 
actually received.  
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and letrozole and GDC-0032 exposure. 
Verbatim descriptions of adverse events will be mapped to thesaurus terms.  Adverse 
event data will be listed by study site, treatment arm, patient number, and study day, 
severity, relationship to study drug, outcome, and action taken with the study treatments.  
Events occurring on or after treatment on Day 1 of Week 1 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 and vital sign (heart rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE v4.0 Grade 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized in tables by NCI 
CTCAE v4.0 grade. 
6.6 
PHARMACODYNAMIC ANALYSES  
Ki67 biomarker analyses will include patients with at least one predose and one 
postdose biomarker assessment, with patients grouped according to the treatment 
actually received.  
6.7 
PHARMACOKINETIC ANALYSES  
Individual Cmax and trough plasma concentrations (Cmin) of GDC-0032 and letrozole from 
all patients enrolled will be reported. Mean of trough plasma concentrations of GDC-
0032 and letrozole will be tabulated. The population pharmacokinetics of letrozole and 
GDC-0032 in this study will be compared with historical single-agent pharmacokinetics 
to assess the potential DDI between GDC-0032 and letrozole in this population.   


 
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Additional PK analyses on metabolites of GDC-0032, letrozole, and/or other concomitant 
medications may be conducted as appropriate. 
6.8 
PATIENT-REPORTED OUTCOME ANALYSES 
Patient-reported outcomes of breast cancer symptoms, patient functioning, and HRQoL 
will be assessed by the EORTC QLQ-C30 and the modified Breast Cancer module 
(QLQ-BR23)  
Summary statistics (mean, standard deviation, median and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the modified QLQ-BR23 according to the EORTC scoring manual 
guidelines for each assessment time point. The mean change of the linear transformed 
scores from baseline (and 95% CI using the normal approximation) will also be 
assessed. Line charts depicting the mean changes (and standard errors) of items and 
subscales over time will be provided for each treatment arm from the baseline 
assessment. 
Data analysis will be performed on the final modified BR23 data set in parallel with the 
final data analysis to assess the psychometric properties of the modified instrument and 
will be reported along with the clinical trial results.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data. Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses. The number and 
proportion of patients who improved, worsened, or remained stable for all of the 
symptom and functional domains, global QoL, and single items of the EORTC QLQ-C30 
and QLQ-BR23 will be summarized. 
6.9 
EXPLORATORY ANALYSES  
Additional details on analyses will be specified in the SAP. 
6.10 
INTERIM ANALYSES  
The IDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day, follow-up visit after the surgery, or 2) been 
on study for 20 weeks after the randomization date (for those who do not receive the 
surgery).  All available information of all enrolled patients with all available assessments 
at the respective timepoint will be included in the interim analyses.  In addition, the IDMC 
or the Medical Monitor may request additional ad hoc meetings of the IDMC at any time 
during the study to review safety data. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
ABCSG will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, ABCSG 
and/or all involved clinical research associates (CRAs) will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
ABCSG will produce a Data Management Plan that describes the quality checking to be 
performed on the data. The Sponsor will perform oversight of the data management of 
this study, including review of the ABCSG’s data management plan and corresponding 
specifications.  Data will be transferred electronically from ABCSG to the Sponsor at the 
end of the study and whenever otherwise contractually agreed, and the Sponsor’s 
standard procedures will be used 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 at ABCSG and records retention for the study data will 
be consistent with the ABCSG’s standard procedures. 
Data from paper PRO questionnaires will be entered into the EDC system by site staff. 
Original PRO questionnaires will be kept in the patient’s medical record as source 
documentation. 
7.2 
DATA(BASE) MANAGEMENT 
ABCSG Clinical Data Management will check all e-forms for plausibility and consistency 
by automatic edit checks and manual data review according to study-specific data 
management plan (DMP).  If necessary, web-based data queries (data clarification 
requests [DCRs]) will be generated and subsequently visible for the investigators, 
dedicated site staff, responsible CRAs, and responsible ABCSG staff.  For those eCRFs 
which pass all verification procedures and are regarded as correct and complete, they 
will be frozen subsequently by ABCSG clinical data management. Consequently, no 
further data entries or changes on frozen eCRFs are possible. The status of frozen 
eCRFs is flagged by the specific icon. 
Clinical Data Management ensures that the database is corrected for the following eCRF 
issues without immediate notification to site staff (self-evident corrections). Notification of 
site staff is provided via a specific report after final data cleaning procedures and before 
final data confirmation by the investigator or a designee: 
• 
misspellings/typing errors that do not change the meaning of the word 
• 
location of data recorded at an incorrect variable field or eForm (e.g., moving lab 
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• 
standard time to 24-hour clock 
• 
correction of date format, if required (dd/mm/yyyy) 
• 
if equivalent units of terms are recorded instead of the acceptable ABCSG standard 
• 
data changes due to plausibility checks and eCRF content (e.g., combination of 
several variables and/or eCRFs) 
All data management workflows are described in detail in the relevant SOPs and 
working instructions of ABCSG. 
7.3 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using the Clinical Data Management System “MACRO,” a 
web-interface DATAPORT.  Sites will receive training by the responsible CRAs and have 
access to a manual for appropriate eCRF completion (web data entry).   
All eCRFs should be completed by designated, trained site staff in a timely manner, 
usually within 2 weeks after the patient visit.  Electronic CRFs should be reviewed and 
respective data confirmation eCRF should be electronically signed and dated by the 
investigator or a designee at the end of the study.  
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a storage medium (compact disc [CD], digital video disk [DVD] etc.) 
that must be kept with the study records. Acknowledgement of receipt of the storage 
medium is required. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors (CRAs) will perform ongoing SDV 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 
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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 7.6. 
To facilitate SDV, the investigators and institutions must provide the Sponsor/CRAs 
direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review. The investigational site must also allow inspection 
by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), ICFs, 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 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 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/European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC). 


 
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8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs) 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 ICFs 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. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  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 separate, specific 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 provide a 
separate signature. 
The ICFs must be signed and dated by the patient or the patient’s legally 
authorized representative before 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 eCRF contains a section to document whether the patient has signed the ICF or not. 
The ICFs 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. 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion. After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood. The investigator or designee must also explain that the patients are 


 
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completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason. 
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated ICFs 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 ICF 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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the sponsor, the affiliated 
groups, or contract research organizations (CROs) according to the applicable local laws 
and regulations, if applicable 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 Sponsor, affiliated groups, or CROs are 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 local IRB/EC. The 
Sponsor, affiliated groups, or CROs 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 local 
health authority requirements and the policies and procedures established by their 
IRB/EC, and archived in the site’s study file.  
8.4 
DATA PRIVACY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique 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 only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use and 


 
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disclosure of personal health information) signed by the patient, unless permitted or 
required by local 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, provided 
the patient has given consent. 
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. The patient will have to consent to such access by signing the informed 
consent form. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (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, ICFs, and documentation of IRB/EC and governmental (health authorities) 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
which includes an audit trail containing a complete record of all changes to data. 
9.2 
ON SITE QUALITY CONTROL (MONITORING) 
During the study, CRAs will visit their respective sites on a regular basis as outlined in 
the study specific monitoring plan (MP) and all other relevant specifications, in order to 
guarantee adherence to the protocol and to the principles of GCP and to check for the 
progress of enrolment, adequate storage conditions of IMP and adequate drug 
dispensing and accounting records.  
CRAs will review documented data in the eCRFs for completeness and accuracy 
according to the study-specific MP, subsequently flag all reviewed pages with a specific 
mark (“SDV done”) within the EDC system “MACRO,” web-interface DATAPORT, 
developed by 
.  The CRAs will raise data queries (“DCRs”) in cases of 
missing source data or incorrect data entries. Immediately after electronic issue of the 
queries, they become visible to the investigator, the clinical data managers, and the 
ABCSG clinical safety officers (“raised DCRs”).  CRAs and/or clinical data managers 


 
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and/or ABCSG clinical safety officers will follow up with trial site personnel until final data 
query resolution. 
9.3 
PROTOCOL DEVIATIONS 
The investigator should document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with 
established IRB/EC policies and procedures. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit international and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech in 
collaboration with the Breast International Group (BIG), ABCSG, and the Spanish Breast 
Cancer Research Group (SOLTI). Genentech in collaboration with BIG, ABCSG, and 
SOLTI will provide clinical operations management, data management, and medical 
monitoring.  Approximately 110 U.S. and international sites will participate to enroll 
approximately 330 patients. 
An IDMC will be in place throughout the study and will provide oversight of safety and 
efficacy analyses (see Section 3.1.2). 
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the IxRS system. Once eligibility has been established, the 
patient will be enrolled, and the study site will obtain the patient’s identification number 
from the IxRS. Once results of the tissue analysis are made available, the patient will be 
randomized, and the site will obtain the blinded treatment assignment from the IxRS.  
The IxRS will manage GDC-0032/placebo drug inventory at all sites and letrozole drug 
inventory at all study sites outside the United States.  IxRS will be required to randomize 
patients, to monitor enrollment and patient status, and to manage study treatment 
requests and shipments.  
Patient data will be recorded via an electronic data capture (EDC) system from 
 
, United Kingdom), which will be managed by ABCSG using eCRFs 
(see Section 7.2).   
Central laboratories, including Genentech and Genentech collaborators, will be used for 
PIK3CA mutation detection, Ki67, and PTEN status and/or will provide kits for PK, 
pharmacogenomic, tissue, whole blood, and plasma sample analyses to be conducted at 
central laboratories, Genentech, or Genentech collaborators. 


 
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An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans throughout the trial. The review facility will retain 
copies of scans for centralized assessments of MRI-related endpoints.   
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). 


 
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10. 
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Akazawa K, Tamaki Y, Taguchi T, et al. Preoperative evaluation of residual tumor extent 
by three-dimensional magnetic resonance imaging in breast cancer patients treated with 
neoadjuvant chemotherapy. Breast J 2006;12:130 − 7.  
Awada A, Cardoso F, Fontaine C, et al. The oral mTOR inhibitor RAD001 (everolimus) in 
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  119 
Appendix 1  
Schedule of Assessments 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
Informed consent a 
x 
 
 
 
 
 
 
 
 
Medical history and  
demographic data b 
x 
 
 
 
 
 
 
 
 
Physical examination c 
x 
 
 
x 
x 
x 
x 
 
x 
Clinical breast and regional lymph 
node examination  
x 
x 
 
x 
x 
x 
x 
 
 
Vital signs d 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
x 
12-Lead ECG e 
x 
 
x 
 
 
 
 
 
 
Mammography  
x 
 
 
 
 
 
x 
 
 
Breast ultrasound and axillary lymph 
node status f 
x 
 
 
 
x 
 
x 
 
 
Breast MRI g 
x 
 
 
 
 
 
x 
 
 
Collection of tumor samples h  
x 
 
x 
 
 
 
 
x 
 
Confirmation of receipt of adequate 
tissue for PIK3CA assessment 
x 
 
 
 
 
 
 
 
 
CBC with differential and  
platelet count i 
x 
x 
 
x 
x 
x 
x 
 
x 
Fasting serum chemistry j 
x 
x 
 
x 
x 
x 
x 
 
x 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 2 
 
 
 
 
 
 
 
 
 
  120 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
Glycosylated hemoglobin (HbA1c) 
x 
 
 
 
 
 
 
 
 
Fasting insulin and glucose k 
x 
x 
 
x 
x 
x 
x 
 
x 
Fasting lipid profile and amylase l 
x 
 
 
x 
 
x 
x 
 
x 
Coagulation (INR and aPTT)  
x 
 
 
x 
x 
x 
x 
 
x 
Urinalysis (laboratory) m 
x 
 
 
x 
x 
 
x 
 
x 
DLCO n 
x 
 
 
 
 
 
x 
 
 
Bone mineral density test o 
x 
 
 
 
 
 
 
 
 
Blood sample for plasma protein 
biomarkers p 
 
x 
 
 
x 
 
x 
 
 
Blood sample for ctDNA q 
 
x 
 
 
x 
 
x 
 
 
Blood sample for NGS r 
 
x 
 
 
 
 
 
 
 
Pharmacogenomic sample s  
 
x 
 
 
 
 
 
 
 
Concomitant medication t 
x 
x 
x 
x 
x 
x 
x 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
 
x 
Inclusion/exclusion criteria u 
x 
 
 
 
 
 
 
 
 
Visit with breast surgeon (may occur 
from Week 13) 
 
 
 
 
 
x 
 
 
 
Surgery v 
 
 
 
 
 
 
 
x 
 
Randomization  
x 
 
 
 
 
 
 
 
 
Letrozole accountability/dispensation 
 
x 
x 
x 
x 
x 
x 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 2 
 
 
 
 
 
 
 
 
 
  121 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgic
al Visit) 
W17 − W18 
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 (+ 2) 
29 (± 2) 
57 (± 2) 
85 (± 2) 
106 − 112 
113 − 126 
 
GDC-0032/placebo accountability/ 
dispensation  
 
x 
x 
x 
x 
x 
x 
 
 
Patient-reported outcomes w 
 
x 
 
x 
x 
x 
x 
 
x 
Pharmacokinetic sample (see 
Appendix 2) 
 
x 
x 
 
x 
 
 
 
 
aPTT = activated partial thromboplastin time; CA-125 = cancer antigen 125; CTCs = circulating tumor cells; ctDNA = circulating tumor DNA; 
DLCO = diffusion capacity of the lung for carbon monoxide; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INR = international 
normalized ratio; MRI = magnetic resonance imaging; NGS = next-generation sequencing. 
Note:  All assessments should be performed before dosing, unless otherwise stated.  Some assessments may be performed outside the window indicated 
to accommodate holidays, unforeseen scheduling issues, or ongoing safety issues with the trial and the patient, after approval by the Medical Monitor. 
a Perform within 28 days prior to Day 1 of Cycle 1.  Signed informed consent must be provided prior to any study-specific evaluations.  Assessments 
performed as standard of care within the timeframe may be used. 
b Medical history includes clinically significant diseases that are currently active or that were active within the last 5 years, surgeries, cancer history 
(including date of diagnosis, primary tumor histology, grade, staging, prior cancer therapies, and procedures), reproductive status, smoking history, use 
of alcohol and drugs of abuse. Demographic data include age, sex, and self-reported race/ethnicity. 
c A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; 
height is measured at the screening visit only).  Perform symptom-directed physical examination after baseline assessment. 
d Vital signs include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated position and 
temperature. Oxygen saturation is obtained by pulse oximetry after the patient has been in a seated position for ≥ 5 minutes. Obtain vital signs predose. 
e Triplicate ECG recordings will be obtained at each specified timepoint.  A window of  ± 30 minutes is acceptable for all timepoints.  Submit all ECGs to 
the diagnostic facility for central review. 
f Baseline evaluation of axillary lymph nodes assessed with ultrasound. 
g MRI evaluation is optional at Week 9.  MRI is mandatory at Week 9 in the event that disease progression is suspected, or if the primary lesion is not 
evaluable by ultrasound at baseline.  Send all scans to the central reading facility for evaluation. 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 2 
 
 
 
 
 
 
 
 
 
  122 
h Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen OCT core needle biopsy are required prior to initiation of treatment 
(pretreatment) and also on Day 15.  A formalin-fixed, paraffin-embedded tumor block from a surgical resection is required at surgery (Weeks 17 − 18). 
i Complete blood count includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils, bands, eosinophils, 
basophils, lymphocytes, monocytes, and other cells), and platelet count. Screening results may be valid for Week 1, Day 1 if performed within 7 days 
prior to Week 1, Day 1. 
j Fasting ( ≥ 10-hour fast) serum chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, 
serum bilirubin, alkaline phosphatase, glucose, AST, and ALT. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to 
Week 1, Day 1. 
k Glucose levels may be obtained by fingerstick. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, Day 1. 
l Fasting lipid profile includes total cholesterol, HDL, LDL, triglycerides, amylase, and lipase. Screening results may be valid for Week 1, Day 1 if 
performed within 7 days prior to Week 1, Day 1. 
m Includes specific gravity, pH, glucose, protein, ketones, and blood. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to 
Week 1, Day 1. 
n   DLCO is obtained at screening and prior to surgery.  The DLCO test should be repeated if there is clinical suspicion of pneumonitis.  DLCO 
calculations are described in Appendix 7.  The hemoglobin value used for correcting DLCO should represent the patient’s actual hemoglobin level 
and should be obtained within 7 days of the DLCO test. 
o Baseline bone mineral density will be measured via dual-energy X-ray absorptiometry (DXA) and will need to be obtained in women with a history 
of osteoporosis and/or fractures, or who are at increased risk of osteoporosis.  DXA measurement of both the hip and lumbar spine is suggested.  
When either the hip or lumbar spine is not a valid skeletal site for BMD measurement, then the 33% (one-third) radius should be measured. In some 
patients, measurement of the hip alone could be sufficient. 
p Pretreatment sample for plasma protein biomarkers should be obtained prior to dosing.  Refer to laboratory manual for more information. 
q Pretreatment sample for ctDNA may be obtained on Day 1 prior to dosing.  This sample will also be collected prior to dosing at Week 9 and at 
Week 16.  Refer to laboratory manual for more information. 
r Blood for NGS will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1.   
s Blood for pharmacogenomics will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1. 
t Record all medications used by the patient within 15 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements). 
u All of the study’s inclusion criteria and none of the exclusion criteria should be met prior to study entry. 
v Surgery will take place after at least 16 weeks of combination treatment (i.e., from Week 17 to Week 18), and generally no more than 2 days after the 
last dose of study medication. 
w The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) will be completed by the patients at the investigational site.  All PRO questionnaires 
must be administered prior to any other study assessment(s) and prior to administration of study drug.  
 


 
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Appendix 2  
Schedule of Pharmacokinetic Assessments 
Visit 
Timepoint 
PK Assessments 
Letrozole PK 
Day 1 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
0 − 4 hours prior to letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
Day 15 
( + 2 days) 
3 hours ( ± 60 min) post letrozole and 
GDC -0032/placebo administration 
ECG before PK 
GDC-0032 PK 
Day 57 
( + / − 2 days) 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
Letrozole PK 
GDC-0032 PK 
ECG = electrocardiogram; min = minutes; PK = pharmacokinetics.  
Record exact time of dose administration and sample collection. 
 


 
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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 
therapy in early breast cancer.  Ultrasound, mammography, and clinical exam are all 
                                            
 
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.) 
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Protocol GO28888, Version 2 
  125 
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 
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.   


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Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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 
 
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. 


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Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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 
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. 


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Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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.  
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.  


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Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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. 


 
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Appendix 4  
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures   
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
____________________ 
Your birthdate (Day, Month, Year): 
____________________ 
Today's date (Day, Month, Year):  
 
____________________ 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to 
which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
31. Did you have a dry mouth? 
1 
2 
3 
4 
 
32. Did food and drink taste different than usual? 
1 
2 
3 
4 
 
33. Were your eyes painful, irritated or watery? 
1 
2 
3 
4 
 
34. Have you lost any hair? 
1 
2 
3 
4 
 
35. Answer this question only if you had any hair loss: 
Were you upset by the loss of your hair? 
1 
2 
3 
4 
 
36. Did you feel ill or unwell? 
1 
2 
3 
4 
 
37. Did you have hot flushes? 
1 
2 
3 
4 
 
38. Did you have headaches? 
1 
2 
3 
4 
 
39. Have you felt physically less attractive 
as a result of your disease or treatment? 
1 
2 
3 
4 
 
40. Have you been feeling less feminine as a 
result of your disease or treatment? 
1 
2 
3 
4 
 
41. Did you find it difficult to look at yourself naked? 
1 
2 
3 
4 
 
42. Have you been dissatisfied with your body? 
1 
2 
3 
4 
 
43. Were you worried about your health in the future? 
1 
2 
3 
4 
 
 
44. Have you had skin problems (e.g. itchy, dry)?  
1 
2 
3 
4 
 
45. Did itching of your skin bother you? 
1 
2 
3 
4 
  46. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
47. Have you had trouble swallowing? 
1 
2 
3 
4 
 
 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past four weeks: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
48. To what extent were you interested in sex? 
1 
2 
3 
4 
 
49. To what extent were you sexually active? 
(with or without intercourse) 
1 
2 
3 
4 
 
50. Answer this question only if you have been sexually 
active: To what extent was sex enjoyable for you? 
1 
2 
3 
4 
 


 
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Appendix 5  
New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients 
NYHA 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation or dyspnea. 
No objective evidence 
of cardiovascular 
disease. 
II 
Mild 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or 
dyspnea 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or 
dyspnea. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical 
activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 


 
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Appendix 6  
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
DCIS 
Tis (LCIS) 
LCIS 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the 
underlying breast parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on 
the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. 
T1 
Tumor  ≤20 mm in greatest dimension 
T1mi 
Tumor  ≤1 mm in greatest dimension 
T1a 
Tumor  >1 mm but  ≤5 mm in greatest dimension 
T1b 
Tumor  >5 mm but  ≤10 mm in greatest dimension 
T1c 
Tumor  >10 mm but  ≤20 mm in greatest dimension 
 
 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Tumor (T) 
T2 
Tumor  >20 mm but  ≤50 mm in greatest dimension 
T3 
Tumor  >50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)a 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for 
inflammatory carcinoma 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp 347−76. 
DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. 
Note: The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both.  Size should 
be measured to the nearest millimeter.  If the tumor size is slightly less than or greater than a cut-off for a given T classification, it is recommended 
that the size be rounded to the millimeter reading that is closest to the cut-off.  For example, a reported size of 1.1 mm is reported as 1 mm, or a 
size of 2.01 cm is reported as 2 cm.  Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was 
determined by clinical (physical examination or radiologic) or pathologic measurements, respectively.  In general, pathologic determination should 
take precedence over clinical determination of T size. 
a Invasion of the dermis alone does not qualify as T4.  


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Regional Lymph Nodes (N) 
Clinical   
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted 
OR 
N2 
Metastases in clinically detected a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures 
N2b Metastases only in clinically detected a ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph 
node metastases 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement 
OR 
Metastases in clinically detected a ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node 
metastases 
OR 
N3 
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Regional Lymph Nodes (N) 
Clinical 
N3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 34776.   
a Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics 
highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination.  
Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, for 
example, cN3a(f).  Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a 
clinical N, for example, cN1.  Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine 
needle aspiration, core biopsy, or sentinel lymph node biopsy.  Pathologic classification (pN) is used for excision or sentinel lymph node biopsy 
only in conjunction with a pathologic T assignment. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
Note: ITCs are defined as small clusters of cells  ≤ 0.2 mm, or single tumor cells, or a cluster of  < 200 cells in a single histologic cross-section.  
ITCs may be detected by routine histology or by IHC methods.  Nodes containing only ITCs are excluded from the total positive node count for 
purposes of N classification but should be included in the total number of nodes evaluated. 
pN0(i–) 
No regional lymph node metastases histologically, negative IHC 
pN0(i + ) 
Malignant cells in regional lymph node(s)  ≤ 0.2 mm (detected by H&E or IHC including ITC) 
pN0(mol–) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0(mol + ) 
Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC 
Micrometastases 
OR 
Metastases in 1–3 axillary lymph nodes 
AND/OR 
pN1 
Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected a 
pN1mi 
Micrometastases ( >0.2 mm and/or >200 cells but none  > 2 mm) 
pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis  > 2 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but 
not clinically detected a 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected 
Metastases in 4–9 axillary lymph nodes 
OR 
pN2 
Metastases in clinically detected a internal mammary lymph nodes in the absence of axillary lymph node metastases 
pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit  > 2 mm) 
pN2b Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases 
Metastases in  ≥ 10 axillary lymph nodes 
OR 
Metastases in infraclavicular (level III axillary) lymph nodes 
OR 
Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary 
lymph nodes 
OR 
Metastases in  > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
OR 
pN3 
Metastases in ipsilateral supraclavicular lymph nodes 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit >2 mm) 
OR 
pN3a 
Metastases to the infraclavicular (level III axillary lymph) nodes. 
Metastases in clinically detected b ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph 
nodes; 
OR 
pN3b 
Metastases in > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
Post-treatment ypN  
Post-treatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above.  The modifier "SN" is used only if a sentinel node 
evaluation was performed after treatment.  If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND. 
The X classification will be used (ypNX) if no yp post-treatment SN or AND was performed 
N categories are the same as those used for pN 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse 
transcriptase/polymerase chain reaction. 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
1 Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  Classification based solely on sentinel lymph 
node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).   
a "Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.   
b "Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having 
characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic 
examination.   
 
Distant Metastases (M) 
 
M0 
No clinical or radiographic evidence of distant metastases 
cM0(i + ) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in 
circulating blood, bone marrow, or other non-regional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of 
metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
 
Post-treatment yp M classification.  The M category for patients treated with neoadjuvant therapy is the category assigned in the 
clinical stage, prior to initiation of neoadjuvant therapy.  Identification of distant metastases after the start of therapy in cases where 
pre-therapy evaluation showed no metastases is considered progression of disease.  If a patient was designated to have detectable 
distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Anatomic Stage/Prognostic Groupsa  
Stage 
T 
N 
Mc 
0 
Tis 
N0 
M0 
IA 
T1c 
N0 
M0 
IB 
T0 
N1mi 
M0 
 
T1c 
N1mi 
M0 
IIA 
T0 
N1b 
M0 
 
T1c 
N1b 
M0 
 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
 
T1c 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Stage 
T 
N 
Mc 
 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
Note: Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are 
carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.  
Post-neoadjuvant therapy is designated with "yc" or "yp" prefix.  Of note, no stage group is assigned if there is a complete pathologic response (CR) 
to neoadjuvant therapy, for example, ypT0cM0.   
a T1 includes T1mi.   
b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.   
c M0 includes M0(i+); The designation pM0 is not valid; any M0 should be clinical.  If a patient presents with M1 prior to NAST, the stage is 
considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.   
 


 
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Appendix 7  
Correction of Predicted DLCO for Hemoglobin and Alveolar 
Volume 
All DLCO measurements will be obtained as per the American Thoracic Society and 
European Respiratory Society (ATS/ERS) guidelines (MacIntyre et al. 2005).  
The predicted DLCO value should be corrected for both hemoglobin (Hb) and alveolar 
volume (va).   
Pulmonary function test laboratories that follow the ATS/ERS guidelines should be able 
to provide the value for DLCO, corrected for va.  A single breath va may be used to 
obtain DLCO, corrected for va.  Use the following equation to determine the predicted 
DLCO, corrected for Hb and va: 
Predicted DLCO, corrected for Hb and va = [DLCO, corrected for va] × [1.7 × Hb / 
(9.38 + Hb)] 
Use the formula below to determine the percentage of predicted DLCO value (now 
corrected both for Hb and va):  
% of predicted DLCO (corrected for Hb and va) = [actual DLCO / (predicted 
DLCO corrected for Hb and va)] × 100  
 




GDC-0032—Genentech, Inc. 
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Principal Investigators: 
 
Author(s): 
Affiliation 
, Memorial Sloan Kettering Cancer Center, New 
York, NY, USA 
 
, Belgium 
, Diputació 256 4º1ª 08007 Barcelona, Spain 
, Genentech, South San Francisco, CA, 
USA 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Nussdorfer Platz 8, 1190 Wien, Austria 
, ABCSG, Austria 
, Genentech, South San Francisco, CA, USA 
, Genentech, South San Francisco, CA, USA 
 
 Spain 
 
 Spain 
, Genentech, South San Francisco, USA 
 
, 
Belgium 
 
 Belgium 
 
, Spain 
 Spain 
 
 
, Spain 
  


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TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 26 
1.1 
Background on the Phosphatidylinositol-3-Kinase 
Pathway................................................................................. 26 
1.2 
Background on Estrogen Receptor-Positive, 
Her2-Negative Breast Cancer................................................ 26 
1.3 
Background on the Pi3k/Akt/Mtor Pathway and 
Breast Cancer........................................................................ 27 
1.4 
Background on Reversing Hormonal Resistance 
by Inhibiting the Pi3k/Mtor/Akt Pathway................................. 27 
1.5 
Background on Neoadjuvant Therapy in Breast 
Cancer................................................................................... 28 
1.6 
Background on GDC-0032 .................................................... 29 
1.6.1 
Toxicology ............................................................................. 31 
1.7 
Summary of Clinical Data for GDC-0032............................... 32 
1.7.1 
Clinical Safety Data with GDC-0032...................................... 32 
1.7.1.1 
Preliminary Pharmacokinetics ............................................... 33 
1.7.1.2 
Preliminary Pharmacodynamics ............................................ 34 
1.8 
Study Rationale and Benefit-Risk Assessment...................... 35 
2. 
OBJECTIVES.............................................................................................. 37 
2.1 
Efficacy Objectives ................................................................ 37 
2.2 
Safety Objectives................................................................... 37 
2.3 
Patient-Reported Outcome Objectives .................................. 38 
2.4 
Exploratory Objectives........................................................... 38 
3. 
STUDY DESIGN ......................................................................................... 38 
3.1 
Description of Study .............................................................. 38 
3.1.1 
Surgery.................................................................................. 42 
3.1.2 
Independent Data Monitoring Committee .............................. 43 
3.2 
End of Study.......................................................................... 44 
3.3 
Rationale for Study Design.................................................... 44 


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3.3.1 
Rationale for Conducting the Study in the 
Neoadjuvant Setting .............................................................. 44 
3.3.2 
Rationale for Patient Population ............................................ 44 
3.3.3 
Rationale for Control Group................................................... 45 
3.3.4 
Rationale for the Efficacy Outcome Measure of 
Response Rate Assessed by Magnetic 
Resonance Imaging............................................................... 46 
3.3.4.1 
Rationale for Efficacy Outcome Measure of 
Pathologic Complete Response ............................................ 47 
3.3.4.2 
Rationale for Ki67 Measurements ......................................... 47 
3.3.4.3 
Rationale for Using the Preoperative Endocrine 
Prognostic Index Score.......................................................... 48 
3.3.4.4 
Rationale for Assessing ORR by Clinical Breast 
Exam (Palpation), Mammography, and Breast 
Ultrasound ............................................................................. 49 
3.3.4.5 
Rationale for Assessing Enhancing Tumor 
Volume by Breast Magnetic Resonance Imaging.................. 49 
3.3.5 
Rationale for Independent Review Facility............................. 49 
3.3.6 
Rationale for Interim Safety Review ...................................... 49 
3.3.7 
Rationale for GDC-0032 Dosage........................................... 49 
3.3.8 
Rationale for Biomarker Assessments................................... 51 
3.3.9 
Rationale for Day 15 Biopsy .................................................. 52 
3.3.10 
Rationale for Collection of Blood Sample for the 
Detection of Plasma Protein Biomarkers ............................... 52 
3.3.11 
Rationale for Collection of Blood Sample for DNA 
Sequencing to Identify Mutations in Plasma.......................... 52 
3.3.12 
Rationale for Collection of Blood Sample for Next 
Generation Sequencing......................................................... 52 
3.3.13 
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 53 
3.3.14 
Rationale for the Collection of DNA for 
Exploratory Pharmacogenetic Polymorphisms ...................... 53 
3.3.15 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 54 
3.4 
Outcome Measures ............................................................... 55 
3.4.1 
Efficacy Outcome Measures.................................................. 55 
3.4.1.1 
Co-Primary Efficacy Outcome Measures............................... 55 


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3.4.1.2 
Secondary Efficacy Outcome Measures................................ 55 
3.4.2 
Safety Outcome Measures .................................................... 55 
3.4.3 
Patient-Reported Outcome Measures ................................... 56 
3.4.4 
Exploratory Outcome Measures ............................................ 56 
4. 
MATERIALS AND METHODS .................................................................... 57 
4.1 
Patients.................................................................................. 57 
4.1.1 
Inclusion Criteria.................................................................... 57 
4.1.2 
Exclusion Criteria................................................................... 58 
4.2 
Method of Treatment Assignment and Blinding..................... 59 
4.2.1 
Patient Randomization........................................................... 59 
4.2.2 
Stratification........................................................................... 60 
4.2.3 
Blinding.................................................................................. 60 
4.3 
Study Treatment.................................................................... 60 
4.3.1 
Formulation, Packaging, and Handling.................................. 60 
4.3.1.1 
GDC-0032 and Placebo......................................................... 60 
4.3.1.2 
Letrozole................................................................................ 61 
4.3.2 
Dosage, Administration, and Compliance.............................. 61 
4.3.2.1 
GDC-0032 and Placebo......................................................... 61 
4.3.2.2 
Letrozole................................................................................ 62 
4.3.3 
Investigational Medicinal Product Accountability ................... 62 
4.3.4 
Post-Trial Access to GDC-0032............................................. 62 
4.4 
Concomitant Therapy ............................................................ 63 
4.4.1 
Permitted Therapy ................................................................. 63 
4.4.2 
Prohibited Therapy ................................................................ 64 
4.5 
Study Assessments ............................................................... 64 
4.5.1 
Informed Consent Forms and Screening Log........................ 65 
4.5.2 
Medical History and Demographic Data ................................ 65 
4.5.3 
Physical Examination ............................................................ 65 
4.5.4 
Vital Signs.............................................................................. 65 
4.5.5 
Electrocardiograms................................................................ 65 
4.5.6 
Distant Sites Tumor Assessment........................................... 65 
4.5.7 
Tumor and Response Evaluations......................................... 66 
4.5.8 
Surgical Treatment Plan ........................................................ 67 


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4.5.9 
Surgical Specimen – Pathology............................................. 67 
4.5.10 
Laboratory Assessments ....................................................... 67 
4.5.11 
Assay Methods...................................................................... 69 
4.5.11.1 
Mutational Analysis for PIK3CA............................................. 69 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor 
Tissues .................................................................................. 69 
4.5.11.3 
Analysis of Phosphatase Tensin Homolog 
Expression............................................................................. 70 
4.5.11.4 
Confirmation of Estrogen Receptor, 
Progesterone Receptor, and HER2 Status............................ 70 
4.5.11.5 
Circulating Tumor DNA Analysis ........................................... 70 
4.5.11.6 
Messenger RNA Expression Profiling.................................... 70 
4.5.11.7 
Next Generation Sequencing................................................. 70 
4.5.11.8 
Copy Number Analysis .......................................................... 70 
4.5.11.9 
Plasma Biomarker Analyses.................................................. 70 
4.5.11.10 
Plasma Pharmacokinetic Samples ........................................ 71 
4.5.11.11 
Pharmacogenetic Polymorphism Assay ................................ 71 
4.5.11.12 
Electrocardiograms................................................................ 71 
4.5.12 
Patient-Reported Outcomes .................................................. 71 
4.5.13 
Samples for Clinical Repository............................................. 72 
4.5.13.1 
Confidentiality........................................................................ 73 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 73 
4.6.1 
Patient Discontinuation.......................................................... 73 
4.6.2 
Study Treatment Discontinuation........................................... 73 
4.6.3 
Conditions for Terminating the Study .................................... 74 
5. 
ASSESSMENT OF SAFETY....................................................................... 74 
5.1 
Safety Plan ............................................................................ 74 
5.1.1 
Management of Specific Adverse Events of 
GDC-0032 ............................................................................. 75 
5.1.1.1 
Management of Hyperglycemia............................................. 75 
5.1.1.2 
Management of Pneumonitis................................................. 76 
5.1.1.3 
Management of Rash ............................................................ 77 
5.1.1.4 
Management of Gastrointestinal Toxicity............................... 78 


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5.1.2 
Management of Other Clinically Significant 
Adverse Events ..................................................................... 82 
5.1.3 
General Guidance for Dose Modifications and 
Delays for Letrozole............................................................... 82 
5.1.4 
Management of Increases in QT Interval............................... 83 
5.1.5 
Safety Monitoring for Letrozole.............................................. 83 
5.2 
Safety Parameters and Definitions ........................................ 84 
5.2.1 
Adverse Events ..................................................................... 84 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to ABCSG)............................................................................. 85 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to ABCSG)..................................... 85 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86 
5.3.1 
Adverse Event Reporting Period ........................................... 86 
5.3.2 
Eliciting Adverse Event Information ....................................... 86 
5.3.3 
Assessment of Severity of Adverse Events ........................... 86 
5.3.4 
Assessment of Causality of Adverse Events ......................... 87 
5.3.5 
Procedures for Recording Adverse Events............................ 88 
5.3.5.1 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 89 
5.3.5.2 
Persistent or Recurrent Adverse Events................................ 89 
5.3.5.3 
Abnormal Laboratory Values ................................................. 89 
5.3.5.4 
Abnormal Vital Sign Values ................................................... 90 
5.3.5.5 
Abnormal Liver Function Tests.............................................. 91 
5.3.5.6 
Deaths ................................................................................... 91 
5.3.5.7 
Preexisting Medical Conditions.............................................. 91 
5.3.5.8 
Hospitalization or Prolonged Hospitalization.......................... 92 
5.3.5.9 
Adverse Events Associated with an Overdose ...................... 92 
5.3.5.10 
Patient-Reported Outcome Data ........................................... 92 
5.4 
Immediate Reporting Requirements from 
Investigator to ABCSG........................................................... 93 
5.4.1 
Emergency Medical Contacts................................................ 93 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 94 


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5.5 
Follow-Up of Patients after Adverse Events .......................... 94 
5.5.1 
Investigator Follow-Up........................................................... 94 
5.5.2 
Sponsor Follow-Up ................................................................ 94 
5.6 
Post-Study Adverse Events................................................... 95 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 95 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 95 
6.1 
Determination of Sample Size ............................................... 96 
6.2 
Summaries of Conduct of Study............................................ 96 
6.3 
Summaries of Treatment Group Comparability ..................... 97 
6.4 
Efficacy Analyses .................................................................. 97 
6.4.1 
Primary Efficacy Endpoint...................................................... 97 
6.4.2 
Secondary Efficacy Endpoints............................................... 97 
6.5 
Safety Analyses..................................................................... 98 
6.6 
Pharmacodynamic Analyses ................................................. 98 
6.7 
Pharmacokinetic Analyses..................................................... 98 
6.8 
Patient-Reported Outcome Analyses .................................... 99 
6.9 
Exploratory Analyses............................................................. 99 
6.10 
Interim Analyses .................................................................... 99 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 100 
7.1 
Data Quality Assurance....................................................... 100 
7.2 
Data(Base) Management..................................................... 100 
7.3 
Electronic Case Report Forms............................................. 101 
7.4 
Source Data Documentation................................................ 101 
7.5 
Use of Computerized Systems ............................................ 102 
7.6 
Retention of Records........................................................... 102 
8. 
ETHICAL CONSIDERATIONS.................................................................. 102 
8.1 
Compliance with Laws and Regulations .............................. 102 
8.2 
Informed Consent ................................................................ 103 
8.3 
Institutional Review Board or Ethics Committee.................. 104 
8.4 
Data Privacy ........................................................................ 104 
8.5 
Financial Disclosure ............................................................ 105 


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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 105 
9.1 
Study Documentation .......................................................... 105 
9.2 
On Site Quality Control (Monitoring).................................... 105 
9.3 
Protocol Deviations.............................................................. 106 
9.4 
Site Inspections ................................................................... 106 
9.5 
Administrative Structure....................................................... 106 
9.6 
Protocol Amendments ......................................................... 107 
10. REFERENCES ......................................................................................... 108 
 
 
LIST OF TABLES 
Table 1 
Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events........................................................................... 75 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose)..................... 76 
Table 3 
Dose Modification and Management Guidelines for 
Pneumonitis ................................................................................ 77 
Table 4 
GDC-0032 Dose Modification and Management Guidelines 
for Rash ...................................................................................... 78 
Table 5 
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea................................................................................. 79 
Table 6 
GDC-0032 Dose Modification and Management Guidelines 
for Colitis..................................................................................... 81 
Table 7 
GDC-0032 Dose Delay and Modification Guidelines for 
Stomatitis and Oral Mucositis ..................................................... 82 
Table 8 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events .......................................... 82 
Table 9 
Adverse Event Severity Grading Scale ....................................... 87 
Table 10 
Causal Attribution Guidance ....................................................... 88 
 


GDC-0032—Genentech, Inc. 
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LIST OF FIGURES 
Figure 1 
GDC-0032 Potency in Non-PIK3CA Mutant Breast Cancer 
Cell Lines .................................................................................... 30 
Figure 2 
Combination Effects between Letrozole and GDC-0032 in 
the Aromatase-Expressing MCF7.2x3 Breast Cancer Cell 
Line ............................................................................................. 30 
Figure 3 
Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse 
Xenografts................................................................................... 31 
Figure 4 
Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT 
and WT Tumors .......................................................................... 34 
Figure 5 
Study Schema............................................................................. 40 
Figure 6 
Schematic Representing Confirmation of Progression................ 42 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 114 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 118 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer........................................................................... 119 
Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 
Measures .................................................................................. 124 
Appendix 5 
New York Heart Association Classifications.............................. 128 
Appendix 6 
American Joint Committee on Cancer TNM Classification of 
Malignant Tumors ..................................................................... 129 


GDC-0032—Genentech, Inc. 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY 
OF NEOADJUVANT LETROZOLE PLUS GDC-0032 
VERSUS LETROZOLE PLUS PLACEBO IN 
POSTMENOPAUSAL WOMEN WITH 
ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE 
BREAST CANCER 
PROTOCOL NUMBER: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
MEDICAL MONITOR: 
, M.D., Ph.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 return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY OF 
NEOADJUVANT LETROZOLE PLUS GDC-0032 VERSUS 
LETROZOLE PLUS PLACEBO IN POSTMENOPAUSAL WOMEN 
WITH ER-POSITIVE/HER2- NEGATIVE, EARLY STAGE BREAST 
CANCER 
PROTOCOL NUMBER: 
GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2013-000568-28 
IND NUMBER: 
110184 
TEST PRODUCT: 
GDC-0032 
PHASE: 
II 
INDICATION: 
Early stage breast cancer 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Efficacy Objectives 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus 
letrozole plus placebo in women with estrogen receptor-positive/human epidermal growth factor 
receptor 2-negative (ER+/HER2-) early stage breast cancer, as measured by the following co-
primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA mutant (MT) patients 
• 
Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local 
evaluation in all enrolled patients and PIK3CA MT patients 
The secondary efficacy objectives of this study are the following: 
• 
Tumor objective response rate (ORR), assessed by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA 
wildtype (WT) patients  
The following secondary objectives will be performed in all enrolled patients and separated by 
PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally assessed 
ORR using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery.  


 
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• 
Compare the centrally assessed, preoperative endocrine prognostic index (PEPI) score 
upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, 
ypNX (breast pCR). 
Safety Objective 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
Patient-Reported Outcome Objectives  
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL) between treatment arms as measured by the 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23) 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited to 
somatic cancer associated mutations, PTEN expression, pro-survival pathways (such as 
PI3K/AKT, MAPK etc.), apoptotic markers, and levels of RNA and DNA expression are 
predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream 
markers in tumor tissue and to examine the relationship to anti-tumor activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline biopsy 
and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole and GDC-
0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or letrozole 
on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in letrozole 
plus GDC-0032 versus letrozole plus placebo. 
Study Design 
Description of Study 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the 
effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal 
women with ER+/HER2- untreated, Stage I-III operable breast cancer whose primary tumors 
are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  Standard of care 
assessments/procedures (e.g., bilateral mammogram) performed within 28 days of Day 1 
dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal cutting 
temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]). Two pretreatment 
FFPE core biopsies and one freshly frozen core biopsy must be obtained for all patients prior to 
beginning study drug treatment.  Prior diagnostic FFPE core biopsies may be used for 
enrollment eligibility purposes.  For the purpose of enrollment, ER, progesterone receptor (PR), 
and HER2 will be locally determined prior to beginning of study treatment. ER, PR, HER2, and 


 
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the percentage of Ki67-positive cells will also be centrally assessed, but the results do not have 
to be available prior to enrollment in the study.  Remaining tissue will be retained for future 
translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not allowed. 
Patients will be randomized into one of the two treatment arms with a 1:1 randomization ratio.  
Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 6 mg or placebo on a 
5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see Figure 5).  A maximum of 
16 weeks of GDC-0032 can be administered.  Letrozole can be continued up to surgery per the 
investigator’s discretion. 
After confirmation of all the eligibility criteria, patients will be randomized to one of the treatment 
arms.  A second biopsy will be performed on Day 15 (Week 3) for biomarker analyses. Biopsies 
should be performed at least 2 hours after GDC-0032 dose administration. 
Randomization will be stratified according to 2 factors: 
1. 
Tumor size (T1-T2 vs. T3) 
2. 
Nodal status (cytologically positive vs. radiologically or cytologically negative) 
The study will enroll approximately 330 patients at approximately 110 global sites. 
At Weeks 1, 5, 9, 13, and 16 the primary breast tumor and axillary lymph nodes will be 
assessed by clinical breast examination (palpation and caliper measurement).  Suspicion of 
progression based on clinical exam at any time should be further evaluated (Figure 6).  
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive disease 
and for the purpose of surgery planning. Suspicion of progressive disease on breast ultrasound 
should be confirmed by investigator-assessed breast MRI.  Patients with primary disease not 
evaluable by ultrasound at baseline should be assessed by MRI at Week 9.  Suspected 
progression in nodes should also be confirmed by fine needle aspiration (FNA) if these nodes 
had not been previously shown to be cytologically positive for cancer.  Patients with progressive 
disease (as defined by modified RECIST, Appendix 3), can either proceed directly to surgery or 
be taken off of the study, according to the investigator’s decision. If the patient goes off-study, 
every reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. Clinical 
breast exam, breast ultrasound, and mammography will also be conducted prior to surgery for 
the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected at screening, at Week 3, and 
prior to surgery. 
Surgery 
Surgery will take place after at least 16 weeks of treatment, during Weeks 17 − 18.  Surgery 
should be performed within 4 days after the last dose of GDC-0032, if possible, to best observe 
pharmacodynamic knockdown with GDC-0032 in the surgical specimen.  Surgery may be 
delayed due to toxicity or other safety issues, upon discussion with the Medical Monitor (see 
Section 5.4.1) or recommendations from the Independent Data Monitoring Committee (IDMC; 
see below).  A maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be 
continued up to surgery per the investigator’s discretion.   
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. Surgery specimens will be 
collected for histological examination to assess for pCR and for other endpoint analyses. 
Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the end of 
the study. Assessment of adverse events and general safety will be collected at this visit and 
the plan for future treatment will be recorded. 


 
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The patient should be evaluated at baseline and after Week 13 of treatment for planning of the 
surgical procedure (BCS or mastectomy), and both physician recommendation and final patient 
decision should be documented in the electronic Case Report Form (eCRF).  
The co-primary efficacy endpoint, pathological complete response (pCR–ypT0/is, ypN0) will be 
established via a local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and directions 
for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  IRF 
procedures are detailed in the IRF charter. 
Number of Patients 
The study will enroll approximately 330 patients at approximately 110 global sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age ≥ 18 years. Postmenopausal status is defined as follows: 
– 
Age ≥ 60 years or 
– 
Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) 
and plasma estradiol levels within postmenopausal range by local laboratory 
assessment or 
– 
Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated as the “target” lesion for 
all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as determined by 
institutional practice (in patients where there may be a reasonable suspicion of 
advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and 
symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable 
for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 
– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5  ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be 
enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase 
≤ 1.5 × ULN  


 
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• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the basis of the 
Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × ULN and activated partial thromboplastin time 
(aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is 
required.  If anticoagulation is required for a prosthetic heart valve, then INR should be 
between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply with the 
protocol, in the investigator’s judgment 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric absorption 
• 
History of prior or currently active small or large intestine inflammation (such as Crohn’s 
disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
> 470 msec 
• 
Clinically significant (i.e., active) cardiovascular disease, like uncontrolled hypertension, 
unstable angina, history of myocardial infarction, cardiac failure class II-IV (New York Heart 
Association, Appendix 5), or any other that in the judgment of the investigator could 
jeopardize patient safety or study outcomes 
• 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 


 
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• 
Clinically significant history of liver disease, including viral or other known hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, that may affect 
the interpretation of the results, or renders the patients at high risk from treatment 
complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine 
cancer 
Concomitant 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 7 days prior to 
screening to the study completion/discontinuation visit.   
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak time 
dependent inhibitor of CYP3A4.  Although in vitro induction studies in human hepatocytes 
suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, preliminary data 
from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 daily for 2 weeks in 
patients had no apparent effect on the pharmacokinetics of midazolam (a sensitive CYP3A4 
substrate).  Therefore, GDC 0032 may be administered concomitantly with CYP3A4 substrates 
without the risk of a pharmacokinetic drug-drug interaction (DDI).  
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy (other than letrozole permitted in this protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is receiving 
these at the moment of registration, treatment should be discontinued prior to 
randomization.  
• 
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.  Patients who develop osteopenia or osteoporosis in the follow-up 
period may receive bone-targeted therapy as per the clinician’s discretion.  Primary use of 
bisphosphonates as a prevention of bone metastasis or as a prevention of bone loss is 
prohibited.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an alternate 
medication with no or minimal potential to inhibit CYP3A4.  If a strong CYP3A4 inhibitor is 
co-administered with GDC-0032, patients should be closely monitored for adverse reactions. 
Length of Study 
The total duration of the study is expected to be approximately 24 months for enrollment, plus 
5.5 months after last patient in. 
End of Study 
The end of the study is defined as the date when the last patient has her postsurgery visit.  


 
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Outcome Measures 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR via centrally assessed breast MRI via modified RECIST (Appendix 3) in all 
enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the American Joint 
Committee on Cancer staging system (Appendix 6) by local evaluation in all enrolled 
patients and PIK3CA MT patients 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST (Appendix 3) 
in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients 
The following secondary outcome measures will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 
versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to 
surgery 
• 
Compare the centrally assessed PEPI score upon treatment with letrozole plus GDC-0032 
with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by 
breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) yoT0/is, 
ypNX (breast pCR) 
Safety Outcome Measures 
The safety and tolerability of GDC-0032 will be assessed using the following primary safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, or delay 
• 
Serious adverse events 
• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during the 
adverse event reporting period (see Section 5.3.1) 
Patient-Reported Outcome Measures  
The PRO outcome measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty swallowing, 
diarrhea, skin problems), and patient functioning as measured using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ–C30) and the modified breast cancer module QLQ–BR23 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 


 
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• 
Expression of biomarkers before, during, and after therapy.  These include, but are not 
limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
Circulating tumor DNA (ctDNA) 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 versus 
letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug safety 
response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing enzymes and 
transporters and other patient-specific covariates with PK of GDC-0032 or letrozole and/or 
drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a marker of 
tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, diffusion 
metrics], ultrasound, mammography) in measuring tumor response 
Investigational Medicinal Products 
Study treatment is neoadjuvant (pre-operative) therapy.   
Test Product 
The test product for this study is GDC-0032.  Patients will receive an oral, daily dose of 6 mg 
GDC-0032 or placebo on a schedule of 5 days on/2 days off for a maximum of 16 weeks.  
Patients will take GDC-0032 at the same time of day ± 2 hours, unless otherwise instructed.  
Patients will be instructed as to the number of tablets to take.  
Information on the formulation, packaging, handling, and administration of GDC-0032 are 
provided in the GDC-0032 Investigator’s Brochure. 
Non-Investigational Medicinal Products 
Letrozole 
Letrozole is a marketed product that is approved in the European Union and the United States 
for the treatment of hormone receptor-positive breast cancer.  Based upon the different 
mechanisms of action of GDC-0032 and the well-established safety profile of letrozole, there 
are no expected overlapping, significant toxicities between letrozole and GDC-0032.   
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of surgery 
at the investigator’s discretion).   
Statistical Methods 
Primary Analysis 
This study is designed for testing the effect of GDC-0032 on the two co-primary endpoints in all 
enrolled patients and in the PIK3CA MT patients and plans to enroll 330 patients in total. 
Assuming the PIK3CA mutation status will not be available (unknown) for approximately 10% of 
the patients and the prevalence of PIK3CA mutant is 40%, there will be approximately 120 
patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, there 
might be a possible imbalance between treatment arms within the PIK3CA MT cohort, which 
may reduce the statistical power in this cohort. To ensure the study provides sufficient statistical 
power even when the treatment assignment is imbalanced, the sample size was calculated 
based on a conservative scenario by assuming that the treatment assignment imbalance in 


 
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PIK3CA MT is 40% vs. 60%. The sample size was calculated based on a chi²-test using 
continuity correction (Ury and Fleiss 1980). 
To control an overall two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 enrolled 
patients and 108 patients in the PIK3CA MT cohort will be evaluable for analyses. This sample 
size allows us to detect an absolute percentage increase of 24% in MRI ORR rate in the GDC-
0032 plus letrozole arm (64%) versus the letrozole-only arm (40%; Smith et al. 2005; Ellis and 
Ma 2007) in the PIK3CA MT cohort at 80% power and 16% two-sided significance level.  The 
minimal detectable difference for ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled patients and 
120 in the PIK3CA MT cohort), this sample size provides 80% power to detect an absolute 
percentage increase of 18% in pCR in the GDC-0032 plus letrozole arm (19%) versus the 
letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at the 
4% two-sided significance level.  The minimal detectable difference for pCR rate is 
approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more substantial 
treatment assignment imbalance in the PIK3CA MT cohort than assumed, or there is an 
increased number of unevaluable patients for the MRI ORR, the sample size may be increased 
to obtain the level of power at 80%, and the enrollment may be limited to patients with PIK3CA 
MT.   
Secondary Analysis 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by 
breast MRI in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT 
patients.  
These endpoint measures will be summarized by treatment arm and will be analyzed analogue 
to the primary efficacy endpoint. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
ORR by clinical breast examination, mammography and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery 
(centrally assessed) 
• 
PEPI score (centrally assessed) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast MRI 
• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
These endpoint measures will be summarized by treatment arm and will be compared between 
the two treatment arms within each population based on appropriate statistical analyses: ORR 
will be compared using a Cochrane Mantel-Haenszel test, stratified by tumor size and nodal 
status; PEPI, Ki67, and tumor volume change will be compared by regression analyses, 
adjusted for tumor size and nodal status. All secondary endpoints will be tested at a two-sided 
type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
Determination of Sample Size   
 Please refer to the primary analysis in the Statistical Methods section. 
 Interim Analyses 
An Independent Data Monitoring Committee (IDMC) will monitor accumulating patient safety 
data at a minimum of once every 6 months until the last patient has completed study treatment.  


 
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Additional details (e.g., IDMC members, communication, affiliations) will be provided in the 
IDMC charter.   
The IDMC will conduct interim analyses to review the unblinded safety data after the first 20 
patients have either 1) finished the 30-day follow-up visit after the surgery, or 2) been on study 
for 20 weeks after the randomization date (for those who do not receive the surgery).  The 
IDMC will create and review unblinded, pooled summaries of the safety and available PK 
summaries (all interim analyses).  While this review is being conducted, patient accrual into the 
study will continue.  The Medical Monitor may also request additional safety analysis and may 
call for additional meetings of the IDMC to review ongoing safety data.  
The IDMC will share results from interim safety analyses with the study team.  The study team 
will share interim safety results with study investigators as needed for the conduct of the study 
and the safety of the patients.  Specific potential safety issues anticipated in this trial, as well as 
measures intended to avoid, minimize, and manage such toxicities, are outlined in the following 
sections. 
All available information of all enrolled patients with all available assessments at the respective 
timepoint will be included in the interim analyses.  


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABCSG 
Austrian Breast and Colorectal Cancer Study Group 
ADC 
apparent diffusion coefficient 
AE 
adverse events 
AI 
aromatase inhibitors 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ASCO-CAP 
American Society of Clinical Oncology-College of 
American Pathologists 
AST 
aspartate aminotransferase 
AUC0-24 
area under the concentration–time curve from 0 to 24 
hours 
BCS 
breast conserving surgery 
BIG 
Breast International Group 
BUN 
blood urea nitrogen 
CD 
compact disc 
CI 
confidence interval 
Cmax 
maximum plasma concentration observed  
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
cPR 
confirmed partial responses 
CRA 
clinical research associate 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTNeoBC 
Collaborative Trials in Neoadjuvant Breast Cancer 
DCR 
data clarification request 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DMP 
data management plan 
DVD 
digital video disk 
EC 
Ethics Committee 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 


 
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Abbreviation 
Definition 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER+ 
estrogen receptor-positive 
E.U. 
European Union 
FFPE 
formalin-fixed paraffin-embedded 
FDA 
Food and Drug Administration 
FNA 
fine needle aspiration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HLM 
human liver microsomes 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
ISH 
in situ hybridization 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LDL 
low-density lipoprotein 
LPLV 
last patient, last visit 


 
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Abbreviation 
Definition 
MAPK 
mitogen-activated protein kinase 
MDD 
minimum detected difference 
MP 
monitoring plan 
MRI 
magnetic resonance imaging 
MT 
mutant 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSCLC 
non − small-cell lung cancer 
nu/nu 
immunocompromised nune (mice) 
OCT 
Optimal cutting temperature 
ORR 
objective response rate 
pAKT 
phosphorylated form of AKT 
pCR 
pathologic complete response 
PD 
progressive disease 
PEPI 
preoperative endocrine prognostic index 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PI3K 
phosphatidylinositol-3-kinase 
PIP2 
phosphatidylinositol-4,5-bisphosphate 
PIP3 
phosphatidylinositol 3,4,5 trisphosphate 
PK 
pharmacokinetic 
PO 
oral 
PR 
progesterone receptor 
PRO 
patient-reported outcome 
PTEN 
phosphatase tensin homolog 
QD 
once daily 
QLQ-BR23 
Quality of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT-PCR 
real-time polymerase chain reaction 
RFS 
relapse-free survival 
RPPA 
reverse phase protein array 


 
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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
source data verification 
SLNB 
sentinel lymph node biopsy 
PFT 
pulmonary function test 
SOLTI 
Spanish Breast Cancer Research Group 
SOP 
standard operating procedure 
SmPC 
summary of product characteristics 
t1/2 
terminal half-life 
TGI 
tumor growth inhibition 
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
WT 
wildtype 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON THE PHOSPHATIDYLINOSITOL-3-KINASE 
PATHWAY 
Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase involved in tumor cell proliferation, 
survival, and migration upon activation by growth factor receptors and integrins.  
PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) 
to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Cantley 2002), 
a second messenger involved in the phosphorylation of AKT and associated proteins in 
the AKT-mammalian target of rapamycin (mTOR) pathway (Guertin and Sabatini 2007 
[29]).  Activating and transforming mutations, as well as amplification, in the p110α 
subunit of PI3K are commonly found in solid and hematological tumors (Li et al. 1997 
[38]).  In addition, the PI3K-AKT pathway is activated in numerous types of cancer by 
receptor tyrosine kinase signaling, the loss of the phosphatase tensin homolog (PTEN), 
or RAS mutations (Shayesteh et al. 1999 [58]; Cantley 2002 [11]; Massion et al. 2004 
[42]; Wu et al. 2005 [68]). 
1.2 
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE, 
HER2-NEGATIVE BREAST CANCER 
Breast cancer is the most frequently diagnosed cancer worldwide and the leading cause 
of cancer death among females, accounting for 23% of the total cancer cases and 14% 
of total cancer deaths (Jemal et al. 2011 [34]).  As a large proportion of breast cancer 
cases, especially in developed countries, are now diagnosed in early stages, they are 
amenable to cure with a stage-appropriate combination of surgery, systemic therapy 
(chemotherapy and/or hormonal therapy), and radiotherapy. 
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative 
(HER2-) breast cancer accounts for about 60% − 70% of all breast cancers.  However, 
not all ER+ breast cancers respond optimally to endocrine therapy (Davies et al. 2011 
[15]).  There are several mechanisms that can lead to primary and/or secondary 
hormonal resistance in ER+ breast cancer:  decrease of ER expression, loss of ER 
expression, or upregulation of growth factor signaling pathways, like the epidermal 
growth factor receptor (EGFR)/HER2, the mitogen-activated protein kinase (MAPK), or 
the PI3K/AKT/mTOR pathways (Johnston 2009 [35]). 
In the setting of ER + /HER2-negative breast cancer, the PI3K/AKT/mTOR pathway plays 
an important role in mediating hormonal resistance and is a viable therapeutic target to 
explore (Miller et al. 2010 [47]). 


 
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1.3 
BACKGROUND ON THE PI3K/AKT/MTOR PATHWAY AND 
BREAST CANCER 
Genes in the PI3K/AKT/mTOR signaling pathway are frequently mutated or amplified in 
breast cancer, especially in the ER+ subtype (Cancer Genome Atlas Network 2012 [10]).  
Molecular alterations of the PI3K/AKT/mTOR pathway include the following: (1) 
Mutations or amplifications in PIK3CA, the gene encoding the alpha catalytic subunit of 
PI3K (p110α) (Saal et al. 2005 [52]; Wu et al. 2005 [68]); (2) Alterations in the tumor 
suppressor gene PTEN, either by loss of protein expression (PTEN null), inactivation 
mutations and/or epigenetic deregulation through promoter hypermethylation (García et 
al. 2004 [27]); (3) PDKP1 amplification and/or overexpression (Brugge et al. 2007 [9]); (4) 
AKT1 somatic gain of function mutations (Stemke-Hale et al. 2008 [61]) and AKT2 
amplifications (Bellacosa et al. 1995 [7]). Overall, it is estimated that up to 70% of breast 
cancers can have some form of molecular aberration of the PI3K/AKT/mTOR pathway 
(CGAN 2012).   
1.4 
BACKGROUND ON REVERSING HORMONAL RESISTANCE BY 
INHIBITING THE PI3K/MTOR/AKT PATHWAY 
In the setting of ER+ breast cancer, PI3K seems to play an important role in mediating 
hormonal resistance and may be a viable therapeutic target. Hyperactivation of this 
signaling pathway was proved to promote both de novo and acquired resistance to 
hormone therapy in ER+ breast cancer cell lines and xenograft models (Sabnis et al. 
2007 [53]), and simultaneous blocking of the PI3K/AKT/mTOR pathway with everolimus 
and the ER pathway with letrozole enhances antitumor activity of either agent alone 
(Boulay et al. 2005 [8]). Importantly, a baseline protein signature of PI3K activation was 
found to be predictive of a poor prognosis after adjuvant endocrine therapy (Miller et al. 
2010 [47]). 
In the clinical setting, impressive results of the combination of exemestane and 
everolimus, an mTOR inhibitor, were reported in the BOLERO-2 trial (Baselga et al. 
2009 [6]). This trial compared everolimus and exemestane with placebo and 
exemestane in 724 postmenopausal patients with ER+ advanced breast cancer who had 
experienced recurrence or progression while receiving previous therapy with a 
nonsteroidal aromatase inhibitor in the adjuvant setting and/or in advanced disease. 
Median progression-free survival (PFS) in the everolimus group was 6.9 months, as 
compared to 2.8 months in the placebo group.  Hazard ratio (HR) for progression or 
death was 0.43, with a 95% confidence interval (CI) of 0.35 − 0.54 (p < 0.001), as per the 
investigator’s assessment, and the magnitude of the effect was even greater as per 
central assessment (HR, 0.36, 95% CI, 0.27 − 0.47; p < 0.001).  In the open-label Phase 
II TAMRAD trial, patients with aromatase inhibitors (AI) resistant metastatic breast 
cancer received tamoxifen plus everolimus or tamoxifen alone (Bachelot et al. 2012 [4]). 
The 6-month clinical benefit rate was 61% (95% CI, 47% − 74%) with tamoxifen plus 
everolimus and 42% (95% CI, 29% − 56%) with tamoxifen alone. Time to progression 
increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus 


 
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everolimus, corresponding to a 46% reduction in risk of progression with the combination 
(HR, 0.54; 95% CI, 0.36 − 0.81).  Risk of death was reduced by 55% with tamoxifen plus 
everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 − 0.81). 
In the neoadjuvant setting, combination of letrozole and everolimus also resulted in 
improved responses over letrozole alone in patients with ER+ breast cancer (Baselga et 
al. 2009 [6]).  In this study, 270 postmenopausal patients with operable ER+ breast 
cancer were randomly assigned to receive 4 months of neoadjuvant treatment with 
letrozole and either everolimus or placebo. The primary endpoint of the trial, clinical 
response by palpation, was higher in the everolimus arm than in the control arm (68.1% 
vs. 59.1%, p = 0.062), a statistically significant result (one-sided, α = 0.1 level). 
An important finding in trials with mTOR-targeting drugs like everolimus is that they 
produce a pharmacodynamic paradox:  while inhibiting mTOR, they lead to an 
upregulation of the phosphorylated form of AKT (pAKT), resulting in feedback 
PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009 [62]). This finding suggests 
that alternative pharmacologic strategies to effectively shut down the pathway upstream 
of AKT should be pursued.  One of these strategies is inhibiting the PI3K/AKT/mTOR 
pathway at the level of PI3K. 
1.5 
BACKGROUND ON NEOADJUVANT THERAPY IN 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 and Smith 2003 [44]; Scholl et al. 1994 [56]; Semiglazov et 
al. 2004 [57]; Fisher et al. 2012 [26]; Wolff and Davidson 2000 [67]).  The randomized 
studies evaluating neoadjuvant therapy as well as meta-analyses of these studies have 
shown that neoadjuvant therapy can improve breast conservation rates, decreasing the 
number of women obligated to undergo mastectomy (Mieog et al. 2007 [46]; Fisher et al. 
2012).  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 [43]).  The concept of neoadjuvant therapy is now well 
established and a standard treatment option for patients with early breast cancer.  The 
Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis was 
recently conducted evaluating over 12,000 patients treated with neoadjuvant 
chemotherapy as part of clinical trials (Cortazar et al. 2012 [12]).  The results of this 
meta-analysis confirmed an association of pathologic complete response [pCR] with 
favorable long-term outcomes in high-risk populations (i.e., HER2-positive, high-grade 
hormone receptor positive and triple negative subtypes), although the magnitude of pCR 
improvement predictive of the long-term survival benefits could not be determined.  In 
September 2013, the Food and Drug Administration (FDA) granted accelerated approval 


 
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of Perjeta as part of a complete treatment regimen for patients with HER2-positive, 
locally advanced, inflammatory, or early stage breast cancer in the neoadjuvant setting. 
1.6 
BACKGROUND ON GDC-0032 
GDC-0032 is a potent selective inhibitor of Class I PI3K alpha, delta, and gamma 
isoforms, with 30-fold less potent inhibition of the beta isoform that is being developed as 
a therapy for human cancers.  Nonclinical studies with GDC-0032 demonstrate that 
GDC-0032 inhibits proliferation of p110α-mutant breast cell lines, inhibits tumor growth 
in human breast xenograft models harboring PIK3CA mutations, and results in a 
substantial reduction of PI3K pathway markers, including pAkt, pPRAS40, and pS6.   
GDC-0032 has demonstrated activity in nonclinical models of PIK3CA-mutant breast 
tumors in vivo as a single agent and in combination with standard of care (e.g., paclitaxel 
or docetaxel) or endocrine therapies (e.g., letrozole or fulvestrant).  GDC-0032 has a 
favorable in vitro and nonclinical in vivo absorption, distribution, metabolism, and 
elimination profile that has characteristics consistent with a compound that can be 
delivered orally to achieve clinical exposure similar to the nonclinical efficacy findings 
described herein.  Additional studies, including 16-week toxicity studies in rats and dogs, 
phototoxicity studies, and an embryo-fetal development study, support the Phase II 
neoadjuvant trial with GDC-0032 in combination with endocrine therapy.   
In vitro, single-agent GDC-0032 potency is also observed in cell lines that do not harbor 
PIK3CA mutations (Figure 1).  In in vitro combination studies, the aromatase-expressing 
breast cancer cell line (MCF7X2.3.ARO) showed positive combination effects between 
GDC-0032 and endocrine therapies (see Figure 2).  In this cell line, GDC-0032 alone 
caused growth inhibition (50% effective concentration [EC50]  = 95 nM). Effects on growth 
were also observed with letrozole and fulvestrant.  Combined treatment of cells with 
GDC-0032 and letrozole caused dose-dependent inhibition of cell viability at lower 
concentrations of either GDC-0032 or letrozole resulting in enhanced activity for the 
combination. In addition, combination activity was demonstrated in the PIK3CA wild-type 
(WT) cell line ZR75-1 when GDC-0032 was added to either fulvestrant or tamoxifen 
endocrine therapies (combination with letrozole not available in this cell line).  However, 
in vivo data in a PIK3CA WT model are not available, because these cell lines do not 
grow as xenografts. 




 
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Figure 3 Efficacy of Tamoxifen in Combination with GDC-0032 in 
MCF7-Neo/Her2 Estrogen Receptor-Positive Mouse Xenografts 
 
 
QD = once daily; PO = oral gavage. 
Vehicle was MCT (0.5% methycellulose/0.2% Tween-80). 
Tamoxifen pellets (5 mg/pellet, 60-day release) were implanted on Day 0 of dosing (8 days post 
tumor implantation).  Tumor volumes after QD oral administration of GDC-0032 for 21 days are 
depicted by dose group. 
 
Please refer to the GDC-0032 Investigator’s Brochure for additional nonclinical data for 
GDC-0032 supporting this clinical trial.    
 
1.6.1 
Toxicology 
Please refer to the GDC-0032 Investigator’s Brochure for details on the toxicology 
program to support this clinical trial.   
 


 
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1.7 
SUMMARY OF CLINICAL DATA FOR GDC-0032  
1.7.1 
Clinical Safety Data with GDC-0032 
As of 5 July 2013, a total of 144 patients have been treated with GDC-0032 either as 
single agent (90, 63%) or in combination with endocrine therapy (54, 37%). 
GDC-0032 is currently in Phase I (Study PMT4979g).  Study PMT4979g is an open-label, 
dose-escalation trial using a 3 + 3 design to assess the safety, tolerability, and 
pharmacokinetics of GDC-0032 administered orally daily for 28 days to patients with 
locally advanced or metastatic solid tumors and in combination with endocrine therapy in 
ER+ breast cancers.  As of 5 July 2013, enrollment into the dose-escalation stage of 
Study PMT4979g had been completed with 34 patients enrolled at doses with a range of 
3  to 16 mg daily.  GDC-0032 was well tolerated in the first three cohorts (3, 5, and 8 mg), 
with no patients experiencing a dose-limiting toxicity (DLT).  At the 16-mg dose level, 
2 of the 11 safety-evaluable patients experienced a DLT (Grade 4 hyperglycemia and 
Grade 3 fatigue).  At the 12-mg dose level, 1 of the 10 safety-evaluable patients 
experienced a DLT of Grade 3 acute renal failure.  Although the single-agent GDC-0032 
maximum tolerated dose (MTD) was not exceeded at the 16-mg dose level, the 
recommended GDC-0032 dose and schedule for the single-agent expansion cohorts is 
9 mg daily on the basis of long-term safety data through multiple treatment cycles.  As of 
the cutoff date, a total of 53 patients have been enrolled in the 9-mg daily dosing 
expansion cohorts.  
As of 5 July 2013, adverse events that occurred in ≥ 10% of the 87 patients treated with 
daily single-agent GDC-0032 and were assessed as related to GDC-0032 were as 
follows:  diarrhea (47%), hyperglycemia (38%), nausea (36%), fatigue (34.5%), 
decreased appetite (31%), rash (16%), stomatitis (13%), vomiting (13%), and mucosal 
inflammation (11.5%).  Study−drug-related Grade 3 and 4 adverse events included 
hyperglycemia (9.4%), colitis (7.5%), pneumonitis (3.8%), rash (including maculopapular 
rash with or without itching, redness, and peeling) 5.7%, asymptomatic increased 
aminotransferase levels in the blood (1.9%), anemia (1.9%), increase in blood creatinine 
(1.9%), diarrhea (1.9%), fatigue (1.9%), hypokalemia (1.9%), hypophosphatemia (1.9%), 
pneumonia (1.9%) and stomatitis (1.9%).    
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (19 patients at 6 mg, and 8 patients at 
9 mg) daily in combination with letrozole (Cohort E).  No DLTs were observed at either 
dose level.  Adverse events that occurred in ≥ 10% of the 27 safety-evaluable patients 
assessed as related to GDC-0032 were diarrhea (67%), fatigue (30%), nausea (30%), 
decreased appetite (26%), hyperglycemia (26%), stomatitis (26%), dysgeusia (22%), 
mucosal inflammation (18.5%), rash (18.5%), asthenia (15%), pruritis (15%), vomiting 
(15%), dry mouth (11%), dry skin (11%) and muscle spasms (11%). Study − drug-related 
Grade 3 and 4 adverse events included diarrhea (11%), mucosal inflammation (7.4%), 
increased amylase in the blood (3.7%), increased aspartate aminotransferase (AST) in 


 
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the blood (3.7%), increased alkaline phosphate in the blood (3.7%), fatigue (3.7%), 
increased gamma-glutamyltransferase in the blood (3.7%), hyperglycemia (3.7%), 
hypokalemia (3.7%), increased lipase in the blood (3.7%), papilloedema (3.7%) and 
stomatitis (3.7%). 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of 
GDC-0032 at dose levels of 6 and 9 mg daily (21 patients at 6 mg and 6 patients at 9 mg) 
in combination with fulvestrant (Cohort F).  No DLTs were observed at either dose level.  
One patient has been enrolled in the Phase II part of the study with 6 mg GDC-0032 in 
combination with fulvestrant.  Adverse events that occurred in ≥ 10% of the 27 patients 
and were assessed as related to GDC-0032 were diarrhea (46%), hyperglycemia (32%), 
nausea (32%), decreased appetite (25%), fatigue (25%), rash (21%), stomatitis (21%), 
asthenia (18%), muscle spasms (14%), vomiting (14%), dysgeusia (11%), 
gastroesophageal reflux disease (11%) and mucosal inflammation (11%).  Study− drug-
related Grade 3 and 4 adverse events included hyperglycemia (14%), diarrhea (7%), 
dyspnea (4%), flank pain (4%), hyponatremia (4%), neutropenia (4%), rash (4%) and 
vomiting (4%). 
Please refer to the GDC-0032 Investigator’s Brochure for additional information. 
1.7.1.1 
Preliminary Pharmacokinetics 
Pharmacokinetic (PK) data are available from 34 patients treated with GDC-0032 at 3, 5, 
8, 12, and 16 mg in the ongoing Phase I/II clinical trial (Study PMT4979g).  The cohort 
mean apparent clearance and the terminal half-life (t1/2) following a single, oral dose of 
GDC-0032 had a range of 4.77−9.17 L/hour and 36.7−43.8 hours, respectively.  
Following daily oral dosing for 8 days, there was a 2- to 4-fold accumulation of 
GDC-0032.  The pharmacokinetics of GDC-0032 appears to be dose linear and time-
independent.  Preliminary PK data from Cohort E suggest there is no drug-drug 
interaction (DDI) between letrozole plus GDC-0032.  Mean plasma exposure of letrozole 
when given in combination with GDC-0032 (maximum concentration observed 
[Cmax] = 0.407 μM and area under the concentration–time curve from 0 to 24 hours 
[AUC0-24 ] = 8.01 μM*hr) was comparable with the historical single-agent exposure 
(Cmax = 0.495 μM and AUC0-24  = 10.1 μM*hr) (Awada et al. 2008 [3]). Similarly, plasma 
concentrations of GDC-0032, when given in combination with letrozole, were within the 
range predicted by the population PK model. Therefore, letrozole plus GDC-0032 can be 
co-administered without the risk of a DDI.  
GDC-0032 was metabolized primarily by CYP3A4 in human liver microsomes (HLMs) 
and appeared to be a weak time-dependent inhibitor of CYP3A4.  Although in vitro 
induction studies in human hepatocytes suggested that GDC-0032 has low to moderate 
potential to induce CYP3A4, preliminary data from the Phase I/II study (PMT4979g) 
indicate that 9 mg of GDC-0032 daily for 2 weeks in patients had no apparent effect on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate).  Therefore, 


 
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GDC-0032 may be administered concomitantly with CYP3A4 substrates without the risk 
of a PK DDI.  
For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.7.1.2 
Preliminary Pharmacodynamics 
Paired tumor biopsies were obtained from both PIK3CA MT and PIK3CA WT non-small 
cell lung cancer (NSCLC) patients treated at either the 3-mg or 16-mg GDC-0032 dose 
level, respectively, at screening (pretreatment biopsy) and during Cycle 1 in 
Study PMT4979g (on-treatment biopsy).  Inhibition of PI3K pathway markers, including 
decreases of > 60% in pAKT and pS6 (compared with baseline), were demonstrated in 
these patients’ paired tumor biopsies (see Figure 4).  
Figure 4 Decrease in PI3K Pathway Activation in Tumor Biopsies 
Observed upon GDC-0032 Treatment in Both PIK3CA MT and WT 
Tumors 
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
AKT (S473)
AKT (T308)
S6 (S235/236)
S6 (S240/244)
PRAS40 (T246)
P70S6K (T389)
4EBP1 (S65)
4EBP1 (T37/46)
ERK (T202/Y204)
Bim
-100
-50
0
50
100
% Inhibition
(16mg): NSCLC adeno 
PIK3CA wt, EGFR (exon 19 del) 
 (3mg): NSCLC (squam) 
PIK3CA (H1047R) 
 
 
MT = mutant; NSCLC = non − small-cell lung cancer; WT = wild type. 
 
As of 5 July 2013, metabolic partial responses via FDG-PET ( ≥ 20% decrease in 
maximum standardized uptake value) were observed in 23 out of 38 patients assessed 
(61%) and included patients from the lowest dose tested (3 mg).  Thirteen of these 23 
were breast cancer patients.  Of the 13 response-evaluable patients treated with 
GDC-0032 plus letrozole, 10 patients (77%) had a partial metabolic response.  Of the 15 
response-evaluable patients treated with GDC-0032 plus fulvestrant, 11 (73%) had a 
partial metabolic response.  


 
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For additional details, refer to the GDC-0032 Investigator’s Brochure.   
1.8 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Cancer is one of the leading causes of death worldwide, with solid tumors accounting for 
the majority of these deaths.  An estimated 1.38 million women across the world were 
diagnosed with breast cancer in 2008, accounting for 23% of all cancers diagnosed in 
women.  Breast cancer is the most common cause of death from cancer in women 
worldwide, estimated to be responsible for almost 460,000 deaths in 2008 (Ferlay et al. 
2010 [25]). 
A neoadjuvant study in a similar patient population with the combination of letrozole and 
the mTOR inhibitor everolimus has already been completed (Baselga et al. 2009 [6]).  
Please refer to Sections 1.4, 1.5, and 3.3 for further rationale supporting the proposed 
trial design of combining GDC-0032 with letrozole in the neoadjuvant setting for this 
patient population.  In postmenopausal women with hormone receptor-positive 
metastatic breast cancer, it is hypothesized that the combination of decreasing estrogen 
levels with letrozole and inhibition of the PI3K pathway with GDC-0032 may have 
improved anti-tumor activity as compared to endocrine therapy alone.  This is supported 
by the nonclinical and clinical data outlined below. 
GDC-0032 is a potent, selective small molecule inhibitor of Class 1 PI3K that is being 
developed by Roche/Genentech as an anti-cancer therapeutic agent.  Activating and 
transforming mutations in the p110 alpha subunit of PI3K are commonly found in tumors.  
GDC-0032 has been shown to be a potent inhibitor of growth in various human cancer 
cell lines, and especially in nonclinical models of PIK3CA MT tumors.  In addition, 
combination activity was demonstrated in the PIK3CA WT cell line ZR75-1 when 
GDC-0032 was added to either fulvestrant or tamoxifen endocrine therapies 
(combination with letrozole not available in this cell line).   
GDC-0032 has also shown additive efficacy in combination with endocrine therapy in a 
hormone receptor-positive breast cancer xenograft model as outlined in Section 1.6. 
Nonclinical data support the investigation of GDC-0032 as a single-agent in solid tumors 
and in combination with endocrine therapy in patients with hormone receptor-positive, 
advanced breast cancer.  
Available clinical data with single-agent GDC-0032 suggest that GDC-0032 has 
dose-linear pharmacokinetics with a half-life of approximately 37− 44 hours.  
Pharmacodynamic markers of PI3K pathway inhibition upon treatment with GDC-0032 
have been observed.  These include decreases in phospho-S6 in platelet-rich plasma 
and decreases in F- flurodeoxyglucose-positron emission tomography uptake.  Available 
clinical data also include multiple confirmed partial responses in patients treated with 
GDC-0032.  These include a patient with PIK3CA MT lung adenocarcinoma treated at 
the 3 mg daily dose and another patient with PIK3CA MT, hormone receptor-positive, 
HER2-positive metastatic breast cancer treated at the 5 mg daily dose.  In addition, a 


 
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patient with PIK3CA WT lung cancer treated at the 3 mg daily dose has had prolonged 
stable disease and remained on study for over 11 months.  These data show that single-
agent GDC-0032 doses below 6 mg have been shown to have anti-tumor activity.  
These aggregate data support the use of 6 mg in combination with letrozole.   
Letrozole is a marketed product that is approved in the European Union (E.U.) and the 
United States (U.S.) for the treatment of hormone receptor-positive breast cancer.  
Based upon the different mechanisms of action of GDC-0032 and the well-established 
safety profile of letrozole, there are no expected overlapping, significant toxicities 
between letrozole and GDC-0032.  
As of 5 July 2013, efficacy data are available for 24 patients treated with GDC-0032 in 
combination with letrozole; 3 patients (12.5%) had a partial response as best overall 
response, 2 of which were confirmed partial responses (cPRs) (1 cPR at 6 mg; 1 cPR at 
9 mg).  Of the 25 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 7 patients (28%) had a partial response as best overall response, of which 3 
were cPRs (1 cPR at 6 mg; 1 partial response at 9 mg).  cPRs have been observed in 
both PIK3CA mutant and PIK3CA WT breast cancer patients.  Maintenance of cPR has 
been observed in a patient who had a dose reduction from 6 mg to 3 mg for an adverse 
event.  In addition, no additional safety concerns have been observed with GDC-0032 in 
combination with letrozole in the ongoing Phase I study compared to GDC-0032 given 
as single agent. 
A number of clinically appropriate strategies to minimize risk to patients have been built 
into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, 
protocol design, and management guidelines.  These will also be clearly highlighted and 
discussed in detail at investigator meetings and site visits.  In addition, please refer to 
the GDC-0032 Investigator’s Brochure for details regarding potential risks, associated 
precautions, and other relevant nonclinical and clinical safety information. 
Due to the need to develop improved therapies to reverse or delay resistance to current 
endocrine therapy in HER2-negative, hormone receptor-positive breast cancer and on 
the basis of the clinical and nonclinical data available for GDC-0032, Genentech/Roche 
feels that the risk-benefit profile of GDC-0032 in combination with letrozole in 
postmenopausal patients with HER2-negative, hormone receptor-positive early stage 
breast cancer is favorable for proceeding with the proposed randomized Phase II clinical 
trial. 


 
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2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 
versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as 
measured by the following co-primary endpoints: 
• 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) in all enrolled patients and PIK3CA MT patients 
• 
pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled 
patients and PIK3CA MT patients  
The secondary efficacy objectives of this study are the following: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified Response 
Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in 
PIK3CA WT patients  
 
The following secondary objectives will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally assessed, preoperative endocrine prognostic index (PEPI) 
score upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI via central assessment. 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is as follows: 
• 
Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo 
 


 
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2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objectives for this study are as follows: 
• 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, 
and health-related quality of life (HRQoL) between treatment arms as measured by 
the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module 
(QLQ-BR23) 
2.4 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
• 
To evaluate changes in tumor cellular composition as assessed by diffusion-
weighted MRI 
• 
To assess whether biomarkers from tumor tissue or blood, including but not limited 
to somatic cancer associated mutations, PTEN expression, pro-survival pathways 
(such as PI3K/AKT, MAPK etc.), apoptotic markers, hormone receptor expression 
levels, and levels of RNA and DNA expression are predictive of response  
• 
To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to anti-tumor 
activity 
• 
To assess concordance and percentage of PIK3CA mutation status from baseline 
biopsy and surgical specimen 
• 
To assess emergence of resistance alleles from tumor tissue or blood  
• 
To assess concordance of the different imaging modalities (MRI [volume, 
enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor 
response 
• 
To assess the pharmacokinetics and possible drug interaction between letrozole 
and GDC-0032 upon concomitant administration 
• 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or adverse events [e.g., colitis, rash]) 
• 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or 
letrozole on pharmacokinetics and response (either efficacy and/or adverse events) 
• 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in 
letrozole plus GDC-0032 versus letrozole plus placebo. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate 
the effect of combining letrozole and GDC-0032 versus letrozole and placebo in 
postmenopausal women with ER+/HER2- untreated, Stage I-III operable breast cancer 
whose primary tumors are ≥ 2 cm.  Patients with cT4 or cN3 tumors are not eligible.  


 
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Standard of care assessments/procedures (e.g., bilateral mammogram) performed 
within 28 days of Day 1 dosing do not need to be repeated for screening purposes. 
All patients will undergo pretreatment tumor tissue acquisition (snap-frozen [optimal 
cutting temperature; OCT] and formalin-fixed paraffin-embedded cores [FFPE]).  Two 
pretreatment FFPE core biopsies and one freshly frozen core biopsy must be obtained 
for all patients prior to beginning study drug treatment.  Tumor tissue from prior 
diagnostic FFPE core biopsies may be used for enrollment eligibility purposes. For the 
purpose of enrollment, ER, progesterone receptor (PR), and HER2 will be locally 
determined prior to beginning of study treatment. Remaining tissue will be retained for 
future translational studies. Pre-surgical sentinel lymph node biopsy (SLNB) is not 
allowed.   
Patients will be randomized into one of the two treatment arms with a 1:1 randomization 
ratio.  Letrozole at 2.5 mg will be dosed once daily plus either GDC-0032 at 6 mg or 
placebo on a 5 − days-on/ 2 − days-off schedule for a total of 16 weeks (see Figure 5).  A 
maximum of 16 weeks of GDC-0032 can be administered.  Letrozole can be continued 
up to surgery per the investigator’s discretion. 




 
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At Week 9, a breast ultrasound will be performed to ensure that there is no progressive 
disease and for the purpose of surgery planning. Suspicion of progressive disease on 
breast ultrasound should be confirmed by investigator-assessed breast MRI.  Patients 
with primary disease not evaluable by ultrasound at baseline should be assessed by 
MRI at Week 9.  Suspected progression in nodes should also be confirmed by fine 
needle aspiration (FNA) if these nodes had not been previously shown to be 
cytologically positive for cancer.  Patients with progressive disease (as defined by 
modified RECIST, Appendix 3), can either proceed directly to surgery or be taken off of 
the study, according to the investigator’s decision. If the patient goes off-study, every 
reasonable effort should be made to obtain a new biopsy prior to beginning another 
systemic treatment. 
From Week 13, the patient will visit with the surgeon.  The purpose of this visit is two-fold:  
tentative planning of the type of breast surgery to be performed (breast conservative vs. 
mastectomy) and scheduling the date for definitive surgery.  
During Week 16, breast MRI will be done for the purpose of primary endpoint analysis. 
Clinical breast exam, breast ultrasound, and mammography will also be conducted prior 
to surgery for the purpose of the secondary endpoint analysis.  
Blood sample for exploratory endpoint analysis will be collected at screening, at Week 3, 
and prior to surgery. 




 
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Following surgery, follow-up will proceed according to local standards of care.  Adjuvant 
endocrine therapy and/or chemotherapy will be delivered as per the investigator’s choice. 
Postoperative radiotherapy is required if BCS is performed.  In the event of mastectomy, 
radiotherapy is to be administered according to local guidelines. 
A postsurgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the 
end of the study. Assessment of adverse events and general safety will be collected at 
this visit and the plan for future treatment will be recorded. 
The patient should be evaluated at baseline and after Week 13 of treatment for planning 
of the surgical procedure (BCS or mastectomy), and both physician recommendation 
and final patient decision should be documented in the electronic Case Report Form 
(eCRF).  
The co-primary efficacy endpoint, pCR (pCR–ypT0/is, ypN0) will be established via a 
local review following completion of neoadjuvant therapy and surgery.  
Please refer to the pathology manual for further guidance of evaluation for pCR and 
directions for sending a copy of the pathology report.  
A schedule of assessments is provided in Appendix 1.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI.  
IRF procedures are detailed in the IRF charter. 
3.1.2 
Independent Data Monitoring Committee  
An IDMC will monitor accumulating patient safety data at a minimum of once every 
6 months until the last patient has completed study treatment.  Additional details 
(e.g., IDMC members, communication, affiliations) will be provided in the IDMC charter.   
The IDMC will convene for an interim safety analysis to evaluate safety and 
pharmacokinetics after the first 20 patients have completed surgery and have had 
30 days of follow-up.  The IDMC will create and review unblinded, pooled summaries of 
the safety and available PK summaries (all interim analyses).  While this review is being 
conducted, patient accrual into the study will continue.  The Medical Monitor may also 
request additional safety analysis and may call for additional meetings of the IDMC to 
review ongoing safety data.  
The IDMC will share results from interim safety analyses with the study team.  The study 
team will share interim safety results with study investigators as needed for the conduct 
of the study and the safety of the patients.  Specific potential safety issues anticipated in 
this trial, as well as measures intended to avoid, minimize, and manage such toxicities, 
are outlined in the following sections. 


 
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3.2 
END OF STUDY  
The end of the study is defined as the date when the last patient has her postsurgery 
visit. The total duration of the study is expected to be approximately 24 months for 
enrollment, plus 5.5 months after last patient in.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Conducting the Study in the Neoadjuvant Setting 
Breast cancer is a heterogeneous disease, and not every breast tumor responds equally 
to a specific agent.  Studies based on global gene expression analyses have provided 
additional insights into this complex scenario.  Over the past 10 years, four major 
classes of breast cancer (Luminal A, Luminal B, HER2-enriched, and Basal-like) and a 
Normal Breast-like group have been identified and intensively studied (Perou et al. 2000 
[49]; Sørlie et al. 2001 [60]). Known as the intrinsic subtypes of breast cancer, these 
groups of tumors have revealed critical differences in incidence, survival, and response 
to treatment. As genomic studies evolve, further sub-classifications of breast tumors are 
expected to emerge. Thus, a major challenge in breast cancer management is how to 
prospectively select patients who will derive the maximum benefit from a given drug 
regimen, minimizing unnecessary toxicities for patients with non-responsive disease. 
Neoadjuvant therapy, a systemic therapy administered prior to breast cancer surgery, is 
now widely used in the 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 [43]), and the former offers clear advantages to patients, 
especially those with larger tumors. The tumor may shrink prior to surgery, thus 
increasing the rate of BCS (Coudert et al. 2006 [13]), and since the response to therapy 
can be monitored, the patient might be also spared further treatment with inactive 
medications.  
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 treatment response at a biological level. Finally, the surgical 
specimen, if pCR is not reached, can be utilized as well. 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 (von Minckwitz and Fontanella 
2013 [64]; Cortazar et al. 2012 [12]). 
3.3.2 
Rationale for Patient Population 
Postmenopausal patients with HER2-negative, ER+, early stage breast cancer will be 
enrolled in this study.  This patient population is usually treated with a combination of 
surgery, anti-hormonal therapy and/or chemotherapy, according to staging and biological 
features.  


 
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Recently, everolimus was approved by the FDA and European Medicines Agency in 
combination with exemestane for the treatment of advanced or metastatic breast cancer 
in patients after recurrence or progression following treatment with nonsteroidal AIs. In 
the neoadjuvant setting, a combination of letrozole and everolimus resulted in improved 
responses over letrozole alone in patients with ER+ breast cancer (Baselga et al. 2009 
[6]). 
Important findings in trials with drugs targeting mTOR, like everolimus, produce a 
pharmacodynamic paradox:  while inhibiting mTOR, they lead to an upregulation of the 
pAKT, resulting in feedback PI3K/AKT/mTOR pathway activation (Tabernero et al. 2009 
[62]). This finding suggests that alternative pharmacologic strategies to shut down the 
pathway upstream of AKT should be pursued. One of these strategies is to inhibit the 
PI3K/AKT/mTOR pathway at the PI3K level. PI3K-inhibitors are central regulators of the 
mTOR signaling pathway, and nonclinical findings show that PI3K-inhibitors and dual 
PI3K-mTOR inhibitors induce a greater amount of apoptosis than everolimus in 
estrogen-deprived in vitro models (Sanchez et al. 2011 [55]); therefore, it is 
hypothesized that PI3K-inhibitors may be active and demonstrate greater anti-tumor 
activity as compared to AIs alone in the neoadjuvant setting. 
3.3.3 
Rationale for Control Group  
Aromatase inhibitors (AIs) have been found to be more effective than tamoxifen as a 
neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer. 
Several trials have assessed the efficacy and safety of neoadjuvant endocrine therapy 
using AIs in patients with postmenopausal breast cancer (Eiermann et al. 2001 [18]; 
Smith et al. 2005 [59]; Ellis et al. 2011 [23]). 
The P024 trial was a worldwide, prospective, randomized, multicenter trial that 
randomized 337 postmenopausal patients with ER +  breast cancer to receive either 
4 months of neoadjuvant letrozole or tamoxifen (Eiermann et al. 2001 [18]). The primary 
endpoint of P024 was the percentage of patients in each treatment arm with objective 
response as determined by clinical palpation. Secondary endpoints included ORR 
determined by mammogram and ultrasound, and included the percentage of patients in 
each arm who had become eligible for BCS. The trial demonstrated a significantly higher 
clinical response rate for letrozole when compared to tamoxifen (55% vs. 36%; p < 0.001) 
in the intent-to-treat (ITT) population. An improved ORR for letrozole was also observed 
with ultrasound (35% vs. 25%; p < 0.042) and mammogram (34% vs. 16%; p < 0.001). 
The higher response rate assessed by clinical palpation translated into a significantly 
higher rate of women undergoing BCS in tumors that had initially been considered 
unsuitable for this procedure (45% vs. 35%; p = 0.022). Median time-to-response was 66 
days in the letrozole group and 70 days in the tamoxifen group, and both treatments 
were well tolerated. 


 
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The IMPACT trial was a randomized, Phase II, double-blind, double-dummy, multicenter 
trial that randomly assigned 330 postmenopausal women with ER+ operable or locally 
advanced, potentially operable breast cancer in a 1:1:1 ratio to receive a daily dose of 
anastrozole 1 mg and tamoxifen placebo, tamoxifen 20 mg and anastrozole placebo, or 
a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks before surgery. 
The tumor ORR was assessed by both caliper and ultrasound. No significant differences 
in ORR in the ITT population between patients receiving tamoxifen, anastrozole, or the 
combination were seen. However, in a predefined analysis, there was a nonsignificant 
trend towards more patients requiring mastectomy at baseline actually receiving BCS 
with anastrozole than with tamoxifen (44% vs. 31%, respectively; p = 0.23); this 
difference became significant for patients deemed by their surgeon to be eligible for BCS 
after treatment (46% vs. 22%, respectively; p = 0.03). All treatments were well tolerated. 
The ACOSOG Z1031 trial compared three AIs in a randomized, Phase II, neoadjuvant 
trial designed to select agents for Phase III investigations. Three hundred seventy-seven 
postmenopausal women with clinical Stage II to III ER+ breast cancer were randomly 
assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary 
endpoint was clinical response. No formal comparison between arms was pre-specified 
in the statistical plan. ORR was 62.9%, 74.8%, and 69.1% for the exemestane, letrozole 
and anastrozole arms, respectively. On the basis of clinical response rates, letrozole and 
anastrozole were selected for further investigation; however, no other differences in 
surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for 
mastectomy-only patients at presentation was 51%. 
Results from these trials suggest that neoadjuvant endocrine therapy can be beneficial 
in postmenopausal patients with hormone-sensitive breast cancer, and that it offers an 
alternative to neoadjuvant chemotherapy. 
3.3.4 
Rationale for the Efficacy Outcome Measure of Response Rate 
Assessed by Magnetic Resonance Imaging  
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, non-registrational, neoadjuvant trials in combination with endocrine therapy 
(Smith et al. 2005 [59]; Ellis and Ma 2007 [21]; Baselga et al. 2009 [6]).  
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 computed tomography (CT) 
and mammography (Eisenhauer et al. 2009 [19]). 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 (Akazawa et al. 
2006 [2]; Balu-Maestro et al. 2002 [5]; Yeh et al. 2005 [69]), including the I-SPY trial 


 
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(Hylton et al. 2012 [32]).  For these reasons, ORR as assessed by breast MRI has been 
chosen as a co-primary endpoint for this trial.  
3.3.4.1 
Rationale for Efficacy Outcome Measure of Pathologic 
Complete Response 
pCR is a recognized efficacy endpoint of neoadjuvant trials, especially those with 
neoadjuvant chemotherapy, as it has been correlated with long-term outcomes, such as 
event-free survival (von Minckwitz and Fontanella 2013 [64]).  
In trials of neoadjuvant hormonal therapy, pCR is an unlikely event.  For instance, in the 
neoadjuvant trial comparing everolimus plus letrozole to letrozole, pCR rates were 1.4% 
and 0.8%, respectively (Baselga et al. 2009 [6]). 
In the ongoing Phase I/II trial that combines letrozole with GDC-0032, tumor shrinkage 
has been observed, and some patients presented sustained partial responses. As pCR 
is a recognized indicator of activity to a given regimen, it would be useful to assess it as 
a co-primary efficacy endpoint of this trial. Furthermore, for the same trial size, this 
would represent a minimal increase in the minimum detected difference (MDD) of the 
co-primary endpoint for pCR ORR (from MDD of 12% to MDD of 13%). 
In September of 2013, the FDA granted accelerated approval of Perjeta as part of a 
complete treatment regimen for patients with HER2-positive, locally advanced, 
inflammatory or early stage breast cancer in the neoadjuvant setting.   
3.3.4.2 
Rationale for Ki67 Measurements 
Ki67 is a well-established proliferation biomarker with prognostic value in ER+ breast 
cancer (Dowsett et al. 2011 [17]). Efficacy of endocrine therapy relies on induction of 
cell-cycle arrest, and during neoadjuvant treatment, Ki67 levels reflect the ability of 
endocrine agents to suppress proliferation (Smith et al. 2005 [59]; Ellis et al. 2011 [23]).  
In the neoadjuvant trial of letrozole with everolimus, by using the definition that patients 
with natural log (Ki67) < 1 at Day 15 have an antiproliferative response, 57% of 
everolimus-treated patients were responders vs. 30% in the placebo arm, with a 
significant p value of < 0.01 (Baselga et al. 2009 [6]). Furthermore, the mean reduction in 
the percentage of Ki67-positive tumor cells at Day 15 relative to baseline was greater in 
the everolimus-treated patients (90.7% ± 3.2%) than in the placebo group (74.8% ± 6.8%; 
p = 0.0002). In the IMPACT trial, Ki67 was assessed at baseline, on Day 15, and at 
surgery (Smith et al. 2005). For each treatment arm, the reduction in geometric mean 
Ki67 levels was significantly higher for anastrozole than for tamoxifen at both time points 
(p = 0.004, p = 0.001, respectively), but no differences were found between tamoxifen and 
the combination. In the ASCOSOG Z1031 trial (Ellis et al. 2011), although no data on 
Ki67 at Day 15 were available, no differences were found between treatments at 
baseline and at surgery (after 16 − 18 weeks of therapy). The geometric mean 
percentage change in Ki67 for each treatment was similar between the arms 
(anastrozole 78%, exemestane 81.2%, and letrozole 87.1%). 


 
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The issue of whether Ki67 decrease at surgery or at any timepoint during treatment 
correlates with long-term efficacy outcomes has been addressed in the P024 trial 
(Eiermann et al. 2001 [18]). Treatment with letrozole led to higher, treatment-induced 
reduction of Ki67 levels in the tumor at surgery (87% reduction in the letrozole arm vs. 
75% in the tamoxifen arm; analysis of covariance p = 0.0009) based on the 185 
specimens with available data on Ki67 (Ellis et al. 2003 [20]). With a median follow-up of 
61.2 months, low levels of Ki67 in the biopsy at the end of treatment were significantly 
associated with better relapse-free survival (RFS; HR 1.4 per natural log increase in the 
Ki67 value, 95% CI 1.2 − 1.6, p < 0.001), and breast cancer specific survival (HR 1.4, 
95% CI 1.1 − 1.7, p =  0.009).  Finally, in the IMPACT trial, higher Ki67 expression after 2 
weeks of endocrine therapy was statistically significantly associated with lower RFS 
(p = 0.004), whereas higher Ki67 expression at baseline was not (Smith et al. 2005 [59]). 
Importantly, the Ki67 suppression in these hormonal neoadjuvant trials mirrored efficacy 
outcomes in large adjuvant trials: adjuvant BIG1-98 trial (n = 8,010) showed the superior 
efficacy of letrozole over tamoxifen (Regan et al. 2011 [51]), similar to the neoadjuvant 
P024 trial (n = 185); the adjuvant ATAC trial (n = 9,366) showed that anastrozole was 
better than tamoxifen and the combination of anastrozole plus tamoxifen (Cuzick et al. 
2010 [14]), similar to neoadjuvant IMPACT (n = 259); and the adjuvant MA27 trial 
(n = 7,576) showed similar efficacy of anastrozole and exemestane (Goss et al. 2013 
[30]), mirroring neoadjuvant ACOSOG Z1031 (n = 266). These results suggest that a 
biological superiority hypothesis generated by a neoadjuvant study may help the design 
of future adjuvant hormonal therapy trials. 
In summary, reduction in Ki67 after neoadjuvant treatment with AIs is a good marker of 
suppression of cellular proliferation, correlates with long term efficacy outcomes, and 
mirrors results of large adjuvant endocrine trials, which make it an attractive endpoint to 
assess in the present trial. 
3.3.4.3 
Rationale for Using the Preoperative Endocrine Prognostic 
Index Score 
In addition to Ki67, pathologic tumor size (T1 or T2 versus T3 or T4), node status 
(positive or negative), and the ER status (positive Allred score 3–8 versus negative 
Allred score 0–2) of the surgery specimen were also determined to have independent 
prognostic value for relapse and death after relapse in the P024 trial (Ellis et al. 2008 
[22]).  A PEPI score, prognostic for RFS, which weighs each of these factors according 
to their associated hazard ratios, was developed and subsequently validated in an 
independent data set from the IMPACT trial (Ellis et al. 2008). No relapses were 
recorded in either trial in patients with tumors classified as T1N0 and with a PEPI score 
of 0 (residual tumor with a Ki67 level  ≤ 2.7%, and with maintained ER expression) or in 
the rare patient with a pCR. 
In this trial, the PEPI score will be assessed centrally.  


 
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3.3.4.4 
Rationale for Assessing ORR by Clinical Breast Exam 
(Palpation), Mammography, and Breast Ultrasound 
Objective overall response rate will also be assessed by clinical breast exam, 
mammography, and breast ultrasound during screening and prior to surgery. These data 
will allow for more direct comparison of results to other neoadjuvant trials with endocrine 
therapy as described in Section 3.3.3. The concurrent acquisition of ORR data with 
these techniques, in addition to MRI-based measures, will also provide valuable 
comparative information on these methods, which will be important for both future 
neoadjuvant studies and GDC-0032 clinical development.  
3.3.4.5 
Rationale for Assessing Enhancing Tumor Volume by Breast 
Magnetic Resonance Imaging  
As shown in the I-SPY trial, tumor volume measurements based on the percent of tumor 
with enhancing signal after contrast agent administration may be a more sensitive 
measure of response during neoadjuvant treatment than longest dimension measures 
(Hylton et al. 2012 [32]). However, there are no established response criteria for 
volumetric data, and the extrapolation of current one- and two-dimensional criteria to 
volumetric data based on a spherical model may not be appropriate given the range of 
tumor morphologies expected in this population of patients (Loo et al. 2011 [40]).  
Additionally, there are only very limited data on the clinical relevance of any particular 
range in change in tumor volume during the course of neoadjuvant treatment. For these 
reasons, changes in enhancing tumor volume as measured by breast MRI will be a 
secondary endpoint in the trial.     
3.3.5 
Rationale for Independent Review Facility 
Due to the relatively novel nature of using MRI as an imaging endpoint, a central 
assessment by an IRF for the co-primary endpoint of response rate via MRI will be 
performed to ensure consistency across all sites participating in the study.  
3.3.6 
Rationale for Interim Safety Review 
The first 20 patients will be assessed for safety following surgery and 30 days beyond. 
This will allow the IDMC to review all safety data during the treatment period and to 
evaluate any surgery complications that may be attributed to GDC-0032. 
3.3.7 
Rationale for GDC-0032 Dosage 
As of 5 July 2013, 34 patients have been enrolled into the dose-escalation stage of 
Study PMT4979g, and 56 patients have been enrolled into the single-agent expansion 
cohorts at 9 mg in Stage 2 (Cohorts A-D and G).  Five dose-escalation cohorts (i.e., 3, 5, 
8, 12, and 16 mg daily) were tested.  The maximal administered dose was 16 mg.  To 
obtain more safety data on long-term tolerability, the recommended single-agent dose 
and schedule for the single-agent GDC-0032 expansion stage is 9 mg daily. 
In Study PMT4979g, as of the 5 July 2013 data cutoff date, there were 87 safety 
evaluable patients treated with single-agent GDC-0032 (3 − 16 mg daily).  A total of 97% 


 
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of patients experienced at least one adverse event per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4 (NCI CTCAE v4.0).  The 
most frequently reported adverse events, occurring in ≥ 10% safety-evaluable patients 
regardless of causality, were diarrhea (55%), fatigue (49%), nausea (47%), 
decreased appetite (39%), hyperglycemia (38%), vomiting (28%), dizziness (22%), 
rash (22%), dyspnea (18%), hypokalemia (18%), pyrexia (17%), cough (16%), anemia 
(13%), dehydration (13%), headache (13%), stomatitis (13%), AST increased (12%), 
mucosal inflammation (12%) and pruritis (10%).   
As of 5 July 2013, 54 patients have been treated with GDC-0032 in combination with 
endocrine therapy with either letrozole (Cohort E) or fulvestrant (Cohort F) at either 6 mg 
or 9 mg dose levels.  No DLTs were observed during dose escalation in either Cohorts E 
or F.  Expansion cohorts at the 6-mg dose level were enrolled to obtain more safety data 
on long-term tolerability.  Fifty (93%) of the 54 safety-evaluable patients experienced at 
least one adverse event that was assessed as related to GDC-0032.  
Of the 54 patients, 17 patients were treated with GDC-0032 plus letrozole. Adverse 
events that occurred in ≥ 10% of patients that were assessed as related to GDC-0032 
(6mg and 9mg) were diarrhea (67%), nausea (33%), fatigue (30%), rash (30%), 
hyperglycemia (26%), decreased appetite (26%), stomatitis (26%), dysgeusia (22%), 
mucosal inflammation (19%), asthenia (15%), vomiting (15%), pruritis (15%), muscle 
spasms (11%), dry skin (11%), and dry mouth (11%). 
Of the 19 efficacy-evaluable patients treated with GDC-0032 in combination with 
letrozole, one patient at 6 mg had a cPR. The PIK3CA mutation status of this patient is 
unknown. Since efficacy has been observed at 6 mg, and the long-term safety suggests 
that 6 mg is better tolerated, the neoadjuvant study will utilize 6 mg GDC-0032 in 
combination with letrozole.  
Of the 27 efficacy-evaluable patients treated with GDC-0032 in combination with 
fulvestrant, 2 confirmed partial responses were observed at 6 mg and 1 confirmed partial 
response at 9 mg. 
Colitis has been observed with an incidence rate of 6.2% (10/160 patients).  The time 
(from the first dose of study treatment) to onset of colitis ranged from approximately 
82 − 248 days as either a single agent or in combination with letrozole or fulvestrant.  
Most of the colitis cases have been observed at the 9-mg dose level or higher.  Most of 
the colitis cases have been observed at the 9-mg dose level or higher.  To mitigate the 
late-onset adverse events, such as colitis, an intermittent dosing schedule will be applied. 
With the 40-hour half-life, a limited impact on efficacy is anticipated.  PK modeling has 
shown that a schedule of 5 days on/2 days off will maintain GDC-0032 drug exposure 
levels within an efficacious range as assessed by various breast cancer cell lines.  There 
has also been data presented for another PI3K inhibitor BKM120 with a similar half-life in 
combination with letrozole in a Phase Ib study that demonstrated improved tolerability 


 
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with similar efficacy for a schedule of 5 days on/2 days off as compared to daily 
continuous dosing of the PI3K inhibitor (Mayer et al. 2012 [45]). 
3.3.8 
Rationale for Biomarker Assessments  
Breast cancer is a heterogeneous disease, and PIK3CA mutations have been shown to 
vary among patients (CGAN 2012).  Therefore, all patients may not equally likely benefit 
from treatment with GDC-0032.  Predictive biomarker samples collected prior to dosing 
will be assessed in an effort to identify those patients with PIK3CA-driven pathogenesis 
who are most likely to respond to GDC-0032.  Pharmacodynamic biomarkers will be 
assessed to assess the biologic activity of the addition of GDC-0032 to letrozole.  
It has been suggested that not all molecular alterations in the PI3K/AKT/mTOR pathway 
result in pathway activation.  In a comprehensive analysis of tumors from 850 breast 
cancer patients, protein markers of PI3K/AKT/mTOR pathway activation (pAKT, pS6, 
and p4EBP1) correlated strongly with INPP4B and PTEN loss, to a degree with PIK3CA 
amplification, but were not elevated in PIK3CA- MT luminal A cancers (CGAN 2012).  
This apparent disconnect between the presence of PIK3CA mutations and biomarkers of 
pathway activation had been previously noted (Loi et al. 2010 [39]), and stress the need 
to find innovative and robust predictive biomarkers to PI3K/AKT/mTOR pathway 
inhibiting agents (Saini et al. 2013 [54]). 
Next generation sequencing (NGS) techniques, like deep genome sequencing, may offer 
a unique opportunity to identify such biomarkers of response.  For example, using whole 
genome sequencing, a two base-pair deletion in the TSC1 gene was found in a 
metastatic bladder cancer patient with a prolonged response (> 2 years) to everolimus as 
single agent (Iyer et al. 2012 [33]).  Among 13 additional bladder cancer patients treated 
with everolimus in the same trial, those with TSC1 mutant tumors remained on therapy 
longer than those with WT tumors (7.7 vs. 2.0 months, p = 0.004), suggesting that 
mTORC-1 directed therapies may be most effective in cancer patients whose tumors 
harbor TSC1 somatic mutations.  Similar approaches could be of great value when 
analyzing responses to agents targeting the PI3K/AKT/mTOR pathway, especially in the 
neoadjuvant setting. 
In addition to mutational activation of proteins, levels of RNA and DNA can also activate 
the PI3K pathway.  For example, increases in DNA copy number in receptor tyrosine 
kinases such as FGFR1/2 and IGF-1R, which occur at some frequency in breast cancer, 
can activate downstream PI3K pathway.  Hormone receptor positive breast cancer can 
be divided into luminal A and luminal B subtype, with the luminal B subtype displaying a 
higher proliferative index.  Therefore, profiling the RNA and DNA expression of tumors 
will allow intrinsic subtyping of patients enrolled onto study.  In addition, PI3K 
transcription activation signatures may identify additional patients who could respond to 
PI3K inhibitors outside of PIK3CA mutations.  


 
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The use of circulating tumor DNA (ctDNA) to monitor response to treatment is an area of 
great interest.  It could allow for an early, non-invasive, and quantifiable method for use 
in the clinical setting to identify candidates for specific therapies and monitoring of 
disease mutation status over time (Higgins et al. 2012 [31]).  The neoadjuvant setting is 
ideal to prospectively test these approaches. 
3.3.9 
Rationale for Day 15 Biopsy 
On-study biopsies can provide valuable information regarding target engagement and 
downstream pathway suppression. Assessing how GDC-0032 interacts with letrozole in 
this previously untreated patient population provides a unique opportunity to understand 
the interaction between two anti-cancer molecules.  When available, FFPE tumor 
samples will be assessed for pathway modulation using immunohistochemistry (IHC) 
methodologies, and fresh frozen OCT samples will be assessed using reverse phase 
protein array (RPPA) technologies, or equivalent.  Measurement of Ki67 after 2 weeks of 
continuous letrozole and GDC-0032 combination treatment versus letrozole and placebo 
will give a good benchmark to prior neoadjuvant studies that demonstrated a larger 
decrease in Ki67 at this 2-week timepoint for a combination of letrozole and everolimus 
as compared to letrozole and placebo (Baselga et al. 2009 [6]).  This Day 15 biopsy will 
also be useful in identifying potential biomarkers that may help predict a tumor response 
for patients treated with GDC-0032.   
3.3.10 
Rationale for Collection of Blood Sample for the Detection 
of Plasma Protein Biomarkers 
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate response 
to drugs, particularly targeted agents such as GDC-0032 (Wilson et al. 2012 [66]).  
Assays to assess the expression of soluble, systemic cytokines and chemokines from 
the plasma of patients will be carried out using ELISA-based mass spectrometry or 
equivalent methodologies.   
3.3.11 
Rationale for Collection of Blood Sample for DNA Sequencing 
to Identify Mutations in Plasma 
There is increasing evidence that circulating DNA obtained from blood specimens of 
cancer patients is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008 [16]; Maheswaran et al. 2008 [41]).  Assays are available that can 
detect the major PI3K mutations (and other cancer-related genes) in plasma, and results 
from this analysis will be correlated with tumor specimens. 
3.3.12 
Rationale for Collection of Blood Sample for Next Generation 
Sequencing 
Next generation sequencing (NGS) technologies generate a large quantity of 
sequencing data.  Tumor DNA can contain both reported and unreported chromosomal 
alterations due to tumorigenesis process.  To help control for sequencing calls in 


 
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previously unreported genomic alterations, a normal blood sample will be taken during 
pre-screening to determine whether the alteration is somatic or germline.  
3.3.13 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected from early breast cancer patients in this study to assess the 
pharmacokinetics of GDC-0032 and possible DDI between letrozole and GDC-0032 in 
this population.  Considering the lack of DDI between GDC-0032 and letrozole upon 
concomitant administration in the 24 metastatic breast cancer patients in the Phase I 
study (preliminary data), this drug interaction in early breast cancer patients is unlikely.  
Hence, extensive PK sample collection is not needed; sparse PK sampling from patients 
enrolled in this study is adequate.  The proposed PK sample collection schedule will also 
enable assessment of a concentration and response relationship to better understand 
the following:  pharmacokinetics/pharmacodynamics (efficacy), PK/safety correlation, 
and population pharmacokinetics.  Additional PK samples may be collected for safety 
concerns (e.g., severe adverse event) in order to better characterize drug levels in these 
patients at the time of the adverse event.   
3.3.14 
Rationale for the Collection of DNA for Exploratory 
Pharmacogenetic Polymorphisms 
One sample (approximately 3 mL of whole blood) will be collected from all patients using 
K3-EDTA collection tubes. Samples  will be used for the evaluation of genetic 
polymorphisms of drug metabolic enzymes including, but not limited to, CYP2C9, 
CYP3A4/5, and UGT1A1, and transporters (e.g., OATP1B1) and for genetic variants 
which could contribute to potentially drug-related rash and/or colitis safety assessments 
(including but not limited to human leukocyte antigen [HLA]).  For sample handling 
procedures, storage conditions, and shipment instructions, see the laboratory manual. 
Only in circumstances where there is concern for collection of this genetic material for 
above evaluations, can this assessment be considered not mandatory as part of study 
assessments in this study.  Results of any analyses from these samples will be reported 
outside the clinical study report. 
It is established that genetic variants of drug-metabolizing enzymes and transporters can 
affect the pharmacokinetics of drugs, which affects their safety and efficacy.  For 
example, patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1, which facilitates the metabolism and excretion of SN 38 
(the active metabolite of irinotecan), are at higher risk for adverse effects associated with 
the use of standard doses of irinotecan (O’Dwyer and Catalano 2006 [48]).  Preliminary 
results from in vitro metabolism studies with GDC-0032 suggest that they are partially 
metabolized by multiple Phase I cytochrome P450 enzymes, including CYP3A4.  
Although in vitro studies can help elucidate the roles of enzymes in the metabolism of 
the drug, these results are not always predictive of in vivo metabolism for a number of 
reasons, such as differences in drug concentrations that the enzymes encounter in vitro 
and in vivo.  For this reason, a blood sample for DNA isolation is proposed to be 


 
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collected from all patients in this study for potential pharmacogenetic analysis of genes 
or biomarkers that may affect the pharmacokinetics or response to GDC-0032.  The 
decision to analyze the samples will be based on a review of the pharmacokinetics and 
response data.  Most recently, the role of HLA has been demonstrated to play an 
important role in the development of drug-induced rash for some drugs (carbamazepine, 
abacavir, and allopurinol).  Therefore, evaluation of genetic variants of genes that may 
regulate the immune response (including but not limited to HLA) may also be 
investigated to characterize unusual safety responses that are not predicted by GDC-
0032 pharmacokinetics. 
The analysis will be performed on identifiable DNA samples, because it is necessary to 
link a patient’s PK data with genotype.  This analysis would be restricted to the 
evaluation of genes that may be involved in the pharmacokinetics of GDC-0032, drug 
metabolism, disposition, or elimination and/or response of patients who develop severe 
adverse reactions such as colitis or rash.  Samples may be stored and analyzed up to 
15 years after the completion of the study, at which time all DNA samples collected for 
this analysis will be destroyed. 
3.3.15 
Rationale for Patient-Reported Outcome Assessments  
A PRO is “any report on the status of a patient’s health condition that comes directly 
from the patient, without any interpretation of the patient’s response by a clinician or 
anyone else” (FDA Guidance for Industry 2007 [24]).  PRO measures are able to 
contextualize a patient’s experience on trial, elucidating symptom and treatment burden.  
Since early breast cancer is often asymptomatic, the PRO objective is to evaluate and 
compare PROs of treatment-related symptoms, patient functioning, and the health-
related quality of life between treatment arms (Lemieux et al. 2011 [37]).  
The EORTC QLQ-C30 and associated breast cancer module, QLQ-BR23, were selected 
because they were specifically developed to assess the most salient constructs and 
experiences with breast cancer and its treatment.  The EORTC QLQ-C30 is a widely and 
frequently used PRO measure in oncology trials that contains a global health status 
scale, functional scales (physical, role, emotional, cognitive, and social), and general 
cancer symptom scales/items with a recall period of ‘the past week.’  
The second measure, the QLQ-BR23, is a breast cancer specific modular supplement to 
the EORTC QLQ-C30, and includes additional functioning scales and symptom 
scales/items relating to breast cancer.  
These instruments demonstrate strong psychometric properties, of both reliability and 
validity, and meet the requirements for this study (EORTC QLQ-C30 Scoring Manual, 
1999).  Therefore, PRO data will be collected from patients using the EORTC QLQ-C30 
and modified QLQ-BR23 (Quinten et al. 2009 [50]). 


 
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3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are as follows:  
• 
Tumor ORR, via centrally assessed breast MRI via modified RECIST (Appendix 3) 
in all enrolled patients and PIK3CA MT patients. 
• 
pCR rate in breast and axilla (total pCR) as defined by ypT0/Tis ypN0 in the 
American Joint Committee on Cancer staging system (Appendix 6) by local 
evaluation in all enrolled patients and PIK3CA MT patients.  
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Tumor ORR, assessed by centrally assessed breast MRI via modified RECIST 
(Appendix 3) in PIK3CA WT patients 
• 
pCR rate in breast and axilla (total pCR) by local evaluation in PIK3CA WT patients. 
The following secondary outcome measures will be performed in all enrolled patients 
and separated by PIK3CA mutation status: 
• 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of ORR, as 
measured by modified RECIST criteria (Appendix 3) using the following methods: 
• 
Breast ultrasound 
• 
Clinical breast exam (i.e., palpation) 
• 
Mammography  
• 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
• 
Compare the centrally assessed PEPI score upon treatment with letrozole plus 
GDC-0032 with letrozole plus placebo 
• 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI 
• 
Evaluate different definitions of pCR including the following:  a) ypT0, ypN0, and b) 
yoT0/is, ypNX (breast pCR) 
 
3.4.2 
Safety Outcome Measures  
The safety and tolerability of GDC-0032 will be assessed using the following primary 
safety outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE, v4.0  
• 
Incidence and type of adverse events leading to dose discontinuation, modification, 
or delay 
• 
Serious adverse events 


 
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• 
Protocol-defined adverse events of special interest 
• 
Clinically significant changes in vital signs and in clinical laboratory results during 
the adverse event reporting period (see Section 5.3.1) 
  
3.4.3 
Patient-Reported Outcome Measures   
The PRO measures for this study are as follows: 
• 
HRQoL, including side-effects of therapy (e.g., sore mouth/tongue, difficulty 
swallowing, diarrhea, skin problems), and patient functioning as measured using the 
EORTC QLQ–C30 and the modified breast cancer module QLQ–BR23 
 
3.4.4 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
• 
Expression of biomarkers before, during, and after therapy.  These include, but are 
not limited to, the following: 
• 
PI3K pathway aberrations 
• 
Gene signatures, including intrinsic subtyping and PI3K pathway activity 
• 
Hormone receptor expression levels 
• 
Protein and phospho-protein markers and combinations 
• 
Mutations within cancer-associated genes 
• 
Copy number alterations in cancer-related genes 
• 
Plasma-based protein biomarkers 
• 
ctDNA 
• 
Compare the rates of BCS and conversion to BCS in letrozole plus GDC-0032 
versus letrozole plus placebo 
• 
The relationship between GDC-0032 concentration and tumor response and/or drug 
safety response 
• 
Letrozole concentrations with and without administration of GDC-0032 
• 
The relationship between pharmacogenetic differences in drug metabolizing 
enzymes and transporters and other patient-specific covariates with PK of GDC-
0032 or letrozole and/or drug response 
• 
Changes from baseline to surgery in the apparent diffusion coefficient (ADC), a 
marker of tumor cellularity derived from diffusion-weighted MRI 
• 
Concordance of the different imaging modalities (MRI [volume, enhancement, 
diffusion metrics], ultrasound, mammography) in measuring tumor response  
 


 
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4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients for this study include postmenopausal patients with ER+/HER2- untreated, 
Stage I-III operable breast cancer.  The size of the primary tumor should be  ≥ 2 cm by 
MRI.   
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (ICF) prior to any study-specific procedure 
• 
Female patients 
• 
Postmenopausal status and age  ≥ 18 years. Postmenopausal status is defined as 
follows: 
– 
Age  ≥  60 years or 
– 
Age  <  60 years and 12 months of amenorrhea plus follicle stimulating hormone 
(FSH) and plasma estradiol levels within postmenopausal range by local 
laboratory assessment or 
– 
Prior bilateral oophorectomy ( ≥  28 days prior to Day 1 of treatment) 
• 
Histologically confirmed invasive breast carcinoma, with all of the following 
characteristics: 
– 
Primary tumor ≥ 2 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 ≥ 2 cm and designated 
as the “target” lesion for all subsequent tumor evaluations.   
– 
Stage I to operable Stage III breast cancer 
– 
Documentation confirming the absence of distant metastasis (M0) as 
determined by institutional practice (in patients where there may be a 
reasonable suspicion of advanced disease e.g., large tumors, clinically positive 
axillary lymph nodes, signs and symptoms). 
• 
ER-positive and HER2-negative breast cancer, as per local laboratory or regional 
definition  
• 
Breast cancer eligible for primary surgery 
• 
Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as 
evaluable for PIK3CA mutation status by central histopathology laboratory 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Fasting glucose  ≤ 125 mg/dL  
• 
Adequate hematological, renal, and hepatic function, as follows: 
– 
Absolute neutrophil count ≥ 1500/μL 
– 
Platelets count ≥100,000/μL 


 
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– 
Hemoglobin ≥ 9 g/dL 
– 
Serum bilirubin ≤ 1.5 ×  the upper limit of normal (ULN) 
– 
Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may 
be enrolled 
• 
Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline 
phosphatase ≤ 1.5 ×  ULN  
• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥  50 mL/min on the basis of 
the Cockcroft−Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85) 
72 × (serum creatinine in mg/dL) 
• 
International normalized ratio (INR) < 1.5 × upper limit of normal (ULN) and activated 
partial thromboplastin time (aPTT) < 1.5 × ULN 
For patients requiring anticoagulation therapy with warfarin, a stable INR between 
2−3 is required.  If anticoagulation is required for a prosthetic heart valve, then INR 
should be between 2.5−3.5.  
• 
Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
• 
Ability and willingness to comply with study visits, treatment, testing, and to comply 
with the protocol, in the investigator’s judgment 
4.1.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any prior treatment for primary invasive breast cancer 
• 
Patients with cT4 or cN3 stage breast tumors 
• 
Metastatic (Stage IV) breast cancer 
• 
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 sentinel lymph node biopsy prior to study treatment 
• 
Type 1 or 2 diabetes requiring antihyperglycemic medication 
• 
Inability or unwillingness to swallow pills 
• 
Malabsorption syndrome or other condition that would interfere with enteric 
absorption 
• 
History of prior or currently active small or large intestine inflammation (such as 
Crohn’s disease or ulcerative colitis)  
• 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula 
(QTcF) >  470 msec 


 
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• 
Clinically significant (i.e., active) cardiovascular disease, like uncontrolled 
hypertension, unstable angina, history of myocardial infarction, cardiac failure class 
II-IV (New York Heart Association, Appendix 5), or any other that in the judgment of 
the investigator could jeopardize patient safety or study outcomes 
• 
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  
• 
Active infection requiring intravenous (IV) antibiotics 
• 
Patients requiring any daily supplemental oxygen 
• 
Clinically significant history of liver disease, including viral or other known hepatitis, 
current alcohol abuse, or cirrhosis 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic 
dysfunction, physical examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug, that may affect the interpretation of the results, or renders the 
patients at high risk from treatment complications 
• 
Significant traumatic injury within 3 weeks prior to initiation of study treatment 
• 
Major surgical procedure within 4 weeks prior to initiation of study treatment 
• 
Inability to comply with study and follow-up procedures 
• 
History of other malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
or Stage I uterine cancer 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Patient Randomization 
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain a patient’s identification number and treatment assignment 
using a permuted block randomization algorithm via an interactive voice or web-based 
response system (IxRS).  


 
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4.2.2 
Stratification 
Patients will be randomized into one of the two treatment arms in a 1:1 ratio based on 
the following stratification factors: 
• 
Tumor size (T1-2 vs. T3) 
• 
Nodal status (cytologically positive vs. radiologically or cytologically negative). If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then fine needle aspiration (FNA) or core biopsy is required to 
confirm nodal status. 
 
4.2.3 
Blinding 
Investigators and patients will be blinded to treatment assignment of GDC-0032 or 
placebo. 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS following approval from the Medical Monitor.  Treatment codes should not be 
broken except in emergency situations where unblinding is needed for treatment 
decisions.  Effort should be made to contact the Medical Monitor before unblinding.  
Patient treatment assignment may be unblinded at the time the patient discontinues from 
the blinded treatment phase at the request of the treating physician by contacting the 
IxRS following approval from the Medical Monitor and stating the reason for unblinding.  
Unblinding during the study will result in the withdrawal of a patient from the study.  For 
regulatory reporting purposes, and if required by local health authorities, the Sponsor will 
break the treatment code for all serious, unexpected, suspected adverse reactions that 
are considered by the investigator or Sponsor to be related to study drug. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  The PK 
assay group will be unblinded to patients’ treatment assignments to identify appropriate 
PK samples to be analyzed and bioanalytical methodology to employ.  However, the PK 
scientist does not have access to the PK assay results and therefore stays blinded until 
the PK assay results need to be interpreted and reported.  Samples from patients 
assigned to the comparator arm will be analyzed for letrozole.  However, GDC-0032 
assay will be analyzed by request (i.e., to evaluate a possible error in dosing). 
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0032 and Placebo  
GDC-0032 Drug Substance and Drug Product are manufactured according to current 
Good Manufacturing Practice guidelines for use in the clinical studies.  Each lot of 


 
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GDC-0032 for clinical studies is subjected to a series of quality control tests to confirm 
its identity, purity, potency, and quality. 
GDC-0032 is provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 3 mg strength.  The tablet formulation consists of 
GDC-0032 active, lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, and Opadry 2 white film coating.  All excipients used in the 
formulation are compendial (USP/NF/Ph. Eur/JP) grade with the exception of the film-
coating.  The film-coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, 
polyethylene glycol 3350, and talc, and these ingredients are compendial. 
Placebo tablets will be identical in shape and color to the 3-mg tablets of GDC-0032 and 
will be indistinguishable from the 3-mg tablets of GDC-0032.  The ingredients in the 
placebo tablets are identical to those in the 3-mg tablets of GDC-0032, except for the 
absence of GDC-0032 active. 
The GDC-0032 active and placebo tablets are packaged in high-density polyethylene 
bottles, are labeled for clinical use, and should not be stored above 25°C. 
For further details, see the GDC-0032 Investigator’s Brochure. 
4.3.1.2 
Letrozole 
Letrozole will be labeled according to regulatory requirements in each country, as well as 
in accordance with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and will be labeled for investigational use only.  The Sponsor will provide 
letrozole free of charge to all study sites. 
Refer to the letrozole (e.g., Femara®) Package Insert or summary of product 
characteristics (SmPC) for details on the formulation and storage of letrozole. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0032 and Placebo 
Patients will receive an oral, daily dose of 6 mg GDC-0032 or placebo on a schedule of 
5 days on/2 days off for a maximum of 16 weeks.  Patients will take GDC-0032 at the 
same time of day ± 2 hours, unless otherwise instructed.  Patients will be instructed as to 
the number of tablets to take.  Patients will be asked to record the time and date that 
they take each dose in a medication diary. 
Unless otherwise instructed, GDC-0032 or placebo should be taken on an empty 
stomach (i.e., approximately 1 hour before or 2 hours after a meal). 
If a patient misses a GDC-0032 or placebo dose or vomits up a tablet, she should be 
instructed to skip that dose and to resume dosing with the next scheduled dose.  Missed 
doses will not be made up.  Patients will be instructed to bring their medication diary to 


 
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each study visit for assessment of compliance.  Patients will also be instructed to bring 
all unused tablets to each study visit for GDC-0032 or placebo accountability. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
4.3.2.2 
Letrozole 
Patients will receive an oral, daily dose of 2.5 mg letrozole for 16 weeks (or until time of 
surgery at the investigator’s discretion).  No dose modifications of letrozole are permitted.  
Any overdose or incorrect administration of letrozole should be noted on the letrozole 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of letrozole 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 
(letrozole and GDC-0032) will be provided by the Sponsor where required by local health 
authority regulations.  The investigational site will acknowledge receipt of IMPs, using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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 GDC-0032 
The Sponsor will offer post-trial access to the study drug (GDC-0032, letrozole, or other 
study interventions) 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 


 
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• 
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 would not 
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 untreated, postmenopausal ER + /HER2 −, early 
stage, operable breast cancer 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for untreated, postmenopausal postmenopausal ER + /HER2 −, early stage, operable 
breast cancer 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at 
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 
7 days prior to screening to the study completion/discontinuation visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
GDC-0032 was metabolized primarily by CYP3A4 in HLM and appeared to be a weak 
time-dependent inhibitor of CYP3A4.  Although in vitro induction studies in human 
hepatocytes suggested that GDC-0032 has low-to-moderate potential to induce CYP3A4, 
preliminary data from the Phase I study (PMT4979g) indicate that 9 mg of GDC-0032 
daily for 2 weeks in patients had no apparent effect on the pharmacokinetics of 
midazolam (a sensitive CYP3A4 substrate).  Therefore, GDC-0032 may be administered 
concomitantly with CYP3A4 substrates without the risk of a pharmacokinetic DDI.  
Letrozole is mainly metabolized to a pharmacologically inactive carbinol metabolite by 
CYP2A6 and CYP3A4 in vivo. GDC-0032, which has the potential to induce CYP3A4 
based on in vitro induction studies, was administered in combination with letrozole in the 
expansion phase of Study PMT4979g to assess their DDI potential. Preliminary data 
from 10 patients in this cohort indicated that steady state plasma concentrations of both 
letrozole and GDC-0032, following once daily administration of the combination (2.5 mg 
letrozole plus 6 or 9 mg GDC-0032), were similar to historical, single-agent data 


 
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suggesting lack of DDI between GDC-0032 and letrozole. These preliminary results 
suggest that GDC-0032 and letrozole combination may be administered without the risk 
of a pharmacokinetic DDI.  
In vitro CYP inhibition studies in HLMs and induction studies in human hepatocytes 
suggested a low to moderate potential of GDC-0032 to perpetrate DDIs.  A clinical DDI 
study with rifampin (CYP3A4 inducer) and itraconazole (CYP3A4 inhibitor), to 
understand the effect of CYP inhibitors or inducers on the pharmacokinetics of GDC-
0032, is currently ongoing (Study GP28617). 
4.4.2 
Prohibited Therapy 
Prohibited therapy is as follows: 
• 
Anti-cancer therapy:  No additional investigational or commercial anti-cancer 
agents such as chemotherapy, immunotherapy, targeted therapy, biological 
response modifiers, or endocrine therapy (other than letrozole permitted in this 
protocol) will be allowed.  
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), hormonal contraception, megestrol acetate, and selective 
estrogen-receptor modulators used with prophylactic intent: If a patient is 
receiving these at the moment of registration, treatment should be discontinued prior 
to randomization.  
• 
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.  Patients who develop osteopenia 
or osteoporosis in the follow-up period may receive bone-targeted therapy as per 
the clinician’s discretion.  Primary use of bisphosphonates as a prevention of bone 
metastasis or as a prevention of bone loss is prohibited.   
• 
Potent CYP3A4 inhibitors:  Concomitant use of strong CYP3A4 inhibitors (such as 
ketoconazole and itraconazole) with GDC-0032 should be avoided.  Consider an 
alternate medication with no or minimal potential to inhibit CYP3A4.  If a strong 
CYP3A4 inhibitor is co-administered with GDC-0032, patients should be closely 
monitored for adverse reactions. 
 
4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments to be performed during the 
study. 


 
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4.5.1 
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. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases that are currently active or that 
were active within the previous 5 years, surgeries, cancer history (including prior cancer 
therapies and procedures), reproductive status, smoking history, use of alcohol and 
drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
15 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examination 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems as well as weight and height 
(height is measured at the screening visit only).  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examination may be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressure while the patient is in a seated position, and temperature.  
4.5.5 
Electrocardiograms 
Triplicate electrocardiogram (ECG) recordings will be obtained at each specified 
timepoint (see the schedule of assessments in Appendix 1).  
4.5.6 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
National Comprehensive Cancer Network (NCCN) or national guidelines, within 28 days 
prior to randomization.   


 
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As a reference, as per NCCN guidelines, staging procedures are based on clinical stage:  
• 
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.   
• 
For Stage IIIB and Stage IIIC: bone scan and CT of chest, abdomen, and pelvis 
should be conducted for all patients. 
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.   
4.5.7 
Tumor and Response Evaluations 
All measurable disease must be documented at screening and reassessed at 
subsequent timepoints as outlined in Appendix 1. Responses based on clinical breast 
exam, breast ultrasound, and mammography will be investigator-assessed.  Whenever 
possible, assessments should be performed by the same evaluator to ensure internal 
consistency across visits. Response via breast MRI will be centrally assessed, and all 
assessments will be based on modified RECIST criteria (see Appendix 3).  
Clinical Breast Examination:  Assessment of primary breast tumor and regional lymph 
nodes must be done by physical examination (palpation) during baseline evaluation, 
Weeks 1, 5, 9, 13 and 16 during the treatment phase, and prior to surgery. Breast tumor 
measurement by caliper (preferred) or rule 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.  
Mammogram:  Bilateral mammograms must be obtained at baseline within 28 days 
prior to enrollment and again prior to surgery. Mammographic tumor measurements are 
to be recorded in the eCRF.  
Breast Ultrasound:  Bilateral breast ultrasounds must be obtained at baseline within 
28 days prior to enrollment.  Investigator decision whether to perform unilateral or 
bilateral ultrasounds performed at Week 9 and prior to surgery (Week 16) may be 
unilateral or bilateral and per investigator discretion.  If on ultrasound examination there 
is evidence of suspicious axillary lymph nodes at the baseline examination, then FNA or 
core biopsy is required.  Sonographic tumor measurements are to be recorded in the 
eCRF. The tumor site may be marked with a radiopaque clip or marker via radiographic 
guidance (e.g., ultrasound) prior to initiation of neoadjuvant therapy.  


 
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Breast MRI:  Contrast-enhanced breast MRI scans will be mandatory for all study 
patients at baseline (within 28 days prior to enrollment) and prior to surgery (Week 16).  
MRI is optional at Week 9, but will be mandatory if a primary breast lesion is not 
evaluable by ultrasound, or if there are signs of disease progression on the Week 9 
ultrasound (see Figure 6).   
Breast MRI scans should not be acquired within 48 hours after biopsy, and the 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 as 
assessed by the central reading facility, the scan may be repeated, at least 48 hours 
after the first scan before the start of study treatment. Other MRI acquisition sequences, 
such as diffusion-weighted imaging, may be acquired during this study during the MRI 
scan visits for each patient.  Additional MRI-derived metrics such as ADC value may 
provide additional insight into changes in tumor cellular composition.  
For information about patient preparation, scanner requirements and settings, and image 
acquisition, refer to the Study Imaging Manual. Standard site practice may be followed 
regarding the use of mild sedatives or anti-anxiolytics for claustrophobic patients prior to 
MRI. 
4.5.8 
Surgical Treatment Plan 
The planned and actual surgical treatment (BCS or mastectomy) performed should be 
documented and reported in the eCRF.  Patients should be reassessed after completion 
of neoadjuvant therapy and prior to surgery.  
4.5.9 
Surgical Specimen – Pathology 
The co-primary endpoint of the study (pCR) will be as identified by local pathology 
review. Guidelines regarding pathology specimen preparation, labeling and review are 
outlined in the pathology manual. 
4.5.10 
Laboratory Assessments 
The following assessments will be performed at the local laboratory.  The frequency of 
assessments is provided in Appendix 1. 
• 
Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, and other cells]), and platelet 
count.   
• 
Coagulation (INR and aPTT/PTT) 
• 
Fasting serum chemistry (blood urea nitrogen [BUN], creatinine, sodium, potassium, 
magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, serum 
bilirubin, alkaline phosphatase, glucose, AST, ALT), performed following  ≥ 10-hour 
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• 
Fasting lipid profile and amylase (total cholesterol, high-density lipoprotein [HDL], 
low-density lipoprotein [LDL], triglycerides, amylase, and lipase) performed following 
a  ≥ 10 hour fast 
• 
Fasting insulin and glucose  
• 
Glycosylated hemoglobin (HbA1c) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
The following assessments will be performed at a central laboratory.  Instruction 
manuals outlining sampling procedures, storage conditions, and shipment instructions 
and supply kits will be provided for all central laboratory assessments: 
• 
Mandatory tumor tissue 
• 
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 PIK3CA mutation testing as well as 
for other protocol-mandated exploratory assessments at baseline, Day 15, and at 
surgery. 
• 
Tumor tissue should be of good quality based on total and viable tumor content.  
Evaluation of the patient’s tumor sample for adequate tumor tissue content by a 
central laboratory must occur prior to initiation of study treatment.  A minimum of ten 
unstained slides from a prior diagnostic FFPE core biopsy would be required for 
enrollment eligibility purposes. 
Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen 
OCT core needle biopsy are required at baseline and Day 15 (Week 3).    
A formalin-fixed, paraffin-embedded tumor block from surgical resection 
(Weeks 17 − 18) is required.  If a tumor block cannot be obtained for various reasons 
(e.g., the tumor tissue is not sufficient at surgical resection), the site should discuss 
with the central study team.  In such cases, paraffin-embedded, unstained slides (a 
minimum of 20 and up to 40 unstained slides) from a surgical specimen are required 
at surgery (Weeks 17 − 18). 
The specimens will be used for confirmatory central laboratory assessment of 
PIK3CA mutation status, Ki67, PTEN, ER/PgR and HER2 expression.  In addition, 
other exploratory assessments, including but not limited to, PI3K signaling pathways 
may be evaluated, including protein expression and molecular profiling studies such 
as NGS and gene-expression. 
• 
Plasma samples for exploratory research on candidate biomarkers include, but are 
not limited, to the following:  ctDNA and plasma protein biomarkers 
• 
Blood for NGS (if approved by local regulatory authorities) 
• 
Blood for pharmacogenomics (if approved by local regulatory authorities) 
• 
PK assessment  
 


 
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Plasma samples will be collected to measure letrozole and GDC-0032 
concentrations (see 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. 
 
4.5.11 
Assay Methods 
4.5.11.1 
Mutational Analysis for PIK3CA 
The PIK3CA mutation assay will be performed by a central laboratory. 
Somatic mutations in the PIK3CA gene are found in approximately 35% − 40% of 
ER-positive breast cancers and occur most commonly in Exons 9 and 20 in the codons 
encoding amino acids E542, E545, and H1047 (Saal et al. 2005 [52]).  Real-time 
polymerase chain reaction (RT-PCR) assays that amplify exons that are commonly 
mutated in PIK3CA offer a sensitive and quantitative method to detect mutations from a 
tumor specimen.  DNA will be extracted from tumor samples and subjected to allele-
specific PCR assays that detect the WT allele, as well as to assays for nucleotide 
substitutions that include, but are not limited to, the following amino acid changes:  
R88Q, N345K, C420R, E542K, E545K/A/G/D, E546K/E/R/L, M1043I, H1047R/L/Y, 
H1049R.  Following histopathological review, samples with  < 10% tumor content may 
not be evaluable for the PIK3CA assay. Samples will be run on cobas z480 analyzer, 
and PIK3CA mutation status (mutant or WT) will be made using appropriate cutoffs and 
automated software.   
A designation of PIK3CA status unknown will be assigned to a sample wherein any one 
of the predefined mutations was not conclusively assessed. 
4.5.11.2 
Pharmacodynamic Biomarker Assays in Tumor Tissues 
Ki67 antigen is an important cell cycle-related nuclear protein that is expressed by 
proliferating cells in all phases of the active cell cycle (G1, S, G2, and M phase).  As 
such, it is a useful marker of the proliferative state of a tumor.  Ki67 protein levels will be 
determined by IHC through the use of standard techniques.   
PI3K pathway, and other pro-survival, biomarkers will be tested in the fresh tumor 
biopsies by IHC, including, but not limited to, phospho-S6, phospho-AKT, 
phospho-4EBP1, and phospho-ERK.  If tissue quantity permits, change in expression of 
pathway biomarkers will be measured by the RPPA using OCT fixed tissue.  The basis 
of the technology is to immobilize small amounts of lysate from a tumor biopsy sample in 
serial dilution on a microarray slide.  Multiple samples are thus arrayed on a slide and 
can be probed with antibodies that detect a particular phospho-epitope.  Using this 
technology, we will profile approximately 80 key signaling nodes representing a number 
of pathways known to be dysregulated in cancer, including receptors in the HER family, 
multiple components of PI3K/mTor signaling, as well as key members of the RAS/MAP 
kinase pathway. 


 
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4.5.11.3 
Analysis of Phosphatase Tensin Homolog Expression 
PTEN status will be examined by IHC using a protocol that has been validated for 
specificity using several available cell line controls at a central laboratory.  Tumor 
specimen will be scored only if appropriate staining is observed in internal control 
stromal or normal (non-tumor) tissue elements.  
4.5.11.4 
Confirmation of Estrogen Receptor, Progesterone Receptor, 
and HER2 Status 
ER, PR, and HER2 status will be determined at a central laboratory according to the 
American Society of Clinical Oncology-College of American Pathologists (ASCO-
CAP) guidelines. 
4.5.11.5 
Circulating Tumor DNA Analysis 
ctDNA will be extracted from plasma samples collected from patients and used for the 
detection of oncogenic mutations using appropriate technologies.  The prevalence of 
the mutations measured at baseline and post-treatment may provide information on 
response or resistance to therapy. 
4.5.11.6 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression will be 
performed using gene expression assays conducted on the NanoString platform or 
equivalent.  Analysis may include, but is not limited to, a panel of genes important for 
intrinsic subtyping, breast cancer biology and PI3K signaling.  The goal will be to 
generate a database of expression status to examine whether there are gene expression 
patterns that are associated with clinical response to GDC-0032. 
4.5.11.7 
Next Generation Sequencing 
In cases where there is sufficient material to isolate DNA, NGS will be performed using 
NGS platforms, such as Illumina or equivalent. The goal will be to determine whether the 
percentage of genetic mutations are associated with clinical response to GDC-0032. 
4.5.11.8 
Copy Number Analysis  
The level of copy number alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically using chromosomal in situ hybridization 
(ISH), using next-generation sequencing platforms or by RT-PCR-based or equivalent 
technologies.  For cytogenetic assays, detection may be either fluorescence-based 
(fluorescence in situ hybridization assay) or chromogenic-based (chromogenic in situ 
hybridization).  Increased copy number of PI3K pathways activating genes may provide 
information on response or resistance to therapy.  
4.5.11.9 
Plasma Biomarker Analyses 
Assays to assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be carried out using appropriate methodologies, such as 
enzyme-linked immunosorbent assay (ELISA)-based or mass spectrometry-based or 
equivalent technologies.   


 
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4.5.11.10 
Plasma Pharmacokinetic Samples 
Plasma GDC-0032 and letrozole samples will be analyzed using a validated liquid 
chromatography tandem mass spectrometry. 
After the plasma samples are analyzed, any remaining samples may be used for 
exploratory metabolite profiling and identification, ex vivo protein binding, and PK, or 
pharmacodynamic assay development purposes. 
4.5.11.11 
Pharmacogenetic Polymorphism Assay 
If approved by the local regulatory authority, gene mutations will be assayed using 
multiplex PCR, allele-specific PCR, direct sequencing, or other acceptable methods.  
Results may be correlated to population PK parameters or other clinical measures in order 
to better understand the impact of genetic variants on drug metabolism, exposure, adverse 
events, and/or response.   
A sample will also be utilized as a source of normal DNA to determine whether sequence 
variants in the PIK3CA gene and in other relevant oncogenes in the tumor DNA are 
somatic mutations or single nucleotide polymorphisms. 
4.5.11.12 
Electrocardiograms 
Triplicate ECG recordings will be obtained at each specified timepoint (see the schedule 
of assessments in Appendix 1).  
4.5.12 
Patient-Reported Outcomes  
PRO data will be elicited from the patients in this study to more fully characterize the 
clinical profile of GDC-0032.  The PRO questionnaires, translated as required in the local 
language, will be distributed by the investigator staff and completed in their entirety by 
the patient.  To ensure instrument validity and that data standards meet health authority 
requirements, PRO questionnaires should be self-administered at the investigational site 
prior to the completion of other study assessments and the administration of study 
treatment.  
The EORTC QLQ-C30 and the Modified Breast Cancer module QLQ-BR23 
questionnaires will be used to assess HRQoL, including side-effects of systemic therapy 
(e.g., sore mouth/tongue, difficulty swallowing, diarrhea, skin problems) and patient 
functioning during the neoadjuvant period (refer to schedule of assessments in 
Appendix 1 for a detailed description of timepoints) and post-surgery follow-up.  
The EORTC QLQ-C30 is a widely used HRQoL measure in oncology trials with excellent 
psychometric properties demonstrating both reliability and validity. The measure consists 
of “five functional scales (physical, role, cognitive, emotional, and social); three symptom 
scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life 
scale” with a recall period of “the past week” (Aaronson et al. 1993 [1]). Scale scores can 
be obtained for each of the multi-item scales, global health status/QoL scale, and six 


 
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single items by using a liner transformation for standardization of the calculated raw 
score.   
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of “the past week,” and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment).  As this 
trial will include patients in the neo-adjuvant setting, the last seven items of the original 
BR23 questionnaire, items numbered 47 − 53 that deal with symptoms and side effects 
not relevant to the population under study, will be removed.  These seven items 
addressed symptoms experienced by metastatic breast cancer patients and those 
undergoing radiation.  Therefore, in consultation with the EORTC, these items were 
deleted, as the validity of the measure would not be compromised by their removal.  In 
addition, as “oral mucositis” and “skin problems” are key symptoms of this therapy not 
assessed by currently available tools, validated items from the EORTC item bank were 
added to assess the presence and bothersomeness of oral mucositis (2 items:  sore 
mouth/tongue, difficulty swallowing) and skin problems (2 items).  Data analysis will be 
performed on the final modified BR23 data set in parallel with the final data analysis to 
assess the psychometric properties of the modified instrument and will be reported along 
with the clinical trial results.  Scale scores can be obtained for each of the multi-item and 
single-item scales by using a linear transformation for standardization of the calculated 
raw score. 
The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient.  Patients must 
complete these instruments in the clinic (cannot be taken home) prior to any healthcare 
provider interactions (i.e., prior to administration of study drug and prior to any other 
study assessment) to ensure that the validity of the instruments are not compromised 
and to ensure that data quality meet regulatory requirements. 
Refer to Appendix 4 for the EORTC QLQ-C30 and the modified QLQ-BR23. 
4.5.13 
Samples for Clinical Repository 
All residual samples (or leftover biologic samples after protocol-defined studies are 
completed) obtained during the study (FFPE, fresh-frozen, plasma, etc.) will be stored in 
an academic central repository.  The specimens in the study repository will be made 
available for future biomarker research towards further understanding of treatment with 
GDC-0032, of breast cancer, related diseases, and adverse events, and for the 
development of potential, associated diagnostic assays.  The implementation of study 
repository specimens is governed by the Study Steering Committee, with guidance from 
a dedicated Translational Research Committee to ensure the appropriate use of the 
study specimens. 
All biomarker specimens will be retained for new research related to this study and/or 
disease in accordance with the recommendations and approval of the Study Steering 


 
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Committee.  Samples will be only destroyed if required by local laws relating to the 
collection, storage, and destruction of biological specimens. 
Specimens will be stored up to 15 years or until they are exhausted.  The storage period 
will be in accordance with the institutional review board/ethics committee 
(IRB/EC)-approved ICF and applicable laws (e.g., health authority requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.13.1 
Confidentiality 
Patient medical information associated with biologic specimens is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless 
permitted or required by law. 
Data derived from biologic specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using biologic specimens will be available 
in accordance with the effective Translational Reseach Committee policy on study data 
publication. 
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 
 
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. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 


 
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• 
Disease progression 
• 
Unacceptable toxicity 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Conditions for Terminating the Study 
Both the Sponsor and the investigator reserve the right to terminate their participation in 
the study under the circumstances agreed upon in the site agreement.  Should this be 
necessary, both parties will arrange the procedures on an individual basis after review 
and consultation.  In terminating the study, the Sponsor and investigator will assure that 
adequate consideration is given to the protection of the patients’ interest. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
GDC-0032 is not approved and is currently in early clinical development.  Thus, the 
entire safety profile is not known at this time.  Human experience is currently limited.  
The following information is based on results from ongoing clinical studies.  The safety 
plan for this study is designed to ensure patient safety and will include specific eligibility 
criteria and monitoring assessments as detailed below.  
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events, and laboratory abnormalities (see Section 5.3.5.3), defined 
and graded according to NCI CTCAE v4.0.  General safety assessments will include 
serial interval histories, physical examinations, and specific laboratory studies, including 
serum chemistry and blood counts.  All serious adverse events and non-serious adverse 
events of special interest will be reported in an expedited fashion, via fax to Austrian 
Breast and Colorectal Cancer Study Group (ABCSG) safety department and also 
captured in the electronic data capture (EDC) system.  In addition, the Sponsor and the 
investigators will review and evaluate observed adverse events on a regular basis. 
All adverse events will be recorded during the trial and for 30 days after the last dose of 
study treatment or until the end of study visit, whichever occurs later.  Patients who have 
an ongoing study treatment-related adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the adverse event. 
All adverse events should be attributed by the investigator to study drug or to another 
clearly identified etiology by the investigator (see Table 10).  


 
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Specific potential safety issues anticipated in this trial, as well as measures intended to 
avoid, minimize, and manage such toxicities, are outlined in the following sections. 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study. 
5.1.1 
Management of Specific Adverse Events of GDC-0032  
Guidelines for management of specific adverse events are outlined in Table 1.  
Additional guidelines are provided in the subsections below.  
Due to the approximately 40-hour half-life for GDC-0032, investigators should consider 
holding GDC-0032 for certain Grade 2 toxicities until the adverse event resolves to 
Grade ≤ 1 as discussed below (e.g., stomatitis/mucositis, colitis, rash, diarrhea, 
pneumonitis).  Certain toxicities can occur within 1−2 weeks of holding or discontinuing 
GDC-0032 drug (e.g., pneumonitis, colitis, rash).  In these cases, the adverse event 
eventually resolves.  Investigators should follow management guidelines and dose 
modifications for toxicities as described below, including administration of topical or 
systemic corticosteroids as appropriate.   
Table 1 Overall Dose Modification Guideline for GDC − 0032-Related 
Adverse Events 
 
GDC-0032 
Starting dose 
6 mg at 5 days on / 2 days off 
First reduction 
3 mg at 5 days on / 2 days off  
Second reduction  
3 mg at 3 days on / 4 days off a 
 a If the patient continues to experience specified drug-related adverse 
events after the second dose reduction, the treatment should be 
discontinued. 
 
5.1.1.1 
Management of Hyperglycemia 
Hyperglycemia has been observed in patients who received GDC-0032 in the single-
agent Phase I study.   
Patients with diabetes requiring daily anti-hyperglycemic medication or who have a 
fasting blood glucose level > 125 mg/dL will be excluded from the study.  HbA1c and 
fasting glucose levels will be monitored at baseline, and additional monitoring of fasting 
glucose levels during the study will be implemented, as outlined in the schedule of 
assessments.  Patients should be instructed to report symptoms associated with 
hyperglycemia such as thirst, frequent urination, and blurred vision. 
Metformin is the first antihyperglycemic medication of choice because of the lower risk of 
hypoglycemia with this agent.  Because metformin in some patients may also cause 
diarrhea and not be well tolerated, other antihyperglycemic medications such as 
sulfonylureas (e.g., glimepiride, glipizide) can be used.  Extra caution should be used 


 
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with other drugs such as sulfonylureas because of the increased risk for hypoglycemia 
with these agents.  Consultation with an endocrinologist can be helpful in managing 
hyperglycemia.   
Specific dose modification and management guidelines for hyperglycemia are provided 
in Table 2. 
Table 2 
Dose Modification and Management Guidelines for 
Hyperglycemia (Based on Fasting Blood Glucose) 
Grade 
Dose Modification and Management Guidelines for Hyperglycemia 
(based on fasting blood glucose) 
Grade 2 
Initiation of an anti-hyperglycemic agent (e.g., metformin) and 
additional glucose monitoring will be implemented.   
Dosing with GDC-0032 may either be held or continued per 
investigator evaluation. 
Grade 3  
(asymptomatic) 
GDC-0032 dosing will be suspended and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of an anti-hyperglycemic therapy (e.g., metformin).   
If the hyperglycemic event does not improve to Grade ≤  1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 
Grade 3  
(symptomatic) a, 
Grade 3 
(requiring 
hospitalization),  
or Grade 4 
GDC-0032 dosing will be suspended, and the patient will be 
managed as per standard of care, including implementation of 
additional glucose monitoring and initiation of, or an increase in, the 
dose of anti-hyperglycemic therapy.   
If the hyperglycemic event does not improve to Grade ≤ 1 within 
28 days, GDC-0032 will be permanently discontinued.   
If the hyperglycemic event improves to Grade ≤ 1 within 28 days, 
GDC-0032 dosing may resume at one dose level lower, with 
approval by the Medical Monitor. 
a For example, blurred vision, frequent urination, excessive thirst. 
 
5.1.1.2 
Management of Pneumonitis 
Patients who require any daily supplemental oxygen are not eligible for the study.  
Patients will be assessed for pulmonary signs and symptoms throughout the study.  
Management guidelines for patients with possible pneumonitis are listed in Table 3. 


 
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Table 3 
Dose Modification and Management Guidelines for Pneumonitis 
Grade
Intervention 
Investigations 
GDC-0032 a  
Dose Adjustment 
1 
No specific therapy 
required. 
CT scan.  Consider PFTs b 
Repeat CT scan every 
8 weeks until return to 
baseline. 
No change. 
2 
Symptomatic only.  
Prescribe 
corticosteroids if cough 
is troublesome. 
CT scan.  Repeat CT scan 
every 4 weeks until return 
to baseline.  Consider PFTs 
and bronchoscopy. 
Reduce dose until improvement 
to Grade ≤ 1; consider 
interruption if symptoms are 
troublesome. 
Interrupt treatment as long as 
corticosteroids are being given. 
Restart GDC-0032 at the same 
dose if clinical benefit evident.  
Consider restarting at reduced 
dose if recurrent event or per 
discussion with Medical Monitor. 
Discontinue treatment if recovery 
to Grade ≤ 1 is not evident within 
28 days. 
3 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
every 4 weeks until return 
to baseline.  Consider 
PFTs. Bronchoscopy is 
recommended. 
Interrupt treatment until 
improvement to Grade ≤ 1. 
Restart therapy within 28 days at 
a reduced dose if clinical benefit 
is evident. 
Interrupt treatment as long as 
corticosteroids are being given. 
4 
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  Taper as 
clinically indicated. 
CT scan.  Repeat CT scan 
every 4 weeks until return 
to baseline.  Consider 
PFTs. Bronchoscopy is 
recommended. 
Discontinue treatment. 
Table modified from White et al. 2010 [65].  
CT = computed tomography; PFT = pulmonary function test. 
PFTs include tests for diffusion capacity for carbon monoxide and room air oxygen saturation at 
rest (pulse oximetry).   
a Dose reductions per Section 5.1.1. 
b PFTs may be useful to monitor the effect of interventions such as dose 
reduction/discontinuation and corticosteroids, in conjunction with imaging (White et al. 2010 
[65]). 
 
5.1.1.3 
Management of Rash 
Rash and other dermatological events should be closely monitored, and patients with 
severe rash should be monitored for associated signs and symptoms such as fever and 
hypotension that may be suggestive of a systemic hypersensitivity reaction.  For severe 
rash, dosing of GDC-0032 should be interrupted, and patients should be treated with 


 
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supportive therapy per standard of care.  Use of antihistamines, as well as topical or 
systemic corticosteroids, may be considered (see Table 4).   
Table 4 
GDC-0032 Dose Modification and Management Guidelines for 
Rash 
Grade of Rash 
GDC-0032  
Grade 1 
Continue dosing at current dose and monitor for change in severity.  
Consider prescribing topical corticosteroids a 
Grade 2 
Consider holding GDC-0032 or reducing to the next lower dose if 
rash is troublesome.   
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b). 
Grade 3 or 4 
Hold GDC-0032 until Grade ≤ 1. 
Consider treatment with supportive therapy (e.g., topical or oral 
corticosteroids a, b).  
Consider dermatological consultation.  
Consider obtaining photographs of rash if permitted by local 
regulations. 
After rash improves to Grade ≤ 1, restart GDC-0032 at the next 
lower dose upon discussion with Medical Monitor, or permanently 
discontinue. 
AE = adverse event. 
AE grading is based on NCI CTCAE, Version 4.0. 
a Suggested topical steroids include hydrocortisone 2.5% to face twice daily, 
triamcinolone 0.1%, or fluocinonide 0.1% cream to body twice daily. 
b Suggested oral steroids include a methylprednisolone dose pack or prednisone 
60 mg daily followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, 
etc.). 
 
 
5.1.1.4 
Management of Gastrointestinal Toxicity 
5.1.1.4.1 
Management of Diarrhea 
Patients should be closely monitored for gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhea, abdominal pain, stomatitis, and changes in stool, including checking 
for blood in stool if clinically indicated).  Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is mild.  Gastrointestinal symptoms should 
be managed per protocol guidelines and institutional standard of care.  For example, 
prompt management of diarrhea with antidiarrheal medications should be implemented.  
Because of the approximately 40-hour half-life of GDC-0032, investigators should hold 
GDC-0032 for Grade ≥ 2 diarrhea until it improves to Grade ≤ 1.   
Specific dose modification and management guidelines for diarrhea are provided in 
Table 5.  


 
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Table 5 GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea 
Grade of Diarrhea 
Dose Modification and Management Guidelines  
Grade 1 
• Manage per institutional standard of care that includes 
antidiarrheals. a 
Grade 2 
• Hold GDC-0032 and manage per institutional standard of care 
until Grade  ≤ 1.  These include antidiarrheals. a 
• For persistent Grade 2 non-infectious diarrhea despite treatment 
with antidiarrheals, additional coadministration of corticosteroids 
(e.g., budesonide 9 mg PO QD) are recommended. b  Non-
infectious diarrhea can be diagnosed by stool culture. 
• For persistent Grade 2 diarrhea lasting longer than 1 week with 
an adequate trial of anti-diarrheal medications, or for recurrent 
Grade 2 diarrhea, restarting at the next lower dose level should 
be strongly considered after diarrhea improves to Grade  ≤  1.  
• If Grade 2 diarrhea is persistent despite treatment with SOC, 
consider work-up for colitis (e.g., performing abdominal/pelvis CT 
and/or endoscopy, and stool culture as appropriate).   
Grade 3 or 4 
• Hold GDC-0032 and manage per institutional standard of care 
until Grade  ≤ 1. These include antidiarrheals. a   
• Consider work-up for colitis (e.g., performing abdominal/pelvis 
CT and/or endoscopy, and stool culture as appropriate). 
• Restart GDC-0032 at the next lower dose level upon resolution 
to Grade ≤ 1. 
• For persistent Grade 3 − 4 non-infectious diarrhea despite 
treatment with antidiarrheals, administration of systemic 
corticosteroids should be considered. b 
• For Grade 3 diarrhea, may consider restarting at the same dose 
if event occurred because of lack of optimal medical 
management with antidiarrheal medications, after discussion with 
and approval by the medical monitor.   
• For Grade 4 diarrhea, consider permanent discontinuation of 
GDC-0032. 
CT = computed tomography; PO = oral; QD = once daily; SOC = standard of care. 
a Suggested antidiarrheals include the following: loperamide (initial: 4 mg, followed by 
2 mg after each loose stool, up to 16 mg/day); diphenoxylate and atropine 
(Diphenoxylate 5 mg 4 times/day until control achieved [maximum:  20 mg/day], then 
reduce dose as needed; some patients may be controlled on doses of 5 mg/day; tincture 
of opium (6 mg of undiluted opium tincture [10 mg/mL]) 4 times daily. 
b Examples of corticosteroid regimens include the following:  For the steroid taper, 
suggested steroids include a methylprednisolone dose pack or prednisone 60 mg daily 
followed by a taper (e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, etc.).  Can also 
consider budesonide 9 mg PO QD or prednisone 5 mg to 10 mg PO QD. 
 
 


 
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5.1.1.4.2 
Management of Colitis 
Data as of October 2013 show an incidence rate for colitis of 6.2% (10/160) (1 at 16 mg; 
8 at 9 mg; 1 at 6 mg + fulvestrant) with onset at approximately 100 days or longer after 
initiation of treatment with daily GDC-0032 dosing.  Some patients have developed 
Grade 2 or Grade 3 diarrhea, which is non-responsive to anti-diarrheal medication.  In 
some of these patients, a CT scan or colonoscopy has revealed colitis, which has 
resolved upon treatment with systemic corticosteroids. 
For persistent Grade 2 diarrhea that does not resolve or for Grade ≥ 3 diarrhea, further 
evaluation should include colitis in the differential diagnosis with the appropriate work-up 
(e.g., abdominal/ pelvis CT scan, endoscopy with biopsy, stool cultures for 
cytomegalovirus, Clostridium difficile, and parasites).  Grade ≥ 2 colitis should be 
managed by interruption of study treatment.  In addition, discontinuation of nonsteroidal 
anti-inflammatory medications or any other medications known to exacerbate colitis 
symptoms should be considered.  If noninfectious colitis is suspected, treatment with 
corticosteroids per institutional standard of care should be considered.  It is suggested 
that prednisone (for oral administration) or solumedrol (for IV administration) are the 
corticosteroids of choice in the treatment of colitis.  For severe symptoms, prednisone 
60 mg or equivalent may be required to control initial symptoms, and the dose should be 
gradually tapered.  Lower doses of prednisone, oral budesonide, or mesalamine 
(or other 5-aminosalicyclic acid derivatives) may be considered for less severe cases of 
colitis. 
Specific dose modification and management guidelines for colitis are provided in Table 6.  


 
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Table 6 GDC-0032 Dose Modification and Management Guidelines 
for Colitis 
Grade of Colitis 
Dose Modification and Management Guidelines  
Grade 2 or Grade 3 
(first event) 
• 
Hold GDC-0032 and manage per institutional standard of 
care until Grade ≤ 1.   
• 
Initiate corticosteroid therapy for noninfectious colitis. a 
• 
Recommend discontinuation of any nonsteroidal anti-
inflammatory medications or any other medications known 
to exacerbate colitis symptoms. 
• 
Restart GDC-0032 at the next lower dose level upon 
resolution to Grade ≤ 1.  In cases where risk/benefit is 
deemed favorable, may consider restarting at the same 
dose after discussion with and approval by the Medical 
Monitor. 
Grade 3 (first 
recurrence) 
• 
Hold GDC-0032. 
• 
Initiate corticosteroid therapy for noninfectious colitis. a   
• 
Permanently discontinue GDC-0032.  In cases where 
risk/benefit is deemed favorable, may consider restarting at 
the next lower dose level upon resolution to Grade ≤ 1 after 
discussion with and approval by the Medical Monitor.   
Grade 3 (second 
recurrence) or Grade 4 
• 
Permanently discontinue GDC-0032. 
• 
Initiate corticosteroid therapy for noninfectious colitis. a 
a Examples of corticosteroid regimens include the following:  For the steroid taper, suggested 
steroids include methylprednisolone dose pack or prednisone 60 mg daily followed by a taper 
(e.g., 60 mg × 2 days, 40 mg × 2 days, 20 mg × 2 days, etc.). 
 
5.1.1.4.3 
Management of Stomatitis and Oral Mucositis 
Aggressive mouth care for oral mucositis and stomatitis with mouthwash formulations 
(e.g., combinations of local anesthetic, antihistamine, corticosteroid, antacid, antifungal 
and/or antibiotics) may also be helpful in managing symptoms, and it is recommended 
that these are implemented with early signs of dry mouth, Grade 1 mucositis, or Grade 1 
stomatitis (see Table 7).  Avoidance of spicy foods may also be helpful.   


 
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Table 7 GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis 
Grade of 
Stomatitis/Mucositis 
GDC-0032  
All grades 
• 
Aggressive mouth care that includes mouthwash 
formulations (e.g., combinations of local anesthetic, 
antihistamine, corticosteroid, antacid, antifungal and/or 
antibiotics)  
• 
Diet management (e.g., avoidance of spicy foods) 
Grade 1 
• 
Monitor symptoms and initiate management (see above). 
Re-evaluate within 48 − 72 hours.   
Grade 2 
• 
Hold GDC-0032 and manage until Grade ≤ 1.   
• 
Restart GDC-0032 at the same dose.   
• 
If Grade 2 stomatitis/oral mucositis recurs, hold GDC-0032 
until Grade ≤ 1.  Restart GDC-0032 at the next lower dose. 
Grade 3 or 4 
• 
Hold GDC-0032 and manage until Grade ≤ 1.  Restart 
GDC-0032 at the next lower dose.  
• 
For Grade 3 event that was not adequately managed upon 
initial presentation, consider restarting at same dose upon 
discussion with Medical Monitor.   
• 
For Grade 4 event, consider permanent discontinuation of 
GDC-0032. 
  
5.1.2 
Management of Other Clinically Significant Adverse Events 
See Table 8 for the dose modifications for other clinically significant adverse events. 
Table 8 
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events 
Grade 
GDC-0032  
Grade 3:  first event 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Consider restarting at next lower dose. 
Grade 3:  recurrent 
Grade 4:  non-life-threatening 
• 
Hold GDC-0032 until Grade ≤ 1.  
• 
Restart at next lower dose. 
Grade 4:  life-threatening 
• 
Permanently discontinue GDC-0032.  
 
5.1.3 
General Guidance for Dose Modifications and Delays for 
Letrozole 
The letrozole dose level cannot be modified.  In general, the investigator can consider 
continuing letrozole if it is not thought to be letrozole-related.   
All dose modifications should be based on the adverse event requiring the greatest 
modification and should be properly documented in the source documents. 


 
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5.1.4 
Management of Increases in QT Interval  
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
1. 
Sustained (at least two ECG measurements  > 30 minutes apart) QTcF that 
is  > 500 msec and  > 60 msec longer than the baseline value 
2. 
Sustained absolute QTcF that is  > 515 msec  
3. 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, as this represents an increase in 
QTcF unrelated to alterations in repolarization.  Also of note, it is not uncommon to 
record arrhythmias such as non-sustained ventricular tachycardia, supraventricular 
tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving placebo during 
periods of extended ECG monitoring.  Therefore, it is critical that expert 
electrophysiologic advice be sought to confirm any ECG changes and to ascertain the 
likelihood of a drug-induced arrhythmia versus the background occurrence of this 
arrhythmia.  In such a situation, saving all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients. 
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied. 
5.1.5 
Safety Monitoring for Letrozole 
Letrozole is a nonsteroidal AI indicated for first line treatment of hormone receptor 
positive, locally advanced, or metastatic breast cancer in postmenopausal women.  
Letrozole is also indicated for adjuvant treatment in postmenopausal hormone-receptor 
positive patients and for the treatment of advanced breast cancer in postmenopausal 
women with disease progression following anti-estrogen therapy. 
The most frequently reported adverse events in a first line, breast cancer clinical trial 
with letrozole were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea.  
Clinically significant adverse events also include bone effects (osteoporosis and bone 
fractures) and hypercholesterolemia.  Discontinuations for adverse events other than 
progression of tumor occurred in 2% of patients on letrozole.  Refer to the U.S. letrozole 
Package Insert or SmPC for additional information.   


 
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There are no expected significant overlapping toxicities between letrozole and 
GDC-0032. Routine safety monitoring and periodic laboratory tests for the letrozole and 
GDC-0032 combination will occur throughout the study. 
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; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and 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 ABCSG) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (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 ABCSG safety 
department 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 ABCSG)  
Non-serious adverse events of special interest are required to be reported by the 
investigator to ABCSG safety department 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: 
• 
Grade 4 hyperglycemia 
• 
Grade  ≥  3 symptomatic hyperglycemia 
• 
Grade  ≥  2 colitis or enterocolitis  
• 
Grade ≥ 3 diarrhea 
• 
Grade  ≥  3 rash 
• 
Grade  ≥  2 pneumonitis  


 
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• 
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 5.3.5.5) 
• 
Suspected transmission of an infectious agent by the study drug  
 
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 additionally reported to ABCSG 
safety department in case they fulfill the criteria for expedited reported in accordance 
with instructions provided in this section and in Section 5.4 −Section 5.6. 
For each adverse event recorded on the Adverse Event CRF, 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 
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 until the end of 
study visit, whichever occurs later.  After this period, investigators should report any 
deaths, serious adverse events, or other adverse events of concern deemed related to 
prior study drug treatment or study procedures (Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v 4.0) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 9 
Adverse Event Severity Grading Scale 
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 (v 4.0), 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 one's self, 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 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 10): 
• 
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 (where 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 
 


 
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Table 10 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 
Adverse events will be considered related, unless they fulfill the criteria as 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. 
If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


 
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5.3.5.1 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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. 
5.3.5.2 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The progression (increase and decrease) of an adverse 
event must be documented in the Adverse Event eCRF.   
The initial severity of the event should be recorded, and the severity should be updated 
to reflect the most extreme severity any time the event worsens. If the event becomes 
serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.3 
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: 
• 
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 
• 
Clinically significant in the investigator’s judgment 
 


 
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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 times the 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 
5.3.5.4 
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: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens or improves. 


 
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5.3.5.5 
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 ABCSG safety department immediately (i.e., no more than 24 hours 
after learning of the event), either as serious adverse event or a non-serious adverse 
event of special interest (see Section 5.4.2). 
5.3.5.6 
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 ABCSG safety department 
(see Section 5.4.2). This includes death attributed to progression of breast cancer. 
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 only be used 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 of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive 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. 
5.3.5.7 
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 CRF. 
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”). 


 
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5.3.5.8 
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: 
• 
Perform an efficacy measurement for the study 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol for breast cancer surgery  
• 
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 suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
• 
Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care 
• 
Hospitalization for protocol mandated biopsies 
 
5.3.5.9 
Adverse Events Associated with an Overdose 
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 serious 
criteria, the event should be reported to the ABCSG safety department immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.10 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO ABCSG 
Certain events require immediate reporting to allow ABCSG safety department to take 
appropriate measures to address potential new risks in a clinical trial.  The investigator 
must report such events to ABCSG safety department 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 
ABCSG safety department 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 
ABCSG safety department immediately (i.e., no more than 24 hours after becoming 
aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
U.S. Medical Monitor Contact Information  
Genentech’s Medical Monitor Contact Information: 
Medical Monitor: 
, M.D., Ph.D. 
Telephone No. 
Alternate Telephone No.: 
 
Medical Monitor Contact Information for Sites outside the United States:  
Please refer to the country/region-specific phone numbers provided in the study binder. 


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the paper Serious Adverse Event reporting form and transmit to ABCSG 
safety department via fax. In addition the serious adverse event and non-serious 
adverse event of special interest information will be captured in the EDC system.   
Worldwide Sites: 
ABCSG safety department  
Fax No.: 
+43 1 409 09 90 
Relevant follow-up information should be submitted to ABCSG safety department as 
soon as it becomes available and/or upon request. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification (SDV).  For follow-up reports of serious adverse events and non-serious 
adverse events of special interest, investigators should record all follow up information 
immediately (i.e., within 24 hours) on the paper Serious Adverse Event reporting form 
and transmit to ABCSG safety department via fax. In addition the serious adverse event 
and non-serious adverse event of special interest follow-up information will be captured 
in the EDC system. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF and paper 
Serious Adverse Event form, if applicable.   
All pregnancies reported during the study should be followed until pregnancy outcome, 
and they should be reported according to the instructions provided in Section 5.4. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor and/or ABCSG safety department 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. 


 
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5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator should report these events directly to Genentech Safety Risk 
Management via telephone at 1-888-835-2555. 
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: 
• 
GDC-0032 Investigator's Brochure  
• 
Local prescribing information for letrozole SmPC 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An IDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
Primary and secondary efficacy analyses will include all patients who were included 
in the randomization. Final analysis will be performed after last patient, last visit (LPLV) 
and subsequent data cleaning, with patients allocated to the treatment arm associated 
by randomization. 
Safety analyses will include all patients who were included in the randomization and 
received at least one dose of study treatment, with patients allocated to the treatment 
arm associated with the regimen actually received.  


 
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6.1 
DETERMINATION OF SAMPLE SIZE  
This study is designed for testing the effect of GDC-0032 on the two co-primary 
endpoints in all enrolled patients and in the PIK3CA MT patients and plans to enroll 330 
patients in total. Assuming the PIK3CA mutation status will not be available (unknown) 
for approximately 10% of the patients and the prevalence of PIK3CA mutant is 40%, 
there will be approximately 120 patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, 
there might be a possible imbalance between treatment arms within the PIK3CA MT 
cohort, which may reduce the statistical power in this cohort. To ensure the study 
provides sufficient statistical power even when the treatment assignment is imbalanced, 
the sample size was calculated based on a conservative scenario by assuming that the 
treatment assignment imbalance in PIK3CA MT is 40% vs. 60%. The sample size was 
calculated based on a chi²-test using continuity correction (Ury and Fleiss 1980 [63]). 
To control an overall, two-sided, family-wise error rate under 20%, we use a two-sided 
significance level of 16% and 4% for the co-primary endpoints MRI ORR, and pCR, 
respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 
enrolled patients and 108 patients in the PIK3CA MT cohort will be evaluable for 
analyses. This sample size allows us to detect an absolute percentage increase of 24% 
in MRI ORR rate in the GDC-0032 plus letrozole arm (64%) versus the letrozole-only 
arm (40%; Smith et al. 2005 [59]; Ellis and Ma 2007 [21]) in the PIK3CA MT cohort at 
80% power and 16% two-sided significance level.  The minimal detectable difference for 
ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled 
patients and 120 in the PIK3CA MT cohort), this sample size provides 80% power to 
detect an absolute percentage increase of 18% in pCR in the GDC-0032 plus letrozole 
arm (19%) versus the letrozole-only arm (1%, Smith et al. 2005 [59]; Ellis and Ma 2007 
[21]) in the PIK3CA MT cohort at the 4% two-sided significance level.  The minimal 
detectable difference for pCR rate is approximately 13%. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more 
substantial treatment assignment imbalance in the PIK3CA MT cohort than assumed, or 
there is an increased number of unevaluable patients for the MRI ORR, the sample size 
may be increased to obtain the level of power at 80%, and the enrollment may be limited 
to patients with PIK3CA MT.   
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 incidence of study treatment 
discontinuation for reasons other than disease progression will be tabulated. 


 
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6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized by treatment arm. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the ITT population; that is, all 
randomized patients will be included in the analyses, with patients grouped according to 
the treatment assigned at randomization.  
6.4.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are (1) tumor ORR, assessed by modified RECIST 
criteria by breast MRI and (2) the rate of pCR in breast and axilla (total pCR) after 
completion of study drug. 
The tumor ORR will be calculated by treatment arm in all enrolled population and in 
PIK3CA MT population. Within each population, the ORR for the two treatment arms will 
be compared at a two-sided alpha of 16% using a Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status. The pCR rate will also be calculated and 
compared at a two-sided alpha of 4% based on the same analytical approach as ORR. 
The two alpha values account for a family-wise type I error rate of 20%. Patients with 
early study termination and hence missing efficacy outcome will be considered as non-
responders. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Tumor ORR after completion of study treatment, assessed by modified RECIST 
criteria by breast MRI in PIK3CA WT patients. 
• 
Rate of pCR in breast and axilla (total pCR) after completion of study drug in 
PIK3CA WT patients.  
These endpoint measures will be summarized by treatment arm and will be analyzed 
analogue to the primary efficacy endpoint. 
The following secondary efficacy endpoints will be performed in all enrolled patients and 
separated by PIK3CA mutation status: 
• 
ORR by clinical breast examination, mammography, and breast ultrasound 
• 
Ki67 values at baseline, Week 3, and surgery (centrally assessed) 
• 
Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to 
surgery (centrally assessed) 
• 
PEPI score (centrally assessed) 
• 
Change in enhancing tumor volume from baseline to surgery as measured by breast 
MRI 


 
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• 
Evaluation of different definitions of pCR including the following:  a) ypT0, ypN0, and 
b) ypT0/is, ypNX (breast pCR) 
These endpoint measures will be summarized by treatment arm and will be compared 
between the two treatment arms within each population based on appropriate statistical 
analyses:  ORR will be compared using a Cochrane Mantel-Haenszel test, stratified by 
tumor size and nodal status; PEPI, Ki67, and tumor volume change will be compared by 
regression analyses, adjusted for tumor size and nodal status. All secondary endpoints 
will be tested at a two-sided type I error of 5%. 
More details of the analyses will be provided in the Statistical Analysis Plan (SAP). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all patients who received at least one dose of study 
treatment, with patients allocated to the treatment arm associated with the regimen 
actually received.  
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and letrozole and GDC-0032 exposure. 
Verbatim descriptions of adverse events will be mapped to thesaurus terms.  Adverse 
event data will be listed by study site, treatment arm, patient number, and study day, 
severity, relationship to study drug, outcome, and action taken with the study treatments.  
Events occurring on or after treatment on Day 1 of Week 1 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 and vital sign (heart rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE v4.0 Grade 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized in tables by NCI 
CTCAE v4.0 grade. 
6.6 
PHARMACODYNAMIC ANALYSES  
Ki67 biomarker analyses will include patients with at least one predose and one 
postdose biomarker assessment, with patients grouped according to the treatment 
actually received.  
6.7 
PHARMACOKINETIC ANALYSES  
Individual Cmax and trough plasma concentrations (Cmin) of GDC-0032 and letrozole from 
all patients enrolled will be reported. Mean of trough plasma concentrations of GDC-
0032 and letrozole will be tabulated. The population pharmacokinetics of letrozole and 
GDC-0032 in this study will be compared with historical single-agent pharmacokinetics 
to assess the potential DDI between GDC-0032 and letrozole in this population.   


 
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Additional PK analyses on metabolites of GDC-0032, letrozole, and/or other concomitant 
medications may be conducted as appropriate. 
6.8 
PATIENT-REPORTED OUTCOME ANALYSES 
Patient-reported outcomes of breast cancer symptoms, patient functioning, and HRQoL 
will be assessed by the EORTC QLQ-C30 and the modified Breast Cancer module 
(QLQ-BR23)  
Summary statistics (mean, standard deviation, median and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire, and the modified QLQ-BR23 according to the EORTC scoring manual 
guidelines for each assessment time point. The mean change of the linear transformed 
scores from baseline (and 95% CI using the normal approximation) will also be 
assessed. Line charts depicting the mean changes (and standard errors) of items and 
subscales over time will be provided for each treatment arm from the baseline 
assessment. 
Data analysis will be performed on the final modified BR23 data set in parallel with the 
final data analysis to assess the psychometric properties of the modified instrument and 
will be reported along with the clinical trial results.  
Completion and compliance rates will be summarized at each timepoint by treatment 
arm with reasons for missing data. Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses. The number and 
proportion of patients who improved, worsened, or remained stable for all of the 
symptom and functional domains, global QoL, and single items of the EORTC QLQ-C30 
and QLQ-BR23 will be summarized. 
6.9 
EXPLORATORY ANALYSES  
Additional details on analyses will be specified in the SAP. 
6.10 
INTERIM ANALYSES  
The IDMC will conduct interim analyses to review the unblinded safety data after the first 
20 patients have either 1) finished the 30-day, follow-up visit after the surgery, or 2) been 
on study for 20 weeks after the randomization date (for those who do not receive the 
surgery).  All available information of all enrolled patients with all available assessments 
at the respective timepoint will be included in the interim analyses.  In addition, the IDMC 
or the Medical Monitor may request additional ad hoc meetings of the IDMC at any time 
during the study to review safety data. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
ABCSG will be responsible for data management of this study, including quality checking 
of the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, ABCSG 
and/or all involved clinical research associates (CRAs) will request data clarification from 
the sites, which the sites will resolve electronically in the EDC system. 
ABCSG will produce a Data Management Plan that describes the quality checking to be 
performed on the data. The Sponsor will perform oversight of the data management of 
this study, including review of the ABCSG’s data management plan and corresponding 
specifications.  Data will be transferred electronically from ABCSG to the Sponsor at the 
end of the study and whenever otherwise contractually agreed, and the Sponsor’s 
standard procedures will be used 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 at ABCSG and records retention for the study data will 
be consistent with the ABCSG’s standard procedures. 
Data from paper PRO questionnaires will be entered into the EDC system by site staff. 
Original PRO questionnaires will be kept in the patient’s medical record as source 
documentation. 
7.2 
DATA(BASE) MANAGEMENT 
ABCSG Clinical Data Management will check all e-forms for plausibility and consistency 
by automatic edit checks and manual data review according to study-specific data 
management plan (DMP).  If necessary, web-based data queries (data clarification 
requests [DCRs]) will be generated and subsequently visible for the investigators, 
dedicated site staff, responsible CRAs, and responsible ABCSG staff.  For those eCRFs 
which pass all verification procedures and are regarded as correct and complete, they 
will be frozen subsequently by ABCSG clinical data management. Consequently, no 
further data entries or changes on frozen eCRFs are possible. The status of frozen 
eCRFs is flagged by the specific icon. 
Clinical Data Management ensures that the database is corrected for the following eCRF 
issues without immediate notification to site staff (self-evident corrections). Notification of 
site staff is provided via a specific report after final data cleaning procedures and before 
final data confirmation by the investigator or a designee: 
• 
misspellings/typing errors that do not change the meaning of the word 
• 
location of data recorded at an incorrect variable field or eForm (e.g., moving lab 
data from general comments to the appropriate lab table) 


 
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• 
standard time to 24-hour clock 
• 
correction of date format, if required (dd/mm/yyyy) 
• 
if equivalent units of terms are recorded instead of the acceptable ABCSG standard 
• 
data changes due to plausibility checks and eCRF content (e.g., combination of 
several variables and/or eCRFs) 
All data management workflows are described in detail in the relevant SOPs and 
working instructions of ABCSG. 
7.3 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using the Clinical Data Management System “MACRO,” a 
web-interface DATAPORT.  Sites will receive training by the responsible CRAs and have 
access to a manual for appropriate eCRF completion (web data entry).   
All eCRFs should be completed by designated, trained site staff in a timely manner, 
usually within 2 weeks after the patient visit.  Electronic CRFs should be reviewed and 
respective data confirmation eCRF should be electronically signed and dated by the 
investigator or a designee at the end of the study.  
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a storage medium (compact disc [CD], digital video disk [DVD] etc.) 
that must be kept with the study records. Acknowledgement of receipt of the storage 
medium is required. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors (CRAs) will perform ongoing SDV 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 
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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 7.6. 
To facilitate SDV, the investigators and institutions must provide the Sponsor/CRAs 
direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review. The investigational site must also allow inspection 
by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data (if applicable), ICFs, 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 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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 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/European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC). 


 
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8.2 
INFORMED CONSENT 
The Sponsor’s sample ICF (and ancillary sample ICFs) 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 ICFs 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. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  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 separate, specific 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 provide a 
separate signature. 
The ICFs must be signed and dated by the patient or the patient’s legally 
authorized representative before 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 eCRF contains a section to document whether the patient has signed the ICF or not. 
The ICFs 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. 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion. After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood. The investigator or designee must also explain that the patients are 


 
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completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason. 
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated ICFs 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 ICF 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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the sponsor, the affiliated 
groups, or contract research organizations (CROs) according to the applicable local laws 
and regulations, if applicable 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 Sponsor, affiliated groups, or CROs are 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 local IRB/EC. The 
Sponsor, affiliated groups, or CROs 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 local 
health authority requirements and the policies and procedures established by their 
IRB/EC, and archived in the site’s study file.  
8.4 
DATA PRIVACY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique 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 only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use and 


 
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disclosure of personal health information) signed by the patient, unless permitted or 
required by local 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, provided 
the patient has given consent. 
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. The patient will have to consent to such access by signing the informed 
consent form. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (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, ICFs, and documentation of IRB/EC and governmental (health authorities) 
approval. In addition, at the end of the study, the investigator will receive the patient data, 
which includes an audit trail containing a complete record of all changes to data. 
9.2 
ON SITE QUALITY CONTROL (MONITORING) 
During the study, CRAs will visit their respective sites on a regular basis as outlined in 
the study specific monitoring plan (MP) and all other relevant specifications, in order to 
guarantee adherence to the protocol and to the principles of GCP and to check for the 
progress of enrolment, adequate storage conditions of IMP and adequate drug 
dispensing and accounting records.  
CRAs will review documented data in the eCRFs for completeness and accuracy 
according to the study-specific MP, subsequently flag all reviewed pages with a specific 
mark (“SDV done”) within the EDC system “MACRO,” web-interface DATAPORT, 
developed by 
.  The CRAs will raise data queries (“DCRs”) in cases of 
missing source data or incorrect data entries. Immediately after electronic issue of the 
queries, they become visible to the investigator, the clinical data managers, and the 
ABCSG clinical safety officers (“raised DCRs”).  CRAs and/or clinical data managers 


 
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and/or ABCSG clinical safety officers will follow up with trial site personnel until final data 
query resolution. 
9.3 
PROTOCOL DEVIATIONS 
The investigator should document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with 
established IRB/EC policies and procedures. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit international and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech and will be managed by Genentech in 
collaboration with the Breast International Group (BIG), ABCSG, and the Spanish Breast 
Cancer Research Group (SOLTI). Genentech in collaboration with BIG, ABCSG, and 
SOLTI will provide clinical operations management, data management, and medical 
monitoring.  Approximately 110 U.S. and international sites will participate to enroll 
approximately 330 patients. 
An IDMC will be in place throughout the study and will provide oversight of safety and 
efficacy analyses (see Section 3.1.2). 
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the IxRS system. Once eligibility has been established, the 
patient will be enrolled, and the study site will obtain the patient’s identification number 
from the IxRS. Once results of the tissue analysis are made available, the patient will be 
randomized, and the site will obtain the blinded treatment assignment from the IxRS.  
The IxRS will manage GDC-0032/placebo drug inventory at all sites and letrozole drug 
inventory at all study sites outside the United States.  IxRS will be required to randomize 
patients, to monitor enrollment and patient status, and to manage study treatment 
requests and shipments.  
Patient data will be recorded via an electronic data capture (EDC) system from 
 
(
, United Kingdom), which will be managed by ABCSG using eCRFs 
(see Section 7.2).   
Central laboratories, including Genentech and Genentech collaborators, will be used for 
PIK3CA mutation detection, Ki67, and PTEN status and/or will provide kits for PK, 
pharmacogenomic, tissue, whole blood, and plasma sample analyses to be conducted at 
central laboratories, Genentech, or Genentech collaborators. 


 
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An independent radiologic review facility will be used for the purpose of collecting and 
assessing the quality of patient scans throughout the trial. The review facility will retain 
copies of scans for centralized assessments of MRI-related endpoints.   
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). 


 
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10. 
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Appendix 1  
Schedule of Assessments 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgical 
Visit) 
W17 − W18
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
57 
(± 2) 
85 
(± 2) 
106 − 112 
113 − 126 
 
Informed consent a 
x 
 
 
 
 
 
 
 
 
Medical history and  
demographic data b 
x 
 
 
 
 
 
 
 
 
Physical examination c 
x 
 
 
x 
x 
x 
x 
 
x 
Clinical breast and regional lymph 
node examination  
x 
x 
 
x 
x 
x 
x 
 
 
Vital signs d 
x 
x 
x 
x 
x 
x 
x 
 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
x 
12-Lead ECG e 
x 
 
x 
 
 
 
 
 
 
Mammography  
x 
 
 
 
 
 
x 
 
 
Breast ultrasound and axillary lymph 
node status f 
x 
 
 
 
x 
 
x 
 
 
Breast MRI g 
x 
 
 
 
 
 
x 
 
 
Collection of tumor samples h  
x 
 
x 
 
 
 
 
x 
 
Confirmation of receipt of adequate 
tissue for PIK3CA assessment 
x 
 
 
 
 
 
 
 
 
CBC with differential and  
platelet count i 
x 
x 
 
x 
x 
x 
x 
 
x 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
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                                                                               115 
Treatment Phase 
Surgery a,f 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgical 
Visit) 
W17 − W18
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
57 
(± 2) 
85 
(± 2) 
106 − 112 
113 − 126 
 
Fasting serum chemistry j 
x 
x 
 
x 
x 
x 
x 
 
x 
Glycosylated hemoglobin (HbA1c) 
x 
 
 
 
 
 
 
 
 
Fasting insulin and glucose k 
x 
x 
 
x 
x 
x 
x 
 
x 
Fasting lipid profile and amylase l 
x 
 
 
x 
 
x 
x 
 
x 
Coagulation (INR and aPTT)  
x 
 
 
x 
x 
x 
x 
 
x 
Urinalysis (laboratory) m 
x 
 
 
x 
x 
 
x 
 
x 
Blood sample for plasma protein 
biomarkers n 
 
x 
 
 
x 
 
x 
 
 
Blood sample for ctDNA o 
 
x 
 
 
x 
 
x 
 
 
Blood sample for NGS p 
 
x 
 
 
 
 
 
 
 
Pharmacogenomic sample q  
 
x 
 
 
 
 
 
 
 
Concomitant medication r 
x 
x 
x 
x 
x 
x 
x 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
 
x 
Inclusion/exclusion criteria s 
x 
 
 
 
 
 
 
 
 
Visit with breast surgeon (may occur 
from Week 13) 
 
 
 
 
 
x 
 
 
 
Surgery t 
 
 
 
 
 
 
 
x 
 
Randomization  
x 
 
 
 
 
 
 
 
 
Letrozole accountability/dispensation 
 
x 
x 
x 
x 
x 
x 
 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0032—Genentech, Inc. 
Protocol GO28888, Version 1 
                                                                               116 
Treatment Phase 
Surgery a,g 
Post Surgery 
Study procedures 
Screening 
W1 
W3 
W5 
W9 
W13 
W16 
(Presurgical 
Visit) 
W17 − W18
(Surgery) 
4 Weeks (+1W) 
from Surgery 
Days 
-28 to -1 
1 
15 
(+ 2) 
29 
(± 2) 
57 
(± 2) 
85 
(± 2) 
106 − 112 
113 − 126 
 
GDC-0032/placebo accountability/ 
dispensation  
 
x 
x 
x 
x 
x 
x 
 
 
Patient-reported outcomes u 
 
x 
 
x 
x 
x 
x 
 
x 
Pharmacokinetic sample (see 
Appendix 2) 
 
x 
x 
 
x 
 
 
 
 
aPTT = activated partial thromboplastin time; CA-125 = cancer antigen 125; CTCs = circulating tumor cells; ctDNA = circulating tumor DNA; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; INR = international normalized ratio; MRI = magnetic resonance imaging; 
NGS = next-generation sequencing. 
Note:  All assessments should be performed before dosing, unless otherwise stated.  Some assessments may be performed outside the window 
indicated to accommodate holidays, unforeseen scheduling issues, or ongoing safety issues with the trial and the patient, after approval by the 
Medical Monitor. 
a Perform within 28 days prior to Day 1 of Cycle 1.  Signed informed consent must be provided prior to any study-specific evaluations.  Assessments 
performed as standard of care within the timeframe may be used. 
b Medical history includes clinically significant diseases that are currently active or that were active within the last 5 years, surgeries, cancer history 
(including date of diagnosis, primary tumor histology, grade, staging, prior cancer therapies, and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse. Demographic data include age, sex, and self-reported race/ethnicity. 
c A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; 
height is measured at the screening visit only).  Perform symptom-directed physical examination after baseline assessment. 
d Vital signs include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated position 
and temperature. Oxygen saturation is obtained by pulse oximetry after the patient has been in a seated position for ≥ 5 minutes. Obtain vital signs 
predose. 
e Triplicate ECG recordings will be obtained at each specified timepoint.  A window of  ± 30 minutes is acceptable for all timepoints.  Submit all ECGs 
to the diagnostic facility for central review. 
f Baseline evaluation of axillary lymph nodes assessed with ultrasound. 


Appendix 1  
Schedule of Assessments (cont.) 
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g MRI evaluation is optional at Week 9.  MRI is mandatory at Week 9 in the event that disease progression is suspected, or if the primary lesion is 
not evaluable by ultrasound at baseline.  Send all scans to the central reading facility for evaluation. 
h Two formalin-fixed, paraffin-embedded core needle biopsies and one freshly frozen OCT core needle biopsy are required prior to initiation of 
treatment (pretreatment) and also on Day 15.  A formalin-fixed, paraffin-embedded tumor block from a surgical resection is required at surgery 
(Weeks 17 − 18). 
i Complete blood count includes red blood cell count, hemoglobin, hematocrit, white blood cell count with differential (neutrophils, bands, 
eosinophils, basophils, lymphocytes, monocytes, and other cells), and platelet count. Screening results may be valid for Week 1, Day 1 if 
performed within 7 days prior to Week 1, Day 1. 
j Fasting ( ≥ 10-hour fast) serum chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, 
albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT. Screening results may be valid for Week 1, Day 1 if performed within 
7 days prior to Week 1, Day 1. 
k Glucose levels may be obtained by fingerstick. Screening results may be valid for Week 1, Day 1 if performed within 7 days prior to Week 1, Day 1. 
l Fasting lipid profile includes total cholesterol, HDL, LDL, triglycerides, amylase, and lipase. Screening results may be valid for Week 1, Day 1 if 
performed within 7 days prior to Week 1, Day 1. 
m Includes specific gravity, pH, glucose, protein, ketones, and blood. Screening results may be valid for Week 1, Day 1 if performed within 7 days 
prior to Week 1, Day 1. 
n Pretreatment sample for plasma protein biomarkers should be obtained prior to dosing.  Refer to laboratory manual for more information. 
o Pretreatment sample for ctDNA may be obtained on Day 1 prior to dosing.  This sample will also be collected prior to dosing at Week 9 and at 
Week 16.  Refer to laboratory manual for more information. 
p Blood for NGS will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1.   
q Blood for pharmacogenomics will be collected if allowed by local regulatory authorities and may be obtained prior to dosing on Week 1. 
r Record all medications used by the patient within 15 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements). 
s All of the study’s inclusion criteria and none of the exclusion criteria should be met prior to study entry. 
t Surgery will take place after at least 16 weeks of combination treatment (i.e., from Week 17 to Week 18), and generally no more than 2 days after 
the last dose of study medication. 
u The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) will be completed by the patients at the investigational site.  All PRO 
questionnaires must be administered prior to any other study assessment(s) and prior to administration of study drug.  
 
 


 
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Appendix 2  
Schedule of Pharmacokinetic Assessments 
Visit 
Timepoint 
PK Assessments 
Letrozole PK 
Day 1 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
0 − 4 hours prior to letrozole and 
GDC-0032/placebo administration 
GDC-0032 PK 
Letrozole PK 
Day 15 
( + 2 days) 
3 hours ( ± 60 min) post letrozole and 
GDC -0032/placebo administration 
ECG before PK 
GDC-0032 PK 
Day 57 
( + / − 2 days) 
3 hours post ( ± 60 min) letrozole and 
GDC-0032/placebo administration 
Letrozole PK 
GDC-0032 PK 
ECG = electrocardiogram; min = minutes; PK = pharmacokinetics.  
Record exact time of dose administration and sample collection. 
 
 
 


 
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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 
therapy in early breast cancer.  Ultrasound, mammography, and clinical exam are all 
                                            
 
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.) 
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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 
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.   


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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 
 
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. 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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 
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. 


Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors:  
Assessment of Response of Neoadjuvant Therapy in Early 
Breast Cancer (cont.) 
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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.  
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. 


 
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Appendix 4  
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures   
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
____________________ 
Your birthdate (Day, Month, Year): 
____________________ 
Today's date (Day, Month, Year):  
 
____________________ 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to 
which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
31. Did you have a dry mouth? 
1 
2 
3 
4 
 
32. Did food and drink taste different than usual? 
1 
2 
3 
4 
 
33. Were your eyes painful, irritated or watery? 
1 
2 
3 
4 
 
34. Have you lost any hair? 
1 
2 
3 
4 
 
35. Answer this question only if you had any hair loss: 
Were you upset by the loss of your hair? 
1 
2 
3 
4 
 
36. Did you feel ill or unwell? 
1 
2 
3 
4 
 
37. Did you have hot flushes? 
1 
2 
3 
4 
 
38. Did you have headaches? 
1 
2 
3 
4 
 
39. Have you felt physically less attractive 
as a result of your disease or treatment? 
1 
2 
3 
4 
 
40. Have you been feeling less feminine as a 
result of your disease or treatment? 
1 
2 
3 
4 
 
41. Did you find it difficult to look at yourself naked? 
1 
2 
3 
4 
 
42. Have you been dissatisfied with your body? 
1 
2 
3 
4 
 
43. Were you worried about your health in the future? 
1 
2 
3 
4 
 
 
44. Have you had skin problems (e.g. itchy, dry)?  
1 
2 
3 
4 
 
45. Did itching of your skin bother you? 
1 
2 
3 
4 
  46. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
47. Have you had trouble swallowing? 
1 
2 
3 
4 
 
 
 
 
Please go on to the next page 
 


 
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Appendix 4 
EORTC QLQ-Core 30 and Modified EORTC QLQ-BR23 Measures 
(cont.) 
During the past four weeks: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
48. To what extent were you interested in sex? 
1 
2 
3 
4 
 
49. To what extent were you sexually active? 
(with or without intercourse) 
1 
2 
3 
4 
 
50. Answer this question only if you have been sexually 
active: To what extent was sex enjoyable for you? 
1 
2 
3 
4 
 


 
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Appendix 5  
New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients 
NYHA 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation or dyspnea. 
No objective evidence 
of cardiovascular 
disease. 
II 
Mild 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or 
dyspnea 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or 
dyspnea. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical 
activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 


 
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Appendix 6  
American Joint Committee on Cancer TNM Classification of Malignant Tumors 
Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
DCIS 
Tis (LCIS) 
LCIS 
Tis (Paget) 
Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the 
underlying breast parenchyma.  Carcinomas in the breast parenchyma associated with Paget disease are categorized based on 
the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. 
T1 
Tumor  ≤20 mm in greatest dimension 
T1mi 
Tumor  ≤1 mm in greatest dimension 
T1a 
Tumor  >1 mm but  ≤5 mm in greatest dimension 
T1b 
Tumor  >5 mm but  ≤10 mm in greatest dimension 
T1c 
Tumor  >10 mm but  ≤20 mm in greatest dimension 
 
 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Tumor (T) 
T2 
Tumor  >20 mm but  ≤50 mm in greatest dimension 
T3 
Tumor  >50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)a 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for 
inflammatory carcinoma 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp 347−76. 
DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. 
Note: The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both.  Size should 
be measured to the nearest millimeter.  If the tumor size is slightly less than or greater than a cut-off for a given T classification, it is recommended 
that the size be rounded to the millimeter reading that is closest to the cut-off.  For example, a reported size of 1.1 mm is reported as 1 mm, or a 
size of 2.01 cm is reported as 2 cm.  Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was 
determined by clinical (physical examination or radiologic) or pathologic measurements, respectively.  In general, pathologic determination should 
take precedence over clinical determination of T size. 
a Invasion of the dermis alone does not qualify as T4.  


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant Tumors (cont.) 
Regional Lymph Nodes (N) 
Clinical   
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted 
OR 
N2 
Metastases in clinically detected a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures 
N2b Metastases only in clinically detected a ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph 
node metastases 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement 
OR 
Metastases in clinically detected a ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node 
metastases 
OR 
N3 
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Regional Lymph Nodes (N) 
Clinical 
N3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 34776.   
a Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics 
highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination.  
Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) suffix, for 
example, cN3a(f).  Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a 
clinical N, for example, cN1.  Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine 
needle aspiration, core biopsy, or sentinel lymph node biopsy.  Pathologic classification (pN) is used for excision or sentinel lymph node biopsy 
only in conjunction with a pathologic T assignment. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
Note: ITCs are defined as small clusters of cells  ≤ 0.2 mm, or single tumor cells, or a cluster of  < 200 cells in a single histologic cross-section.  
ITCs may be detected by routine histology or by IHC methods.  Nodes containing only ITCs are excluded from the total positive node count for 
purposes of N classification but should be included in the total number of nodes evaluated. 
pN0(i–) 
No regional lymph node metastases histologically, negative IHC 
pN0(i + ) 
Malignant cells in regional lymph node(s)  ≤ 0.2 mm (detected by H&E or IHC including ITC) 
pN0(mol–) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0(mol + ) 
Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC 
Micrometastases 
OR 
Metastases in 1–3 axillary lymph nodes 
AND/OR 
pN1 
Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected a 
pN1mi 
Micrometastases ( >0.2 mm and/or >200 cells but none  > 2 mm) 
pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis  > 2 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but 
not clinically detected a 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected 
Metastases in 4–9 axillary lymph nodes 
OR 
pN2 
Metastases in clinically detected a internal mammary lymph nodes in the absence of axillary lymph node metastases 
pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit  > 2 mm) 
pN2b Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases 
Metastases in  ≥ 10 axillary lymph nodes 
OR 
Metastases in infraclavicular (level III axillary) lymph nodes 
OR 
Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary 
lymph nodes 
OR 
Metastases in  > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
OR 
pN3 
Metastases in ipsilateral supraclavicular lymph nodes 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Pathologic (pN)1 
Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit >2 mm) 
OR 
pN3a 
Metastases to the infraclavicular (level III axillary lymph) nodes. 
Metastases in clinically detected b ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph 
nodes; 
OR 
pN3b 
Metastases in > 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected a 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
Post-treatment ypN  
Post-treatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above.  The modifier "SN" is used only if a sentinel node 
evaluation was performed after treatment.  If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND. 
The X classification will be used (ypNX) if no yp post-treatment SN or AND was performed 
N categories are the same as those used for pN 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse 
transcriptase/polymerase chain reaction. 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
1 Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  Classification based solely on sentinel lymph 
node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).   
a "Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.   
b "Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having 
characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic 
examination.   
 
Distant Metastases (M) 
 
M0 
No clinical or radiographic evidence of distant metastases 
cM0(i + ) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in 
circulating blood, bone marrow, or other non-regional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of 
metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
 
Post-treatment yp M classification.  The M category for patients treated with neoadjuvant therapy is the category assigned in the 
clinical stage, prior to initiation of neoadjuvant therapy.  Identification of distant metastases after the start of therapy in cases where 
pre-therapy evaluation showed no metastases is considered progression of disease.  If a patient was designated to have detectable 
distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout. 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Anatomic Stage/Prognostic Groupsa  
Stage 
T 
N 
Mc 
0 
Tis 
N0 
M0 
IA 
T1c 
N0 
M0 
IB 
T0 
N1mi 
M0 
 
T1c 
N1mi 
M0 
IIA 
T0 
N1b 
M0 
 
T1c 
N1b 
M0 
 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
 
T1c 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 


 
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Appendix 6 
American Joint Committee on Cancer TNM Classification of Malignant (cont.) 
Stage 
T 
N 
Mc 
 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Reprinted with permission from AJCC: Breast.  In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed.  New York, 
NY: Springer, 2010, pp. 347−76.   
Note: Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are 
carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.  
Post-neoadjuvant therapy is designated with "yc" or "yp" prefix.  Of note, no stage group is assigned if there is a complete pathologic response (CR) 
to neoadjuvant therapy, for example, ypT0cM0.   
a T1 includes T1mi.   
b T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.   
c M0 includes M0(i+); The designation pM0 is not valid; any M0 should be clinical.  If a patient presents with M1 prior to NAST, the stage is 
considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.   
 

SAP_001.pdf: 
Document Type:         SAP 
Official Title: 
A Phase II Randomized, Double-Blind Study of Neoadjuvant 
Letrozole Plus GDC-0032 Versus Letrozole plus Placebo in 
Postmenopausal Women with ER-positive/HER2-negative, Early 
Stage Breast Cancer 
NCT Number: 
NCT02273973 
Document Date: 
SAP: 22 Jan 2018 
 
 








ABCSG 
Austrian Breast and Colorectal Cancer Study Group 
Nussdorfer Platz 8/12-13, A-1190 Vienna, Austria 
Phone: +43 (0) 1 408 92 30 / 27, Fax: +43 (0) 1 409 09 90 
ABCSG Statistics 
Confidential 
Page 1 of 31 
ABCSG 38 - Version 3.0 
Compilation Date: 2017-03-15 
 
 
Statistical Analysis Plan 
 
Drug substances: Letrozole, GDC-0032  
Study code: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 
 
 
 
A PHASE II RANDOMIZED, DOUBLE-BLIND STUDY OF NEOADJUVANT 
LETROZOLE PLUS GDC-0032 VERSUS LETROZOLE PLUS PLACEBO IN 
POSTMENOPAUSAL WOMEN WITH ER POSITIVE/HER2-NEGATIVE, EARLY 
STAGE BREAST CANCER  
 
 
Austrian Breast and Colorectal Cancer Study Group 
ABCSG Protocol number 38 
 
 
Compiled/edited by: 
ABCSG 
 
Date  
(dd/mmm/yyyy) 
 
Signature 
 
 
Reviewed by: 
ABCSG 
 
Date 
(dd/mmm/yyyy) 
 
Signature 
 
 
Approved by: 
VHIO 
 
BIG 
 
Date 
(dd/mmm/yyyy) 
 
Date 
(dd/mmm/yyyy) 
 
Signature 
 
Signature 
 
ABCSG 
 
Genentech 
 
Date 
(dd/mmm/yyyy) 
 
Date  
(dd/mmm/yyyy) 
 
Signature 
 
Signature 
 
 
 
Document status / version: 
3.0                       
Release date:  
2017-09-28 
1/22/2018


ABCSG 
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Phone: +43 (0) 1 408 92 30 / 27, Fax: +43 (0) 1 409 09 90 
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Table of contents 
 
 
Glossary of abbreviations ........................................................................................... 4 
1. 
Introduction ...................................................................................................... 6 
2. 
Study details .................................................................................................... 6 
2.1. 
Study objectives ...................................................................................................... 6 
2.1.1. 
Primary objective ................................................................................................ 6 
2.1.2. 
Secondary objectives .......................................................................................... 6 
2.1.3. 
Safety objectives ................................................................................................. 8 
2.1.4. 
Patient-reported outcome objectives .................................................................. 8 
2.1.5. 
Exploratory objectives ........................................................................................ 8 
2.2. 
Study design ............................................................................................................ 9 
2.2.1. 
Surgery .............................................................................................................. 10 
2.2.2. 
Study duration – end of study ........................................................................... 11 
2.3. 
Randomization and stratification criteria .............................................................. 11 
2.3.1. 
Blinding ............................................................................................................ 11 
2.4. 
Number of subjects - sample size estimation ........................................................ 12 
3. 
Statistical methods ......................................................................................... 13 
3.1. 
Data handling conventions .................................................................................... 13 
3.1.1. 
Data entry errors and potential outliers ............................................................ 13 
3.1.2. 
Missing data ...................................................................................................... 13 
3.1.3. 
Stratification errors ........................................................................................... 14 
3.1.4. 
Derived endpoints ............................................................................................. 14 
3.1.5. 
Statistical considerations .................................................................................. 16 
3.2. 
Types and timepoints of analyses .......................................................................... 16 
3.2.1. 
Main analyses ................................................................................................... 16 
3.2.2. 
Independent Data Monitoring Committee analyses ......................................... 17 
3.3. 
Analysis populations ............................................................................................. 17 
3.3.1. 
Intention-to-Treat population ........................................................................... 17 
3.3.2. 
Per-protocol population .................................................................................... 17 
3.3.3. 
Safety population .............................................................................................. 18 
3.4. 
Significance level .................................................................................................. 18 
3.5. 
Patient status .......................................................................................................... 18 
3.5.1. 
Study disposition .............................................................................................. 18 
3.5.2. 
Baseline demographic and disease characteristics ........................................... 18 
3.5.3. 
Important protocol deviations ........................................................................... 18 
3.5.4. 
Treatment disposition and exposure to study drug ........................................... 19 
3.6. 
Primary endpoint evaluation ................................................................................. 19 
3.6.1. 
Primary endpoints ............................................................................................. 19 
3.6.2. 
Analysis for primary endpoints ........................................................................ 20 
3.6.3. 
Sensitivity analysis for primary endpoints ....................................................... 20 
3.7. 
Secondary endpoint evaluation ............................................................................. 20 
3.7.1. 
Secondary endpoints ......................................................................................... 20 
3.7.2. 
Analysis for secondary endpoints ..................................................................... 21 
3.8. 
Safety endpoint evaluation .................................................................................... 21 
3.8.1. 
Safety endpoints ............................................................................................... 21 


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3.8.2. 
AEs and SAEs .................................................................................................. 21 
3.8.3. 
Laboratory data and vital signs ......................................................................... 22 
3.9. 
Patient-reported endpoint evaluation ..................................................................... 22 
3.9.1. 
Patient-reported endpoints ................................................................................ 22 
3.9.2. 
Analysis for patient-reported endpoints ........................................................... 22 
3.10. 
Exploratory endpoint evaluation ........................................................................... 23 
3.10.1. 
Exploratory endpoints ....................................................................................... 23 
3.10.2. 
Analysis for exploratory endpoints ................................................................... 23 
3.11. 
Listings .................................................................................................................. 23 
3.12. 
Covariates .............................................................................................................. 24 
3.13. 
Software ................................................................................................................. 24 
4. 
Changes of analysis compared to study protocol ........................................... 24 
5. 
Addendum to the statistical analysis plan ...................................................... 24 
6. 
References ..................................................................................................... 26 
7. 
Appendices .................................................................................................... 27 
7.1. 
Appendix 1 ............................................................................................................ 27 
 
 


ABCSG 
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Nussdorfer Platz 8/12-13, A-1190 Vienna, Austria 
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Glossary of abbreviations 
Abbreviation 
Definition 
ABCSG 
AJCC 
Austrian Breast and Colorectal Cancer Study Group 
American Joint Committee on Cancer 
AE 
AESI 
BC 
adverse events 
adverse event of special interest 
breast cancer 
BCS 
BTR 
breast conserving surgery 
BioTelemetry Research 
Cmax 
maximum plasma concentration  
Cmin 
minimum concentration under steady-state conditions 
within a dosing interval 
CR 
complete response 
CT 
DLCO 
ECOG 
computed tomography 
Diffusing capacity of the lung for carbon monoxide 
Eastern Cooperative Oncology Group 
EORTC 
 
European Organisation for Research and Treatment of 
Cancer 
EOS 
End of study 
EOT 
End of treatment 
ER 
estrogen receptor  
FNA 
HER2 
fine needle aspiration 
human epidermal growth factor receptor 2  
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
ICH 
Informed Consent Form 
International Conference on Harmonisation of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IDMC 
IP 
IPD 
Independent Data Monitoring Committee 
Investigational product 
Important protocol deviation 
IRF 
Independent Review Facility 
ITT 
Intention-to-treat 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
LoPO 
List of Planned Outputs 
MAPK 
MedDRA 
mitogen-activated protein kinase 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MT 
NCI CTCAE 
mutant 
National Cancer Institute Common Terminology Criteria 


ABCSG 
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Phone: +43 (0) 1 408 92 30 / 27, Fax: +43 (0) 1 409 09 90 
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Abbreviation 
Definition 
 
ND 
NE 
for Adverse Events 
no disease 
not evaluable 
ORR 
objective response rate 
pCR 
pathologic complete response 
PD 
progressive disease 
PEPI 
PgR 
PP 
PR 
PT 
preoperative endocrine prognostic index 
progesterone receptor 
Per-protocol 
partial response 
Preferred Term 
PTEN 
phosphatase tensin homolog 
QD 
once daily 
QLQ-BR23 
Quality of Life Questionnaire Breast Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
SAF 
SAP 
serious adverse event 
Safety 
Statistical Analysis Plan 
SD 
SOC 
TLR 
TSAP 
U/S 
WT 
stable disease 
System Organ Class 
Top Line Results 
Translational Statistical Analysis Plan 
Ultrasound 
Wild type 


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1. Introduction 
This Statistical Analysis Plan (SAP) is based on the Clinical Study Protocol for the ABCSG 
study 38 (external study code: GO28888/BIG-3-13/SOLTI 1205) in its third amended version 
from July 27, 2015) and provides a detailed description of all statistical analyses planned to 
be conducted within this trial at predefined timepoints. 
All analyses described herein are performed in accordance to the guidelines of the 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). 
 
2. Study details 
2.1. 
Study objectives 
2.1.1. 
Primary objective 
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 
versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as 
measured by the following co-primary objectives: 
- 
Tumor overall objective response rate (ORR) by centrally assessed breast magnetic 
resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 (Appendix 1Appendix 1) in all enrolled patients and PIK3CA mutant 
(MT) patients 
- 
pCR rate in breast and axilla (ypT0/Tis, ypN0 as defined in the American Joint 
Committee on Cancer (AJCC) staging system) by local evaluation in all enrolled 
patients and PIK3CA MT patients  
Information on PIK3CA mutation status is assessed centrally. 
2.1.2. 
Secondary objectives 
The secondary efficacy objectives of this study are the following: 
- 
Tumor overall ORR, assessed by centrally assessed breast MRI via modified 
RECIST 1.1 in PIK3CA wild type (WT) patients 
- 
pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA 
WT patients  
The following secondary objectives will be performed in all enrolled patients and separated 
by PIK3CA mutation status: 


ABCSG 
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- 
Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally 
assessed ORR as measured by modified RECIST 1.1 criteria using the following 
methods: 
o Breast ultrasound 
o Clinical breast exam (i.e., palpation) 
o Mammography  
- 
Central assessment of changes in Ki67 levels upon treatment with letrozole plus 
GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to 
surgery; and Week 3 to surgery  
- 
Compare the centrally derived, preoperative endocrine prognostic index (PEPI) score 
upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo. 
- 
Evaluate the changes in enhancing tumor volume from baseline to surgery as 
measured by breast MRI via central assessment. 
- 
Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) 
ypT0/is, ypNX (breast pCR). 


ABCSG 
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2.1.3. 
Safety objectives 
The safety objective for this study is to evaluate the safety of letrozole plus GDC-0032 versus 
letrozole plus placebo.  
The safety and tolerability of GDC-0032 will be assessed using the following safety outcome 
measures: 
- 
Incidence, nature, and severity of adverse events (AEs) graded according to National 
Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE), v4.0  
- 
Incidence and type of AEs leading to dose discontinuation, modification, or delay 
- 
Serious adverse events (SAEs) 
- 
Protocol-defined AEs of special interest (AESI) 
- 
Clinically significant changes in vital signs and in clinical laboratory results during the 
AE reporting period 
2.1.4. 
Patient-reported outcome objectives 
The patient-reported outcome (PRO) objectives for this study are as follows: 
- 
Evaluate and compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL), including side-effects of therapy (e.g., sore 
mouth/tongue, difficulty swallowing, diarrhea, skin problems), between treatment 
arms as measured by the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the modified 
Breast Cancer Module (QLQ-BR23) 
2.1.5. 
Exploratory objectives 
The exploratory objectives for this study are as follows: 
- 
ORR, pCR rate, and PEPI scores according to the decrease in Ki67 after 2 weeks of 
letrozole plus GDC-0032 and letrozole plus placebo. 
- 
To evaluate changes in tumor cellular composition as assessed by diffusion-weighted 
MRI 
- 
To assess whether biomarkers from tumor tissue or blood, including but not limited to 
somatic cancer associated mutations, phosphatase tensin homolog (PTEN) 
expression, pro-survival pathways (such as phosphatidylinositol-3-kinase (PI3K)/AKT, 
mitogen-activated protein kinase (MAPK) etc.), apoptotic markers, hormone receptor 
expression levels, and levels of RNA and DNA expression are predictive of response  
- 
To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to anti-tumor 
activity 
- 
To assess concordance and percentage of PIK3CA mutation status from baseline 
biopsy and surgical specimen 
- 
To assess emergence of resistance alleles from tumor tissue or blood  


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- 
To assess concordance of the different imaging modalities (MRI [volume, 
enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor 
response 
- 
To assess the pharmacokinetics and possible drug interaction between letrozole and 
GDC-0032 upon concomitant administration 
- 
To assess the correlation of GDC-0032 drug levels and GDC-0032 related response 
(efficacy or AEs [e.g., colitis, rash]) 
- 
To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or 
letrozole on pharmacokinetics (e.g. drug metabolizing enzymes and transporters) and 
response (either efficacy and/or AEs) 
- 
Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in 
letrozole plus GDC-0032 versus letrozole plus placebo 
 
2.2. 
Study design 
This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the 
effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal 
women with estrogen receptor positive (ER+) / human epidermal growth factor receptor 2 
negative (HER2-) untreated, Stage I-III operable breast cancer whose primary tumors 
are  2 cm.  Patients with cT4 or cN3 tumors are not eligible. Standard of care 
assessments/procedures (e.g., bilateral mammogram) performed within 28 days of Day 1 
dosing do not need to be repeated for screening purposes. After confirmation of all the 
eligibility criteria, patients will be randomized to one of the two treatment arms. The study will 
enroll approximately 330 patients at approximately 110 global sites. 
At Weeks 1, 5, 9, 13, and 16 the primary breast tumor and axillary lymph nodes will be 
assessed by clinical breast examination (palpation and caliper measurement). Suspicion of 
progression based on clinical exam at any time should be further evaluated. In addition to the 
safety assessments conducted at the scheduled follow-up visits, patients will be contacted by 
telephone for a general assessment of adverse events at Weeks 7 and 11. 
At Week 9, a breast ultrasound will be performed to ensure that there is no progressive 
disease (PD) and for the purpose of surgery planning. Suspicion of PD on breast ultrasound 
should be confirmed by investigator-assessed breast MRI. Patients with primary disease not 
evaluable (NE) by ultrasound at baseline should be assessed by MRI at Week 9.  Suspected 
progression in nodes should also be confirmed by fine needle aspiration (FNA) if these 
nodes had not been previously shown to be cytologically positive for cancer. Patients with 
PD (as defined by modified RECIST 1.1, Appendix 1Appendix 1), can either proceed directly 
to surgery or be taken off of the study, according to the investigator’s decision. If the patient 
goes off-study, every reasonable effort should be made to obtain a new biopsy prior to 
beginning another systemic treatment. 




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for other endpoint analyses. The co-primary efficacy endpoint of the primary objective, i.e. 
pCR (ypT0/is, ypN0), will be established via a local review following completion of 
neoadjuvant therapy and surgery.  
An Independent Review Facility (IRF) will be used to determine the tumor ORR via MRI. IRF 
procedures are detailed in the IRF charter. 
A post-surgery visit will be performed 4 weeks (+ 1 week) after surgery, and will mark the end 
of the study. Assessment of AEs and general safety will be collected at this visit. 
2.2.2. 
Study duration – end of study 
The end of study (EOS) is defined as the date when the last patient has her post-surgery 
visit. The total duration of the study is expected to be approximately 24 months for 
enrollment, plus 5.5 months after last patient in. 
 
2.3. 
Randomization and stratification criteria 
After written informed consent form (ICF) has been obtained and eligibility has been 
established, the study site will obtain a patient’s identification number and treatment 
assignment using a permuted block randomization algorithm via an interactive voice or web-
based response system (IxRS).  
Patients will be randomized into one of the two treatment arms in a 1:1 ratio based on the 
following stratification factors: 
- 
Tumor Size (T1-T2 vs. T3) 
- 
Nodal Status (cytologically positive vs. radiologically or cytologically negative). If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then FNA or core biopsy is required to confirm nodal status. 
2.3.1. 
Blinding 
Investigators and patients will be blinded to treatment assignment of GDC-0032 or placebo. 
For emergency situations, the investigator will be able to break the treatment code by 
contacting the IxRS. The responsibility to break the treatment code in emergency situations 
resides solely with the investigator. For non-emergency situations, the investigator needs to 
obtain approval from the Medical Monitor to break the treatment code. Unblinding during the 
study will result in the withdrawal of a patient from the study. For regulatory reporting 
purposes, and if required by local health authorities, the Sponsor will break the treatment 
code for all serious, unexpected or suspected adverse reactions that are considered by the 
investigator or Sponsor to be related to study drug. 


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While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  The PK assay 
group will be unblinded to patients’ treatment assignments to identify appropriate PK 
samples to be analyzed and bioanalytical methodology to employ. However, the PK scientist 
does not have access to the PK assay results and therefore stays blinded until the PK assay 
results need to be interpreted and reported.  Samples from patients assigned to the 
comparator arm will be analyzed for letrozole. However, GDC-0032 assay will be analyzed 
by request (i.e., to evaluate a possible error in dosing). 
 
2.4. 
Number of subjects - sample size estimation 
This study is designed for testing the effect of GDC-0032 on the two co-primary endpoints in 
all enrolled patients and in the PIK3CA MT patients and plans to enroll 330 patients in total. 
Assuming the PIK3CA mutation status will not be available (unknown) for approximately 10% 
of the patients and the prevalence of PIK3CA MT is 40%, there will be approximately 120 
patients in the PIK3CA MT cohort. 
Given that the PIK3CA mutation status is not a stratification factor for randomization, there 
might be a possible imbalance between treatment arms within the PIK3CA MT cohort, which 
may reduce the statistical power in this cohort. To ensure the study provides sufficient 
statistical power even when the treatment assignment is imbalanced, the sample size was 
calculated based on a conservative scenario by assuming that the treatment assignment 
imbalance in PIK3CA MT is 40% vs. 60%. The sample size was calculated based on a chi²-
test using continuity correction (Ury and Fleiss 1980). 
To control an overall, two-sided, family-wise error rate under 20% for each analysis 
population, we use a two-sided significance level of 16% and 4% for the co-primary 
endpoints MRI ORR, and pCR, respectively. 
Assuming 10% of the patients are unevaluable for the MRI ORR, approximately 300 enrolled 
patients and 108 patients in the PIK3CA MT cohort will be evaluable for analyses. This 
sample size allows us to detect an absolute percentage increase of 24% in MRI ORR rate in 
the letrozole plus GDC-0032 arm (64%) versus the letrozole plus placebo arm (40%; Smith 
et al. 2005; Ellis and Ma 2007) in the PIK3CA MT cohort at 80% power and 16% two-sided 
significance level.  The minimal detectable difference for ORR is approximately 15%. 
Assuming that all patients are evaluable for pCR (i.e., approximately 330 enrolled patients 
and 120 in the PIK3CA MT cohort), this sample size provides 80% power to detect an 
absolute percentage increase of 18% in pCR in the letrozole plus GDC-0032 arm (19%) 
versus the letrozole-only arm (1%, Smith et al. 2005; Ellis and Ma 2007) in the PIK3CA MT 
cohort at the 4% two-sided significance level. The minimal detectable difference for pCR rate 
is approximately 13%. 


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The study is considered positive if at least one population shows a statistically significant 
result regarding the co-primary endpoints. 
If the prevalence of the PIK3CA mutation is lower than assumed, if there is more substantial 
treatment assignment imbalance in the PIK3CA MT cohort than assumed, or there is an 
increased number of unevaluable patients for the MRI ORR, the sample size may be 
increased to obtain the level of power at 80%, and the enrollment may be limited to patients 
with PIK3CA MT.   
 
3. Statistical methods 
3.1. 
Data handling conventions 
3.1.1. 
Data entry errors and potential outliers 
Patients may have potential outliers for particular observations. Observations will be checked 
for correctness by the study team before data freeze and at the time point of data freeze all 
data should be correct. Remaining potential outliers based on correct values will be included 
in analysis. If assumptions or data structure do not allow planned analyses, analyses will be 
updated appropriately. However, sensitivity analyses excluding these measurements may be 
calculated to evaluate the influence of such extreme values. Values found to be incorrect due 
to data entry error after database closure will be excluded from all analyses as missing 
values. Incidence of incorrect values and potential outliers will be listed and summarized by 
treatment arm. 
3.1.2. 
Missing data 
Subjects may have missing specific data points for a variety of causes.  In general, data may 
be missing due to a missed visit, non-evaluability of a specific clinical measurement at its 
planned clinical visit or a subject’s early withdrawal from study. The general procedures 
outlined below describe what will be done when a data point is missing. 
3.1.2.1. 
Imputations of missing data 
Generally, only evaluable measurements are considered for the analyses. No values are 
imputed for missed or non-evaluable visits. In case of primary and secondary efficacy 
endpoints possible specific requirements are stated in the according analysis sections. 
3.1.2.2. 
Partial dates 
Partially incomplete dates (day or day/month missing) will be imputed for dates related to 
AEs, to concomitant medication and medical history. Completely missing dates and missing 
years will not be imputed.  
For DOB imputed dates will be used to derive the age of the patients since only month and 
year are captured due to regulatory reasons in some participating countries. DOB must not 


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have missing month information and hence, missing months will not be imputed. DOB will be 
imputed as described in the following table: 
 
Missing 
Impute 
Exception 
DOB 
Day 
15 
-- 
 
Dates belonging to AEs and concomitant medication will be imputed as described in the 
following table: 
 
Missing 
Impute 
Exception 
Start date 
Day 
01 
Date of first dose of study drug if imputed 
date would be prior to date of first dose of 
study drug 
Day/Month 
01JAN 
Date of first dose of study drug if imputed 
date would be prior to date of first dose of 
study drug  
Stop date 
Day 
Last day of the month 
Patient EOS date if the imputed date 
would be after patient EOS date 
Day/Month 
31DEC 
 
3.1.3. 
Stratification errors 
Stratification errors are defined as different values in the stratification factors compared 
between IxRS and actual patient values from the electronic case report forms (eCRF). 
Variables compiled in both systems are:  
 
Tumor Size (T1-T2 vs. T3) 
 
Nodal Status (Cytologically Positive vs. Radiologically or Cytologically Negative). If on 
ultrasound examination there is evidence of suspicious axillary lymph nodes at the 
baseline examination, then FNA or core biopsy is required to confirm nodal status. 
As tumor size has to be measured by MRI for actual patient values in the eCRF, but may be 
measured by other devices for stratification in IxRS (for which information on device type is 
not available), there may be several stratification errors for this strata.  
Stratified analyses that are intended to evaluate the treatment effect will be based on the 
randomized stratum (ie, from IxRS) regardless of the subject’s actual value throughout the 
document unless otherwise specified. Sensitivity analyses repeating the main primary and 
secondary analyses using the actual stratum (i.e. stratum as given in the eCRF) may be 
performed additionally. If assumptions or data structure do not allow for stratified analyses, 
appropriate non-stratified analyses (e.g. Fisher’s exact test) will be performed. Covariate 
analyses where covariates are stratification factors should be based on subject’s actual 
value.  
3.1.4. 
Derived endpoints 
EOS visit: The date of end of study visit of each patient is defined as the maximum date of all 
dates during the post-surgery visit for patients who ended the study per protocol and it is the 
date of early EOS for patients who ended the study due to other reasons. Early EOS occurs 


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when a patient does not undergo surgery and/or post-surgery visit (independent of the 
treatment visits).  
Early end of treatment (EOT): Early discontinuation from treatment occurs when a patient 
does not take more than 90% of investigational product (IP; =14.5 weeks=72days of dosing). 
Age: Age will be calculated as the time from imputed DOB to date of randomization based on 
eCRF information. 
PEPI score: The PEPI score will be calculated (for relapse-free survival and breast cancer-
specific survival) on the basis of pathological tumor size (locally assessed – as ypTStage), 
node status (locally assessed – as ypNStage), Ki67 level (centrally assessed - VHIO: 
variable Ki67ResN), and ER status (centrally assessed - VHIO: variable ERResN, Allred 
score) according to Ellis et al (2008). 
Tumor overall ORR assessed by modified RECIST 1.1 criteria:  
Lesions should be evaluated and documented at all assessments (even if they have 
disappeared – laterality and location for the lesion will be set to ‘not available’). 
Documentation should be done at all subsequent visits for the modality where it was 
detected. For each modality, subject response is always relative to screening (baseline 
assessment) of that modality. Subject overall response per modified RECIST 1.1 criteria is 
assessed only at Week 16. Assessments of disease at visits prior to Week 16 visit are to rule 
out progression. 
Target and non-target lesions are identified at screening, while new lesions are only 
identified after screening. If a new finding is equivocal on a particular modality, and not 
deemed suspicious enough to warrant clinical follow-up it should not be documented as a 
new lesion on that modality. Lymph nodes may be identified as non-target lesions at 
screening or as new lesions at another visit. Lymph nodes are not expected to disappear; a 
complete response (CR) may be documented if the lymph node becomes completely non-
pathologic in appearance (~equivalent to non-lymph node lesion disappearing). 
If a target lesion was present at screening the response at Week 16 should be documented 
as given in Table 1 in Appendix 1Appendix 1. 
If no target lesion was present at screening (but documented as a non-target lesion) the 
response at Week 16 should be documented as follows: 


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The latter case should not occur on MRI assessments since a measurable lesion is required 
for study entry, but it may occur on clinical breast examination, mammography, and/or breast 
U/S assessments. An overall response of PR is not possible per RECIST 1.1 if only non-
target lesions are documented at screening.   
 
3.1.5.  Statistical considerations 
Cochran-Mantel-Haenszel (CMH) tests will be used for several comparisons (e.g. ORR, 
pCR) between treatment arms, stratified by tumor size and nodal status. No clear rule 
regarding the requirements for using stratified CMH test based on the combined cell 
frequencies over all strata could be found in literature (compare Glenn A. Walker 2004: 
Common Statistical Methods for Clinical Research, 2nd Edition, p 316). Hence, the CMH test 
will be used only if there is at least 1 responder in each stratum and the number in each cell 
of the unstratified 2x2 table is greater than 5. Otherwise, unstratified Fisher’s Exact test will 
be used. 
 
3.2. Types and timepoints of analyses 
3.2.1.  Main analyses 
The main analysis used for preparing the Top Line Results (TLR) will be done after all 
patients underwent their post-surgery visit or dropped out of the study early and after clinical 
database closure and data management review.  
The following data were not captured in the clinical database, but were assessed and/or 
gathered by external vendors: 
 Response by centrally assessed MRI 
 PIK3CA mutation status 
 Data on KI67, ER status (Allred score) and expression of biomarkers 
 PTEN (phosphatase tensin homolog) 


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 
MRI volume 
 
ECG data 
External vendor data available, received and checked by ABCSG prior to clinical database 
closure will be examined for the main analysis. After clinical database closure unblinding will 
occur at ABCSG with randomization information received from the IxRS vendor.  
ABCSG will receive additional information regarding the concentration of GDC-0032 and 
letrozole for the pharmacokinetic, pharmakogenetic and biomarker endpoints after 
unblinding. The final analysis will be performed after all external vendor data are available, 
received and checked by ABCSG.  
3.2.2. 
Independent Data Monitoring Committee analyses 
The Independent Data Monitoring Committee (IDMC) will conduct an interim analysis to 
review the unblinded safety data after the first 20 patients have either 1) finished the 30-day, 
follow-up visit after the surgery, or 2) been on study for 20 weeks after the randomization 
date (for those who do not receive the surgery), whichever occurs first.  All available 
information of all randomized (i.e. enrolled) patients with all available assessments at the 
respective time point will be included in the interim analyses.   
In addition, the IDMC will monitor accumulating patient safety data at a minimum of once 
every 6 months until the last patient has completed study treatment.  Additional details 
(e.g., IDMC members, communication, affiliations) will be provided in the IDMC charter and 
the details of the scope of analysis for IDMC will be documented separately. Furthermore, 
the IDMC or the Medical Monitor may request additional ad hoc meetings of the IDMC at any 
time during the study to review safety data. 
 
3.3. 
Analysis populations 
3.3.1. 
Intention-to-Treat population 
Primary and secondary analyses, as well as patient-reported and exploratory analyses, will 
include the Intention-to-Treat (ITT) population; that is, all patients who were randomized 
regardless of whether they received any study drug (GDC-0032 or placebo). Patients will be 
analyzed according to the treatment group to which they were assigned at randomization.  
3.3.2. 
Per-protocol population 
Sensitivity analyses will be based on the Per-Protocol (PP) population; that is, all patients 
who were randomized, received study drug (GDC-0032 or placebo), received more than 90% 
and less than 110% of the per protocol intake of GDC-0032 and who do not have any 
protocol violations that mandate their exclusion from the PP population. Hence, patients with 
Important Protocol Deviations (IPDs) that are expected to impact the primary endpoint of the 
study will be excluded (compare Study GO28888 (LORELEI)_Note-to-File_02-Feb-2016-


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Signed.pdf): [ipd-DO01], [ipd-IN04n], [ipd-PE02n], [ipd-EX01], [ipd-EX02], [ipd-EX05], [ipd-
EX06], [ipd-EX07], [ipd-EX12], [ipd-EX13], [ipd-EX20] and [ipd-EX26]. Patients will be 
analyzed according to the treatment actually received. Hence, randomized patients who 
wrongly received active drug at any time point will be included in the experimental arm in the 
PP population.  
3.3.3. 
Safety population 
Safety analyses will be based on the safety (SAF) population and include all randomized and 
treated patients (patients who received at least one dose of study treatment). Patients will be 
analyzed according to the treatment actually received. Hence, randomized patients who 
wrongly received active drug at any time point will be included in the experimental arm in the 
SAF population.   
 
3.4. 
Significance level 
A two-sided significance level of 16% and 4% is used for the co-primary endpoints MRI ORR 
and pCR, respectively, resulting in an overall, two-sided, family-wise type I error rate for the 
primary endpoints of 20% for each analysis population (all randomized and PIK3CA MT 
patients). All other tests will be performed at a two-sided significance level of 5%. 
 
3.5. 
Patient status 
3.5.1. 
Study disposition 
Recruitment status and patient discontinuation from study including reasons for 
discontinuation will be summarized by treatment arm.  
3.5.2. 
Baseline demographic and disease characteristics 
Demographic variables, stratification factors and other baseline characteristics will be 
summarized descriptively by treatment arm. The demographic variables age (metric), gender 
(female, male), ethnicity (Hispanic/Latino, not Hispanic/Latino) and race (American 
Indian/Alaska Native, Asian, Black/African American, Native Hawaiian/Other Pacific Islander, 
White) will be reported. Tumor size (T1-T2, T3) and nodal status (cytologically positive, 
radiologically or cytologically negative) are the two observed stratification factors by IxRS. 
Additionally, the tumor specific variables tumor stages (N-Stage; M-Stage) and tumor 
grading, and hormone receptor statuses (ER and progesterone receptor (PgR)), KI67, ER 
status (Allred score), PEPI score as well as the Eastern Cooperative Oncology Group 
(ECOG) status will be analyzed.  
Frequencies and percentages, means and standard deviations or medians and interquartile 
ranges will be given depending on the scale of the variable.Important protocol deviations  


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IPDs include inclusion and exclusion criteria, as well as selected variables belonging to 
additional relevant screening assessments, study treatment administration/dispensation, 
concomitant medication, primary endpoint, study treatment/randomization, study 
procedures/assessments, withdrawal/termination criteria and safety reporting. The IPDs are 
defined in a separate document listing all IPDs, their classification and additional details. 
IPDs will be summarized in total and by treatment arm and will be listed by study site, 
treatment arm and patient number.  
3.5.4. 
Treatment disposition and exposure to study drug 
Patient disposition and early discontinuation from treatment (GDC-0032/Placebo as well as 
letrozole) including reasons for discontinuation will be summarized by treatment arm. 
Study medication intake including dose interruptions and dose reductions will be summarized 
overall and per treatment arm.  
 
3.6. 
Primary endpoint evaluation 
3.6.1. 
Primary endpoints  
The co-primary efficacy endpoints are (1) tumor ORR (ICON: dataset RVIS, variable 
RRESPONS – CR, partial response (PR), stable disease (SD), Non-CR/Non-PD, PD, NE, no 
disease (ND)), centrally assessed by modified RECIST 1.1 criteria by breast MRI after 
completion of study drug, and (2) the rate of total pCR (tpCR - yes, no, not assessed) in 
breast and axilla, locally evaluated after completion of study drug and surgery, each in all 
randomized patients and PIK3CA MT patients. Information on PIK3CA mutation status 
(HistoGeneX: variable PIK3CAResC) is assessed centrally. 
The null- and alternative hypotheses for tumor ORR is as follows: 
H0: 
Tumor ORR is equal in patients receiving letrozole plus GDC-0032 compared to 
patients receiving letrozole plus placebo  
H1: 
Tumor ORR differs between patients receiving letrozole plus GDC-0032 compared to 
patients receiving letrozole plus placebo  
The pCR endpoint results in the following null- and alternative hypotheses: 
H0: 
Total pCR rate is equal in patients receiving letrozole plus GDC-0032 compared to 
patients receiving letrozole plus placebo  
H1: 
Total pCR rate differs between patients receiving letrozole plus GDC-0032 compared 
to patients receiving letrozole plus placebo  


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3.6.2. 
Analysis for primary endpoints 
The efficacy endpoint tumor ORR will be calculated by treatment arm in all randomized 
population and in PIK3CA MT population. Within each population, summary tables will be 
given and the ORR for the two treatment arms will be compared at a two-sided alpha of 16% 
using a Cochran Mantel-Haenszel test, stratified by tumor size and nodal status. The efficacy 
endpoint pCR rate will also be calculated and compared at a two-sided alpha of 4% based on 
the same analytical approach as ORR. The two alpha values account for a family-wise type I 
error rate of 20% for each population (all randomized patients and PIK3CA MT patients).  
Patients with early study termination and hence missing efficacy outcome (ORR or pCR), as 
well as patients who are NE for MRI by central review (ORR only) will be included and 
considered as non-responders in the analysis. 
3.6.3. 
Sensitivity analysis for primary endpoints 
As sensitivity analysis for the primary efficacy endpoints, according analyses are repeated 
based on the PP population. 
 
3.7. 
Secondary endpoint evaluation 
3.7.1. 
Secondary endpoints  
As secondary efficacy endpoints (1) tumor ORR (ICON: dataset RVIS, variable RRESPONS 
– CR, PR, SD, Non-CR/Non-PD, PD, NE, ND), centrally assessed by modified RECIST 1.1 
criteria by breast MRI after completion of study drug, and (2) the rate of total pCR (tpCR - 
yes, no, not assessed) in breast and axilla, locally evaluated after completion of study drug 
and surgery, both are evaluated in PIK3CA WT patients.  
Furthermore, secondary efficacy endpoints contain tumor overall ORR (CR, PR, SD, PD, not 
measurable/not assessed), locally assessed by modified RECIST 1.1 criteria by clinical 
breast examination (CaPalpOverResp), mammography (CaMammoOverResp), and breast 
ultrasound (CaSonoOverResp), after completion of study drug evaluated in all randomized 
patients and separately by PIK3CA mutation status.  
Additionally, (1) change in Ki67 values (VHIO: variable Ki67ResN), centrally assessed, from 
baseline to Week 3, baseline to surgery, and Week 3 to surgery, (2) PEPI score (for relapse-
free survival and breast cancer-specific survival, derived – classified into risk groups 
according to Ellis et al 2008 as PEPIR and PEPIB, respectively), at surgery, and (3) change 
in enhancing tumor volume (ICON: dataset VLES, variable TSHOLD1 - metric), centrally 
evaluated using breast MRI, from baseline to surgery, are considered as secondary efficacy 
endpoints in all randomized patients and in each of the PIK3CA mutation cohorts.  
Last, different definitions of pCR, locally assessed after completion of study drug and 
surgery, are evaluated in all randomized patients and in each of the PIK3CA mutation 
cohorts.  Included are the following possibilities: a) ypT0, ypN0 (according levels for 


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ypTStage and ypNStage), and b) ypT0/is, ypNX (breast pCR as nodal stage is not 
considered; bpCR - yes, no, not assessed).   
3.7.2. 
Analysis for secondary endpoints 
The two secondary efficacy endpoint measures in PIK3CA WT population will be 
summarized by treatment arm and will be analyzed analogous to the primary efficacy 
endpoints. Information on PIK3CA mutation status (HistoGeneX: variable PIK3CAResC) is 
assessed centrally. Patients with early study termination and hence missing efficacy 
outcome, as well as patients who are NE for MRI by central review will be considered as 
non-responders in the analysis. 
The further endpoint measures will be summarized by treatment arm and will be compared 
between the two treatment arms within each population based on appropriate statistical 
analyses:  locally assessed ORR will be compared using a Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status within each method; change in Ki67, PEPI score and 
change in enhancing tumor volume will be compared by appropriate regression analysis 
models (depending on the distribution of the variables), e.g. logistic regression models, 
adjusted for tumor size and nodal status. For each of the different definitions of pCR, 
comparisons between treatment arms will be done by Cochran Mantel-Haenszel test, 
stratified by tumor size and nodal status.   
 
3.8. 
Safety endpoint evaluation 
3.8.1. 
Safety endpoints  
Safety endpoints will be assessed through summaries of AEs, changes in laboratory test 
results and vital signs in all treated patients. 
3.8.2. 
AEs and SAEs 
Verbatim descriptions of AEs will be mapped to thesaurus terms (Medical Dictionary for 
Regulatory Activities (MedDRA) v19. 1). Only treatment-emergent AEs, hence, AEs outlined 
during protocol treatment period (on or after the first dose of study drug until 30 days after 
the last dose of study drug or until the end of study visit, whichever occurs later) or after this 
period, in case of deaths, serious adverse events, or other adverse events of concern 
deemed related to prior study drug treatment or study procedures, will be tabulated. 
All AE data will be given by System Organ Class (SOC), preferred term (PT) and grade and 
will be summarized overall and by treatment arm. Additionally, serious AEs, deaths, AESIs 
(protocol defined – based on type and severity of AE or laboratory data), as well as AEs at 
NCI CTCAE v4.0 Grade 3 to 4 and Grade 5 and AEs leading to discontinuation, modification 
(i.e. reduction) or delay (i.e. interruption) of treatment will be summarized separately.  
Furthermore, AE data will be listed by study site, patient number, treatment arm, date of first 
dose of study drug, onset and resolved study day, seriousness, duration, severity, outcome 
and the relationship to study drug to understand the cumulative incidence as well as the time 


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to onset of first event when treated with GDC-0032+letrozole. The time to AE of special 
interest (time from first dose of study drug to first AE of special interest) will be shown 
graphically. 
3.8.3. 
Laboratory data and vital signs 
For relevant laboratory data (ALT, AST, bilirubin, calcium, glucose, hemoglobin, platelets, 
serum creatinine, white blood cells and HbA1C – all metric) shifts from baseline to minimum 
and maximum NCI CTCAE v4.0 grades will be given. Vital sign data (heart rate, blood 
pressure, and temperature – all metric) will be summarized in total and by treatment arm. 
Abnormal ECG data (based on BioTelemetry Research (BTR) data) will be listed. 
 
3.9. 
Patient-reported endpoint evaluation 
3.9.1. 
Patient-reported endpoints  
Patient reported outcomes of disease/treatment-related symptoms, patient functioning, and 
HRQoL will be assessed using the EORTC QLQ-C30 and the modified QLQ-BR23 
(Aaronson et al. 1993) for all randomized patients. Hence, patient-reported endpoints are the 
mean and mean change scores (of the base questionnaire and of the supplementary breast 
cancer module) of the scales, which are described in the scoring procedures (Fayers et al. 
2001). 
3.9.2. 
Analysis for patient-reported endpoints 
Completion rates of the measures will be summarized at each time point by treatment arm. 
The population for analysis will be defined as all randomized patients who have completed 
baseline and at least one post-baseline assessment. Summary statistics (mean, mean 
change, standard deviation, median and 95% CI ) of linear transformed scores will be 
reported for all subscales of the EORTC QLQ-C30 questionnaire, and the modified QLQ-
BR23 (including the added items of skin problems, itching, sore mouth/tongue, and trouble 
swallowing, which will be assessed independently). Both measures and additional scales 
from the EORTC item bank will be scored according to the EORTC scoring manual 
guidelines (Fayers et al., 2001). Line charts depicting the mean changes (and standard 
errors) of items and subscales over time will be provided for each treatment arm from the 
baseline assessment.  Clinically meaningful differences will be assessed relative to 
established thresholds (Osoba et al., 1998; Cocks et al., 2011). 
Additional patient reported outcomes analyses might be conducted. 
 


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3.10. Exploratory endpoint evaluation 
Details on evaluation (endpoints and analyses) of all translational science objectives will be 
described in the Translational Statistical Analysis Plan (TSAP). Analyses will include 
pharmacodynamics and pharmacokinetic, as well as biomarker endpoint evaluation.  
3.10.1. 
Exploratory endpoints  
ORR (centrally assessed, ICON: dataset RVIS, variable RRESPONS – CR, PR, SD, Non-
CR/Non-PD, PD, NE, ND), pCR rate (local, tpCR - yes, no, not assessed), PEPI score 
(derived – classified into risk groups according to Ellis et al 2008 as PEPIR and PEPIB, 
respectively) according to the decrease in Ki67 after 2 weeks of treatment are hypothesized 
to differ between patients receiving letrozole plus GDC-0032 compared to patients receiving 
letrozole plus placebo. Each will be evaluated in all randomized patients and, if statistically 
significant within all randomized patients, also in PIK3CA MT patients. 
The concordance of the different imaging modalities in measuring tumor response after 
completion of study drug (MRI, central, ICON: dataset RVIS, variable RRESPONS – CR, PR, 
SD, Non-CR/Non-PD, PD, NE, ND; clinical, ultrasound and mammography, local, OverResp 
for each  - CR, PR, SD, PD, not measurable/not assessed) will be observed. Concordance 
will be evaluated in all randomized patients. 
Rates of planned BCS (local, SurgTypePlan - breast conserving, other levels) and 
conversion to BCS (local, SurgType - breast conserving, other levels) between patients 
receiving letrozole plus GDC-0032 and patients receiving letrozole plus placebo will be 
compared. Rates will be evaluated in all randomized patients. 
3.10.2. 
Analysis for exploratory endpoints 
Comparisons between treatment arms in ORR (grouped as responder vs. non-responder), 
pCR rate and PEPI score according to the decrease in Ki67 will be analyzed using 
appropriate regression analysis models (depending on the distribution of the variables), e.g. 
logistic regression models , adjusting for tumor size and nodal status in all randomized 
population and in PIK3CA MT population. Concordance will be examined by frequencies and 
percentages. Rates will be summarized descriptively. 
 
3.11. Listings 
To review the snapshot clinical data for a patient, in case a safety event occurred, additional 
patient summary listings will be performed. For the following categories listings may be 
presented: demographics, medical history, history of primary breast cancer, surgery, physical 
examination, vital signs, radiological examinations, hematology, chemistry, electrolytes, 
DLCO, GDC-0032/placebo administration, letrozole administration, concomitant medication, 
treatment completion and surgery at treatment completion. 
 


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3.12. Covariates 
To adjust for the possible effect of demographic or prognostic factors multivariate analyses 
will be performed. To avoid multi-collinearity between the covariates, prior correlation 
analyses will be performed. Depending on the statistical results and the clinical relevance, 
highly correlated covariates may be excluded from multivariate analyses. Binary dependent 
variables will be analyzed using logistic regression models. Metric dependent variables will 
be analyzed using general linear models or a non-parametric equivalent if appropriate. 
Forest plots will be given where appropriate. 
 
3.13. Software 
Analyses will be done by members of the biostatistics group at ABCSG using statistical 
analysis system (SAS) software (SAS® version 9.3 or higher). If necessary, selected other 
software will be used.  
 
4. Changes of analysis compared to study protocol 
Abbreviation of progesterone receptor changed to PgR as PR is used for partial response. 
The following exploratory objective was included to be consistent with the outcome measures 
given in the protocol: ‘ORR, pCR rate, and PEPI scores according to the decrease in Ki67 
after 2 weeks of letrozole plus GDC-0032 and letrozole plus placebo.’. 
 
5. Addendum to the statistical analysis plan 
The Addendum to the SAP lists additional analyses for secondary endpoints calculated after 
finalization of the SAP (V2), including a description of and a rationale for these additions. 
As addition to the main results for the two secondary efficacy endpoint measures in PIK3CA 
WT population, bar charts for rates (%) by treatment arm were given.  
Also for further secondary endpoint measures several figures were created:  
 
Bar charts for rates (%) of locally assessed ORR by alternative methods were given 
by treatment arm for all three patient populations;  
 
for change in Ki67 boxplots either by treatment arm or by mutation status grouped by 
time point, individual patients plots for each treatment arm and either with/without 
ORR or mutation/wild type by with/without ORR as well as bar charts for proportional 


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change by treatment arm grouped by time difference (BL-W3, BL-SU, W3-SU) for all 
three patient populations were shown;  
 
Bar charts for frequency (%) of PEPI score as well as PEPI score risk groups by 
treatment arm for relapse-free/breast cancer-specific survival were created;  
 
Bar charts for change in enhancing tumor volume by treatment arm grouped by 
mutation status for absolute/percentage change were presented. 
Additionally, because of the unexpected results with regard to the changes in Ki67 and the 
PEPI score, frequencies and percentages of time from EOT to surgery for GDC, Letrozole 
and overall were calculated. 


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6. References 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst 1993; 85:365-76. 
 
Cocks K, King MT, Velikova G, Martyn St-James M, Fayers PM, Brown JM. Evidence-based 
guidelines for determination of sample size and interpretation of the European Organisation 
for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J. Clin. 
Oncol. 2011;29:89–9610 
 
Ellis MJ and Ma C. Letrozole in the neoadjuvant setting: the P024 Trial. Breast Cancer 
Res Treat 2007;105(Suppl 1):33−43. 
 
Ellis MJ, Tao Y, Luo J, A'Hern R, Evans DB, Bhatnagar AS, Chaudri Ross HA, von Kameke A, 
Miller WR, Smith I, Eiermann W, Dowsett M. Outcome prediction for estrogen receptor-
positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J 
Natl Cancer Inst 2008;100:1380–1388 
 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC  
Quality  
of  
Life  
Group. EORTC  
QLQ-C30  
Scoring  
Manual. 3rd 
edn. EORTC, Brussels; 2001. 
 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998;16:139 44 
 
Smith IE, Dowsett M, Ebbs SR, et al. IMPACT Trialists Group: neoadjuvant treatment of 
postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: 
the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen 
(IMPACT) multicenter double-blind randomized trial. J Clin Oncol 
2005;23:5108−16. 
 
Ury HK and Fleiss JL. on approximate sample sizes for comparing two independent 
proportions with the use of yates’ correction. Biometrics 1980;36:347−51. 
 
Walker GA. Common Statistical Methods for Clinical Research, 2nd Edition, 2004. 


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7. Appendices 
7.1. 
Appendix 1 
 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:  
ASSESSMENT OFRESPONSE 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 
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 therapy in early breast 
                                                 
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. 


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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 
time point, 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 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 time point.   
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 


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– 
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 
 
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 


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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 
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. 
Time point Response (Overall Response) 
Table 1 provides a summary of the overall response status calculation at each protocol-
specified time point for which a response assessment occurs.  


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Table 1  Time point Response:  Patients with Target Lesions 
(with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR, 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 time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response. 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.