Conditions: Solid Cancers Non-Hodgkin's Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 674
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter, Phase I/II study to assess the safety, tolerability, and pharmacokinetics of GDC-0032. The Phase I portion will be divided into two stages. During Stage 1, GDC-0032 will be administered every day orally and at escalating doses in participants with locally advanced or metastatic solid tumors. During Stage 2, GDC-0032 will be administered alone or as combination therapy within indication-specific cohorts. In Phase II of the study, the efficacy and safety of the combination GDC-0032 and fulvestrant will be evaluated in post-menopausal female participants with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer.

Detailed description:

Arms:
arm 1: Participants with locally advanced or metastatic solid tumors will receive increasing doses of GDC-0032 administered orally daily in 28-day cycles. Dose escalation decisions will be based upon the observed incidence of DLTs. arm 2: Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression. arm 3: Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression. arm 4: Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression. arm 5: Participants (Cohort C) will receive GDC-0032 in combination with midazolam. arm 6: Post-menopausal females with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer will receive GDC-0032 in combination with fulvestrant until disease progression.

Interventions: intervention 1: Fulvestrant intervention 2: GDC-0032 intervention 3: Letrozole intervention 4: Midazolam
Intervention descriptions: intervention 1: Participants will receive fulvestrant 500 milligrams (mg) via intramuscular injection (as per package insert or Summary of Product Characteristics \[SmPC\]) on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent cycle, until disease progression (Cycle length: 28 days). intervention 2: Participants will receive GDC-0032 at escalating (Phase I, Stage 1) or fixed (Phase II and Phase I, Stage 2) doses until disease progression. Cycle 1 may be 35 days in length to allow for a 7-day washout following the initial dose; thereafter, GDC-0032 will be administered orally once daily in 28-day cycles. intervention 3: Participants will receive letrozole 2.5 mg orally (as per Package Insert or SmPC) once daily in 28-day cycles until disease progression. intervention 4: Participants will receive midazolam 5 mg (as per Package Insert or SmPC) in hydrochloride syrup on Days 1 and 16 of Cycle 1.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
An Open-Label, Phase I/II, Dose-Escalation Study Evaluating the 
Safety and Tolerability of GDC-0032 in Patients with Locally 
Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma 
and in Combination with Endocrine Therapy in Patients With Locally 
Advanced or Metastatic Hormone Receptor-Positive Breast Cancer 
NCT Number: 
NCT01296555 
Document Date: 
Protocol Version A10: 12 July 2018 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This is a Genentech, Inc., document that contains confidential information.  It is intended solely 
for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other proposed 
use requires written consent from Genentech, Inc.
Protocol:  GDC-0032—Genentech, Inc.
P PMT4979g (GO00886)-A10
PROTOCOL
TITLE:
AN OPEN-LABEL, PHASE I/II, DOSE-ESCALATION STUDY EVALUATING 
THE SAFETY AND TOLERABILITY OF GDC-0032 IN PATIENTS WITH 
LOCALLY ADVANCED OR METASTATIC SOLID TUMORS OR NON-
HODGKIN’S LYMPHOMA AND IN COMBINATION WITH ENDOCRINE 
THERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
HORMONE RECEPTORPOSITIVE BREAST CANCER
PROTOCOL NUMBER:
PMT4979g (GO00886)
VERSION NUMBER
A10
EUDRACT NUMBER:
2012-002042-21
TEST PRODUCT:
GDC-0032
IND NUMBER:
110184
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
14 December 2010
 
12-Jul-2018 07:38:15
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Protocol:  GDC-0032—Genentech, Inc.
2/P PMT4979g (GO00886)-A10
DATES AMENDED:
Version A1:  15 August 2011
Version A2:  18 April 2012
Version A3:  30 October 2012 (Spain only)
Version A4:  7 March 2013
Version A5:  24 June 2013
Version A6:  16 December 2013
Version A7:  12 May 2014
Version A8:  31 March 2015
Version A9:  29 September 2016
Version A10:  See electronic date stamp below.


Protocol:  GDC-0032—Genentech, Inc.
3/P PMT4979g (GO00886)-A10
PROTOCOL AMENDMENT VERSION A10:
RATIONALE
Protocol PMT4979g (GO00886) has been amended to reflect the Sponsor's decision to 
discontinue enrollment in the study as of 28 June 2018 and discontinue manufacturing of 
GDC-0032.  This decision was based on results of the primary analysis of 
Study GO29058, a Phase III, double-blind study of GDC-0032 in combination with 
fulvestrant for the treatment of metastatic hormone receptorpositive breast cancer, 
which showed that GDC-0032 plus fulvestrant had modest clinical benefit and limited
overall tolerability. Patients currently participating in the study as of 28 June 2018 will 
continue to receive treatment and undergo assessments as outlined in Appendix A-7 
until 6 months after enrollment of the last patient (last patient in [LPI]6 months).  After 
this time, patients who are deriving clinical benefit from GDC-0032, as determined by the 
investigator, may continue their assigned treatment regimen until disease progression, 
unacceptable toxicity, expiration of the last batch of GDC-0032 (expected by May 2021), 
or discontinuation of the study by the Sponsor, whichever occurs first.  Patients 
continuing treatment beyond LPI6 months will undergo a reduced set of assessments, 
as outlined in a new schedule of assessments in Appendix A-9.  The following sections 
have been updated to reflect these changes: 

Section 3.1 (Description of the Study)

Section 4.5 (Study Assessments) 

Section 4.5.3 (Assessments during Treatment)

Appendix A-7 (Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, 
and X [X1X11] before LPI 6 Months)
New GDC-0032 adverse drug reactions were detected during the primary analysis for 
Study GO29058.  The new adverse drug reactions have been added to Section 3.4.3, 
and management guidelines for infection have been added to Section 3.4.5.
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.


Protocol:  GDC-0032—Genentech, Inc.
4/P PMT4979g (GO00886)-A10
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND ........................................................................................... 30
1.1
The Phosphoinositide 3-Kinase Pathway ........................................... 30
1.2
Nonclinical Summary.......................................................................... 30
1.2.1
Pharmacology .............................................................................. 31
1.2.2
Pharmacokinetics......................................................................... 32
1.2.3
Toxicology .................................................................................... 33
1.3
Summary of Clinical Data for GDC-0032............................................ 34
1.3.1
Clinical Safety Data with GDC-0032............................................. 34
1.3.2
Preliminary Pharmacokinetics ...................................................... 36
1.3.3
Preliminary Pharmacodynamics................................................... 37
1.4
Study Rationale and Benefit-Risk Assessment .................................. 37
1.4.1
Rationale for Phase I.................................................................... 37
1.4.1.1 Rationale for Phase I Stage 2 Cohorts E, F, J, K, 
L, M, N, P, Q, R, and S: GDC-0032 in Combination with 
Letrozole or Fulvestrant in Hormone ReceptorPositive 
HER2-Negative Breast Cancer........................................................... 38
1.4.1.2
Rationale for Phase I Stage 2 Cohort T: 
GDC-0032 Single Agent in Non-Hodgkin’s Lymphoma ...................... 39
1.4.1.3
Rationale for Phase I Stage 2 Cohort T2: 
GDC-0032 Single Agent in Diffuse Large B-Cell 
Lymphoma.......................................................................................... 39
1.4.1.4
Rationale for Phase I Stage 2 Cohort X: “Basket 
Cohort” ............................................................................................. 39
1.4.2
Rationale for Phase II................................................................... 40
1.4.3
Benefit-Risk Assessment ............................................................. 41
2.
OBJECTIVES............................................................................................... 42
2.1
Phase I:  Objectives (Stage 1 and Stage 2)........................................ 42
2.1.1
Phase I:  Primary Objectives ........................................................ 42
2.1.2
Phase I:  Secondary Objectives ................................................... 42
2.1.3
Phase I:  Exploratory Objectives .................................................. 43
2.2
Phase II:  Objectives........................................................................... 43


Protocol:  GDC-0032—Genentech, Inc.
5/P PMT4979g (GO00886)-A10
2.2.1
Phase II:  Primary Objective......................................................... 43
2.2.2
Phase II:  Secondary Objectives .................................................. 43
2.2.3
Phase II:  Exploratory Objectives ................................................. 44
3.
STUDY DESIGN.......................................................................................... 44
3.1
Description of the Study ..................................................................... 44
3.1.1
Phase I......................................................................................... 45
3.1.2
Phase II........................................................................................ 51
3.1.3
Stage 1:  Dose Escalation to Estimate the Maximum 
Tolerated Dose ........................................................................................ 52
3.1.4
Stage 2:  Expanded Cohorts in Specific Disease or 
Patient Subsets........................................................................................ 55
3.1.5
Phase II Portion for GDC-0032 and Fulvestrant........................... 72
3.2
Rationale for Study Design................................................................. 72
3.2.1
Rationale for Patient Group Selection in Stage 1 ......................... 72
3.2.2
Rationale for Starting Dose and Schedule and 
Dose-Escalation Rules in Stage 1 of Phase I .......................................... 73
3.2.3
Rationale for the Pharmacokinetic Evaluation 
Schedule.................................................................................................. 73
3.2.4
Rationale for the Food–Effect Analysis in the Stage 2, 
Cohort A................................................................................................... 74
3.2.5
Rationale for Selection of the Recommended Dose 
for Future Trials ....................................................................................... 74
3.2.6
Rationale for Dosing beyond Cycle 1 ........................................... 75
3.2.7
Rationale for Evaluating Patients with 
PIK3CA-Mutant Solid Tumors Treated with Single-Agent 
GDC-0032 (Stage 2, Cohorts A, B, H, and X).......................................... 75
3.2.8
Rationale for Assessing the Effect of GDC-0032 on 
Midazolam Pharmacokinetics (Stage 2, Cohort C) .................................. 77
3.2.9
Rationale for Evaluating Patients with HER2-Positive 
Breast Cancer at the Recommended Dose for Future Trials 
(Stage 2, Cohort D).................................................................................. 77
3.2.10
Rationale for Evaluating Patients with Solid Tumors 
with Increased PIK3CA Copy Number at the Recommended 
Dose for Future Trials (Stage 2, Cohort G).............................................. 78
3.2.11
Rationale for Evaluating Hormone 
ReceptorPositive Breast Cancer at the Recommended 
Dose for Future Trials with Alternate Schedules in 


Protocol:  GDC-0032—Genentech, Inc.
6/P PMT4979g (GO00886)-A10
Combination with Endocrine Therapy (Stage 2, Cohorts E, F, 
JM, and NS)......................................................................................... 78
3.2.12
Rationale for Evaluating Hormone 
ReceptorPositive Breast Cancer at 2-mg Tablets (Stage 2, 
Cohorts M and N) .................................................................................... 80
3.2.13
Rationale for Implementing GDC-0032 in Tablet 
Form for Cohorts HX.............................................................................. 80
3.2.14
Rationale for Assessing the Pharmacokinetics of 
GDC-0032 in Combination with Letrozole (Stage 2, 
Cohorts E and NS)................................................................................. 80
3.2.15
Rationale for Assessing the Pharmacokinetics of 
GDC-0032 in Combination with Fulvestrant (Stage 2, 
Cohorts F, J, K, L, and M; Phase II)......................................................... 81
3.2.16
Rationale for Evaluating Patients with Non-
Hodgkin’s Lymphoma (Stage 2, Cohort T)............................................... 81
3.2.17
Rationale for the Patient Population for Phase II 
Portion ................................................................................................... 81
3.2.18
Rationale for Assessing the Safety and Efficacy of 
GDC-0032 in Combination with Fulvestrant                
(Phase II Portion)..................................................................................... 82
3.2.19
Rationale for Selection of the Recommended 
GDC-0032 Dose in Combination with Fulvestrant for the 
Phase II Portion ....................................................................................... 82
3.2.20
Rationale for QT/QTc Assessments........................................... 83
3.2.21
Rationale for FDG-PET Evaluation............................................. 84
3.2.22
Rationale for Surrogate Pharmacodynamic Samples................. 84
3.2.23
Rationale for Pharmacogenetic Blood Sample 
Collection................................................................................................. 84
3.2.24
Rationale for Collection of Archival Tumor 
Specimens............................................................................................... 85
3.2.25
Rationale for Collection of Fresh Tumor Specimens .................. 86
3.2.26
Rationale for Collection of Blood for DNA Mutation 
Analysis in Plasma................................................................................... 86
3.2.27
Rationale for Collection of Blood Sample for the 
Detection of Circulating Tumor Cells........................................................ 87
3.2.28
Rationale for Collection of Blood Sample for the 
Detection of Cytokine and Chemokines in the Plasma ............................ 87


Protocol:  GDC-0032—Genentech, Inc.
7/P PMT4979g (GO00886)-A10
3.2.29
Rationale for Suspension (Extemporaneous 
Formulation) for Patients with Head and Neck Squamous 
Cell Carcinoma ........................................................................................ 87
3.2.30
Rationale for Cycle 1, Day 8 Visit for Cohort H........................... 87
3.2.31
Rationale for Evaluating NHL using 4-mg Tablets 
(Stage 2, Cohort T and T2)...................................................................... 88
3.2.32
Rationale for Pneumocystis Jirovecii Pneumonia 
Prophylaxis in Cohorts T and T2.............................................................. 88
3.2.33
Rationale for Change in Starting Dose from 6 mg to 
4 mg in Cohort X...................................................................................... 89
3.2.34
Rationale for Collecting Tumor TypeSpecific 
Cancer History and Tumor Pathology...................................................... 89
3.3
Outcome Measures ............................................................................ 89
3.3.1
Safety Outcome Measures........................................................... 89
3.3.2
Pharmacokinetic Outcome Measures........................................... 90
3.3.3
Activity Outcome Measure ........................................................... 90
3.3.4
Exploratory Outcome Measures................................................... 91
3.4
Safety Plan ......................................................................................... 91
3.4.1
Nonclinical Toxicity with GDC-0032 ............................................. 91
3.4.2
Toxicity with PI3K Inhibitors in the Clinic...................................... 92
3.4.3
Toxicities Observed with GDC-0032 in Clinical 
Studies..................................................................................................... 93
3.4.4
Safety Monitoring of GDC-0032 ................................................... 95
3.4.5
Management of Toxicities ............................................................ 96
3.4.6
Safety Monitoring for Midazolam................................................ 106
3.4.7
Safety Monitoring for Letrozole................................................... 106
3.4.8
Safety Monitoring for Fulvestrant................................................ 107
3.5
Dosing Considerations ..................................................................... 107
3.6
Compliance with Laws and Regulations........................................... 107
4.
MATERIALS AND METHODS ................................................................... 108
4.1
Patients ............................................................................................ 108
4.1.1
Patient Selection ........................................................................ 108
4.1.2
Inclusion Criteria......................................................................... 108
4.1.3
Exclusion Criteria ....................................................................... 112
4.2
Method of Treatment Assignment..................................................... 115


Protocol:  GDC-0032—Genentech, Inc.
8/P PMT4979g (GO00886)-A10
4.3
Study Treatment............................................................................... 115
4.3.1
Formulation and Storage............................................................ 115
4.3.2
Dosage and Administration ........................................................ 116
4.3.3
Dose Modification....................................................................... 122
4.4
Concomitant and Excluded Therapies.............................................. 126
4.4.1
Concomitant Therapy................................................................. 126
4.4.1.1
Infection Prophylaxis.......................................................... 126
4.4.2
Excluded Therapy and Foods .................................................... 127
4.5
Study Assessments.......................................................................... 128
4.5.1
Definitions of Study Assessments .............................................. 128
4.5.2
Screening and Pretreatment Assessments ................................ 139
4.5.3
Assessments during Treatment.................................................. 139
4.5.4
Study Completion/Early Termination Visit .................................. 140
4.5.5
Follow-Up Assessments............................................................. 140
4.6
Patient Discontinuation..................................................................... 140
4.7
Post-Trial Access.............................................................................. 142
4.8
Assay Methods................................................................................. 142
4.9
Statistical Methods ........................................................................... 145
4.9.1
Analysis of the Conduct of the Study.......................................... 145
4.9.2
Safety Analyses.......................................................................... 145
4.9.3
Pharmacokinetic Analyses ......................................................... 145
4.9.4
Food-Effect Analyses ................................................................. 146
4.9.5
Analyses of Effect of GDC-0032 on the 
Pharmacokinetics of Midazolam ............................................................ 146
4.9.6
Analyses of the Pharmacokinetics of GDC-0032 in 
Combination with Letrozole.................................................................... 146
4.9.7
Analyses of the Pharmacokinetics of GDC-0032 in 
Combination with Fulvestrant................................................................. 146
4.9.8
Activity Analyses ........................................................................ 147
4.9.9
Exploratory Analyses.................................................................. 148
4.9.10
Determination of Sample Size.................................................. 149
4.10
Data Quality Assurance.................................................................. 155
5.
ASSESSMENT OF SAFETY...................................................................... 156
5.1
Safety Parameters and Definitions ................................................... 156


Protocol:  GDC-0032—Genentech, Inc.
9/P PMT4979g (GO00886)-A10
5.1.1
Adverse Events .......................................................................... 156
5.1.2
Serious Adverse Events ............................................................. 157
5.1.3
Protocol-Defined Events of Special Interest/Non-
Serious Expedited Adverse Events........................................................ 158
5.2
Methods and Timing for Capturing and Assessing 
Safety Parameters............................................................... 158
5.2.1
Adverse Event Reporting Period ................................................ 158
5.2.2
Eliciting Adverse Event Information............................................ 158
5.2.3
Assessment of Severity and Causality of Adverse 
Events ................................................................................................... 159
5.3
Procedures for Recording Adverse Events....................................... 160
5.3.1
Recording Adverse Events on the eCRF.................................... 160
5.4
Expedited Reporting Requirements for Serious 
Adverse Events and Protocol-Defined Events of 
Special Interest.................................................................... 164
5.4.1
Reporting Requirements for Fatal/Life-Threatening 
Serious Adverse Events Related to Investigational Product .................. 164
5.4.2
Reporting Requirements for All Serious Adverse 
Events and Non-Serious Adverse Events of Special Interest ................ 165
5.5
Type and Duration of Follow Up of Patients after 
Adverse Events ................................................................... 165
5.6
Post-Study Adverse Events.............................................................. 165
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics 
Committees ......................................................................... 166
6.
INVESTIGATOR REQUIREMENTS .......................................................... 166
6.1
Study Initiation.................................................................................. 166
6.2
Study Completion ............................................................................. 167
7.
ETHICAL CONSIDERATIONS................................................................... 168
7.1
Compliance with Laws and Regulations........................................... 168
7.2
Informed Consent Form.................................................................... 168
7.3
Communication with the Institutional Review Board or 
Ethics Committee ................................................................ 169
7.4
Confidentiality................................................................................... 170
7.5
Financial Disclosure ......................................................................... 170


Protocol:  GDC-0032—Genentech, Inc.
10/P PMT4979g (GO00886)-A10
8.
DATA COLLECTION AND MANAGEMENT .............................................. 171
8.1
Data Quality Assurance.................................................................... 171
8.2
Study Monitoring Requirements ....................................................... 171
8.3
Electronic Case Report Forms ......................................................... 171
8.4
Source Data Documentation ............................................................ 171
8.5
Use of Computerized Systems ......................................................... 172
8.6
Study Medication Accountability....................................................... 172
8.7
Disclosure of Data ............................................................................ 173
8.8
Retention of Records........................................................................ 173
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 174
9.1
Study Documentation ....................................................................... 174
9.2
Protocol Deviations........................................................................... 174
9.3
Site Inspections ................................................................................ 174
9.4
Administrative Structure ................................................................... 174
9.5
Dissemination of Data and Protection of Trade Secrets .................. 175
9.6
Protocol Amendments ...................................................................... 176
10. REFERENCES ......................................................................................... 177
LIST OF TABLES
Table 1
Dose Conversion between GDC-0032 Capsules and Tablets ............ 80
Table 2
GDC-0032 Dose Delay and Modification Guidelines for 
Hyperglycemia ............................................................................ 97
Table 3
Management of Pneumonitis .............................................................. 98
Table 4
GDC-0032 Dose Delay and Modification Guidelines for Rash............ 99
Table 5
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis ............................................................. 101
Table 6
GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis .................................................................... 103
Table 7
Neutropenia Management Guidelines............................................... 105
Table 8
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events ........................................ 106
Table 9
Dose Modifications for GDC-0032 in Stage 2, Cohorts AD and 
GX, and for Cycles 2 and Greater in Stage 1 and Stage 2, 
Cohorts E and F........................................................................ 124
Table 10
Dose Modifications for Phase II ...................................................... 125


Protocol:  GDC-0032—Genentech, Inc.
11/P PMT4979g (GO00886)-A10
Table 11
Probability for the Dose-Escalation Rules with Different 
Underlying Rates of Dose-Limiting Toxicity............................... 150
Table 12
Confidence Intervals under Different Response Rates ................... 154
Table 13
Confidence Intervals under Different Underlying Adverse Event 
Rates ........................................................................................ 155
Table 14
Adverse Event Grading (Severity) Scale......................................... 159
Table 15
Causal Attribution Guidance ........................................................... 160
LIST OF FIGURES
Figure 1
Phase I Study Schema (Stage 1Dose Escalation) ......................... 49
Figure 2
Phase I Study Schema (Stage 2Expansion).................................... 50
Figure 3
Phase I Study Schema (Stage 2Cohort X)....................................... 51
Figure 4
Phase II Study Schema ..................................................................... 52
Figure 5
Phase I Stage 2 Dosing and Pharmacokinetic Sample Collection..... 66
Figure 6
Phase II:  Pharmacokinetic Sample Collection to Measure 
Fulvestrant and GDC-0032 Concentrations ................................ 72
LIST OF APPENDICES
Appendix A-1
Study Flowchart:  Screening and Cycle 1 Assessments for 
Stage 1 ..................................................................................... 183
Appendix A-2
Study Flowchart:  Screening and Cycle 1 Assessments for 
Stage 2, Cohort A ..................................................................... 187
Appendix A-3
Study Flowchart:  Screening and Cycle 1 Assessments for 
Stage 2, Cohorts B, D, and G ................................................... 191
Appendix A-4
Study Flowchart:  Screening and Cycle 1 Assessments for 
Stage 2, Cohort C ..................................................................... 195
Appendix A-5
Study Flowchart:  Screening and Cycle 1 Assessments for 
Stage 2, Cohorts E and F.......................................................... 199
Appendix A-6
Study Flowchart:  Assessments for Continuation of 
Treatment beyond Cycle 1 (Stage 1; Stage 2, Cohorts AG) ... 203
Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, 
S, T, T2, and X (X1X11) before LPI 6 months...................... 207
Appendix A-8
Study Flowchart:  Phase II Portion of the Study....................... 215
Appendix A-9 Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, 
R, S, T, T2, and X (X1X11) after LPI 6 Months (Patients 
Deriving Benefit from GDC-0032) ........................................... 220
Appendix B-1
Pharmacokinetic, Surrogate Pharmacodynamic, and 
CYP450 Genotyping Flowchart for Patients in Stage 1............. 223
Appendix B-2
Pharmacokinetic, Insulin and Glucose, and CYP450
Genotyping Flowchart for Stage 2, Cohort A (Effect of Food 


Protocol:  GDC-0032—Genentech, Inc.
12/P PMT4979g (GO00886)-A10
on GDC-0032 Pharmacokinetics in Patients with 
PIK3CA-Mutant Breast Cancers) .............................................. 225
Appendix B-3
Pharmacokinetic, Insulin and Glucose, and CYP450 
Genotyping Flowchart for Stage 2, Cohort B (Patients with 
PIK3CA-Mutant Solid Tumors), Cohort D (Patients with 
HER2-Positive Breast Cancers), and Cohort G (Patients with 
PIK3CA-Amplified Solid Tumors).............................................. 228
Appendix B-4
Pharmacokinetic, Insulin and Glucose, and CYP450 
Genotyping Flowchart for Stage 2, Cohort C (Effect of 
GDC-0032 on Midazolam in Patients with Solid Tumors) ......... 230
Appendix B-5
Pharmacokinetic, Insulin and Glucose, and CYP450 
Genotyping Flowchart for Stage 2, Cohort E (GDC-0032 in 
Combination with Letrozole in Patients with Hormone 
ReceptorPositive Breast Cancer)............................................ 232
Appendix B-6
Pharmacokinetic, Insulin and Glucose, and CYP450 
Genotyping Flowchart for Stage 2, Cohort F (GDC-0032 in 
Combination with Fulvestrant in Patients with Hormone 
ReceptorPositive Breast Cancer)............................................ 234
Appendix B-7
Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohorts H and X Patients.......................................................... 236
Appendix B-8
Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohorts J, K, and M Patients .................................................... 237
Appendix B-9
Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohorts N, P, Q, and R Patients ............................................... 238
Appendix B-10 Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohort X3 (Head and Neck Cancer) Patients Taking 
GDC-0032 as Suspension ........................................................ 239
Appendix B-11 Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohort L Patients ...................................................................... 240
Appendix B-12 Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohort S Patients...................................................................... 241
Appendix B-13 Pharmacokinetic Sample Collection:  Phase I, Stage 2, 
Cohorts T and T2 Patients ........................................................ 242
Appendix B-14 Pharmacokinetic Sample Collection:  Phase II Patients........... 243
Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):   
Modified Excerpt from Original Publication ............................... 244
Appendix D
Criteria for PSA Response and Progression for Prostate 
Cancer Patients ........................................................................ 256
Appendix E
Response Criteria for Patients with Ovarian Cancer Who 
Have Evaluable but Non-Measurable Disease.......................... 257
Appendix F
ECOG Performance Status Scale.............................................. 258
Appendix G
Assessment of FDG-PET Responses ....................................... 259
Appendix H
Instructions for Scans in the Event of Isotope Shortage............ 260
Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s 
Lymphoma Cohort T ................................................................. 261
Appendix J
Lugano Response Criteria for DLBCL Cohort T2 ....................... 267


Protocol:  GDC-0032—Genentech, Inc.
13/P PMT4979g (GO00886)-A10
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, PHASE I/II, DOSE-ESCALATION STUDY 
EVALUATING THE SAFETY AND TOLERABILITY OF GDC-0032 
IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
SOLID TUMORS OR NON-HODGKIN’S LYMPHOMA AND IN 
COMBINATION WITH ENDOCRINE THERAPY IN PATIENTS 
WITH LOCALLY ADVANCED OR METASTATIC HORMONE 
RECEPTORPOSITIVE BREAST CANCER
PROTOCOL NUMBER:
PMT4979g (GO00886)
VERSION NUMBER
A10
EUDRACT NUMBER:
2012-002042-21
TEST PRODUCT:
GDC-0032
IND NUMBER:
110184
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
1 DNA Way
South San Francisco, CA  94080-4990  U.S.A.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator Name  (print)
Principal Investigator Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy 
to your local study monitor.


Protocol:  GDC-0032—Genentech, Inc.
14/P PMT4979g (GO00886)-A10
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, PHASE I/II, DOSE-ESCALATION STUDY 
EVALUATING THE SAFETY AND TOLERABILITY OF GDC-0032 
IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
SOLID TUMORS OR NON-HODGKIN’S LYMPHOMA AND IN 
COMBINATION WITH ENDOCRINE THERAPY IN PATIENTS WITH 
LOCALLY ADVANCED OR METASTATIC HORMONE 
RECEPTORPOSITIVE BREAST CANCER
PROTOCOL NUMBER:
PMT4979g (GO00886)
VERSION NUMBER
A10
EUDRACT NUMBER:
2012-002042-21
TEST PRODUCT:
GDC-0032
PHASE:
I/II
INDICATION:
Advanced or Metastatic Solid Tumors 
IND NUMBER:
110184
SPONSOR:
Genentech, Inc.
Objectives
Phase I Objectives (Stage 1 and Stage 2)
Phase I:  Primary Objectives
The primary objectives of this study are the following:

Stage 1:  To evaluate the safety and tolerability of escalating doses of GDC-0032 
administered daily for 28 days to patients with locally advanced or metastatic solid tumors.

Stage 1:  To determine the MTD of GDC-0032 and to characterize dose-limiting toxicities 
(DLTs) associated with GDC-0032 when administered daily for 28 days to patients with 
locally advanced or metastatic solid tumors

To characterize the pharmacokinetic (PK) properties of GDC-0032

To identify a recommended dose and schedule of single-agent GDC-0032 for future trials

To evaluate the safety and tolerability of concomitant daily administration of GDC-0032 and 
letrozole in postmenopausal patients with locally advanced or metastatic hormone 
receptorpositive breast cancer

To evaluate the safety and tolerability of concomitant administration of GDC-0032 and 
fulvestrant in postmenopausal patients with locally advanced or metastatic hormone 
receptorpositive breast cancer

To evaluate the safety and tolerability of GDC-0032 in patients with non-Hodgkin’s 
lymphoma

To evaluate the safety and tolerability of GDC-0032 in patients with PIK3CA-mutant locally 
advanced or metastatic solid tumors
Phase I:  Secondary Objectives
The secondary objectives of this study are the following:

To make a preliminary assessment of the anti-tumor activity of single-agent GDC-0032 in 
patients with locally advanced or metastatic solid tumors, non-Hodgkin’s lymphoma, tumors 
with PIK3CA mutations, HER2-positive breast tumors, and tumors with increased PIK3CA
copy number


Protocol:  GDC-0032—Genentech, Inc.
15/P PMT4979g (GO00886)-A10

To evaluate the effect of food on the pharmacokinetics of GDC-0032

To evaluate the effect of GDC-0032 on the pharmacokinetics of midazolam

To assess the pharmacokinetics of GDC-0032 and letrozole following administration of 
GDC-0032 in combination with letrozole

To assess the pharmacokinetics of GDC-0032 and fulvestrant following administration of 
GDC-0032 in combination with fulvestrant

To make a preliminary assessment of the anti-tumor activity of GDC-0032 in combination 
with letrozole in patients with locally advanced or metastatic hormone receptorpositive 
breast cancer

To make a preliminary assessment of the anti-tumor activity of GDC-0032 in combination 
with fulvestrant in patients with locally advanced or metastatic hormone receptorpositive 
breast cancer
Phase I:  Exploratory Objectives
The exploratory objectives of this study are the following:

To determine the proportion of PI3K mutations, PI3K amplifications, and loss of PTEN 
expression in archival tissue and/or in circulating tumor DNA (ctDNA) and/or circulating 
tumor cells (CTCs) from blood obtained from patients in this study

To make a preliminary assessment of PD, dose, and anti-tumor activity with PI3K mutation 
status, alterations determined by next-generation sequencing (NGS) platforms from 
archival and fresh tumor biopsies, DNA (ctDNA) and/or circulating tumor cells (CTCs), and 
patients’ clinical and pathological characteristics

To make a preliminary assessment of PD, dose, and anti-tumor activity with PI3K mutation 
status, BCL2 and MYC expression, BCL2 and MYC rearrangement, cell-of-origin subtype, 
and DNA and RNA alterations determined by NGS in patients with relapsed or refractory 
DLBCL

To evaluate changes in tumor 18fluorodeoxyglucose (FDG) uptake as assessed by positron 
emission tomography (PET)

To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream 
markers in tumor tissue and to examine the relationship to dose and anti-tumor activity

To explore the potential role of polymorphisms in drug metabolism enzyme and transporter 
genes in the PK of GDC-0032

To explore whether inhibition of PI3K results in changes in metabolic profiles in plasma and 
urine

To obtain pharmacodynamic data on the effects of GDC-0032 in combination with letrozole 
on the PI3-kinase pathway using pre- and on-treatment biopsies 
Phase II Objectives
Phase II:  Primary Objective
The primary objective of the Phase II portion of the study is the following: 

To assess the clinical efficacy of the combination of GDC-0032 and fulvestrant, as 
measured by the clinical benefit rate and objective response rate, in all patients and 
patients with PIK3CA-mutant breast cancer
Phase II:  Secondary Objectives
The secondary objectives of the Phase II portion of this study are the following:

To assess the clinical efficacy of GDC-0032 and fulvestrant, as measured by duration of 
response, PFS, and OS in all patients and patients with PIK3CA mutant breast cancer

To determine the nature, severity, and frequency of adverse events associated with the 
combination of GDC-0032 and fulvestrant 


Protocol:  GDC-0032—Genentech, Inc.
16/P PMT4979g (GO00886)-A10

To evaluate plasma concentrations of GDC-0032 and fulvestrant using a sparse sampling 
approach. 
Phase II:  Exploratory Objectives
The exploratory objectives of the Phase II portion of this study are the following:

To explore the exposure-response relationship for safety and efficacy with GDC-0032 and 
fulvestrant 

To explore predictors of response to the combination of fulvestrant and GDC-0032 based 
on exploratory analyses of tumor tissue, circulating tumor DNA (ctDNA), circulating tumor 
cells (CTCs), and cytokine and chemokine levels from blood obtained from patients in this 
study
Study Design
Description of the Study
This is an open-label, multicenter, Phase I/II study.  The Phase I portion is divided into two 
stages.  Phase I, Stage 1 is a dose-escalation study using a 3 3 design to assess the safety, 
tolerability, and pharmacokinetics of GDC-0032 administered QD orally (PO) as a single agent.  
Phase I Stage 2 includes a cohort-expansion study to assess the safety, tolerability, 
pharmacokinetics, and preliminary activity of GDC-0032 administered as a single agent or in 
combination in multiple tumor types.  In addition, Phase I Stage 2 Cohorts E and F are 
dose-escalation cohorts to assess GDC-0032 in combination with endocrine therapy in patients 
with hormone receptorpositive breast cancer.  Alternate intermittent dosing schedules with 
GDC-0032 as either a single agent or in combination with endocrine therapy will also be 
evaluated in Stage 2.  Patients enrolled in Phase I, Stage 1 and Stage 2 Cohorts AG will 
receive GDC-0032 in capsule formulation, whereas patients in Phase I, Stage 2 Cohorts HX 
will receive GDC-0032 in tablet formulation.  See below for detailed descriptions of the 
individual cohorts.
The Phase II portion is an open-label, single-arm study to assess the clinical activity of 
GDC-0032 in capsule formulation administered QD orally in combination with fulvestrant.
Approximately 563663 patients will be enrolled into Phase I of this study.  Stage 1 
(dose-escalation stage) of the Phase I portion of this study has completed enrollment with 
34 patients enrolled.  Stage 2 (cohort expansion stage) of Phase I will enroll approximately 
529629 patients with locally advanced or metastatic solid tumors or non-Hodgkin’s lymphoma 
for which standard therapy either does not exist or has proven ineffective.
The Phase II portion of this study has completed enrollment with 60 postmenopausal patients 
with locally recurrent or metastatic hormone receptorpositive breast cancer enrolled.
All patients will be carefully followed for adverse events throughout the study, which will be 
graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 4.0 (NCI CTCAE v4.0).
Patients will be enrolled at sites in the United States, Canada, and Europe.
The Sponsor has decided to discontinue enrollment in the study as of 28 June 2018 and 
discontinue manufacturing of GDC-0032.  This decision was based on the results of the 
primary analysis of Study GO29058, a Phase III study of GDC-0032 in combination with 
fulvestrant for the treatment of metastatic, hormone receptorpositive breast cancer 
(GO29058), which showed that GDC-0032 plus fulvestrant had modest clinical benefit and 
limited overall tolerability.  Patients participating in the study as of 28 June 2018 will 
continue to receive treatment and undergo assessments (as outlined in Appendix A-7) until 
6 months after enrollment of the last patient (last patient in [LPI] 6 months).  After this 
time, patients who are deriving clinical benefit from GDC-0032, as determined by the 
investigator, may continue their assigned treatment regimen until disease progression, 
unacceptable toxicity, expiration of the last batch of GDC-0032 (expected by May 2021), or 
discontinuation of the study by the Sponsor, whichever occurs first.  Patients continuing 
treatment beyond LPI 6 months will undergo a reduced set of assessments, as outlined in 
Appendix A-9).  Beyond LPI 6 months, discontinuation of GDC-0032 treatment will also 


Protocol:  GDC-0032—Genentech, Inc.
17/P PMT4979g (GO00886)-A10
constitute discontinuation from the study.  Survival follow-up will be halted as of LPI 6 
months.
Phase 1
There are two stages to the Phase I portion of this study:  Stage 1 (dose escalation) and 
Stage 2 (expansion).  Each stage consists of three study periods:  a screening period of 
14 days or less, followed by a treatment period of up to 5 years, and a 30-day follow-up period.
Stage 1 will examine the safety and pharmacokinetics of increasing doses of GDC-0032 
administered daily in a 28-day cycle in patients with locally advanced or metastatic solid tumors 
for which standard therapy either does not exist or has proven ineffective or intolerable.  
Thirty-four patients were enrolled in Stage 1, which has been completed.  Refer to the Taselisib 
(GDC-0032) Investigator’s Brochure for further information.
DLTs will be assessed during the DLT assessment window (Days 135 of Cycle 1 in Stage 1 
and Days 128 in Stage 2, Cohorts E and F.
Stage 2 is designed to provide a preliminary assessment of single-agent activity with GDC-0032 
and in combination with endocrine therapy to better characterize the safety, tolerability, and PD 
and PK variability of different doses and schedules for future studies.  The pharmacokinetics 
and safety profile of GDC-0032 as a single-agent will be assessed in Cohorts A, B, C, D, G, H, 
T, T2, and X.  The pharmacokinetics and safety profile of GDC-0032 in combination with 
letrozole will be assessed in Cohorts E, N, P, Q, R, and S.  The pharmacokinetics and safety 
profile of GDC-0032 in combination with fulvestrant will be assessed in Cohorts F, J, K, L, and 
M.
Pharmacokinetics (PK):  GDC-0032 pharmacokinetics will be evaluated in both stages.  
Changes to PK sampling times, slower dose escalation, and/or changes to the dosing schedule 
may be implemented on the basis of the results of PK analyses.  Additional PK sampling may 
occur if GDC-0032 is held for an adverse event in order to better characterize the safety profile 
of GDC-0032.
Pharmacodynamics (PD):  PD analyses will include imaging studies and assessments of PD 
biomarkers in both tumor tissue and blood:
Blood samples for platelet-rich plasma:  In Stage 1 only, blood samples will be collected at 
various timepoints and processed to obtain platelet-rich plasma to explore changes in 
surrogate PD markers in response to GDC-0032.
Circulating tumor cells (CTC) analyses:  Blood samples will be collected for analyses of 
CTCs from all patients pretreatment, on Day 15 or Day 16 of Cycle 1, on Day 1 of Cycle 3, 
at the study completion visit, and also at the clinic visit subsequent to a confirmed partial or 
complete tumor response (per Response Evaluation Criteria in Solid Tumors [RECIST]) for 
any patient, except for patients enrolled in Cohorts Q, R, S, T, T2, and X.
Circulating tumor DNA analysis:  Blood samples for DNA sequencing to identify PIK3CA
and cancer-related mutations in ctDNA will be collected from all patients pretreatment, 
Cycle 3 Day 1, Cycle 5 Day 1, at the study completion visit, and also at clinic visits on Day 1 
of every odd-numbered cycle subsequent to a confirmed partial or complete tumor or 
lymphoma response for any patient.
Paired tumor biopsies:  Optional paired tumor biopsy samples for patients in Stages 1 and 2 
will be obtained pretreatment (prior to initiation of treatment with GDC-0032 on Day 1 of 
Cycle 1) and on-treatment during Cycle 1, between Days 1521 (see Section 4.5.1.n).  A 
tumor biopsy upon progression of disease will also be optional in this trial.  From each of 
Cohorts N and P, a minimum of 3 patients with PIK3CA-mutant tumors and 3 patients with 
PIK3CA-wild-type tumors (12 total) are required to provide fresh pre-treatment and on-
treatment (Cycle 1 Days 1521, 14 hours post-GDC-0032 dose) biopsy samples to assess 
the effects of GDC-0032 on the PI3K (and other) pathways in the 2-mg and 4-mg tablet 
doses in combination with letrozole. In Cohort X3, a minimum of 5 patients are required to 
provide fresh pre-treatment and on-treatment biopsy samples to assess the effects of 
GDC-0032 on PI3K (and other cancer-related) pathways in HNSCC.  If the tissue is not 
evaluable for these PD measurements, additional patients may be enrolled to complete the 
cohort.


Protocol:  GDC-0032—Genentech, Inc.
18/P PMT4979g (GO00886)-A10
FDG-PET imaging (includes FDG-PET and/or FDG-PET/CT scans) will be optional for 
patients in Phase I Stage 1, Cohort 1 but mandatory for patients in Stage 1, Cohorts 2 
and in selected cohorts of Phase I Stage 2 (A-G, L, M, N, Q, R, and S).  Patients will 
undergo FDG-PET imaging pretreatment (within 14 days before Cycle 1, Day 1), during the 
last week of Cycle 1 (e.g., between Days 2935 [Stage 1] or Days 2228 [Stage 2]), and at 
the end of Cycle 2 (between Days 2228).  If the pretreatment FDG-PET imaging for a 
patient shows no detectable tumor FDG uptake, then subsequent FDG-PET imaging will not 
be required for that patient.  If there are no significant changes in FDG-PET in Cycle 1, 
FDG-PET imaging should not be obtained in Cycle 2.  FDG-PET results will not be used for 
assessments of response or progression or for decisions regarding continuation of study 
treatment or study discontinuation, as FDG-PET has not been validated as an indicator of 
early response or progression in this setting.
Pharmacogenetic analysis:  A blood sample for DNA isolation will be collected from all patients 
in this study for potential pharmacogenetic analysis of genes that may affect the 
pharmacokinetics of or response to GDC-0032.
Efficacy analysis:  Disease status will be assessed using RECIST v1.1, except for Cohort T, 
which will use the Revised International Working Group (IWG) Response Criteria for Malignant 
Lymphoma and Cohort T2, which will use a modified version of the Lugano Response Criteria 
for Malignant Lymphoma.  Patients will undergo tumor and response assessments at screening 
and then at the end of every even-numbered cycle (i.e., every two cycles), or earlier if clinically 
indicated.  If a patient undergoes an interim tumor evaluation to confirm a partial response 
(i.e., between 47 weeks after previous tumor assessment), the next scheduled tumor 
assessment may be skipped so as to not expose patients to excessive radiation from tumor 
assessments.
In the absence of a DLT, unacceptable toxicity, or disease progression, patients with clinical 
benefit will be offered continued treatment with GDC-0032 for up to 5 years.  Continued dosing 
beyond Cycle 1 will be at the discretion of the investigator, after a careful assessment and 
thorough discussion of the potential risks and benefits of continued treatment with the patient.  
Patients who are benefiting from GDC-0032 after the 5-year treatment period may have the 
possibility of continued treatment, provided that study drug is available.
Patients who experience a DLT during the DLT Assessment Window (Days 135 of Cycle 1 for 
Stage 1 and Days 128 of Cycle 1 for Stage 2, Cohorts E and F), experience disease 
progression or unacceptable toxicity at any time during the study, or, in their opinion or the 
opinion of the investigator, are not benefiting from GDC-0032, will be discontinued from 
GDC-0032 study treatment.  In some cases, if the adverse event is reversible and monitorable 
and the risk/benefit assessment suggests a reasonable rationale for continued treatment with 
study drug, patients may be allowed to continue with study treatment with agreement by the 
investigator and the Medical Monitor.  A Study Completion/Early Termination Visit 
will be performed approximately 30 days after the last dose of GDC-0032.  The end of the study 
is defined as the date on which the last patient has his or her last visit (LPLV).
Phase II
The Phase II portion of this study is designed to provide safety and efficacy data on the 
combination of fulvestrant and GDC-0032.  Based on the Phase I (Stage 1 and Stage 2) clinical 
data, the recommended Phase II dose of GDC-0032 in combination with fulvestrant has been 
determined to be 6 mg QD.
In the Phase II portion of the study, approximately 60 postmenopausal patients with locally 
advanced or metastatic HER2-negative, hormone receptorpositive breast cancer who have not 
previously received fulvestrant will be enrolled in this study at sites in the United States and in 
Europe.  A minimum of 30 patients will have PIK3CA mutant breast cancer.
All patients will be carefully followed for adverse events throughout the study, which will be 
graded according to NCI CTCAE v4.0.
GDC-0032 and fulvestrant plasma concentrations will be evaluated using a sparse sampling 
approach.  Additional PK sampling may occur if GDC-0032 is held for an adverse event in order 
to better characterize the safety profile of GDC-0032.


Protocol:  GDC-0032—Genentech, Inc.
19/P PMT4979g (GO00886)-A10
PD analyses will include assessments of PD biomarkers in both tumor tissue and blood.  Blood 
samples will be collected for analyses of CTCs, ctDNA, and cytokines and chemokines.  Paired 
tumor biopsy samples obtained pretreatment (prior to initiation of treatment with GDC-0032 on 
Day 1 of Cycle 1) and during Cycle 2 will be optional for patients.  A tumor biopsy upon 
progression of disease will also be optional.
Disease status will be assessed using RECIST v1.1.  Patients will undergo tumor and response 
assessments at screening and then at timepoints as described in Appendix A-8, or earlier if 
clinically indicated.  Bone scans will be performed as described in Appendix A-8.
All patients who discontinue from the treatment phase will be followed for survival information 
and subsequent anti-cancer therapies unless the patient requests to be withdrawn from study 
survival follow-up.  Survival follow-up information will be collected via telephone calls, patient’s 
medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
withdrawal of consent, or study termination by Genentech.
Length of Study
The enrollment duration is projected to be approximately 92 months after the first patient is 
enrolled.
End of Study
The end of the study is defined as the date on which the last patient has their last visit (LPLV).  
However, Genentech has the right to terminate this study at any time prior to the LPLV.
Outcome Measures
Safety Outcome Measures
The safety and tolerability of GDC-0032 will be assessed using the following primary safety 
outcome measure:

Incidence of DLTs by NCI CTCAE v4.0 grade and associated dose of GDC-0032
In addition the safety will be assessed using the following secondary safety outcome measures:

Incidence of adverse events by NCI CTCAE v4.0 grade and associated dose of GDC-0032

Incidence of Grade 3 and 4 abnormalities in safety-related laboratory parameters and 
associated dose of GDC-0032
Pharmacokinetic Outcome Measures
The following primary PK parameters will be derived from the plasma concentration–time profile 
of GDC-0032, following administration of single and/or multiple doses, when appropriate as data 
allow:

AUCinf after single dose and AUC0-after single and multiple doses

Maximum plasma concentration (Cmax)

Minimum plasma concentration (Cmin)

Time to maximum plasma concentration (tmax)

Terminal half-life (t1/2)

Apparent clearance (CL/F) after single and multiple doses

Accumulation ratio (AR) at steady-state
The following secondary PK parameters may also be derived, when appropriate as data allow:

Cmax and AUC under fed and fasted conditions (for patients participating in the 
food-effect assessment)

AUC0-24hr, Cmax, tmax, and other PK parameters of midazolam, letrozole, and fulvestrant, 
when applicable


Protocol:  GDC-0032—Genentech, Inc.
20/P PMT4979g (GO00886)-A10

Fraction of dose excreted (fe) and renal CL (CLr)

PK-dose proportionality as assessed with Cmax and AUC

The time to achieve steady state as assessed with trough (predose) concentrations
For Phase II
A sparse sampling approach will be used to assess the plasma concentrations of GDC-0032 
and fulvestrant following single and multiple doses.
Activity Outcome Measures
The following activity outcome measure will be assessed:

Best overall response, duration of objective response, and progression-free survival (PFS) 
for patients with measurable disease according to RECIST v1.1

In Cohort T, response assessment will be based on the 2007 Revised IWG Response 
Criteria in Malignant Lymphoma

In Cohort T2, response assessment will be based on a modified version of the 2014 Lugano 
Response Criteria in Malignant Lymphoma.
Exploratory Outcome Measures
The following correlative biology outcome measures will be assessed:

PET response for patients with detectable FDG tumor uptake at baseline

Change from baseline in pAKT levels and/or other pathway biomarkers in platelet-rich 
plasma (Stage 1 only)

Change in pS6 level as measured by IHC in patients with accessible tumors who provide 
consent for biopsy, and, if tissue quantity permits, change in expression or phosphorylation 
of other PI3-kinase pathway markers, and vascular markers, as measured by IHC and 
reverse phase protein array (RPPA)

DNA mutation and copy number status of tumor type- and pathway-specific biomarkers 
(e.g., PIK3CA), RNA expression analysis, and PTEN expression in archival tumor tissue 
and/or in DNA from blood and in any fresh tumor biopsies obtained

Enumeration of CTCs and assessment of PI3K and cancer biology pathway status, when 
appropriate, (e.g., PIK3CA mutation, PTEN expression, etc.) in CTCs and ctDNA from 
peripheral blood (Cohorts Q, R, S, T, T2, and X excluded from CTC analysis)

Expression of cytokines and chemokines in plasma

QT/QTc interval changes

Tumor typespecific biomarkers as appropriate; examples may include BCL2 and MYC in 
DLBCL and p16 in HNSCC.
Investigational Medicinal Product
GDC-0032
GDC-0032 Drug Product is provided in a capsule formulation consisting of active 
pharmaceutical ingredient (API) powder (at different quantities) and hard gelatin capsule shells.  
The Drug Product will be initially provided as capsules of three strengths:  1 mg, 3 mg, and 
5 mg.  The 1-mg capsules are size 3 and Swedish orange, the 3-mg capsules are size 2 and 
white opaque, and the 5-mg capsules are size 2 and dark green.  The only excipient in 
GDC-0032 Drug Product is the hard gelatin capsule shell.
The Drug Product is packaged in high-density polyethylene (HDPE) bottles.  Each bottle is 
induction sealed and labeled for clinical use.
GDC-0032 capsules will be shipped to the study sites in bulk containers.  GDC-0032 capsules 
should be stored at room temperature between 5986F (1530C) and should be protected 


Protocol:  GDC-0032—Genentech, Inc.
21/P PMT4979g (GO00886)-A10
from light.  Patients will be instructed to store study drug at room temperature between 5986F 
(1530C).
GDC-0032 is also provided for use in clinical studies as a white, film-coated, immediate-release 
tablet formulation of 2 mg strength.  GDC-0032 tablets should not be stored above 25C. 
Patients with gastrostomy tubes who are unable to swallow tablets may receive their GDC-0032 
dose in the form of a suspension prepared extemporaneously from (GDC-0032) 2-mg tablets.  
Patients will be provided with instructions for preparation of the suspension only at sites where 
administration of the extemporaneous suspension is approved by the Institutional Review 
Board/Ethics Committee.
Midazolam (Stage 2, Cohort C Only)
Refer to the midazolam Package Insert or SmPC for details on the formulation and storage of 
midazolam.
Letrozole (Stage 2, Cohorts E, N, P, Q, R, and S)
Refer to the letrozole (e.g., Femara®) package insert or SmPC for details on the formulation and 
storage of letrozole.
Fulvestrant (Stage 2, Cohorts F, J, K, L, and M; Phase II)
Fulvestrant is supplied in sterile single-patient prefilled syringes containing 50 mg/mL fulvestrant 
as a 5-mL injection.  Refer to the fulvestrant (e.g., FASLODEX®) Package Insert or SmPC for 
details on the storage of fulvestrant.
Study Treatment
Dosage and Administration
The starting dose of GDC-0032 is 3 mg (capsule formulation) in the dose-escalation Phase I, 
Stage 1 portion.
On Day 1 of Cycle 1 for patients in Phase I, Stage 1 and Stage 2, Cohorts AG, GDC-0032 will 
be administered to patients in a clinical setting that can accommodate frequent blood draws 
over a period of up to 72 hours after the morning dose is administered.
At each study visit, after establishing patient eligibility for continued administration of GDC-0032, 
a sufficient number of capsules or tablets should be dispensed to the patient to last only until 
the next visit or, at the investigator’s discretion, through one cycle.  Patients will self-administer 
GDC-0032 as detailed below, except on study visit days when the GDC-0032 will be 
administered in the clinic.
Patients will receive a single dose of GDC-0032 on scheduled dosing days.  Patients will take 
GDC-0032 at the same time of day 2 hours, unless otherwise instructed. Patients will be 
instructed as to the number and strength of capsules or tablets to take, according to their 
assigned dose level and schedule.  Patients with head and neck cancer and with gastrostomy 
tubes who are enrolled in Cohort X3 will be provided with special instructions on how to prepare 
a suspension (extemporaneous formulation) from GDC-0032 tablets for easier administration.  
To minimize the number of capsules or tablets administered, doses will be rounded so that a 
combination of no more than two different strengths will be required.  The capsules should 
never be opened.  Patients will be asked to record the time and date that they take each dose in 
a medication diary.
For Stage 1, unless otherwise instructed, GDC-0032 should be taken on an empty stomach 
(i.e., approximately 1 hour before or 2 hours after a meal), except on days of extensive PK 
sampling (Days 1 and 15 of Cycle 1) when administration will be under fasted conditions.  For 
administration under fasted conditions, patients will fast overnight for at least 10 hours before 
dosing and 4 hours postdose and will refrain from drinking water from 1 hour before and until 
1 hour after dosing, with the exception of GDC-0032 administration when the capsules will be 
swallowed whole (not chewed) with 240 mL (8 fluid ounces) of water.
For Stage 2 cohorts, GDC-0032 may be taken with or without food except on days on which 
there is a post-dose PK assessment where administration should be under fasted conditions.  
There is no water restriction around the time of GDC-0032 administration under fasted 
conditions for Stage 2 cohorts.
If a patient misses a GDC-0032 dose or vomits up a capsule or tablet, he or she should be 
instructed to skip that dose and to resume dosing with the next scheduled dose.  Missed doses 


Protocol:  GDC-0032—Genentech, Inc.
22/P PMT4979g (GO00886)-A10
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 capsules or 
tablets to each study visit or, at the investigator’s discretion, at the end of each cycle, for 
GDC-0032 accountability.
On safety assessment days, PK samples will be collected at the same time as other blood tests 
are performed, including fasting lipid panels.  Patients will be instructed to hold the morning 
dose of GDC-0032 until after PK blood samples have been obtained. For Cohorts HX, once 
fasting blood draws have been collected and GDC-0032 administered, the patient need not 
continue to remain fasted for any post-dose, PK blood draw.
Stage 1 Dosing
In Stage 1, Cycle 1 will be 35 days in length and will begin with a PK evaluation, during which all 
patients will receive a single fasting dose of GDC-0032 on Day 1 at their assigned dose level.  
The initial dose will be followed by a 7-day washout and frequent PK sampling up to 72 hours to 
determine the single-dose PK properties of GDC-0032 in humans.  Urine samples will be 
collected up to 24 hours after the first dose to determine urinary elimination of GDC-0032.  
Blood samples will be taken at several scheduled timepoints to explore the surrogate PD 
response after a single dose.  In Cycle 1, continuous GDC-0032 daily dosing will begin on 
Day 8 and will continue for 4 weeks (Days 835).
Subsequent cycles will be 28 days in length (4 weeks of daily dosing with GDC-0032).
Stage 2 Dosing
The dosing regimens for the Stage 2 cohorts are as follows:

Cohort A:  In Cycle 1, patients will receive a single dose of GDC-0032 on Day 1, and then 
daily doses from Day 8 to Day 35.  On Day 1 or 8 of Cycle 1, GDC-0032 administration will 
be under either fasted or fed conditions for the food-effect assessment (i.e., fasted on Day 1 
and fed on Day 8 or vice versa).  Patients will fast overnight for at least 10 hours before the 
morning dose.  If the patient is receiving a high-fat breakfast, the meal must be entirely 
consumed within 30 minutes and GDC-0032 dose will be given 30 minutes after the start 
of the meal.  The high-fat meal (approximately 800 to 1000 calories) will consist of 
approximately 33 g protein, 58 g carbohydrate, and 75 g fat, respectively (e.g., 2 eggs fried 
in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash-brown potatoes, 
and 8 ounces of whole milk).  Patients will refrain from drinking water from 1 hour before 
and until 1 hour after dosing, with the exception of 240 mL (8 fluid ounces) water intake 
required for administration of GDC-0032.  GDC-0032 capsules will be swallowed whole (not 
chewed) with water.  No additional food should be allowed for at least 4 hours postdose.  In 
addition, patients will receive a GDC-0032 dose under fasted conditions on Cycle 1, Day 22 
for assessment of steady state pharmacokinetics.  Subsequent cycles will be 28 days in 
length (4 weeks of daily dosing with GDC-0032).

Cohorts B, D, and G:  In Cycle 1, patients will receive daily oral doses of GDC-0032 on an 
empty stomach (i.e.,1 hour before or 2 hours after a meal) on Days 128, except on Days 1, 
8, and 15 when patients receive GDC-0032 under fasted conditions.  For subsequent cycles 
patients will receive daily oral doses of GDC-0032 on Days 128.

Cohort C:  In Cycle 1, patients will receive midazolam 5 mg in hydrochloride syrup on 
Days 1 and 16.  Each midazolam dose will be administered by oral syringe, followed by 
approximately 200 mL of water to rinse the mouth and swallow.  Midazolam will not be 
mixed with any liquid before ingestion.  Patients will then receive daily doses of GDC-0032 
on Days 229.  All doses will be taken on an empty stomach (i.e., 1 hour before or 2 hours 
after a meal), except on Days 1 and 16 when patients receive the doses under fasted 
conditions.  For subsequent cycles patients will receive daily oral doses of GDC-0032 on 
Days 128.

Cohort E:  In Cycle 1, patients will receive daily oral doses of GDC-0032 and letrozole 
2.5 mg orally on Days 128.  Patients will take the GDC-0032 and letrozole doses on an 
empty stomach (i.e., 1 hour before or 2 hours after a meal), except on Days 1 and 15 when 
patients will receive the doses under fasted conditions.  For subsequent cycles patients will 
continue to take daily oral doses of GDC-0032 and daily oral doses of letrozole 2.5 mg on 
Days 128.  On study visit days, GDC-0032 and letrozole will be administered in the clinic.


Protocol:  GDC-0032—Genentech, Inc.
23/P PMT4979g (GO00886)-A10

Cohort F:  In Cycle 1, patients will receive daily oral doses of GDC-0032 on Days 128.  
Patients will take the GDC-0032 doses on an empty stomach (i.e., 1 hour before or 2 hours 
after a meal), except on Days 1 and 15 when patients will receive the doses under fasted 
conditions.  Fulvestrant is supplied in sterile single-patient prefilled syringes containing a 
250 mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will receive fulvestrant 
500 mg, administered intramuscularly in the buttocks slowly (12 minutes per injection) as 
two 5-mL injections (one in each buttock), in the clinic on Days 1 and 15 of Cycle 1.  For 
subsequent cycles patients will continue to receive daily oral doses of GDC-0032 on 
Days 128 and will receive fulvestrant via intramuscular injections as described above in 
the clinic on Day 1 of each cycle. 

Cohort H:  In Cycle 1, patients will receive daily oral doses of GDC-0032 on Days 121 of 
each 28-day cycle.  For PK testing on Cycle 1 Day 15, patients will receive GDC-0032 
under fasted conditions in the clinic.  For subsequent cycles patients will receive daily oral 
doses of GDC-0032 on Days 121 of each cycle.  For PK testing on Day 1 of Cycles 2 and 
6, GDC-0032 will be administered in the clinic.  Once fasting blood draws have been 
collected and GDC-0032 and fulvestrant have been administered, the patient need not 
continue to remain fasted until the 3hour post-dose PK blood draw.

Cohort J:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in tablet form 
on Days 121.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under fasted 
conditions in the clinic.  Fulvestrant will be supplied in sterile single-patient prefilled syringes 
containing a 250-mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will receive 
fulvestrant 500 mg, administered intramuscularly in the buttocks slowly (12 minutes per 
injection) as two 5-mL injections (one in each buttock), in the clinic on Days 1 and 15 of 
Cycle 1.  For subsequent cycles patients will continue to receive daily oral doses of 
GDC-0032 on Days 121 of each cycle and will receive fulvestrant as described above in 
the clinic on Day 1 of each cycle.  For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 
will be administered in the clinic.  Once fasting blood draws have been collected and 
GDC-0032 and fulvestrant have been administered, the patient need not continue to remain 
fasted until the 3hour post-dose PK blood draw.

Cohort K:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in tablet 
form on Days 15, 812, 1519, and 2226.  For PK testing on Cycle 1 Day 15, patients will 
take GDC-0032 under fasted conditions in the clinic.  Fulvestrant will be supplied in sterile 
single-patient prefilled syringes containing a 250-mg dose (50 mg/mL fulvestrant as a 5-mL 
injection).  Patients will receive fulvestrant 500 mg, administered intramuscularly in the 
buttocks slowly (12 minutes per injection) as two 5-mL injections (one in each buttock), in 
the clinic on Days 1 and 15 of Cycle 1.  For subsequent cycles patients will continue to 
receive daily oral doses of GDC-0032 on Days 15, 812, 1519, and 2226 of each cycle 
and will receive fulvestrant as described above in the clinic on Day 1 of each cycle.  For PK 
testing on Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.  Once 
fasting blood draws have been collected and GDC-0032 and fulvestrant have been 
administered, the patient need not continue to remain fasted until the 3-hour post-dose PK 
blood draw.

Cohort L:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in tablet form 
on Days 17 and 1521.  For PK testing on Cycle 1 Day 1, patients will take GDC-0032 
under fasted conditions in the clinic.  Fulvestrant is supplied in sterile single-patient prefilled 
syringes containing a 250-mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will 
receive fulvestrant 500 mg, administered intramuscularly in the buttocks slowly 
(12 minutes per injection) as two 5-mL injections (one in each buttock), in the clinic on 
Days 1 and 15 of Cycle 1.  For subsequent cycles patients will continue to receive daily oral 
doses of GDC-0032 on Days 17 and Days 1521 of each cycle and will receive fulvestrant 
via intramuscular injections as described above in the clinic on Day 1 of each cycle. For PK 
testing on Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.  Once 
fasting blood draws have been collected and GDC-0032 and fulvestrant administered, the 
patient need not continue to remain fasted until the 3-hour post-dose PK blood draw.


Protocol:  GDC-0032—Genentech, Inc.
24/P PMT4979g (GO00886)-A10

Cohort M:  In Cycle 1, patients will receive a daily oral dose of 2 mg GDC-0032 in tablet 
form on Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under 
fasted conditions in the clinic.  Fulvestrant is supplied in sterile single-patient, prefilled 
syringes containing a 250-mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will 
receive fulvestrant 500 mg, administered intramuscularly in the buttocks slowly (1-2 minutes 
per injection) as two 5-mL injections (one in each buttock), in the clinic on Days 1 and 15 of 
Cycle 1.  For subsequent cycles, patients will continue to receive daily oral doses of 
GDC-0032 on Days 128 and will receive fulvestrant via intramuscular injections, as 
described above, in the clinic on Day 1 of each cycle.  For PK testing on Day 1 of Cycles 2 
and 6, GDC-0032 will be administered in the clinic.  Once fasting blood draws have been 
collected and GDC-0032 and fulvestrant have been administered, the patient need not 
continue to remain fasted until the 3-hour post-dose PK blood draw.

Fulvestrant dosing exceptions (Cohorts F, J, K, L, and M):  For patients with moderate 
hepatic impairment (Child-Pugh Class B), a single-agent dose of 250 mg is recommended 
on the basis of clinical data described in the fulvestrant package insert.

Cohort N:  In Cycle 1, patients will receive a daily oral dose of 2 mg GDC-0032 in tablet 
form and letrozole 2.5 mg orally on Days 128.  For PK testing on Cycle 1 Day 15, patients 
will take GDC-0032 and letrozole doses under fasted conditions in the clinic.  
For subsequent cycles, patients will continue to take daily oral doses of GDC-0032 and 
daily oral doses of letrozole 2.5 mg on Days 128.  For PK testing on Day 1 of Cycles 2 and 
6, GDC-0032 and letrozole will be administered in the clinic.  Once fasting blood draws 
have been collected and GDC-0032 and letrozole have been administered, the patient need 
not continue to remain fasted until the 3-hour post-dose PK blood draw.

Cohort P:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet form 
and letrozole 2.5 mg orally on Days 128.  For PK testing on Cycle 1 Day 15, patients will 
take GDC-0032 and letrozole under fasted conditions in the clinic.  For subsequent cycles, 
patients will continue to take daily oral doses of GDC-0032 and daily oral doses of letrozole 
2.5 mg on Days 128.  For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 and letrozole 
will be administered in the clinic.  Once fasting blood draws have been collected and 
GDC-0032 and letrozole have been administered, the patient need not continue to remain 
fasted until the 3hour post-dose PK blood draw.

Cohort Q:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in tablet 
form on Days 121 and letrozole 2.5 mg orally on Days 128.  For PK testing on Cycle 1 
Day 15, patients will take GDC-0032 under fasted conditions in the clinic.  For subsequent 
cycles, patients will continue to take daily oral doses of GDC-0032 on Days 121 and daily 
oral doses of letrozole 2.5 mg on Days 128.  For PK testing on Day 1 of Cycle 2 and 6, 
GDC-0032 and letrozole will be administered in the clinic.  Once fasting blood draws have 
been collected and GDC-0032 and letrozole have been administered, the patient need not 
continue to remain fasted until the 3-hour post-dose PK blood draw.

Cohort R:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in tablet 
form on Days 15, 812, 1519, and 2226 and letrozole 2.5 mg orally on Days 128.  For 
PK testing on Cycle 1 Day 15, patients will take GDC-0032 and letrozole under fasted 
conditions in the clinic.  For subsequent cycles, patients will continue to take daily oral 
doses of GDC-0032 on Days 15, 812, 1519, and 2226 of every cycle and daily oral 
doses of letrozole 2.5 mg on Days 128.  For PK testing on Day 1 of Cycle 2 and 6, 
GDC-0032 and letrozole will be administered in the clinic.  Once fasting blood draws have 
been collected and GDC-0032 and letrozole have been administered, the patient need not 
continue to remain fasted until the 3-hour post-dose PK blood draw.

Cohort S:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet form 
on Days 17 and 1521 and letrozole 2.5 mg orally on Days 128.  For PK testing on 
Cycle 1 Day 1, patients will take GDC-0032 and letrozole under fasted conditions in the 
clinic.  For subsequent cycles, patients will continue to receive daily oral doses of 
GDC-0032 on Days 17 and Days 1521 and daily oral doses of letrozole 2.5 mg orally on 
Days 128. For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 and letrozole will be 
administered in the clinic.  Once fasting blood draws have been collected and GDC-0032 
and letrozole have been administered, the patient need not continue to remain fasted until 
the 3-hour postdose PK blood draw.


Protocol:  GDC-0032—Genentech, Inc.
25/P PMT4979g (GO00886)-A10

Cohort T:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet form 
on Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under fasted 
conditions in the clinic.  For subsequent cycles, patients will continue to take oral daily 
doses of GDC-0032 on Days 128.  For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 
will be administered in the clinic.  Once fasting blood draws have been collected and 
GDC-0032 has been administered, the patient need not continue to remain fasted until the 
3-hour postdose PK blood draw.

Cohort T2:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet 
form on Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under 
fasted conditions in the clinic.  For subsequent cycles, patients will continue to take oral 
daily doses of GDC-0032 on Days 128.  For PK testing on Day 1 of Cycles 2 and 6, 
GDC-0032 will be administered in the clinic.  Once fasting blood draws have been collected 
and GDC-0032 has been administered, the patient need not continue to remain fasted until 
the 3-hour post-dose PK blood draw.

Cohort X, except sub-Cohort X3 patients who are taking GDC-0032 as suspension:  In 
Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet form on 
Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under fasted 
conditions in the clinic.  For subsequent cycles, patients will continue to take oral daily 
doses of GDC-0032 on Days 128.  For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 
will be administered in the clinic.  Once fasting blood draws have been collected and 
GDC-0032 has been administered, the patient need not continue to remain fasted until the 
3-hour postdose PK blood draw.

Cohort X3:  Patients with head and neck cancer who can swallow tablets will receive daily 
oral doses of 4 mg GDC-0032 in tablet form.  For patients who cannot take tablets orally 
and have gastrostomy (G) tubes, GDC-0032 will be administered via G-tube as an aqueous 
suspension prepared extemporaneously from GDC-0032 tablets.  Patients will be provided 
with special instructions on how to make a suspension from GDC-0032 tablets.  The 
suspension is prepared by placing the GDC-0032 tablets in water (20 mL of water per tablet) 
in a glass container for 15 minutes at room temperature.  The solution is then stirred or 
swirled to generate a suspension before administering into the G-tube, followed by two 
equivalent portions of water.  Suspensions should be prepared immediately prior to dosing.  
Patients or caregivers should wash their hands after the preparation and any utensils used 
to prepare the suspension after administration.  In Cycle 1, patients will receive daily doses 
of 4 mg GDC-0032 via G-tube on Days 128.  Patients or caregivers should prepare 
GDC-0032 suspension under observation in the clinic on Cycle 1 Days 1 and 2.  For PK 
testing, patients will take GDC-0032 on Cycle 1 Days 1 and 15 under fasted conditions in 
the clinic.  For subsequent cycles, patients will continue to take daily doses of GDC-0032 
via G-tube on Days 128.  For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 will be 
administered in the clinic.  Once fasting blood draws have been collected and GDC-0032 
has been administered, the patient need not continue to remain fasted until the 3-hour post-
dose PK blood draw.
Phase II Dosing
In Cycle 1, patients will receive daily oral doses of GDC-0032 on Days 128.  Patients will take 
the GDC-0032 doses on an empty stomach (i.e., 1 hour before or 2 hours after a meal), except 
on Days 1 and 15 when patients will receive the doses under fasted conditions.  Fulvestrant will 
be supplied in sterile single-patient prefilled syringes containing a 250-mg dose (50 mg/mL 
fulvestrant as a 5-mL injection).  Patients will receive fulvestrant 500 mg, administered 
intramuscularly in the buttocks slowly (12 minutes per injection) as two 5-mL injections (one in 
each buttock), in the clinic on Days 1 and 15 of Cycle 1.  For subsequent cycles patients will 
continue to receive daily oral doses of GDC-0032 on Days 128 and will receive fulvestrant as 
described above in the clinic on Day 1 of each cycle.
For patients with moderate hepatic impairment (Child-Pugh Class B), a single-agent dose of 
fulvestrant 250 mg is recommended based upon clinical data described in the fulvestrant 
package insert.
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 


Protocol:  GDC-0032—Genentech, Inc.
26/P PMT4979g (GO00886)-A10
overdose or incorrect administration of study drug should be recorded on the Adverse Event 
eCRF and the physician should be notified immediately.
Statistical Methods
Safety Analyses
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, and changes in vital signs.  All patients who receive any amount of GDC-0032 will be 
included in the safety analyses.  
GDC-0032 exposure, including the proportion of patients with dose modifications, will be 
summarized by assigned dose level and cohort.
All collected adverse event data will be listed by study site, patient number, and cycle.  
All adverse events occurring on or after treatment on Day 1 will be summarized by mapped term, 
appropriate thesaurus levels, and NCI CTCAE v4.0 toxicity grade.  In addition, all serious 
adverse events, including deaths will be listed separately and summarized.  
QT/QTc data will be analyzed using the E14 guidelines and may include analyses of central 
tendency, categorical analyses, analysis of the relationship between drug exposure and 
QT/QTc interval changes, and morphologic analyses of ECG waveforms.
Pharmacokinetic Analyses
Individual plasma GDC-0032 concentration vs. time data and summary statistics will be 
tabulated by dose level and schedule.  Individual and mean (SD) plasma concentration versus 
time profiles will be plotted.
The plasma GDC-0032 pharmacokinetic data obtained after a single dose (Day 1) and at steady 
state (Day 15) will be analyzed using noncompartmental methods to estimate PK parameters, 
which include but are not limited to AUC0-and/or AUC0-inf, Cmax, Cmin, tmax, t1/2, CL/F, 
accumulation (AR), renal excretion fraction (fe), urinary CL (CLr).  Additional PK parameters 
may be determined as data allow.  Estimates for these parameters and summary statistics 
(mean, standard deviation, coefficient of variation, median, minimum, and maximum) will be 
tabulated by dose level and schedule. 
For Phase II, GDC-0032 and fulvestrant plasma concentrations will be tabulated from individual 
patients and presented with appropriate summary statistics (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum).
Determination of Sample Size
A total of approximately 623723 patients are expected to be enrolled in this study.  In the 
single-agent dose-escalation portion of this study (Stage 1 of Phase I), 34 patients have been 
enrolled.  Approximately 529629 patients are expected to be enrolled in Stage 2 of Phase I, 
including with Amendment 8, 6 additional patients each in Cohorts N and P; 20 patients each in 
Cohorts Q, R, and S; 10 lymphoma patients in Cohort T; 1020 patients with DLBCL in 
Cohort T2; 1020 patients in each sub-cohort of the basket Cohort X (X1X10); 2040 patients 
in sub-Cohort X3; and 50 patients in sub-Cohort X11 with PIK3CA-mutant tumor types not 
covered in X1X10.  Phase II has fully enrolled with a total of 60 patients.
Stage 1:  Dose Escalation
The sample size for Stage 1 is based on the dose-escalation rules described in the study design 
section of this protocol.  The sample size for this trial is not based on explicit power or type I 
error considerations.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of observing at 
least one such adverse event in a given cohort of 6 patients is 46.9%, 26.5%, and 5.8%, 
respectively.
Stage 2:  Expansion Cohorts 
To better characterize the safety of single-agent GDC-0032 administered at the recommended 
dose for future studies, approximately 82 patients will be enrolled and treated with single-agent 
GDC-0032 in Stage 2, Cohorts AD and G.  For a given adverse event with a true rate of 10%, 
5%, or 1% the probability of observing at least one such adverse event in 82 patients from the 
single-agent GDC-0032 expansion cohorts (Stage 2, Cohorts AD and G) is >99.9%, 98.5%, 
and 56.1%, respectively.


Protocol:  GDC-0032—Genentech, Inc.
27/P PMT4979g (GO00886)-A10
Cohorts AD and GH of Stage 2 encompass distinct patient populations that may have 
differing safety profiles.  For example, Cohort D includes HER2-positive metastatic breast 
cancer patients whereas Cohort G includes patients with solid tumors that have increased 
PIK3CA copy number.  
Increasing the size of Cohorts A and B to 20 patients will provide more robust safety data in the 
patient populations tested.  For a given adverse event with a true rate of 10%, 5%, or 1%, the 
probability of observing at least one such adverse event in 20 patients is 87.8%, 64.1%, 
and 18.2%, respectively.  Cohort H will also provide more robust safety data on a different 
single-agent schedule of GDC-0032 being given on a 21-day on, 7-day off (21/7) schedule.  For 
a given adverse event with a true rate of 10%, 5%, or 1%, the probability of observing at least 
one such adverse event in an expanded cohort of 40 patients is 98.6%, 87.1%, and 33.1%, 
respectively.
To better characterize the safety of the combination of GDC-0032 with either letrozole (Stage 2, 
Cohort E) or with fulvestrant (Stage 2, Cohort F), approximately 2728 patients will be enrolled 
in each of these expansion cohorts.  This number includes the possibility that two dose levels 
will be tested with 20 patients enrolled at the selected dose level.
Promising anti-tumor activity has been observed at the 6-mg QD capsule dose level of 
GDC-0032 in combination with letrozole (Cohort E) and in combination with fulvestrant 
(Cohort F).  Several alternate dose schedules will be evaluated to obtain additional data on the 
relative tolerability of adding intermittent breaks to the GDC-0032 dosing schedule or lower 
doses of GDC-0032 in combination with either fulvestrant (Cohorts J, K, L, M) or letrozole 
(Cohorts N, P, Q, R, S).
Approximately 20 patients will be enrolled into Stage 2, Cohort J to evaluate an alternative dose 
schedule of GDC-0032 4-mg QD tablet dose level with a 21-day on, 7-day off (21/7) schedule in 
combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort K to evaluate an alternative dose 
schedule of GDC-0032 4-mg QD tablet dose level with a 5-day on, 2-day off (5/2) schedule in 
combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort L to evaluate an alternative dose 
schedule of GDC-0032 4-mg QD tablet dose level with a 7-day on, 7-day off (7/7) schedule in 
combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort M to evaluate an alternative 
dose level of GDC-0032 2-mg QD tablet dose level in combination with fulvestrant.
Approximately 26 patients will be enrolled into Stage 2, Cohort N to evaluate an alternative dose 
level of GDC-0032 2-mg QD tablet dose level in combination with letrozole.  This includes 
six patient slots (three with PIK3CA-mutant and three with PIK3CA-wild-type tumors) in which 
paired pre- and on-treatment tumor biopsies are required.
Approximately 26 patients will be enrolled into Stage 2, Cohort P to evaluate an alternative dose 
level of GDC-0032 4-mg QD tablet dose level in combination with letrozole in a less heavily 
pretreated population as compared with Stage 2, Cohort E.  This includes six patient slots (three 
with PIK3CA-mutant and three with PIK3CA-wild-type tumors) in which paired pre- and on-
treatment tumor biopsies are required.
For the 12 slots in Cohorts N and P in which paired pre- and on-treatment tumor biopsies are 
required, if a patient enrolls in the study and either the pre- or the on-treatment biopsy tissue 
quality is deemed unevaluable by the Central Laboratory, the patient may continue on treatment, 
but additional patients may be enrolled to complete the cohort (at the Sponsor’s discretion).  
The paired tumor biopsies support the exploratory objective of assessing GDC-0032 PD effects 
on the PI3K (and other) pathways.  Therefore a limited number of patients (3 patients with 
PIK3CA-mutant and 3 patients with PIK3CA-wild type tumors in each cohort) was chosen to 
provide a preliminary PD assessment.
Approximately 20 patients will be enrolled into Stage 2, Cohort Q to evaluate an alternative 
dose schedule of GDC-0032 4-mg tablet dose level with a 21-day on, 7-day off (21/7) schedule 
in combination with letrozole.
Approximately 20 patients will be enrolled into Stage 2, Cohort R to evaluate an alternative dose 
schedule of GDC-0032 4-mg QD tablet dose level with a 5-day on, 2-day off (5/2) schedule in 
combination with letrozole.


Protocol:  GDC-0032—Genentech, Inc.
28/P PMT4979g (GO00886)-A10
Approximately 20 patients will be enrolled into Stage 2, Cohort S to evaluate an alternative dose 
schedule of GDC-0032 4 mg QD tablet dose level with a 7-day on, 7-day off (7/7) schedule in 
combination with letrozole.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of observing at
least one such adverse event in an expanded cohort of 20 patients is 87.8%, 64.1%, and 18.2%, 
respectively. This is especially important in characterizing an adverse event such as 
pneumonitis that may occur at a low frequency.  It is important to understand the safety profile 
of GDC-0032 in combination with letrozole as this regimen may be tested in future studies for 
patients with early hormone receptorpositive breast cancer, an indication with a unique 
risk-benefit profile.  The combination of GDC-0032 and fulvestrant may be tested in future 
studies as an early-line therapy for patients with advanced hormone receptorpositive breast 
cancer.
In Cohort T, to characterize the safety and tolerability of single-agent GDC-0032 for patients 
with lymphoma, approximately 10 patients will be enrolled, irrespective of their tumor’s 
PIK3CA-mutation status.  For a given adverse event with a true rate of 10%, 5%, or 1%, the 
probability of observing at least one such adverse event in an expanded cohort of 10 patients is
65.1%, 40.1%, and 9.6%, respectively.
In Cohort T2, to characterize the safety and tolerability of single-agent GDC-0032 for patients 
with DLBCL, approximately 1020 patients will be enrolled, irrespective of their tumor’s 
PIK3CA-mutation status.  If less than 2 responders (CR or PR, confirmed or unconfirmed) are 
observed from the first 10 patients with DLBCL, enrollment will be suspended for Cohort T2; if 2 
or more responders are observed from the first 10 patients, another 10 patients may be enrolled 
into the cohort.  However, if clinical benefit is observed for the first 10 patients with DLBCL in 
Cohort T2 (e.g., a majority of patients demonstrate SD at Week 8 although there are less than 
2 responders), then further enrollment of 10 additional patients may be allowed for this cohort, 
depending on the decision made by the Sponsor.  Assessment for expansion of Cohort T2 will 
be made on a rolling basis, depending on when responses are observed.  
In Cohort X (sub-Cohorts X1X10), to provide preliminary efficacy and safety data of single 
agent GDC-0032 in a diverse population of patients with PIK3CA-mutant cancer, the following 
rule will be applied to each of the sub-cohorts:  if less than 2 responders (CR or PR, confirmed 
or unconfirmed) are observed from the first 10 patients with PIK3CA-mutant cancer, enrollment 
will be suspended for that indication; if 2 or more responders are observed from the first 
10 patients, another 10 patients will be enrolled into the cohort.  However, if clinical benefit is 
observed for the first 10 patients with PIK3CA-mutant cancer in the cohort (e.g., a majority of 
patients demonstrate SD at Week 8 although there are less than 2 responders), then further 
enrollment of 10 additional patients may be allowed for this cohort, depending on the decision 
made by Genentech.  Assessment for expansion of a given sub-cohort will be made on a rolling 
basis, depending on when responses are observed. These expansion rules will also be applied 
for the 10-20 patients with HNSCC with amplification of the PIK3CA gene number and no 
PIK3CA somatic mutations detected in Cohort X3. In addition, if a given indication is expanded 
to 20, a decision about further enrollment of additional patients beyond 20 (up to a maximum of 
40 for any given indication, e.g., PIK3CA-mutant HNSCC) will be made by the Sponsor if clinical 
benefit is observed (e.g., 4 PR in 20 patients).
A positive PIK3CA-mutation or amplification status from local testing will be centrally confirmed 
for patients in Cohort X.  If a patient enrolls as per a positive local test result and a mutation or 
amplification is not detected per central testing, the patient will be allowed to continue in the 
study, and additional patients may be enrolled to meet enrollment goals of patients with 
PIK3CA-mutant or amplified tumors.
With the assumption of an expected true response rate of 30% or higher, there is at most a 15% 
chance of observing less than 2 responses in 10 patients, which is the false negative rate.  If the 
true response rate increases to 40%, the false negative rate decreases to 5%.  Alternately, with 
the assumption of a response rate of 5% or less, there is at most a 9% chance of observing 2 or 
more responses in 10 patients, which is the false positive rate.  If the response rate decreases 
to 4%, the false positive rate decreases to 6%.
Assuming a preferable response rate was observed (20% responders) at Week 8 in Cohort T2 
and X and 10 additional patients were enrolled, with an observed response rate of 20%, a 
sample size of 20 patients within a given indication (i.e., sub-Cohorts X1X10) would result in 


Protocol:  GDC-0032—Genentech, Inc.
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an 80% Pearson-Clopper exact CI of 9% to 36%, excluding a response rate of 8%. Assuming 
that the observed responder rate is 20% with 20 patients in a sub-cohort of Cohort X, and that 
an additional 20 patients were enrolled, the resulting sample size of 40 patients within a given 
indication would result in an 80% Pearson-Clopper exact CI of 12% to 30%, which is narrower 
than when the sample size is 20, thus providing more confidence in the observed response rate.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of observing at 
least one such adverse event in an expanded cohort of 20 patients is 87.8%, 64.2%, and 18.2%, 
respectively.
Phase II
The Phase II portion of the trial will evaluate safety and provide a preliminary evaluation of 
efficacy of the combination of GDC-0032 and fulvestrant as measured by ORR and CBR.  The 
study is designed to estimate the ORR and the CBR with reasonable precision to contrast the 
results of this study with historical data from studies with fulvestrant in a similar patient 
population, which have ORR of 7%10% and CBR rate of 32%46% (Chia et al. 2008; 
Di Leo et al. 2010).  CBR allows for evaluation of bone-only disease patients while ORR does 
not.  Based upon previous literature, bone-only disease is approximately 30% of patients 
(Chia et al. 2008; Di Leo et al, 2010).
The Phase II portion of this trial will be able to detect a large benefit of the combination of 
GDC-0032 and fulvestrant, in terms of ORR.  For example, an observed ORR of 30% in 
21 patients with PIK3CA-mutant tumors (assuming 30% of the 30 patients will have 
non-measurable bone only disease) will have a 95% confidence interval of (14.6%, 57.0%), 
excluding an ORR of 10%.  Similarly, an observed CBR of 67% in 30 patients will have a 95% 
confidence interval of (47.2%, 82.7%), excluding a CBR of 46%.


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1.
BACKGROUND
1.1
THE PHOSPHOINOSITIDE 3-KINASE PATHWAY
Phosphoinositide 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-mTOR pathway (Guertin and Sabatini 2007).  Activating and transforming 
mutations, as well as amplification, in the p110subunit of PI3K are commonly found in 
solid and hematological tumors.  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).
GDC-0032 (also known as taselisib) is a potent, selective small molecule inhibitor of 
Class I PI3K-alpha, gamma, and delta isoforms that is being developed by Genentech, 
Inc. as an anti-cancer therapeutic agent.  PI3K-AKT pathway activation has been 
implicated in several types of cancer (Cantley 2002, 2006; Ward et al. 2003).  Activating 
and transforming mutations in the p110subunit of PI3K are commonly found in tumors 
(Bachman et al. 2004; Samuels et al. 2004; Karakas et al. 2006).  The beta isoform of 
PI3K is involved in glucose metabolism as evidenced by increased glucose levels in 
conditional p110knockout mice compared with wild-type mice following a glucose 
challenge test (Jia et al. 2008).  GDC-0032 has approximately 30-fold biochemical 
selectivity of the alpha isoform relative to the beta isoform and has been shown to be a 
potent inhibitor of growth in nonclinical models of PI3K-mutant tumors.  GDC-0032 has 
higher potency against mutant p110relative to wild-type and higher activity against 
PIK3CA-mutant cell lines and xenografts compared with non-PIK3CA-mutant models.
1.2
NONCLINICAL SUMMARY
A comprehensive nonclinical testing strategy was developed to investigate the 
pharmacology, pharmacokinetics, and toxicology of GDC-0032 and to enable 
the selection of a safe Phase I starting dose.  The intended clinical route of 
administration for GDC-0032 is oral (PO).  Thus, all pivotal in vivo nonclinical studies 
were conducted using PO administration.
Nonclinical studies of GDC-0032 demonstrate that GDC-0032 inhibits proliferation of 
p110-mutant breast cancer cell lines and inhibits tumor growth in human breast 
xenograft models harboring the PI3K mutations.  GDC-0032 treatment also substantially 
reduces levels of the PI3K pathway markers (pAKT, pPRAS40, and pS6).  GDC-0032 
has a favorable in vitro and nonclinical in vivo absorption, distribution, metabolism, and 
elimination profile that is characteristic of an orally administered compound that can 
achieve clinical exposure consistent with nonclinical efficacy findings described below.  
The results of the nonclinical toxicology program for GDC-0032 enabled the proposed 


Protocol:  GDC-0032—Genentech, Inc.
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starting dose of 3 mg capsule formulation once daily (QD) for this study and support the 
evaluation of GDC-0032 as a potential therapeutic agent for cancer.
A summary of the key findings from nonclinical studies is presented below.  See the 
GDC-0032 Investigator Brochure for additional details on the nonclinical studies.
1.2.1
Pharmacology
Extensive in vitro pharmacology studies were performed to characterize the 
inhibitory potency and selectivity of GDC-0032 for PI3K isoforms, and the effects of 
GDC-0032 on cell proliferation, cell cycle progression, and apoptosis.  In vivo efficacy 
was assessed in nude and SCID mice with human tumor xenografts representing 
several types of cancer associated with PI3K pathway activation (i.e., PI3K mutation 
denoted as PIK3CA).  In vitro and in vivo safety pharmacology studies were conducted 
to characterize potential effects on the cardiovascular system.
a.
In Vitro Studies
In vitro studies characterizing the inhibitory potency and selectivity of GDC-0032 toward 
different PI3K isoforms and the effects of GDC-0032 on cell proliferation, cell cycle 
progression, and apoptosis in PI3K-mutant and PTEN-null cell lines were conducted.  
The following results were observed:

GDC-0032 is a potent inhibitor of Class I PI3K alpha, delta, and gamma isoforms 
and a 30-fold less potent inhibitor of the beta isoform relative to the alpha isoform.

GDC-0032 did not potently inhibit PIKK family enzyme DNA-PK.  The 50% inhibitory 
concentration (IC50) was 1000-fold more selective for the PIKK family kinases 
(C2 alpha, C2 beta, and VPS34 was 10 M, 0.29 M, and 0.39 M, respectively), 
and other PIKK family kinases showed no significant inhibition at 1 M.

GDC-0032 inhibits cellular proliferation of KPL-4 and MCF7-neo/HER2 breast 
cancer (p110-mutant) cell lines with mean IC50 values of 0.016 M and 0.026 M, 
respectively.
b.
In Vivo Efficacy Studies
GDC-0032 inhibited tumor growth in nonclinical xenograft models of breast tumor cells 
harboring mutations in the p110(H1047R) (KPL-4) or in the p110E545K helical 
domain (MCF7-neo/HER2) following oral daily dosing.  A pharmacodynamic (PD) and 
pharmacokinetic (PK) study in a KPL-4 xenograft tumor model was also conducted to 
correlate plasma levels of GDC-0032 with PD changes in the tumors.  The following 
results were observed:

Tumor growth was inhibited by an average of 105% at a maximum efficacious dose 
(MED) of 22.5 mg/kg QD (6 partial regressions out of 8 animals) in the 
MCF7-neo/HER2 breast xenograft model in nude mice.  The 50% and 90% of 
maximal response (ED50 and ED90) were determined to be 2.6 and 8.6 mg/kg, 
respectively, with a maximal response of 105% tumor growth inhibition (TGI) 
observed in the highest dose group of 22.5 mg/kg.


Protocol:  GDC-0032—Genentech, Inc.
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
Tumor growth was inhibited by an average of 128% at an MED of 25 mg/kg QD 
(7 partial regressions and 1 complete regression out of 8 animals) in the KPL-4 
human breast xenograft model in SCID beige mice.  The ED50 and ED90 (defined as 
the 50% and 90% of maximal response) were determined to be 0.8 and 14.1 mg/kg, 
respectively, with a maximal response of 128% TGI observed in the highest dose 
group of 25 mg/kg

PI3K pathway markers phosphorylated AKT (pAKT), phosphorylated PRAS40 
(pPRAS40), and phosphorylated S6 (pS6) were reduced for up to 24 hours in 
response to a single dose of GDC-0032, and substantial reduction of pathway 
markers was associated with plasma levels 2.7 M in the KPL4 breast cancer 
xenograft model
1.2.2
Pharmacokinetics
In vitro studies were performed to determine the disposition of GDC-0032, to investigate 
its metabolism in various species, and to assess its potential for drug-drug interaction 
(DDI).  PK studies were performed in mice, rats, dogs, and monkeys and toxicokinetic 
(TK) evaluations were performed in rats and dogs as part of the GLP toxicity studies.  
These studies were conducted to provide information on the nonclinical 
pharmacokinetics or toxicokinetics of GDC-0032, to support the interpretation of 
toxicology studies and to aid in the selection of the appropriate starting dose for use in 
clinical trials.  Human PK parameters and exposure were predicted and the potential for 
DDI was also evaluated.  However, the definitive assessment for DDI potential will be 
based on concentrations achieved in clinical studies.
a.
In Vitro Studies

Plasma protein binding was moderate to high, ranging from 70.7% to 97.6% (mouse, 
rat, rabbit, monkey, dog, and human plasma).  Binding to 1 mg/mL of human 
alpha-1 acid glycoprotein and 40 mg/mL human serum albumin ranged from 45.0 to 
58.3% and 64.7 to 67.3%, respectively.

No human-specific metabolites of GDC-0032 (10 M) were detected in the in vitro 
metabolism studies conducted in rat, dog and human hepatocytes.

GDC-0032 was primarily metabolized by CYP3A4 in human liver microsomes via 
oxidation at the core of the molecule or hydrolysis of the amide group.  
The formation of the main metabolite (M3) appeared to be principally mediated by 
CYP3A4, which was confirmed by incubation of 1 M GDC-0032 with human 
recombinant cytochrome P450 (CYP).

In vitro CYP inhibition studies in human liver microsomes and induction studies in 
human hepatocytes suggest a low-to-moderate potential for DDI.  GDC-0032 
appeared to be a weak time-dependent inhibitor of CYP3A4, with KI and kinact values 
of 77 µM and 0.030 min1, respectively, when testosterone was used as the probe 
substrate.  In cryopreserved human hepatocytes, the mean percent activity of 
CYP3A4/5 compared to vehicle control increased nearly 2- and over 3-fold following 
incubation with 0.1 M and 1 M GDC-0032, respectively.  At these concentrations, 
the level of enzyme induction was 31% of the positive control rifampicin at 25 M.


Protocol:  GDC-0032—Genentech, Inc.
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b.
In Vivo Studies

GDC-0032 has low plasma clearance in mice, rats, and monkeys of 2.73, 1.77, and 
4.15 mL/min/kg, respectively, and moderate clearance of 10.1 mL/min/kg in dogs 
after intravenous (IV) administration.  Renal clearance in monkeys and dogs was 
negligible, accounting for less than 1% of plasma clearance.

Terminal half-life ranged from 1.87 hours in mice to 4.42 hours in dogs.

The volume of distribution at steady-state (Vss) ranged from approximately 41% of 
total body water volume in the rat, to 4-fold total body water volume in the dog.

Bioavailability following oral administration ranged from 41.5% to 117% in 
nonclinical species tested.

In the 28-day GLP rat toxicity study, the increases in maximum concentration 
observed (Cmax) and area under the concentration–time curve from Time 0 to last 
measurable concentration (AUC0-tlast) were generally greater than dose-proportional 
on Day 1, and generally less than dose-proportional on Day 28.  The plasma 
concentrations of GDC-0032 were higher on Day 28 than on Day 1 at the 0.3 mg/kg 
dose level and lower on Day 28 than on Day 1 at the 3 mg/kg dose.  The AUC0-tlast at 
the highest dose of 3 mg/kg on Day 28 was 16400 ng mL/hour (35.6 M hour), 
with a corresponding Cmax of 1960 ng mL (4.3 M).

In the 28-day GLP dog toxicity study, exposure (Cmax and AUC0-tlast) increased in a 
dose-proportional manner in the 28-day toxicity and TK study in dogs given 
GDC-0032 QD, and exposure was generally higher on Day 28 than on Day 1.  
The AUC0-tlast at the mid-dose of 0.3 mg/kg on Day 28 was 294 nghour/mL 
(0.64 M hour), with a corresponding Cmax of 47.5 ng/mL (0.1 M).

No apparent sex differences were observed in GDC-0032 mean Cmax and AUC0-tlast
values for rats or dogs.
c.
Human Pharmacokinetic Predictions
Allometric scaling was performed to predict clearance and volume of distribution of 
GDC-0032 in humans.  Estimates of clearance and volume of distribution from 
nonclinical PK studies were used to predict these parameters in humans.  Human 
clearance (CL) was predicted to be 10 and 3.1 mL/min/kg using the simple allometric 
scaling method and the maximum lifespan potential (MLP) correction, respectively (as 
proposed by the “rule of exponents”; Mahmood and Balian 1996).  Predicted volume of 
distribution was 3.9 L/kg in humans.  Using a CL of 3.1 mL/min/kg, an absorption rate 
constant (ka) derived from dog PK, and an assumed bioavailability of 85%, simulations 
based on a one-compartment model predicted an AUC of approximately 
193 ng hour/mL (0.4 M hour) and a Cmax of 11 ng/mL (0.02 M) at the proposed 
starting dose of 3-mg capsule formulation in humans.
1.2.3
Toxicology
The toxicology program was designed to evaluate the toxicity profile of GDC-0032, 
enable selection of a safe starting dose for the Phase I trial, and support QD oral dose 
administration of GDC-0032 for up to 28 days to cancer patients in clinical trials.  Rats 


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34/P PMT4979g (GO00886)-A10
and dogs were chosen as appropriate species for toxicology studies on the basis of 
metabolic profiles similar to humans in in vitro assays. 
Nonclinical findings were consistent with the anticipated pharmacologic effects of PI3K 
inhibition and include effects on glucose metabolism and manifestations of lymphoid 
depletion in tissues and effects on bone marrow (see Section 3.4.1).  Additional 
nonclinical findings included reversible effects on body weights in rats (decreased body 
weight gain) and in dogs (body weight loss), reversible microscopic formation of cysts in 
ovaries of rats, and reversible GI inflammation in dogs administered GDC-0032.  
The majority of findings was minimal to mild, reversible, and considered not adverse.  
Moreover, these findings are expected to be clinically monitorable (except for 
microscopic ovarian cysts) and manageable in patients.  The severely toxic dose to 10% 
of animals (STD10) in rats was 3 mg/kg and the highest non-severely toxic dose (HNSTD) 
in dogs was 0.3 mg/kg when GDC-0032 was given QD PO for 28 days.  The rat STD10
enabled a safe clinical start dose of 3 mg QD in patients.  The results from the toxicology 
studies provide a robust characterization of the safety profile of GDC-0032 and support 
the administration of GDC-0032 to cancer patients for up to 28 daily doses in the 
proposed Phase I trial.
The maximum recommended starting dosage (MRSD) of 3-mg capsule QD for this 
Phase I trial was calculated after evaluation of all the relevant toxicity data and is aligned 
with current regulatory guidance (DeGeorge et al. 1998; U.S. FDA 2002; ICH S9 2010).
The STD10 in rats was determined to be 3 mg/kg QD (18 mg/m2 QD), and one-tenth of 
the rat STD10 in dogs, on an mg/m2 basis, was not severely toxic to dogs; the rat toxicity 
data formed the basis for the MRSD calculation.  A rat-to-human body surface area 
(BSA) conversion factor of 0.16 and a safety factor of 10 were applied to the STD10 in 
rats and the resulting MRSD is 0.05 mg/kg or 3 mg QD per 60-kg patient.
At the MRSD of 3 mg QD, the human AUC and Cmax are projected to be 
0.4 M hour (193 ng hour/mL) and 0.02 M (11 ng/mL), respectively, on the basis of 
human PK parameters predicted by allometric scaling (MLP scaling) 
(Mahmood and Balian 1996).  These values are approximately 89-fold and 215-fold 
lower, respectively, than the AUC and Cmax observed in rats at the STD10 and 1.5-fold
and 5-fold lower, respectively, than the AUC and Cmax in dogs at the HNSTD.
1.3
SUMMARY OF CLINICAL DATA FOR GDC-0032
1.3.1
Clinical Safety Data with GDC-0032
As of 30 July 2014, 230 patients have been treated with GDC-0032 in the Phase I/II 
Study PMT4979g, either as single-agent (n 115), in combination with fulvestrant 
(n 87), or in combination with letrozole (n 28).
As of 30 July 2014, enrollment into the single-agent dose-escalation stage of 
Study PMT4979g was completed, with 34 patients enrolled at GDC-0032 doses ranging 


Protocol:  GDC-0032—Genentech, Inc.
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from 3- to 16-mg capsules 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.  The 
maximum administered dose was 16 mg.  Although the single-agent GDC-0032 
maximum tolerated dose (MTD) was not exceeded at the 16-mg dose level, on the basis 
of long-term safety data and observed anti-tumor activity through multiple treatment 
cycles, the recommended single-agent dose and schedule for the single-agent 
GDC-0032 capsule expansion stage is 9 mg QD.  In the single-agent expansion cohorts 
in Stage 2, 77 patients have been treated with GDC-0032 9-mg capsules in Cohorts AD 
and G.
An equivalent dose conversion between capsules and tablets was developed (see 
Section 1.3.2).  Four patients have been treated with GDC-0032 6-mg tablet (equivalent 
to 9-mg capsule) in Cohort H.  In Cohort H, patients receive GDC-0032 tablets on a 
21-day-on, 7-day-off (21/7) intermittent schedule.  In addition, lower doses (2 and 4 mg) 
of GDC-0032 tablets are being investigated as a single agent, in combination, and in 
different dosing schedules. 
As of 30 July 2014, adverse events of any grade that occurred in 10% of the 
115 patients treated with single-agent GDC-0032 and assessed by the investigator as 
related to GDC-0032 were diarrhea (52%), hyperglycemia (35%), nausea (35%), fatigue 
(31%), decreased appetite (25%), rash (18%), stomatitis (15%), vomiting (13%), and 
mucosal inflammation (12%).  Among the 115 patients treated with single-agent 
GDC-0032, at least one Grade 3 adverse event was reported for 72 patients (63%).  
Grade 3 or higher adverse events reported for 1 patient were hyperglycemia (14%), 
colitis (6%), diarrhea (5%), hypokalemia (5%), pneumonitis (5%), anemia (4%), fatigue 
(4%), rash (4%), abdominal pain (4%), increased ALT (3%), dyspnea (3%), 
hyponatremia (3%), hypophosphatemia (3%), increased lipase (3%), pneumonia (3%), 
urinary tract infection (3%), congestive cardiac failure (2%), Clostridium difficile infection 
(2%), hypoxia (2%), neutropenia (2%), pruritus (2%), respiratory failure (2%), and 
stomatitis (2%).
As of 30 July 2014, adverse events of any grade that occurred in 10% of the 
87 patients treated with GDC-0032 plus fulvestrant and assessed by the investigator as 
related to GDC-0032 were diarrhea (64%), nausea (32%), fatigue (28%), decreased 
appetite (25%), mucosal inflammation (21%), rash (21%), asthenia (18%), 
hyperglycemia (17%), colitis (16%), stomatitis (16%), dry skin (13%), dyspepsia (12%), 
and dysgeusia (10%).
Among the 87 patients treated with GDC-0032 and fulvestrant, at least one Grade 3 or 
higher adverse event was reported for 42 patients (48%).  Grade 3 or higher adverse 
events reported for 1 patient were colitis (12%), diarrhea (10%), hyperglycemia (9%), 


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rash (5%), increased AST (3%), hypokalemia (3%), hyponatremia (3%), anemia (2%), 
ascites (2%), back pain (2%), mucosal inflammation (2%), and pneumonia (2%).
As of 30 July, 2014, adverse events of any grade that occurred in 10% of the 
28 patients treated with GDC-0032 plus letrozole and were assessed by the investigator 
as related to GDC-0032 were diarrhea (68%), stomatitis (39%), nausea (36%), fatigue 
(29%), rash (29%), decreased appetite (25%), hyperglycemia (25%), dysgeusia (21%), 
mucosal inflammation (21%), vomiting (21%), dry skin (18%), muscle spasms (18%), 
asthenia (14%), dry mouth (14%), pruritus (14%), and AST increased (11%).
Among the 28 patients treated with GDC-0032 and letrozole, at least one Grade 3 or 
higher adverse event was reported for 20 patients (71%).  Grade 3 or higher adverse 
events reported for 1 patient were diarrhea (14%), asthenia (7%), increased blood 
alkaline phosphatase (7%), hyperglycemia (7%), hypokalemia (7%), mucosal
inflammation (7%), and stomatitis (7%).
Refer to the Taselisib (GDC-0032) Investigator’s Brochure for further details.
1.3.2
Preliminary Pharmacokinetics
The pharmacokinetics of GDC-0032 have been characterized following administration of 
3-, 5-, 8-, 12-, and 16-mg QD capsule doses during the Stage 1 dose-escalation portion 
of this study.  The cohort mean apparent clearance (CL/F) 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 
37.2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 were 
approximately dose proportional and time independent.  Preliminary PK data from 
Cohorts E and F suggest that GDC-0032 does not appear to cause or to be a target 
(neither victim nor perpetrator) of a drug-drug interaction with fulvestrant or letrozole.
GDC-0032 was metabolized primarily by CYP3A4 in human liver microsomes 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 DDI.
The impact of formulation on the pharmacokinetics of GDC-0032 has been assessed in 
Study GP28619 in healthy volunteers.  The relative bioavailability of a 3-mg GDC-0032 
tablet versus 3-mg capsule formulation was 152% (90% CI: 142%, 163%) for GDC-0032 
AUC and 196% (90% CI: 177%, 217%) for GDC-0032 Cmax.  In the same study, the 
2-mg GDC-0032 tablet demonstrated pharmacokinetics comparable to the 3-mg capsule 
dose.  Relative bioavailability of a 2-mg tablet versus a 3-mg capsule was 101% (90% CI: 
94.8%, 107%) for AUC and 117% (90% CI: 106%, 128%) for Cmax.  A 4-mg GDC-0032 


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tablet dose is estimated to provide an AUC equivalent to that of a 6-mg capsule dose 
because of the ability of GDC-0032 to demonstrate linear, dose-proportional 
pharmacokinetics over a broad dose-range.
The drug exposure (AUC) for GDC-0032 in a healthy volunteer study (Study GP28619) 
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.
1.3.3
Preliminary Pharmacodynamics
Paired tumor biopsy samples were obtained from a patient with nonsmall cell lung 
cancer (NSCLC) treated at the 3-mg GDC-0032 dose level 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 this patient’s paired tumor biopsy samples.
For additional details, refer to the GDC-0032 Investigator’s Brochure.  
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.4.1
Rationale for Phase I
The PI3K pathway has been implicated in cancer by several important mechanisms in 
human tumors.  It is a key pathway that is activated by upstream receptor 
tyrosine kinases that are known to stimulate cancer cell proliferation, such as human 
epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), 
and insulin-like growth factor 1 receptor (IGF-1R).  Activating mutations, as well 
as amplification, in the p110subunit of PI3K have been identified in many tumor types 
(Shayesteh et al. 1999; Bachman et al. 2004; Massion et al. 2004; Samuels et al. 2004; 
Wu et al. 2005).  These activating mutations have demonstrated promotion of growth 
and invasion in cancer cells that is abrogated by PI3K inhibitors.  The pathway is 
constitutively activated by the loss of the tumor suppressor PTEN, a phosphatase that 
counteracts the kinase activity of PI3K, in many tumor types (Li et al. 1997; 
Steck et al. 1997).  AKT, which is directly downstream of PI3K, has also been shown to 
be overexpressed in some tumor types (Staal 1987; Cheng et al. 1992; 
Bellacosa et al. 1995) and to be transforming (Aoki et al. 1998).  Further downstream, 
PI3K activity leads to the phosphorylation and activation of mammalian target of 
rapamycin (mTOR), and mTOR inhibitors have already demonstrated some efficacy in 
cancer patients (Hudes et al. 2007).
Activation of the PI3KAKT pathway, which promotes proliferation and invasive activity 
of cancer cells, is abrogated by PI3K inhibitors.  The beta isoform of PI3K is involved in 
glucose metabolism as evidenced by increased glucose levels in conditional p110
knockout mice compared with wild-type mice following a glucose challenge test 
(Jia et al. 2008).  These data provide a strong rationale for developing beta 


Protocol:  GDC-0032—Genentech, Inc.
38/P PMT4979g (GO00886)-A10
isoform-sparing PI3K inhibitors that inhibit the PI3K pathway in human tumors while 
minimizing effects on glucose metabolism.
The Phase I portion of this study is composed of two stages.  The open-label, 
first-in-human, Phase I, dose-escalation portion (Stage 1) is designed to define the 
safety profile and PK and PD characteristics of GDC-0032 QD in patients with locally 
advanced or metastatic solid tumors for which standard therapy either does not exist or 
has proven ineffective or intolerable.  In Phase I, Stage 2, several expansion cohorts 
have been added to define the safety profile and PK and PD characteristics of 
GDC-0032 alone or in combination in various patient populations.
1.4.1.1
Rationale for Phase I Stage 2 Cohorts E, F, J, K, L, M, N, P, Q, R, 
and S: GDC-0032 in Combination with Letrozole or Fulvestrant 
in Hormone ReceptorPositive HER2-Negative Breast Cancer
The PI3K pathway is often activated in hormone receptorpositive breast tumors.  
A confirmed partial response has also been observed in a patient with hormone 
receptorpositive, HER2-positive, PIK3CA-mutant breast cancer in Stage 1 Cohort 2 
treated at the 5-mg capsule daily dose of GDC-0032 that was well tolerated.  On the 
basis of the strong scientific rationale and preliminary clinical data for GDC-0032 in 
hormone receptorpositive breast cancer, the combination of GDC-0032 and the 
aromatase inhibitor letrozole will be evaluated in postmenopausal patients with hormone 
receptorpositive metastatic breast cancer to obtain data on the safety profile and 
pharmacokinetics of the combination.  The combination of GDC-0032 and the estrogen 
receptor antagonist fulvestrant will also be evaluated in postmenopausal patients with 
hormone receptorpositive metastatic breast cancer to obtain data on the safety profile 
and pharmacokinetics of the combination.  It is important to test both combinations as 
letrozole and fulvestrant have different mechanisms of action, different pharmacokinetic 
properties, and different potential for DDI with GDC-0032.  Additional cohorts have been 
added to investigate different dosing schedules of GDC-0032 in combination with 
fulvestrant or letrozole.
Preliminary efficacy results from the endocrine therapy combination Stage 2 Cohorts E 
(with letrozole) and F (with fulvestrant) have demonstrated that some patients who 
started at the GDC-0032 6-mg QD capsule dose and then dose-reduced to 3-mg QD 
capsule have been able to maintain partial responses.  Therefore, several alternate dose 
schedules and dose levels will be tested to obtain further data on the relative tolerability 
of adding intermittent breaks to the GDC-0032 dosing schedule and a lower continuous 
GDC-0032 dosing with endocrine therapy.  Data from prior studies with other PI3K 
inhibitors suggest that adding intermittent breaks may help decrease toxicities while 
maintaining an equivalent amount of anti-tumor activity (Mayer et al. 2012).


Protocol:  GDC-0032—Genentech, Inc.
39/P PMT4979g (GO00886)-A10
1.4.1.2
Rationale for Phase I Stage 2 Cohort T: GDC-0032 Single Agent 
in Non-Hodgkin’s Lymphoma
The PI3K pathway is activated in both normal and malignant B-cells, with the PI3K-delta 
isoform playing an important role.  Inhibition of PI3K-delta with idelalisib has shown 
clinical activity in chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and 
small cell lymphocytic lymphoma (SLL) (Miller et al. 2015).  GDC-0032 is a very potent 
PI3K-delta inhibitor in addition to a potent inhibitor of alpha and gamma isoforms and 
thus may provide clinical benefit in patients with hematologic malignancies.  For example, 
resistance to a delta-selective PI3K inhibitor in mantle cell lymphoma can occur through 
activation of p110, and therefore, the addition of alpha inhibition may provide benefit 
(Iyengar et al. 2013).  Nonclinical data show that GDC-0032 is more potent than 
idelalisib against CD20lymphoma cell lines in vitro and delays tumor growth in a 
xenograft model in vivo (Genentech internal data).  On the basis of these promising 
nonclinical data and the demonstrated clinical efficacy of PI3K-delta inhibition, the study 
was expanded in Amendment 8 to add Cohort T in which patients with relapsed and 
refractory non-Hodgkin’s lymphomas will be enrolled to receive GDC-0032 6-mg tablet 
QD as a single agent.  In Amendment 9, the starting dose in Cohort T is changed to 
4-mg tablet QD (see Section 3.2.31 for rationale).
1.4.1.3
Rationale for Phase I Stage 2 Cohort T2: GDC-0032 Single 
Agent in Diffuse Large B-Cell Lymphoma
Cohort T was added to the study in Amendment 8 to examine safety and preliminary 
efficacy of GDC-0032 in patients with relapsed and/or refractory non-Hodgkin’s 
lymphoma.  A PET complete metabolic response was observed in a patient with diffuse 
large B-cell lymphoma (DLBCL), and partial responses were observed in a patient with 
follicular lymphoma and in a patient with MALT lymphoma, among 8 patients enrolled in 
Cohort T as of 18 March 2016.  To better understand the safety, tolerability, and 
preliminary efficacy of GDC-0032 in DLBCL, the study has been amended to add Cohort 
T2 in which patients with relapsed and/or refractory DLBCL will be enrolled to receive 
GDC-0032 4-mg tablet QD as a single agent.  Recruitment into Cohort T2 may be 
expanded from 10 to a total of approximately 20 patients if a 20% response rate has 
been demonstrated in the first 10 patients with an acceptable safety profile.  If further 
clinical benefit is observed, additional enrollment may be allowed (see Section 4.9.10).
1.4.1.4
Rationale for Phase I Stage 2 Cohort X: “Basket Cohort”
Data from patients treated with GDC-0032 indicated enhanced activity in tumors 
harboring mutations in PIK3CA.  Preliminary evidence from the dose-escalation portion 
of Study PMT4979g suggests that GDC-0032 has activity across multiple tumor types 
with PIK3CA mutations, including breast, lung, gynecologic, and head and neck (see 
Section 3.2.7).  On the basis of the prevalence rate of PIK3CA mutations in these 
cancers and to further identify other cancers in which GDC-0032 may have activity, the 
study has been amended to add Cohort X in which patients with PIK3CA-mutant cancers 
will be enrolled to receive GDC-0032 6-mg tablet QD as a single agent.


Protocol:  GDC-0032—Genentech, Inc.
40/P PMT4979g (GO00886)-A10
This basket cohort design will comprise 11 sub-cohorts representing different tumor 
types.  Patients are required to have PIK3CA-mutantpositive tumors for enrollment.  
Because the prevalence of the PIK3CA mutation is widespread across multiple tumor 
types but of variable prevalence in each tumor type, a basket design would be the most 
efficient approach to evaluate GDC-0032 in patients with PIK3CA-mutant tumors based 
on local or central assessment.  For example, in patients with endometrial cancer, data 
from The Cancer Genome Atlas Research Network (2013) showed 53% of a total of 
232 cases had mutant PIK3CA.  In one study of 109 cases of urothelial carcinoma of the 
bladder, 21% had mutant PIK3CA (Kim et al. 2014).  In patients with head and neck 
squamous-cell cancer (HNSCC), data from The Cancer Genome Atlas Research 
Network (2015) showed 21% of a total of 279 cases had mutant PIK3CA.  In other tumor 
types represented in Cohort X, the incidence of PIK3CA mutation had a range of 
5%22% in data from The Cancer Genome Atlas.
PIK3CA amplification is a common genetic alteration in HNSCC and can occur 
independently of PIK3CA point mutations in these patients.  Nonclinical data indicate 
that GDC-0032 has activity in PIK3CA-amplified HNSCC cell lines (Zumsteg et al. 2016).  
To better understand the safety, tolerability, and preliminary efficacy of GDC-0032 in 
patients with HNSCC with amplification of the PIK3CA gene and no PIK3CA somatic 
mutations detected, the study has been amended in Amendment 9 to add 1020 of 
these patients in Cohort X3. Refer to the laboratory manual for definition of PIK3CA
amplification.
Recruitment into a sub-cohort or indication may be expanded to a total of 20 patients if 
a 20% response rate has been demonstrated in the first 10 patients in that particular 
sub-cohort.  If further clinical benefit is observed, additional enrollment may be allowed 
(see Section 4.9.10).  These cohorts will evaluate preliminary safety and efficacy and 
inform whether patients with PIK3CA mutations will benefit from treatment with 
GDC-0032.
1.4.2
Rationale for Phase II
In order to obtain more information on the long-term tolerability and efficacy of 
GDC-0032 in combination with fulvestrant, a single-arm, open-label Phase II portion with 
60 postmenopausal patients with locally recurrent or metastatic HER2-negative, 
hormone receptorpositive breast cancer has been added to this study.  This Phase II 
portion is distinct from Cohort F in that patients cannot have received prior fulvestrant 
and cannot have received more than one prior chemotherapy for treatment of their 
breast cancer.
Multiple lines of nonclinical and clinical data support a key role for the PI3K pathway in 
the generation of resistance to hormonal therapies.  Activation of the PI3K pathway 
(via PIK3CA mutations, loss of PTEN expression, or HER2 overexpression) has been 
demonstrated to promote resistance to anti-estrogen therapy and hormonal 
independence in ER-positive breast cancer models (Shou et al. 2004; 


Protocol:  GDC-0032—Genentech, Inc.
41/P PMT4979g (GO00886)-A10
Miller et al. 2009, 2010).  Proteomic and transcriptional profiling of human hormone 
receptorpositive tumors suggest that increased PI3K signaling is associated with lower 
ER levels, which has been correlated with resistance to endocrine therapy 
(Creighton et al. 2010; Miller et al. 2010).  Retrospective analyses of tumor samples from 
hormone receptorpositive patients treated with tamoxifen lend support to the nonclinical 
observations linking the PI3K pathway to resistance to anti-estrogen therapy; patients 
with an activated PI3K pathway have been found to have decreased overall survival (OS) 
(Kirkegaard et al. 2005) and shorter relapse-free survival (Shoman et al. 2005).  
Inhibition of the PI3K/mTOR pathway in nonclinical models has been shown to 
upregulate ER/PgR expression (Creighton et al. 2010) and enhance the anti-tumor effect 
of letrozole (Boulay et al. 2005).
In the clinical setting, data from two Phase II studies suggest that the combined inhibition 
of the PI3K/mTOR and estrogen-signaling pathway may provide superior benefit when 
compared with single-agent endocrine therapies.  Administration of the rapamycin 
analog, everolimus, increased the efficacy of letrozole in the neoadjuvant setting in a 
Phase II study with patients with ER-positive breast cancer as measured by a decrease 
in Ki67 expression (Baselga et al. 2009).  The addition of everolimus to tamoxifen in a 
Phase II study with ER-positive patients who received prior treatment with an aromatase 
inhibitor (AI) significantly improved the clinical benefit rate (CBR), time to progression, 
and overall survival compared with single-agent tamoxifen (Bachelot et al. 2012).  Finally, 
data from the Phase III BOLERO-2 study demonstrated that the addition of everolimus to 
exemestane more than doubled progression-free survival (PFS) compared with 
single-agent exemestane in ER-positive, HER2-negative patients with metastatic breast 
cancer (MBC) whose disease was refractory to prior treatment with letrozole or 
anastrozole (Baselga et al. 2012).  Therefore, the combined inhibition of the ER and 
PI3K-pathways may prove to be an effective therapy in patients with MBC who 
experience recurrent or progressive disease while receiving treatment with an AI.
1.4.3
Benefit-Risk Assessment
The anticipated or potential safety issues associated with administration of GDC-0032 as 
a single-agent or in combination with either letrozole or fulvestrant and the measures to 
be taken that are intended to avoid or minimize such toxicities in this trial are described 
in detail in Section 3.4.
Due to the need to develop improved anti-cancer therapies and on the basis of the 
clinical and nonclinical data available for GDC-0032, Genentech has assessed the 
risk-benefit profile of GDC-0032 as either a single-agent in patients with solid tumors or 
non-Hodgkin’s lymphoma in combination with either letrozole or fulvestrant in patients 
with hormone receptorpositive advanced breast cancer to be favorable in the proposed 
clinical trial.


Protocol:  GDC-0032—Genentech, Inc.
42/P PMT4979g (GO00886)-A10
2.
OBJECTIVES
2.1
PHASE I:  OBJECTIVES (STAGE 1 AND STAGE 2)
2.1.1
Phase I:  Primary Objectives
The primary objectives of this study are the following:

Stage 1:  To evaluate the safety and tolerability of escalating doses of GDC-0032 
administered daily for 28 days to patients with locally advanced or metastatic solid 
tumors.

Stage 1:  To determine the MTD of GDC-0032 and to characterize dose-limiting 
toxicities (DLTs) associated with GDC-0032 when administered daily for 28 days to 
patients with locally advanced or metastatic solid tumors

To characterize the pharmacokinetic (PK) properties of GDC-0032

To identify a recommended dose and schedule of single-agent GDC-0032 for future 
trials

To evaluate the safety and tolerability of concomitant daily administration of 
GDC-0032 and letrozole in postmenopausal patients with locally advanced or 
metastatic hormone receptorpositive breast cancer

To evaluate the safety and tolerability of concomitant administration of GDC-0032 
and fulvestrant in postmenopausal patients with locally advanced or metastatic 
hormone receptorpositive breast cancer

To evaluate the safety and tolerability of GDC-0032 in patients with non-Hodgkin’s 
lymphoma

To evaluate the safety and tolerability of GDC-0032 in patients with PIK3CA-mutant 
locally advanced or metastatic solid tumors
2.1.2
Phase I:  Secondary Objectives
The secondary objectives of this study are the following:

To make a preliminary assessment of the anti-tumor activity of single-agent 
GDC-0032 in patients with locally advanced or metastatic solid tumors, 
non-Hodgkin’s lymphoma, tumors with PIK3CA mutations, HER2-positive breast 
tumors, and tumors with increased PIK3CA copy number

To evaluate the effect of food on the pharmacokinetics of GDC-0032

To evaluate the effect of GDC-0032 on the pharmacokinetics of midazolam

To assess the pharmacokinetics of GDC-0032 and letrozole following administration 
of GDC-0032 in combination with letrozole

To assess the pharmacokinetics of GDC-0032 and fulvestrant following 
administration of GDC-0032 in combination with fulvestrant

To make a preliminary assessment of the anti-tumor activity of GDC-0032 in 
combination with letrozole in patients with locally advanced or metastatic hormone 
receptorpositive breast cancer


Protocol:  GDC-0032—Genentech, Inc.
43/P PMT4979g (GO00886)-A10

To make a preliminary assessment of the anti-tumor activity of GDC-0032 in 
combination with fulvestrant in patients with locally advanced or metastatic hormone 
receptorpositive breast cancer
2.1.3
Phase I:  Exploratory Objectives
The exploratory objectives of this study are the following:

To determine the proportion of PI3K mutations, PI3K amplifications, and loss of 
PTEN expression in archival tissue and/or in circulating tumor DNA (ctDNA) and/or 
circulating tumor cells (CTCs) from blood obtained from patients in this study

To make a preliminary assessment of PD, dose, and anti-tumor activity with DNA 
and RNA alterations, such as, but not limited to, PI3K-mutation status, alterations 
determined by next-generation sequencing (NGS) platforms from archival and fresh 
tumor biopsies, DNA (ctDNA) and/or circulating tumor cells (CTCs), and patients’ 
clinical and pathological characteristics

To make a preliminary assessment of PD, dose, and anti-tumor activity with 
PI3K-mutation status, BCL2 and MYC expression, BCL2 and MYC rearrangement, 
cell-of-origin subtype, and DNA and RNA alterations determined by NGS in patients 
with relapsed or refractory DLBCL

To evaluate changes in tumor 18fluorodeoxyglucose (FDG) uptake as assessed by 
positron emission tomography (PET)

To determine whether inhibition of PI3K with GDC-0032 results in changes in 
downstream markers in tumor tissue and to examine the relationship to dose and 
anti-tumor activity

To explore the potential role of polymorphisms in drug metabolism enzyme and 
transporter genes in the PK of GDC-0032

To explore whether inhibition of PI3K results in changes in metabolic profiles in 
plasma and urine

To obtain PD data on the effects of GDC-0032 in combination with letrozole on the 
PI3-kinase (and other) pathways using pre- and on-treatment biopsies
2.2
PHASE II:  OBJECTIVES
2.2.1
Phase II: Primary Objective
The primary objective of the Phase II portion of the study is the following:

To assess the clinical efficacy of the combination of GDC-0032 and fulvestrant, as 
measured by the clinical benefit rate and objective response rate, in all patients and 
patients with PIK3CA-mutant breast cancer
2.2.2
Phase II:  Secondary Objectives
The secondary objectives of the Phase II portion of this study are the following:

To assess the clinical efficacy of GDC-0032 and fulvestrant, as measured by 
duration of response, PFS, and OS in all patients and patients with PIK3CA mutant 
breast cancer


Protocol:  GDC-0032—Genentech, Inc.
44/P PMT4979g (GO00886)-A10

To determine the nature, severity, and frequency of adverse events associated with 
the combination of GDC-0032 and fulvestrant 

To evaluate plasma concentrations of GDC-0032 and fulvestrant using a sparse 
sampling approach. 
2.2.3
Phase II:  Exploratory Objectives
The exploratory objectives of the Phase II portion of this study are the following:

To explore the exposure-response relationship for safety and efficacy with 
GDC-0032 and fulvestrant 

To explore predictors of response to the combination of fulvestrant and GDC-0032 
based on exploratory analyses of tumor tissue, circulating tumor DNA (ctDNA), 
circulating tumor cells (CTCs), and cytokine and chemokine levels from blood 
obtained from patients in this study 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is an open-label, multicenter, Phase I/II study.  The Phase I portion is divided into 
two stages.  Phase I, Stage 1 is a dose-escalation study using a 3 3 design to assess 
the safety, tolerability, and pharmacokinetics of GDC-0032 administered QD orally (PO) 
as a single agent.  Phase I Stage 2 includes a cohort-expansion study to assess the 
safety, tolerability, pharmacokinetics, and preliminary activity of GDC-0032 administered
as a single agent or in combination in multiple tumor types.  In addition, Phase I Stage 2 
Cohorts E and F are dose-escalation cohorts to assess GDC-0032 in combination with 
endocrine therapy in patients with hormone receptorpositive breast cancer.  Alternate 
intermittent dosing schedules with GDC-0032 as either a single agent or in combination 
with endocrine therapy will also be evaluated in Stage 2.  Patients enrolled in Phase I, 
Stage 1 and Stage 2 Cohorts A-G will receive GDC-0032 in capsule formulation, 
whereas patients in Phase I, Stage 2 Cohorts H-X will receive GDC-0032 in tablet 
formulation.  See below for detailed descriptions of the individual cohorts.
The Phase II portion is an open-label, single-arm study to assess the clinical activity of 
GDC-0032 in capsule formulation administered QD orally in combination with fulvestrant.
Approximately 563663 patients will be enrolled into Phase I of this study.  Stage 1 
(dose escalation stage) of the Phase I portion of this study has completed enrollment 
with 34 patients enrolled.  Stage 2 (cohort expansion stage) of Phase I will enroll 
approximately 529629 patients with locally advanced or metastatic solid tumors or 
non-Hodgkin’s lymphoma for which standard therapy either does not exist or has proven 
ineffective.
The Phase II portion of this study has completed enrollment with 60 postmenopausal 
patients with locally recurrent or metastatic hormone receptorpositive breast cancer 
enrolled.


Protocol:  GDC-0032—Genentech, Inc.
45/P PMT4979g (GO00886)-A10
All patients will be carefully followed for adverse events throughout the study (see 
Sections 4.5.4 for study duration), which will be graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 
(NCI CTCAE v4.0).
Patients will be enrolled at sites in the United States, Canada, and Europe.
The Sponsor has decided to discontinue enrollment in the study as of 28 June 2018 and 
discontinue manufacturing of GDC-0032.  This decision was based on the results of the 
primary analysis of Study GO29058, a Phase III study of GDC-0032 in combination 
with fulvestrant for the treatment of metastatic, hormone receptorpositive breast 
cancer (GO29058), which showed that GDC-0032 plus fulvestrant had modest clinical 
benefit and limited overall tolerability.  Patients participating in the study as of 
28 June 2018 will continue to receive treatment and undergo assessments (as outlined 
in Appendix A-7) until 6 months after enrollment of the last patient (last patient 
in [LPI] 6 months).  After this time, patients who are deriving clinical benefit from 
GDC-0032, as determined by the investigator, may continue their assigned treatment 
regimen until disease progression, unacceptable toxicity, expiration of the last batch 
of GDC-0032 (expected by May 2021), or discontinuation of the study by the Sponsor, 
whichever occurs first.  Patients continuing treatment beyond LPI 6 months will 
undergo a reduced set of assessments, as outlined in Appendix A-9).  Beyond LPI 6 
months, discontinuation of GDC-0032 treatment will also constitute discontinuation 
from the study.  Survival follow-up will be halted as of LPI 6 months.
3.1.1
Phase I
There are two stages to the Phase I portion of this study:  Stage 1 (dose escalation) and 
Stage 2 (expansion).  Each stage consists of three study periods:  a screening period of 
14 days or less, followed by a treatment period of up to 5 years, and a 30-day follow-up 
period.  See Figure 1Figure 3 for the study schemas.
Stage 1 will examine the safety and pharmacokinetics of increasing doses of GDC-0032 
administered daily in a 28-day cycle in patients with locally advanced or metastatic solid 
tumors for which standard therapy either does not exist or has proven ineffective or 
intolerable.  Thirty-four patients were enrolled in Stage 1, which has been completed.  
See Section 3.1.3 for details on Stage 1.  Refer to the Taselisib (GDC-0032) 
Investigator’s Brochure for further information.
DLTs will be assessed during the DLT assessment window (Days 135 of Cycle 1 in 
Stage 1 and Days 128 in Stage 2, Cohorts E and F; see Section 3.1.4 and 
Section 3.1.5, respectively).
Stage 2 is designed to provide a preliminary assessment of single-agent activity with 
GDC-0032 and in combination with endocrine therapy to better characterize the safety, 
tolerability, and PD and PK variability of different doses and schedules for future studies.  


Protocol:  GDC-0032—Genentech, Inc.
46/P PMT4979g (GO00886)-A10
The pharmacokinetics and safety profile of GDC-0032 as a single-agent will be 
assessed in Cohorts A, B, C, D, G, H, T, T2, and X.  The pharmacokinetics and safety 
profile of GDC-0032 in combination with letrozole will be assessed in Cohorts E, N, P, Q, 
R, and S.  The pharmacokinetics and safety profile of GDC-0032 in combination with 
fulvestrant will be assessed in Cohorts F, J, K, L, and M.  See Section 3.1.4 for details 
on Stage 2.
Pharmacokinetics (PK):  GDC-0032 pharmacokinetics will be evaluated in both stages
(see Sections 3.1.4 and 3.1.5 for specific PK assessments).  Changes to PK sampling 
times, slower dose escalation, and/or changes to the dosing schedule may be 
implemented on the basis of the results of PK analyses.  Additional PK sampling may 
occur if GDC-0032 is held for an adverse event in order to better characterize the safety 
profile of GDC-0032.
Pharmacodynamics (PD):  PD analyses will include imaging studies and assessments of 
PD biomarkers in both tumor tissue and blood:
Blood samples for platelet-rich plasma:  In Stage 1 only, blood samples will be 
collected at various timepoints and processed to obtain platelet-rich plasma to 
explore changes in surrogate PD markers in response to GDC-0032.
Circulating tumor cells (CTC) analyses:  Blood samples will be collected for 
analyses of CTCs from all patients pretreatment, on Day 15 or Day 16 of Cycle 1, 
on Day 1 of Cycle 3, at the study completion visit, and also at the clinic visit 
subsequent to a confirmed partial or complete tumor response (per Response 
Evaluation Criteria in Solid Tumors [RECIST]) for any patient (see Appendices A-1
to A-7), except for patients enrolled in Cohorts Q, R, S, T, T2, and X.
Circulating tumor DNA analysis:  Blood samples for DNA sequencing to identify 
PIK3CA and cancer-related mutations in ctDNA will be collected from all patients 
pretreatment, Cycle 3 Day 1, Cycle 5 Day 1, at the study completion visit, and also 
at clinic visits on Day 1 of every odd-numbered cycle subsequent to a confirmed 
partial or complete tumor or lymphoma response for any patient (see Appendices 
A-1 to A-7).  
Paired tumor biopsies:  Optional paired tumor biopsy samples for patients in 
Stages 1 and 2 will be obtained pretreatment (prior to initiation of treatment with 
GDC-0032 on Day 1 of Cycle 1) and on-treatment during Cycle 1, between 
Days 1521 (see Section 4.5.1.n).  A tumor biopsy upon progression of disease will 
also be optional in this trial.  From each of Cohorts N and P, a minimum of 
3 patients with PIK3CA-mutant tumors and 3 patients with PIK3CA-wild-type tumors 
(12 total) are required to provide fresh pre-treatment and on-treatment (Cycle 1 
Days 1521, 14 hours post-GDC-0032 dose) biopsy samples to assess the effects 
of GDC-0032 on the PI3K (and other) pathways in the 2-mg and 4-mg tablet doses 
in combination with letrozole.  In Cohort X3, a minimum of 5 patients are required to 
provide fresh pre-treatment and on-treatment biopsy samples to assess the effects 
of GDC-0032 on PI3K (and other cancer-related) pathways in HNSCC.  If the tissue 


Protocol:  GDC-0032—Genentech, Inc.
47/P PMT4979g (GO00886)-A10
is not evaluable for these PD measurements, additional patients may be enrolled to 
complete the cohort.
FDG-PET imaging (includes FDG-PET and/or FDG-PET/CT scans) will be optional 
for patients in Phase I Stage 1, Cohort 1 but mandatory for patients in Stage 1, 
Cohorts 2 and in selected cohorts of Phase I Stage 2 (A-G, L, M, N, Q, R, and S).  
Patients will undergo FDG-PET imaging pretreatment (within 14 days before Cycle 1, 
Day 1), during the last week of Cycle 1 (e.g., between Days 2935 [Stage 1] or 
Days 2228 [Stage 2]), and at the end of Cycle 2 (between Days 2228).  If the 
pretreatment FDG-PET imaging for a patient shows no detectable tumor FDG 
uptake, then subsequent FDG-PET imaging will not be required for that patient.  
If there are no significant changes in FDG-PET in Cycle 1, FDG-PET imaging 
should not be obtained in Cycle 2 (see Section 4.5.1 and Appendices A-1A-7).  
FDG-PET results will not be used for assessments of response or progression or for 
decisions regarding continuation of study treatment or study discontinuation, as 
FDG-PET has not been validated as an indicator of early response or progression in 
this setting.
Pharmacogenetic analysis:  A blood sample for DNA isolation will be collected from all 
patients in this study for potential pharmacogenetic analysis of genes that may affect the 
pharmacokinetics of or response to GDC-0032.
Efficacy analysis:  Disease status will be assessed using RECIST v1.1 (see Appendix C), 
except for Cohort T, which will use the Revised International Working Group (IWG) 
Response Criteria for Malignant Lymphoma (see Appendix I) and Cohort T2, which will 
use a modified version of the Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014; see Appendix J).  Patients will undergo tumor and response 
assessments at screening and then at the end of every even-numbered cycle (i.e., every 
two cycles), or earlier if clinically indicated.  If a patient undergoes an interim tumor 
evaluation to confirm a partial response (i.e., between 47 weeks after previous tumor 
assessment), the next scheduled tumor assessment may be skipped so as to not 
expose patients to excessive radiation from tumor assessments.
In the absence of a DLT, unacceptable toxicity, or disease progression, patients with 
clinical benefit will be offered continued treatment with GDC-0032 for up to 5 years.  
Continued dosing beyond Cycle 1 will be at the discretion of the investigator, after a 
careful assessment and thorough discussion of the potential risks and benefits of 
continued treatment with the patient.  Patients who are benefiting from GDC-0032 after 
the 5-year treatment period may have the possibility of continued treatment, provided 
that study drug is available.
Patients who experience a DLT during the DLT Assessment Window 
(Days 135 of Cycle 1 for Stage 1 and Days 128 of Cycle 1 for Stage 2, Cohorts E 
and F), experience disease progression or unacceptable toxicity at any time during the 
study, or, in their opinion or the opinion of the investigator, are not benefiting from 
GDC-0032, will be discontinued from GDC-0032 study treatment.  In some cases, if the 


Protocol:  GDC-0032—Genentech, Inc.
48/P PMT4979g (GO00886)-A10
adverse event is reversible and monitorable and the risk/benefit assessment suggests a 
reasonable rationale for continued treatment with study drug, patients may be allowed to 
continue with study treatment with agreement by the investigator and the Medical 
Monitor.  A Study Completion/Early Termination Visit will be performed approximately 
30 days after the last dose of GDC-0032.  The end of the study is defined as the date on 
which the last patient has his or her last visit (LPLV).
See Section 4.5 and Appendices A-1 to A-7, Appendix A-9, and B-1 to B-14 for the 
study assessments.


Protocol:  GDC-0032—Genentech, Inc.
49/P PMT4979g (GO00886)-A10
Figure 1
Phase I Study Schema (Stage 1Dose Escalation)
DLT dose-limiting toxicity (see Section 3.1.3); MTDmaximum tolerated dose; 
PKpharmacokinetic; QDonce per day; TBDto be determined.
Stage 1:  Dose Escalation

Enroll minimum of 3–6 patients per cohort

Evaluate the safety, tolerability, and 
pharmacokinetics of GDC-0032 QD (28 days in 
a 28-day cycle)
Cohort 1 (QD)
(3 mg)
Cohort 2 (QD)
(5 mg)
Cohort 3 (QD)
(8 mg)
Cohort 4 (QD)
(16 mg)
Cohort 5 (QD)
(12 mg)
Continue dose escalation to the 
MTD.
Patients will undergo intensive PK sampling on Days 1 
and 15 of Cycle 1.
Escalation to the next dose will be based on DLTs 
observed during the DLT assessment window 
(Days 135) and PK data (see Section 3.1.3).


Protocol:  GDC-0032—Genentech, Inc.
50/P PMT4979g (GO00886)-A10
Figure 2
Phase I Study Schema (Stage 2Expansion)
amp amplified; BC breast cancer; CRC colorectal cancer; DDI drug-drug interaction with 
midazolam; exc excluding; mtmutant; DLBCL diffuse large B-cell lymphoma, 
NSCLC nonsmall cell lung cancer.
Note:  Amendment 9 adds Cohort T2 and decreases the dose in Cohorts T and X from 6 mg to 
4 mg.


Protocol:  GDC-0032—Genentech, Inc.
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Figure 3
Phase I Study Schema (Stage 2Cohort X)
exc excluding; GEJ gastroesophageal junction; HNSCC head and neck squamous cell 
carcinoma; inc including; mt mutant.
a Cohorts X1X10:  If response rate 20% in the first 10 patients, an additional 10 patients will 
be added.  
b Cohort X3:  1020 patients with mutant PIK3CA HNSCC, regardless of PIK3CA copy number 
status; and 1020 patients with HNSCC with amplification of the PIK3CA gene and no PIK3CA 
somatic mutations detected.
c Cohort X9:  PIK3CA-mutant squamous cell cancer excluding histologies in Cohorts X1X8 
and X10 and NSCLC.
d Cohort X11:  PIK3CA-mutant solid tumors not otherwise specified in Cohorts X1X10 and 
excluding breast, NSCLC, and colorectal cancer.  Small cell lung cancer is allowed in 
Cohort X11.  
Note:  Amendment 9 eliminates Cohort X6 and changes the Cohort X starting dose of GDC-0032 
from 6 mg to 4 mg.
3.1.2
Phase II
The Phase II portion of this study is designed to provide safety and efficacy data on the 
combination of fulvestrant and GDC-0032.  Based on the Phase I (Stage 1 and Stage 2) 
clinical data, the recommended Phase II dose of GDC-0032 in combination with 
fulvestrant has been determined to be 6 mg QD.
In the Phase II portion of the study, approximately 60 postmenopausal patients with 
locally advanced or metastatic HER2-negative, hormone receptorpositive breast cancer 
who have not previously received fulvestrant will be enrolled in this study at sites in the
United States and in Europe.  A minimum of 30 patients will have PIK3CA-mutant breast 
cancer (see Figure 4).
All patients will be carefully followed for adverse events throughout the study, which will 
be graded according to NCI CTCAE v4.0.


Protocol:  GDC-0032—Genentech, Inc.
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GDC-0032 and fulvestrant plasma concentrations will be evaluated using a sparse 
sampling approach (see Appendices A-8 and B-9).  Additional PK sampling may occur if 
GDC-0032 is held for an adverse event in order to better characterize the safety profile 
of GDC-0032.
PD analyses will include assessments of PD biomarkers in both tumor tissue and blood.  
Blood samples will be collected for analyses of CTCs, ctDNA, and cytokines and 
chemokines as described in Appendix A-8.  Paired tumor biopsy samples obtained 
pretreatment (prior to initiation of treatment with GDC-0032 on Day 1 of Cycle 1) and 
during Cycle 2 will be optional for patients.  A tumor biopsy upon progression of disease 
will also be optional.
Disease status will be assessed using RECIST v1.1 (see Appendix C).  Patients will 
undergo tumor and response assessments at screening and then at timepoints as 
described in Appendix A-8, or earlier if clinically indicated.  Bone scans will be performed 
as described in Appendix A-8.
All patients who discontinue from the treatment phase will be followed for survival 
information and subsequent anti-cancer therapies unless the patient requests to be 
withdrawn from study survival follow-up.  Survival follow-up information will be collected 
via telephone calls, patient’s medical records, and/or clinic visits approximately every 
3 months until death, loss to follow-up, withdrawal of consent, or study termination by 
Genentech.
Figure 4
Phase II Study Schema
IMintramuscular; QDonce per day.
3.1.3
Stage 1:  Dose Escalation to Estimate the Maximum 
Tolerated Dose
Approximately 2442 evaluable patients (36 per dose-level cohort) will be enrolled in 
Stage 1.  The starting GDC-0032 dose will be 3 mg QD PO.  The number of patients and 
cohorts may increase if additional cohorts are enrolled.


Protocol:  GDC-0032—Genentech, Inc.
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In Stage 1, Cycle 1 will be 35 days in length and will begin with a PK evaluation, during 
which all patients will receive a single fasting dose of GDC-0032 on Day 1 at their 
assigned dose level.  The initial dose will be followed by a 7-day washout and frequent 
PK sampling up to 72 hours to determine the single-dose PK properties of GDC-0032 in 
humans.  Urine samples will be collected up to 24 hours after the first dose to determine 
urinary elimination of GDC-0032.  Blood samples will be taken at several scheduled
timepoints to explore the surrogate PD response after a single dose.  Continuous daily 
dosing will begin on Day 8 and will continue for 4 weeks (Days 835).  Subsequent 
cycles will be 28 days in length (4 weeks of daily dosing). 
DLTs will be assessed during the DLT assessment window (Days 135 of Cycle 1 in 
Stage 1).
In Stage 1, steady-state pharmacokinetics of GDC-0032 will be evaluated following the 
dose on Day 15.  Additional blood samples will be taken prior to dosing on Days 8, 16, 
22, and 29 during Cycle 1 and at the start of each subsequent cycle (Cycles 2) 
to monitor the exposures of GDC-0032 after continuous daily dosing (see Appendix B-1).  
Changes to PK sampling times, slower dose escalation, and/or changes to the dosing 
schedule may be implemented on the basis of the results of PK analyses.
Patients will be evaluable for DLT starting after the receipt of a single dose of GDC-0032.  
Patients who withdraw or are withdrawn from the study prior to completing the DLT
assessment window for any reason other than a DLT will be replaced.  In addition, 
patients who miss four or more total doses of GDC-0032 during the DLT assessment 
window for reasons other than a DLT will be replaced by another in that cohort.  Patients 
will not be allowed to make up missed doses at a later time; patients will resume dosing 
at their next scheduled dose.  Continuation of study treatment may occur after an 
assessment of compliance and discussion between the investigator and the Medical 
Monitor.
Dose escalation will continue in accordance with the dose-escalation rules described in 
Section 3.1.3.b until the MTD is exceeded, excessive pill burden is declared, or analysis 
of available PK data indicates that exposure will not increase with further increases in 
the dose of GDC-0032.
a.
Definition of Dose-Limiting Toxicity
All adverse events will be reported, with severity assessed according to the 
NCI CTCAE v4.0.  For dose escalation purposes, DLT assessments will be reviewed by 
the Sponsor.  A DLT is defined as any one of the following toxicities occurring within the 
DLT Assessment Window (Cycle 1, Days 135) assessed by the investigator to be 
possibly related to GDC-0032 per Section 5.2 or Section 5.3:

Grade 3 non-hematologic, non-hepatic organ system, non-metabolic 
(hyperglycemia and hyperlipidemia) toxicity, excluding the following:

Alopecia of any grade


Protocol:  GDC-0032—Genentech, Inc.
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
Grade 3 diarrhea that responds to standard-of-care therapy

Grade 3 nausea or vomiting, in the absence of premedication, that responds to 
standard-of-care therapy

Grade 4 thrombocytopenia

Grade 4 neutropenia (absolute neutrophil count [ANC] 500/L) lasting 5 days
or accompanied by fever (oral or tympanic temperature 38.0C)

Fasting Grade 4 hyperglycemia

Fasting Grade 3 hyperglycemia for 1 week, despite adequate trial of oral 
anti-hyperglycemic therapy

Grade 4 fasting hypercholesterolemia or triglyceridemia for 2 weeks despite 
intervention with a lipid-lowering agent

Grade 3 serum bilirubin or hepatic transaminase (ALT or AST)

For patients with Grade 1 hepatic transaminase at baseline as a result of liver or 
bone metastases, hepatic transaminase 7.5the upper limit of normal (ULN) will 
be considered a DLT.

For patients with liver metastases, total bilirubin 5 the ULN will be considered a 
DLT, or 10the ULN with Gilbert’s disease and with Grade 2 bilirubin at baseline.

For patients with Grade 2 alkaline phosphatase at baseline as a result of bone 
metastasis or alkaline phosphatase-secreting osteosarcoma, an alkaline 
phosphatase at 10 times the ULN will be considered a DLT.
b.
Dose-Escalation Rules
Dose escalation will occur in Stage 1.  Enrollment of the first 2 patients in the first cohort 
will be staggered by approximately 1 week.  Dose escalation will occur in accordance 
with the following rules:

A minimum of 3 patients will be initially enrolled per cohort.  If none of these patients 
experiences a DLT, escalation will proceed to the next higher dose level.  If 1 of 
these patients experiences a DLT, the cohort will be expanded to at least 6 patients.

If 2 patients in a given cohort experience a DLT during the DLT assessment 
window, the MTD (defined as the highest dose level at which 33% of patients 
develop a DLT during the DLT assessment window) will have been exceeded and 
dose escalation will stop; 3 additional patients will be evaluated for DLT at the 
preceding dose level, if 6 patients had not already been dosed at that level.

If the dose level at which the MTD is exceeded or excessive pill burden is 
encountered is 35% of the previous dose level, a subsequent dose level may be 
evaluated and will be an average of the two highest dose levels.  For example, if the 
MTD is exceeded at 1000 mg and the previous dose level was 600 mg 
(a 67% increase), the next dose level would be (600 1000)/2800 mg.
After the first cohort, dose levels will increase by 100% until a safety signal is observed 
(DLT or if 2 patients experience a Grade 2 GDC-0032related adverse event, 
excluding transaminase elevations, anemia, and neutropenia).  Thereafter, dose levels 


Protocol:  GDC-0032—Genentech, Inc.
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will increase by 50% or less until a second safety signal is observed (DLT or if 
2 patients experience a Grade 2 GDC-0032-related adverse event, excluding 
transaminase elevations, anemia, and neutropenia).  There will then be a single dose 
escalation of 40%.  All subsequent dose escalations will be 33%.  The actual dose may 
be rounded up or down based on availability of different capsule strengths.  On the basis 
of the review of real-time safety and available preliminary PK data from this study with 
GDC-0032, dose escalation may be halted or modified by Genentech as deemed 
appropriate.
The decision for dose escalation will be made by a committee composed of the following 
Sponsor representatives:  the Medical Monitor, clinical scientist, statistician, and safety 
scientist, in consultation with the PK scientist and clinical trial manager.  This committee 
will review available data on demographics, safety and adverse events, laboratory 
assessments, ECGs, dose administration, pharmacokinetics, and imaging studies.  
Based on a review of these data and in consultation with the participating investigators, 
a determination will be made as to whether dose escalation should continue and, if so, at 
what dose level.
3.1.4
Stage 2:  Expanded Cohorts in Specific Disease or Patient 
Subsets
Approximately 529-629 patients will be enrolled across 19 cohorts in Phase I, Stage 2 to 
better characterize the safety profile, PK parameters, and preliminary activity of GDC-0032 
at different doses and schedules in specific disease or patient subsets as a single agent 
(Cohorts, A, B, C, D, G, H, T, T2, and X), in combination with letrozole (Cohorts E, N, P, Q, 
R, and S), and in combination with fulvestrant (Cohorts F, J, K, L, and M).  All patients 
enrolled in Cohorts H-X will receive GDC-0032 in tablet form at doses of 2, 4, or 6 mg 
(equivalent to capsules at 3, 6, and 9 mg, respectively).
Additional patients may be enrolled to achieve a sufficient number of patients who are 
evaluable for safety and PK in each cohort as specified below, if some patients do not 
have sufficient safety and PK data for analysis (see Section 4.9.10 for justification of the 
sample size for the expansion cohorts).  The decision as to whether to enroll fewer than 
529 patients in Stage 2 will be made by the Sponsor, based on available safety and 
efficacy data and the rate of enrollment in a particular cohort.  To facilitate optimal 
operation of this complex trial, and taking into account safety and efficacy data, certain 
cohorts may be opened and enrolled in a staggered fashion (e.g., Cohort J before 
Cohort L).  This is especially applicable for expansion cohorts with similar inclusion and 
exclusion criteria (Cohorts JM and NS).
The Stage 2 dose for single-agent GDC-0032 (Cohorts AD, G, H, T, and X) is the 
recommended dose for future studies according to criteria specified in Section 3.2.5 and 
will depend on the overall safety and tolerability while maximizing anticipated biological 
effect on PI3K inhibition.  All patients enrolled in Cohorts AG will receive GDC-0032 in 
capsule form.  All patients enrolled in Cohorts H-X will receive GDC-0032 in tablet form 


Protocol:  GDC-0032—Genentech, Inc.
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at doses of 2, 4, or 6 mg (equivalent to capsules at 3, 6, and 9 mg, respectively).  The 
GDC-0032 dose in combination with endocrine therapy in Stage 2 (Cohorts E and F) will 
be established using the dose escalation rules described in Sections 3.1.4.e and 3.1.4.f.  
Additionally, safety, tolerability, and preliminary efficacy data from Cohorts JN and PS 
will aim to evaluate additional doses and alternative dosing schedules and thus help with 
a robust risk assessment with each of the endocrine therapy combinations.  Dose levels 
and schedules for various cohorts are described below.
In Stage 2, Cycle 1 will be 2835 days in length, depending on the specific cohort.  
Subsequent cycles will be 28 days in length (4 weeks of daily dosing).  See Figure 5 for 
the Stage 2 dosing and PK sample collection.
If the frequency of Grade 3 or 4 toxicities or other unacceptable chronic toxicities in 
Stage 2 suggests that the MTD has been exceeded at that dose level, any remaining 
accrual at that dose level will be halted.  Consideration will then be given to enrolling an 
expansion cohort at the next lower dose level (as defined in Section 4.3.3 and Table 5), 
up to the specified number of patients (as described in Section 3.1).
Capsule Dosing Cohorts (Cohorts A-G):
a.
Cohort A
Approximately 20 patients with PIK3CA-mutant breast cancer will be enrolled in 
Cohort A.  The initial dose of GDC-0032 will be given on Day 1, followed by a 7-day 
washout period.  Continuous daily dosing in Cycle 1 of GDC-0032 will begin on Day 8 
and will continue for 4 weeks (Days 835).  See Appendix A-2 for the schedule of 
assessments and Appendix B-2 for the schedule of PK sample collection.
GDC-0032 appears to be a Biopharmaceutics Classification System (BCS) Class II 
compound (see Section 3.2.4).  Since food impacts the pharmacokinetics of some BCS 
Class II compounds, the effect of food on the pharmacokinetics of GDC-0032 will be 
assessed in Cohort A.
A single standard high-fat meal (according to the U.S. Food and Drug Administration 
[FDA] guidelines) will be given to patients on either Day 1 or Day 8 of Cycle 1, followed 
by their daily dose of GDC-0032 (see Section 3.2.4).  Patients will be assigned in 
an alternating fashion to either Day 1 (odd-numbered patients) or Day 8 (even-numbered 
patients) for the food-effect assessment.  PK profiles up to 24 hours after dosing on 
Days 1 and 8 will be compared to assess food effect (see Section 3.2.4).  Selection of 
the single-agent dose and schedule for future studies will be based on a safe and 
tolerable dose and schedule that achieves a reasonable exposure and PD effect.
b.
Cohort B
Approximately 20 patients with PIK3CA-mutant solid tumors other than breast cancer will 
be enrolled in Cohort B.  GDC-0032 will be administered daily beginning on Day 1 of 


Protocol:  GDC-0032—Genentech, Inc.
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Cycle 1 and will continue for 4 weeks (Days 128).  See Appendix A-3 for the schedule 
of assessments and Appendix B-3 for the schedule of PK sample collection.
c.
Cohort C
Approximately 13 patients with solid tumor (any type) will be enrolled in Cohort C to 
assess the safety profile and the pharmacokinetic interactions of midazolam, a CYP3A4 
substrate, and GDC-0032.  Midazolam will be administered on Days 1 and 16 of Cycle 1.  
Daily oral administration of GDC-0032 will start on Day 2 and will continue for 4 weeks
(Days 229).  Additional patients may be enrolled to obtain a complete data set from 
12 patients who are evaluable for PK analysis.  See Appendix A-4 for the schedule of 
assessments and Appendix B-4 for schedule of PK sample collection.
d.
Cohort D
Approximately 10 patients with HER2-positive breast cancer will be enrolled in this 
cohort to assess the safety profile, pharmacokinetics, and treatment effect of GDC-0032 
in this patient population.  GDC-0032 will be administered daily beginning on Day 1 of 
Cycle 1 and will continue for 4 weeks (Days 1-28).  See Appendix A-3 for the schedule 
of assessments and Appendix B-3 for the schedule of PK sample collection.
e.
Cohort E
Approximately 28 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with letrozole in this patient population.  A minimum of 10 of 
these patients enrolled at the recommended GDC-0032 Phase II dose in combination 
with letrozole will be required to have PIK3CA-mutant breast cancer.  Patients enrolled 
in Cohort E will receive a GDC-0032 dose level in combination with letrozole (see
Section 3.2.5) that will be at or below the recommended single-agent dose and schedule.  
The initial dose level of GDC-0032 in Cohort E will be 6-mg capsule daily.  If the 6 mg 
dose appears to be tolerated, consideration will be given to escalating the dose to 9-mg 
capsule daily, the recommended single-agent dose.  No further dose escalation will 
occur above the recommended single-agent dose.
Definition of Dose-Limiting Toxicity
GDC-0032 and letrozole in Cycle 1 will be administered daily beginning on Day 1 and 
will continue for 4 weeks (Days 1-28).  DLTs will be assessed during the DLT 
assessment window (Days 1-28 of Cycle 1) using the DLT definitions in Section 3.1.3.a.
Patients will be evaluable for a DLT starting after the receipt of a single dose of 
GDC-0032.  Patients who withdraw or are withdrawn from the study prior to completing 
the DLT assessment window for any reason other than a DLT will be replaced.  In 
addition, patients who miss four or more total doses of GDC-0032 during the DLT 
assessment window for reasons other than a DLT will be replaced by another patient in 
that cohort.  Patients in Cohort E who miss four or more total doses of letrozole during


Protocol:  GDC-0032—Genentech, Inc.
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the DLT assessment window for reasons other than a DLT will be replaced by another 
patient in that cohort.  Letrozole doses do not necessarily need to be held for 
GDC-0032-related adverse events.  Patients will not be allowed to make up missed 
doses at a later time; patients will resume dosing at their next scheduled dose.  
Continuation of study treatment may occur after an assessment of compliance and 
discussion between the investigator and the Medical Monitor.
Determination of the Recommended GDC-0032 Dose in Combination with 
Letrozole for Future Studies
Dose escalation will occur in accordance with the following rules:

A minimum of 3 patients will be initially enrolled per cohort.  If none of these patients 
experiences a DLT, escalation may proceed to the next higher dose level.  If 1 of 
these patients experiences a DLT, the cohort will be expanded to at least 6 patients.

If 2 patients in a given cohort experience a DLT during the DLT assessment 
window, the MTD (defined as the highest dose level at which 33% of patients 
develop a DLT during the DLT assessment window) will have been exceeded and 
dose escalation will stop; 3 additional patients will be evaluated for DLT at the 
preceding dose level, if 6 patients have not already been dosed at that level.
If patients in the cohort receiving 6-mg daily GDC-0032 capsule in combination with 
letrozole do not exceed the MTD, then the 9-mg capsule daily dose level in combination 
with letrozole may be tested.
If patients in the cohort receiving 6-mg daily GDC-0032 capsule in combination with 
letrozole exceeds the MTD, then a 3-mg daily GDC-0032 capsule dose level in 
combination with letrozole may be tested. 
On the basis of the review of real-time safety and available preliminary PK data from this 
study with GDC-0032 and letrozole, dosing may be halted or modified by Genentech as 
deemed appropriate.
The decision for dose escalation or de-escalation will be made by a committee 
composed of the following Sponsor representatives:  the Medical Monitor, clinical 
scientist, statistician, and safety scientist, in consultation with the PK scientist and 
clinical trial manager.  This committee will review available data on demographics, safety 
and adverse events, laboratory assessments, ECGs, dose administration, 
pharmacokinetics, and imaging studies.  Based on a review of these data and in 
consultation with the participating investigators, a determination will be made as to 
whether dose escalation or de-escalation should continue and, if so, at what dose level.
The selection of the recommended GDC-0032 dose in combination with letrozole for 
future studies will be based on safety, tolerability, PK data, and consideration of other 
factors pertaining to the patient population treated with letrozole.  These factors include 


Protocol:  GDC-0032—Genentech, Inc.
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expected duration of therapy, the overall tolerability in patients who may have a 
prolonged time to progression, and clinical benefit of the combination of letrozole and 
GDC-0032.
Schedule of Assessments and Pharmacokinetic Sample Collection
See Appendix A-5 for the schedule of assessments and Appendix B-5 for schedule of 
PK sample collection.
Enrollment at the Recommended GDC-0032 Dose in Combination with Letrozole 
for Future Studies
To establish a robust and tolerable dose of GDC-0032 in combination with letrozole, 
approximately 20 patients will be enrolled into Cohort E at the recommended GDC-0032 
dose in combination with letrozole for future studies (e.g., 6-mg capsule dose level).  
More than one dose may be evaluated if it appears that there may be differences in the 
adverse event profile to select a dose for future studies.  To evaluate less common but 
potentially important side effects such as pneumonitis, which is a class effect for these 
molecules, an enrollment of 20 patients should allow a better estimate of frequency, 
should this be observed (see Section 4.9.10).
f.
Cohort F
Approximately 27 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with fulvestrant in this patient population.  A minimum of 10 of 
these patients enrolled at the recommended GDC-0032 Phase II dose in combination 
with fulvestrant will be required to have PIK3CA-mutant breast cancer.  The initial dose 
level of GDC-0032 in Cohort F will be 6-mg capsule daily.  If the 6-mg dose appears to 
be tolerated, consideration will be given to escalating the dose to 9-mg capsule daily, the 
recommended single-agent dose.  No further dose escalation will occur above the 
recommended single-agent dose. 
Definition of Dose-Limiting Toxicity
GDC-0032 and fulvestrant in Cycle 1 will be administered daily beginning on Day 1 and 
will continue for 4 weeks (Days 1-28).  DLTs will be assessed during the DLT 
assessment window (Days 1-28 of Cycle 1), using the DLT definitions in Section 3.1.3.a.
Patients will be evaluable for DLT starting after the receipt of a single dose of GDC-0032.  
Patients who withdraw or are withdrawn from the study prior to completing the DLT 
assessment window for any reason other than a DLT will be replaced.  In addition, 
patients who miss four or more total doses of GDC-0032 during the DLT assessment 
window for reasons other than a DLT will be replaced by another patient in that cohort.  
Patients will not be allowed to make up missed doses at a later time; patients will 
resume dosing at their next scheduled dose.   Patients who miss a fulvestrant dose 


Protocol:  GDC-0032—Genentech, Inc.
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during the DLT assessment window for reasons other than a DLT will be replaced by
another in that cohort.  Fulvestrant doses do not necessarily need to be held for 
GDC-0032-related adverse events.  Continuation of study treatment may occur after an 
assessment of compliance and discussion between the investigator and the Medical 
Monitor. 
Determination of the Recommended GDC-0032 Dose in Combination with 
Fulvestrant for Future Studies
Dose escalation will occur in accordance with the following rules:

A minimum of 3 patients will be initially enrolled per cohort.  If none of these patients 
experiences a DLT, escalation may proceed to the next higher dose level.  If 1 of 
these patients experiences a DLT, the cohort will be expanded to at least 6 patients.

If 2 patients in a given cohort experience a DLT during the DLT assessment 
window, the MTD (defined as the highest dose level at which 33% of patients 
develop a DLT during the DLT assessment window) will have been exceeded and 
dose escalation will stop; 3 additional patients will be evaluated for DLT at the 
preceding dose level, if 6 patients have not already been dosed at that level.
If patients in the cohort receiving 6-mg daily GDC-0032 capsule in combination with 
fulvestrant do not exceed the MTD, then the 9-mg capsule daily dose level in 
combination with fulvestrant may be tested.
If patients in the cohort receiving 6-mg daily GDC-0032 capsule in combination with 
fulvestrant exceeds the MTD, then a 3-mg daily GDC-0032 capsule dose level in 
combination with fulvestrant may be tested.
On the basis of the review of real-time safety and available preliminary PK data from this 
study with GDC-0032 and fulvestrant, dosing may be halted or modified by Genentech 
as deemed appropriate.
The decision for dose escalation or de-escalation will be made by a committee 
composed of the following Sponsor representatives:  the Medical Monitor, clinical 
scientist, statistician, and safety scientist, in consultation with the PK scientist and 
clinical trial manager.  This committee will review available data on demographics, safety 
and adverse events, laboratory assessments, ECGs, dose administration, 
pharmacokinetics, and imaging studies.  Based on a review of these data and in 
consultation with the participating investigators, a determination will be made as to 
whether dose escalation or de-escalation should continue and, if so, at what dose level.
The selection of the recommended GDC-0032 dose in combination with fulvestrant for 
future studies will be based on safety, tolerability, PK data, and consideration of other 
factors pertaining to the patient population treated with fulvestrant.  These factors 
include expected duration of therapy, the overall tolerability in patients who may have a 


Protocol:  GDC-0032—Genentech, Inc.
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prolonged time to progression, and clinical benefit of the combination of fulvestrant and 
GDC-0032.
Schedule of Assessments and Pharmacokinetic Sample Collection
See Appendix A-5 for the schedule of assessments and Appendix B-6 for the schedule 
of PK sample collection.
Enrollment at the Recommended GDC-0032 Dose in Combination with Fulvestrant 
for Future Studies
To establish a robust and tolerable dose of GDC-0032 in combination with fulvestrant 
approximately 20 patients may be enrolled at the recommended GDC-0032 dose in 
combination with fulvestrant for future studies.  More than one dose may be evaluated if 
it appears that there may be differences in the adverse event profile to select a dose for 
future studies (e.g., 6-mg capsule dose level).  To evaluate less common but potentially 
important side effects such as pneumonitis, which is a class effect for these molecules, 
an enrollment of 20 patients should allow a better estimate of frequency, should this be 
observed (see Section 4.9.10).
g.
Cohort G
Approximately 20 patients with solid tumors with increased PIK3CA copy number will be 
enrolled in this cohort to assess the safety profile, pharmacokinetics, and treatment 
effect of GDC-0032 in this patient population.  GDC-0032 will be administered daily 
beginning on Day 1 of Cycle 1 and will continue for 4 weeks (Days 128).  See 
Appendix A-3 for the schedule of assessments and Appendix B-3 for the schedule of PK 
sample collection. 
Tablet Dosing Cohorts (Cohorts H-X):
h.
Cohort H
Approximately 40 patients with PIK3CA-mutant solid tumors that are nonbreast and 
noncolorectal cancer will be enrolled in Cohort H.  GDC-0032 tablets at the 6-mg dose 
level will be administered daily on a 21-day on, 7-day off (21/7) schedule.  
See Appendix A-7 and Appendix A-9 for the schedule of assessments and 
Appendix B-7 for the schedule of PK sample collection.  Cohort H must include a 
minimum 5 patients with cervical cancer and a minimum of 20 patients with NSCLC.
i.
Cohort J
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with fulvestrant in this patient population.  This cohort will 
evaluate an alternative schedule of GDC-0032 tablets administered daily on a 21-day on, 
7-day off (21/7) schedule at the 4-mg QD dose level.  A minimum of 10 of these patients 
enrolled will be required to have PIK3CA-mutant breast cancer.  See Appendix A-7 and 


Protocol:  GDC-0032—Genentech, Inc.
62/P PMT4979g (GO00886)-A10
Appendix A-9 for the schedule of assessments and Appendix B-8 for the schedule of 
PK sample collection.
j.
Cohort K
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with fulvestrant in this patient population.  This cohort will 
evaluate an alternative schedule of GDC-0032 tablets administered daily on a 5-day on, 
2-day off (5/2) schedule at the 4-mg dose level.  A minimum of 10 of these patients 
enrolled will be required to have PIK3CA-mutant breast cancer.  See Appendix A-7 and 
Appendix A-9 for the schedule of assessments and Appendix B-8 for the schedule of 
PK sample collection.
k.
Cohort L
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with fulvestrant in this patient population.  This cohort will 
evaluate an alternative schedule of GDC-0032 tablets administered daily on a 7-day on, 
7-day off (7/7) schedule at the 4-mg dose level.  A minimum of 10 of these patients 
enrolled will be required to have PIK3CA-mutant breast cancer.  See Appendix A-7 and 
Appendix A-9 for the schedule of assessments and Appendix B-11 for the schedule of
PK sample collection.
l. 
Cohort M
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 in combination with fulvestrant in this patient population.  This cohort will 
evaluate a schedule of GDC-0032 tablets administered daily in each 28-day cycle at the 
2-mg dose level.  A minimum of 10 of these patients enrolled will be required to have 
PIK3CA-mutant breast cancer. See Appendix A-7 and Appendix A-9 for the schedule of 
assessments and Appendix B-8 for the schedule of PK sample collection.
m. Cohort N
Approximately 26 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 tablets in combination with letrozole in this patient population.  This cohort 
will evaluate a schedule of GDC-0032 administered daily at the 2-mg QD tablet dose 
level.  A minimum of 10 of these patients enrolled will be required to have 
PIK3CA-mutant breast cancer.  A minimum of 6 of these patients (3 patients with 
PIK3CA-wild-type and 3 patients with PIK3CA-mutant tumors) will be required to 
undergo paired pre-treatment and on-treatment (Cycle 1 Days 1521, 14 hours 
post-GDC-0032 dose) tumor biopsy samples.  If the paired tumor biopsy samples are 
not evaluable, additional patients may be enrolled to complete the cohort.  


Protocol:  GDC-0032—Genentech, Inc.
63/P PMT4979g (GO00886)-A10
See Appendix A-7 and Appendix A-9 for the schedule of assessments and 
Appendix B-9 for the schedule of PK sample collection. 
n.
Cohort P
Approximately 26 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 tablets in combination with letrozole in this patient population.  This cohort 
will evaluate GDC-0032 administered daily at the 4-mg QD tablet dose level.  A 
minimum of 10 of these patients enrolled will be required to have PIK3CA-mutant breast 
cancer.  A minimum of 6 of these patients (3 patients with PIK3CA-wild-type and 
3 patients with PIK3CA-mutant tumors) will be required to undergo paired pre-treatment 
and on-treatment (Cycle 1 Days 1521, 14 hours post-GDC-0032 dose) tumor biopsy 
samples.  If the paired tumor biopsy samples are not evaluable, additional patients may 
be enrolled to complete the cohort.  See Appendix A-7 and Appendix A-9 for the
schedule of assessments and Appendix B-9 for the schedule of PK sample collection.
o. Cohort Q
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 tablets in combination with letrozole in this patient population.  This cohort 
will evaluate GDC-0032 administered on a 21-day-on, 7-day-off (21/7) schedule at the 
4-mg tablet dose level.  A minimum of 10 of these patients enrolled will be required to 
have PIK3CA-mutant breast cancer.  See Appendix A-7 and Appendix A-9 for the
schedule of assessments and Appendix B-9 for the schedule of PK sample collection.
p. Cohort R
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 tablets in combination with letrozole in this patient population.  This cohort 
will evaluate GDC-0032 administered on a 5-day-on, 2-day-off (5/2) schedule at the 
4-mg tablet dose level.  A minimum of 10 of these patients enrolled will be required to 
have PIK3CA-mutant breast cancer.  See Appendix A-7 and Appendix A-9 for the 
schedule of assessments and Appendix B-9 for the schedule of PK sample collection.
q. Cohort S
Approximately 20 postmenopausal patients with hormone receptorpositive breast 
cancer will be enrolled to characterize the safety, tolerability, and pharmacokinetics of 
GDC-0032 tablets in combination with letrozole in this patient population.  This cohort 
will evaluate GDC-0032 administered on a 7-day-on, 7-day-off (7/7) schedule at the 
4-mg tablet dose level.  A minimum of 10 of these patients enrolled will be required to 
have PIK3CA-mutant breast cancer.  See Appendix A-7 and Appendix A-9 for the
schedule of assessments and Appendix B-12 for the schedule of PK sample collection.


Protocol:  GDC-0032—Genentech, Inc.
64/P PMT4979g (GO00886)-A10
r. Cohort T
Approximately 10 patients with non-Hodgkin’s lymphoma that has progressed or has 
failed to respond to at least one prior regimen will be enrolled to characterize the safety, 
tolerability, and pharmacokinetics of GDC-0032 in this patient population.  This cohort 
will evaluate GDC-0032 administered daily at the 6-mg tablet dose level. In 
Amendment 9, the starting dose of GDC-0032 is changed to 4-mg tablet (see 
Section 3.2.31). There is no minimum number of patients who are required to have the 
PIK3CA mutation.  See Appendix A-7 and Appendix A-9 for the schedule of 
assessments and Appendix B-7 for the schedule of PK sample collection.
s. Cohort T2
Approximately 1020 patients with DLBCL who have progressed or have failed to 
respond to at least one prior regimen will be enrolled to characterize the safety, 
tolerability, and pharmacokinetics of GDC-0032 in this patient population.  This cohort 
will evaluate GDC-0032 administered daily at the 4-mg tablet dose level.  There is no 
minimum number of patients who are required to have the PIK3CA mutation.  Patients 
must have available a representative tumor specimen and the corresponding pathology 
report for retrospective central confirmation of the diagnosis of DLBCL and for 
exploratory research on candidate biomarkers. See Appendix A-7 and Appendix A-9 for 
the schedule of assessments and Appendix B-7 for the schedule of PK sample collection.
t. Cohort X (Basket Cohort)
Approximately 150230 patients with PIK3CA-mutant solid tumors that have progressed 
or failed to respond to at least one prior regimen will be enrolled to characterize the 
safety, tolerability, pharmacokinetics, and efficacy of GDC-0032 in this patient population.  
This cohort will evaluate GDC-0032 administered daily at the 6-mg tablet dose level.  In 
Amendment 9, the starting dose of GDC-0032 is changed to 4-mg tablet (see 
Section 3.2.33).  For sub-Cohort X3 patients with HNSCC who have gastrostomy tubes, 
GDC-0032 will be administered as an extemporaneous suspension prepared at home 
only at sites where administration of the extemporaneous suspension is approved by the 
Institutional Review Board/Ethics Committee (IRB/EC).
This cohort comprises 10 different tumor types (sub-Cohorts X1 through X10) and 
another sub-Cohort, X11, to enroll patients with PIK3CA-mutant cancers not otherwise 
captured in the other cohorts, as shown in Figure 3.  Each sub-cohort will enroll 
approximately 1020 patients (sub-Cohort X11 will enroll approximately 50 patients) on 
the basis of initial response rates and central laboratory confirmation of 
PIK3CA-mutation status.  See Section 4.9.10.b for sample size determination.  As it is 
expected that enrollment into individual sub-cohorts may be halted independent of one 
another because of low enrollment or lack of responses, the total number of patients in 
Cohort X will be capped at approximately 230.  In Amendment 9, Cohort X6 (SCLC) was 
removed; any such patients will be allowed to enroll in Cohort X11.  During Amendment 
9, Cohort X3 was expanded to include an additional 1020 patients with HNSCC with 


Protocol:  GDC-0032—Genentech, Inc.
65/P PMT4979g (GO00886)-A10
amplification of the PIK3CA gene and no detectable PIK3CA somatic mutations.  The 
total number of patients in Cohort X3 is now 2040. 
Tumor tissue can be initially assessed for PIK3CA mutation or amplification status at a 
local or central laboratory.  If locally assessed, refer to laboratory manual for definition of 
PIK3CA amplification.  Tumor tissue must be submitted for evaluation of adequate tumor 
tissue content by a central laboratory, which must occur prior to initiation of study 
treatment.  A minimum of 10 slides, preferably 1520, should be submitted and be of 
good quality based on total and viable tumor content (as defined in the Laboratory 
Manual).  If patients are enrolled in the study on the basis of a local positive test result 
and a mutation or amplification is not detected per central testing, additional patients 
may be enrolled.
See Appendix A-7 and Appendix A-9 for the schedule of assessments and Appendix B-
7 and B-14 for the schedule of PK sample collection.


Protocol:  GDC-0032—Genentech, Inc.
66/P PMT4979g (GO00886)-A10
Figure 5
Phase I Stage 2 Dosing and Pharmacokinetic Sample Collection
Cohort A:  PIK3CA-Mutant Breast Cancer (Food-Effect Assessment)
Cohort B (PIK3CA-Mutant Solid Tumors), Cohort D (HER2-Positive Breast Cancer), and 
Cohort G (Solid Tumors with Increased PIK3CA Copy Number)
Cohort C:  Solid Tumors (Midazolam Drug-Drug Interaction Assessment)
MDZmidazolam








Protocol:  GDC-0032—Genentech, Inc.
70/P PMT4979g (GO00886)-A10
Figure 5
Phase I Stage 2 Dosing and Pharmacokinetic Sample Collection
(cont.)
Cohort Q:  HER2-Negative, Hormone ReceptorPositive Breast Cancer (4-mg GDC-0032 Tablet 
on a 21-Day on, 7-Day off [21/7] Schedule) in Combination with Letrozole:
Cohort R:  HER2-Negative, Hormone ReceptorPositive Breast Cancer (4-mg GDC-0032 Tablet 
on a 5-Day on, 2-Day off [5/2] Schedule) in Combination with Letrozole:
Cohort S:  HER2-Negative, Hormone ReceptorPositive Breast Cancer (4-mg GDC-0032 Tablet 
on a 7-Day on, 7-Day off [7/7] Schedule) in Combination with Letrozole:


Protocol:  GDC-0032—Genentech, Inc.
71/P PMT4979g (GO00886)-A10
Figure 5
Phase I Stage 2 Dosing and Pharmacokinetic Sample Collection
(cont.)
Cohort T:  Non-Hodgkin’s Lymphoma (4-mg GDC-0032 Tablet Daily Dosing Schedule):
Cohort T2:  DLBCL (4-mg GDC-0032 Tablet Daily Dosing Schedule):
Cohort X:  PIK3CA Mutant Solid Tumors (4-mg GDC-0032 Tablet Daily Dosing Schedule):
Cohort X3:  Head and Neck Squamous Cell Carcinoma (4-mg GDC-0032 Suspension Daily 
Dosing Schedule):


Protocol:  GDC-0032—Genentech, Inc.
72/P PMT4979g (GO00886)-A10
3.1.5
Phase II Portion for GDC-0032 and Fulvestrant
Approximately 60 patients who are postmenopausal with hormone receptorpositive 
breast cancer will be enrolled to make preliminary assessment of efficacy and to 
characterize the safety, tolerability, and pharmacokinetics of GDC-0032 in combination 
with fulvestrant in this patient population.  A minimum of 30 of these patients will be 
required to have PIK3CA-mutant breast cancer.  Patients enrolled in the Phase II portion 
will receive GDC-0032 at 6 mg QD in combination with fulvestrant (see Section 3.2.5) 
based upon results from Stage 1 and Stage 2 of this study.
GDC-0032 and fulvestrant will be administered daily beginning on Cycle 1 Day 1 and will 
continue for 4 weeks (Days 1-28).  Fulvestrant doses do not necessarily need to be held 
for GDC-0032-related adverse events.  GDC-0032 doses do not necessarily need to be 
held for fulvestrant-related adverse events.  See Appendix A-8 for the schedule of 
assessments and Appendix B-10 for schedule of PK sample collection (see Figure 6).
Based on review of real-time safety and available preliminary PK data from this study 
with GDC-0032 and fulvestrant, dosing may be halted or modified by the Sponsor as 
deemed appropriate.
Figure 6
Phase II:  Pharmacokinetic Sample Collection to Measure 
Fulvestrant and GDC-0032 Concentrations
CCycle; DDay; PKpharmacokinetic.
Note:  PK sample collection will be as follows:
GDC-0032:  C1D1 predose; C1C15 predose and 4 hours postdose; C2D1 predose; 
C6D1 predose.
Fulvestrant:  C1D1 predose; C1D15 predose; C2D1 predose; C6D1 predose.
3.2
RATIONALE FOR STUDY DESIGN
3.2.1
Rationale for Patient Group Selection in Stage 1
The patient population (patients with locally advanced or metastatic solid malignancy 
that has progressed or failed to respond to at least one prior regimen or for which there 
is no standard therapy) for this study has been selected primarily to assess the safety 
and pharmacokinetics of GDC-0032 in patients who would provide the best information 


Protocol:  GDC-0032—Genentech, Inc.
73/P PMT4979g (GO00886)-A10
for future studies with GDC-0032.  Hematologic malignancies and primary malignancies 
of the brain or spinal cord are excluded from the Phase I Stage 1 portion of the study.  
While PI3K pathway activation has been implicated in hematologic malignancies, the 
potential for bone marrow toxicities with GDC-0032 may make this drug less safe for a 
first-in-human study in this patient population and may make it difficult to attribute 
toxicities to disease or the introduction of this agent.
3.2.2
Rationale for Starting Dose and Schedule and Dose-Escalation 
Rules in Stage 1 of Phase I
The maximum recommended starting dose (MRSD) for the proposed Phase I trial was 
calculated after evaluation of all the relevant toxicity data and is aligned with current 
regulatory guidance (DeGeorge et al. 1998; U.S. FDA 2002; ICH S9 2010).
Considering the STD10 in rats was determined to be 3 mg/kg QD (18 mg/m2 QD), 
one-tenth of the rat STD10 in dogs, on a milligram per meter squared (mg/m2) basis, was 
not severely toxic to dogs, the rat data formed the basis for the maximum recommended 
starting dose (MRSD) calculation. A rat-to-human BSA conversion factor of 0.16 and a 
safety factor of 10 were applied to the STD10 in rats, and the resulting MRSD is 
0.05 mg/kg or 3 mg QD per 60-kg patient.  
At the MRSD of 3 mg QD, the human AUC and Cmax are projected to be 0.4 M hour 
(193 ng hour/mL) and 0.02 M (11 ng/mL), respectively, based on human PK 
parameters predicted by allometric scaling (maximum lifespan potential (MLP) scaling) 
(Mahmood and Balian 1996).  These values are approximately 89-fold and 215-fold 
lower, respectively, than the AUC and Cmax observed in rats at the STD10 and 1.5-fold 
and 5-fold lower, respectively, than the AUC and Cmax in dogs at the HNSTD.
3.2.3
Rationale for the Pharmacokinetic Evaluation Schedule
The PK evaluation schedule during Cycle 1 is based on the predicted GDC-0032 
PK profile in humans using the MLP method of allometric scaling.  The half-life (t1/2) is 
predicted to be approximately 14 hours; and time to maximum concentration (Tmax) is 
predicted to be approximately 4 to 5 hours postdose.
After a single dose on Day 1, the frequent sampling schedule up to 72 hours is designed 
to characterize the absorption, distribution, and elimination profile.  PK sampling up to 
72 hours postdose (~5t1/2 after Tmax) is expected to allow for characterization of the 
complete PK profile.  Urine samples will be collected in Stage 1 up to 24 hours after the 
dose on Day 1 to determine urinary excretion of GDC-0032.
Steady-state pharmacokinetics of GDC-0032 will be evaluated following the dose on 
Day 15.  Additional blood samples will be taken prior to dosing on Days 8, 22, and 29 
during Cycle 1 and at the start of each subsequent cycle (Cycles 2) to monitor the 
exposures of GDC-0032 after continuous daily dosing.  In addition, PK samples will be 


Protocol:  GDC-0032—Genentech, Inc.
74/P PMT4979g (GO00886)-A10
collected on Day 8 in Stage 2, Cohort A for food-effect assessment (see Sections 3.1.4
and 3.2.4).
PK data obtained from patients in early cohorts will be used to determine whether 
GDC-0032 PK can be adequately characterized with the planned PK sampling schedule.  
If, upon analysis of these data, it is apparent that the pharmacokinetics of GDC-0032 
cannot be adequately characterized with the planned PK sampling schedule, up to four 
additional samples may be collected from each patient or the PK sampling times may be 
adjusted.  Similarly, sampling time points that are not informative may be eliminated.  If 
changes are made to the PK sampling schedule, revised Appendices B-1 to B-14 will be 
provided to investigators.
After the plasma and urine samples are analyzed for GDC-0032 concentrations, 
any leftover samples may be used for exploratory research provided that the patient has 
specifically consented to this optional research testing.
3.2.4
Rationale for the Food–Effect Analysis in the Stage 2, Cohort A
Co-administration of food may affect the pharmacokinetics of many drugs, 
including anti-cancer agents (Singh 1999, 2004).  Assessments of the effects of food on 
pharmacokinetics are routinely incorporated in Phase I trials of orally administered 
oncology drugs (Hoekstra et al. 2005; LoRusso et al. 2005).  Drugfood interactions are 
classified into five categories based on the effect on absorption:  no effect, reduced,
delayed, increased, or accelerated absorption (Welling 1996).
GDC-0032 appears to be a BCS Class II compound (low and pH-dependent solubility as 
a weak base, high permeability); these compounds generally have positive food effects 
in humans (i.e., food increases the exposure of these compounds).  Potential food effect 
on the pharmacokinetics of GDC-0032 will be assessed in Stage 2, Cohort A (see 
Section 4.3.2).
3.2.5
Rationale for Selection of the Recommended Dose for Future 
Trials
The recommended daily dose for single-agent GDC-0032 for future trials will be based 
on safety, tolerability, and PK data.  Determination of an adequate dose will require that 
reasonable exposure consistent with minimal activity in nonclinical models is achieved.  
In addition, clear evidence of tumor PD modulation would need to be observed at a 
reasonably tolerated dose.  This may be a decrease in downstream PD markers of the 
PI3K pathway detected in the tumor biopsy, modulation of FDG-PET results supporting 
an effect on tumor metabolism, or anti-tumor activity as evidenced by tumor marker 
decreases or tumor shrinkage per RECIST v1.1.  The dose and schedule selection will 
depend on the overall tolerability while maximizing exposure and anticipated effect on 
PI3K inhibition.


Protocol:  GDC-0032—Genentech, Inc.
75/P PMT4979g (GO00886)-A10
Clinical PK/PD modeling may be conducted to aid the selection of the recommended 
dose for future trials.
The recommended daily dose for GDC-0032 in combination with endocrine therapy in 
Phase I, Stage 2, Cohorts E and F will also be based on safety, tolerability, and PK data.  
In addition, consideration of the patient population that is treated with endocrine therapy 
will be factored into the dose level chosen.  These factors include expected duration of 
therapy, the overall tolerability in patients who may have a prolonged time to progression, 
and clinical benefit of the combination.  As described in Section 3.1.4, the GDC-0032 
dose in Cohorts E and F may be less than the single-agent GDC-0032 dose in 
Cohorts AD.  Additionally, different schedules and doses of GDC-0032 in combination 
with endocrine therapy will be evaluated for long-term safety and tolerability in 
Cohorts J-M for fulvestrant and Cohorts N-S for letrozole.
3.2.6
Rationale for Dosing beyond Cycle 1
Patients who comply with the requirements of the protocol, are tolerating GDC-0032, 
and have not experienced signs or symptoms of disease progression may be offered 
dosing with GDC-0032 beyond Cycle 1 for up to 5 years, at the discretion of the 
investigator after a careful assessment and a thorough discussion of the potential risks 
and benefits with the patient.  Patients receiving benefit from GDC-0032 may have the 
possibility of continued treatment beyond 5 years at Genentech’s discretion and 
provided that GDC-0032 is available.  However, if the study is terminated, GDC-0032 
may not be offered after study termination (see Section 3.3).
3.2.7
Rationale for Evaluating Patients with PIK3CA-Mutant Solid 
Tumors Treated with Single-Agent GDC-0032 (Stage 2, 
Cohorts A, B, H, and X)
In nonclinical models, GDC-0032 has a stronger anti-tumor effect on PIK3CA-mutant 
tumors than on PIK3CA wild-type tumors.  Activating mutations of PIK3CA, which 
belongs to the Class IA PI3K family, have been observed in a number of different tumor 
types, including breast cancer (Bachman et al. 2004; Samuels et al. 2004).  
These activating mutations have been shown to promote growth and invasion in cancer 
cells, effects that are abrogated by PI3K inhibitors.  Preliminary clinical data with 
GDC-0032 showed a confirmed partial response observed in a patient with hormone 
receptorpositive, PIK3CA-mutant breast cancer in Stage 1, Cohort 2 treated at the 
5-mg capsule daily dose of GDC-0032 that was well tolerated.  Clinical activity has also 
been seen in a patient with PIK3CA-mutant lung cancer in Cohort 1 treated at the 3-mg
capsule daily dose of GDC-0032.  Approximately 20 patients with PIK3CA-mutant breast 
cancer in Stage 2, Cohort A and 20 patients with PIK3CA-mutant solid tumors other than 
breast cancer in Stage 2, Cohort B will be enrolled and treated at the recommended 
dose for future trials in order to obtain preliminary data on the anti-tumor activity 
of GDC-0032 in tumors with PIK3CA mutations.  This information will help inform future 
trials planned for this diagnostic subpopulation.  Evaluating 20 patients in Stage 2, 


Protocol:  GDC-0032—Genentech, Inc.
76/P PMT4979g (GO00886)-A10
Cohort A will provide a better estimate of the safety profile of single-agent GDC-0032 at 
the recommended dose for future trials in the breast cancer patient population that has a 
higher frequency of PIK3CA mutations.  Evaluating 20 patients in Stage 2, Cohort B, will 
provide a better estimate of the safety profile of single-agent GDC-0032 at the 
recommended dose for future trials in a variety of solid tumors in patients that may 
benefit based upon GDC-0032 nonclinical and preliminary clinical data.
Evaluating 40 patients in Stage 2, Cohort H will provide a better estimate of the safety 
profile of single-agent GDC-0032 at the recommended dose for future trials on a 
different schedule of 21 days on and 7 days off in a variety of solid tumors in patients 
that may benefit based upon GDC-0032 nonclinical and preliminary clinical data.  The 
21-day on, 7-day off (21/7) schedule may improve overall tolerability as compared to 
Cohort B, while maintaining anti-tumor activity.  Cohort H must include a minimum of 
5 patients with cervical cancer (based upon preliminary clinical data, including a 
confirmed partial response observed in a patient with endocervical cancer in Cohort B) 
and a minimum of 20 patients with NSCLC tumors (based upon clinical activity with 
single agent GDC-0032 seen in PIK3CA-mutant NSCLC beginning at the 3-mg QD 
capsule dose level).  Cohort H patients will also be nonbreast cancer patients since 
those have been enrolled in Cohort A.  In addition, Cohort H patients will be 
non-colorectal cancer patients.  Patients with colorectal cancer frequently have 
concomitant mutations of other genes in their tumors such as KRAS that render the 
tumors more resistant to GDC-0032.  Such patients may be less likely to benefit from 
single-agent GDC-0032 treatment.
Data from patients treated with GDC-0032 in Cohorts A, B, and H have shown enhanced 
activity in multiple tumor types with PIK3CA mutations, including breast, lung, 
gynecologic, and head and neck cancers.  Preliminary data have also suggested that 
patients with squamous cancers may benefit from single-agent GDC-0032 treatment, 
including HNSCC, NSCLC, and endocervical and anal cancers.  As of 30 July 2014, in 
patients with nonbreast cancer solid tumors treated with single-agent GDC-0032 in 
Study PMT4979g, there were individual patients with PIK3CA-mutant cervical, 
nonsmall cell lung, and vulvar cancers that had a confirmed partial response.  In 
addition, multiple patients with PIK3CA-mutant endometrial, head and neck, laryngeal, 
nonsmall cell lung, uterine, rectal, squamous cell, or ovarian cancers had a best 
confirmed response of stable disease (Genentech internal data).
To further identify cancers in which GDC-0032 may have activity, Study PMT4979g has 
been amended to add Cohort X (“basket” cohort), in which patients with PIK3CA-mutant 
cancers will receive GDC-0032 daily at the 6-mg or 4-mg tablet dose level.  The 10 
tumor subtypes were selected for the basket cohort on the basis of nonclinical and 
clinical efficacy data and PIK3CA-mutation frequency.  These include endometrial, 
bladder, HNSCC, cervical, gastric/gastroesophageal junction, small-cell lung, triple-
negative breast, colorectal (KRAS wild-type), squamous, ovarian, and other cancers with 
PIK3CA mutation not otherwise specified (excluding breast, NSCLC, and colorectal).  


Protocol:  GDC-0032—Genentech, Inc.
77/P PMT4979g (GO00886)-A10
Patients with colorectal cancer with KRAS mutation will be excluded, because KRAS
mutation may render tumors more resistant to inhibition of the PI3K/AKT/mTOR pathway 
(Di Nicolantonio et al. 2010).  In Study PMT4979g Stage 1, 2 patients with 
PIK3CA-mutant, KRAS-mutant colorectal cancer who were treated with GDC-0032 
(5-mg and 8-mg capsule daily doses) experienced progressive disease.  In
Amendment 9, Cohort X6 (SCLC) was removed, but these patients will be allowed to 
enroll in Cohort X11.  In Amendment 9, Cohort X3 was expanded to include an 
additional 10-20 patients with HNSCC with amplification of the PIK3CA gene and no 
detectable PIK3CA somatic mutations.  GDC-0032 administration for Cohort X was 
chosen at the 6-mg tablet daily dose and schedule on the basis of the tolerable safety 
profile of patients treated with the recommended single-agent equivalent 9-mg capsule 
daily dose and schedule (see Section 3.2.13 for further details).  In Amendment 9, the 
starting dose of GDC-0032 in Cohort X was changed to 4-mg tablet daily dose (see 
Section 3.2.33).
3.2.8
Rationale for Assessing the Effect of GDC-0032 on Midazolam 
Pharmacokinetics (Stage 2, Cohort C)
In vitro studies suggest that GDC-0032 has the potential to induce CYP3A4 (refer to the 
Investigator’s Brochure for details regarding the nonclinical studies).
A preliminary DDI assessment will be conducted in Stage 2, Cohort C, in which the 
pharmacokinetics of midazolam will be assessed before dosing with GDC-0032 and 
following multiple doses of GDC-0032.  This assessment may help design future clinical 
trials with treatment combinations (that may have potential CYP3A4 interaction) and 
concomitant drug inclusion and exclusion criteria with respect to CYP3A4 substrates. 
3.2.9
Rationale for Evaluating Patients with HER2-Positive Breast 
Cancer at the Recommended Dose for Future Trials (Stage 2, 
Cohort D)
The PI3K signaling pathway is a major downstream effector of receptor tyrosine kinases 
that stimulate cell proliferation, promote survival, and inhibit apoptosis, such as HER2.  
PI3K is required for HER2-mediated transformation (Zhao et al. 2006), which suggests a 
central role for the PI3K pathway in oncogenic HER2-mediated signal transduction.  
A high frequency of genetic alterations leading to activation of the PI3K pathway 
(mutations in PI3K [25%30%] or PTEN loss [22%27%]) has been observed in breast 
cancer, including HER2-positive breast cancer (Saal et al. 2005; Berns et al. 2007).  
In addition, a PI3K inhibitor has been shown to inhibit the proliferation of HER2-positive 
breast cancer cell lines that are both trastuzumab-sensitive and trastuzumab-resistant 
(Junttila et al. 2009).  A confirmed partial response has also been observed in a patient 
with hormone receptorpositive, HER2-positive, PIK3CA-mutant breast cancer in 
Cohort 2 treated at the 5 mg capsule daily dose of GDC-0032 that was well tolerated.  
Taken together, these data provide a strong rationale for developing inhibitors of PI3K 
pathway signaling as a therapeutic strategy for HER2-positive breast cancer.


Protocol:  GDC-0032—Genentech, Inc.
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3.2.10
Rationale for Evaluating Patients with Solid Tumors with 
Increased PIK3CA Copy Number at the Recommended Dose 
for Future Trials (Stage 2, Cohort G)
The PI3K signaling pathway is a major downstream effector of receptor tyrosine kinases 
that stimulate cell proliferation, promote survival, and inhibit apoptosis.  A high frequency 
of genetic alterations can lead to the activation of the PI3K pathway other than PI3K 
mutation.  For instance, increased PIK3CA copy number, encoding the p110-alpha 
subunit of PI3K, occurs in a variety of tumors including squamous cell lung cancer (33%; 
Yamamoto et al. 2008), head and neck cancer (37%; Pedrero et al. 2005), ovarian 
cancer (24%; Kolasa et al. 2009), endometrial cancer (12%; Konopka et al. 2011), and 
gastric cancer (36%; Byun et al. 2003).  Increased PIK3CA copy number has been 
associated with PI3K pathway activation in both cell lines and tumors 
(Shayesteh et al. 1999; Yamamoto et al. 2008; Shi et al. 2012) and a PI3K inhibitor has 
been shown to inhibit the proliferation of PIK3CA amplified cancer cell lines 
(Shayesteh et al. 1999).  Stable disease for 11 months occurred in a patient with
squamous lung carcinoma with increased PIK3CA copy number who was treated with 
GDC-0032 daily at the 3-mg capsule dose.  Taken together, these data provide a strong 
rationale for developing inhibitors of PI3K pathway signaling as a therapeutic strategy for 
tumors with increased PIK3CA copy number.  Evaluating 20 patients in Stage 2, 
Cohort G, will provide a better estimate of the safety profile of single-agent GDC-0032 at 
the recommended dose for future trials in a variety of solid tumors in patients who may 
benefit based upon nonclinical data and preliminary GDC-0032 clinical data. 
3.2.11
Rationale for Evaluating Hormone ReceptorPositive Breast 
Cancer at the Recommended Dose for Future Trials with 
Alternate Schedules in Combination With Endocrine Therapy 
(Stage 2, Cohorts E, F, JM, and NS)
Approximately one-third of patients with hormone receptorpositive breast cancer have 
mutations in PIK3CA, the gene encoding the alpha catalytic subunit of PI3K (p110), 
and an additional one-fifth of patients have loss of PTEN protein expression (PTEN null).  
These alterations are generally mutually exclusive in breast cancer tumor samples.  Both 
alterations result in up-regulation of the PI3K pathway (Saal et al. 2005; 
Stemke-Hale et al. 2008) and sensitize nonclinical models to inhibition by selective PI3K 
inhibitors.  In addition, multiple lines of nonclinical and clinical data support a key role of 
the PI3K pathway in the generation of resistance to hormonal therapies in patients with 
breast cancer (Johnston 2009; Osborne and Schiff 2011), making hormone 
receptorpositive breast cancer a rational indication for PI3K inhibitors.  Recent clinical 
data have also demonstrated an additive clinical benefit of combining the aromatase 
inhibitor exemestane with everolimus, a rapamycin analogue that inhibits TOR pathway 
signaling for the treatment of advanced hormone receptorpositive breast cancer 
(Baselga at al. 2011).  Preliminary clinical data with GDC-0032 showed a confirmed 
partial response observed in a patient with hormone receptorpositive, PIK3CA-mutant 
breast cancer in Cohort 2 treated at the 5 mg capsule daily dose of GDC-0032 that was 


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well tolerated.  Based on the strong scientific rationale and preliminary clinical data for 
GDC-0032 in hormone receptorpositive breast cancer, the combination of GDC-0032 
and endocrine therapy (letrozole or fulvestrant) will be tested.
Letrozole is a non-steroidal aromatase inhibitor and an effective treatment of 
postmenopausal patients with hormone receptorpositive breast cancer that is relatively 
well tolerated.  The expected toxicities for GDC-0032 and letrozole are not overlapping, 
as discussed in Sections 3.4.2 and 3.4.7.
Fulvestrant is an estrogen receptor antagonist and an effective treatment of 
postmenopausal patients with hormone receptorpositive breast cancer that is relatively 
well tolerated.  The expected toxicities for GDC-0032 and fulvestrant are not overlapping, 
as discussed in Sections 3.4.2 and 3.4.8.
To fully establish a combination with endocrine therapy (letrozole and fulvestrant) with 
GDC-0032 in a population that might require dosing for longer periods relative to a 
Phase I patient population, and to obtain a better estimate of less common toxicities 
such as pneumonitis, enrollment of 20 patients each in Cohorts E and F will establish a 
robust safety and tolerability profile as these combinations are evaluated in larger 
subsequent studies (see Section 4.9.10).
It is important to test both combinations as letrozole and fulvestrant have different 
mechanisms of action, different pharmacokinetic properties, and different potential for 
DDIs with GDC-0032.  A minimum of 10 patients will be required to have PIK3CA-mutant 
breast cancer in each of the cohorts (Cohorts JM and NS).  In nonclinical models, 
GDC-0032 has a stronger anti-tumor effect on PIK3CA-mutant breast tumors than on 
PIK3CA wild-type tumors.  Preliminary clinical data with GDC-0032 showed a confirmed 
partial response observed in a patient with hormone receptorpositive, PIK3CA-mutant 
breast cancer in Cohort 2 treated at the 5-mg capsule daily dose of GDC-0032 that was 
well-tolerated.
Initial data from Cohort F (GDC-0032 in combination with fulvestrant) with multiple partial 
responses at 6-mg capsule QD suggests that this dose has anti-tumor activity.  Based 
upon updated safety data, certain adverse events, such as diarrhea, colitis, and rash, 
sometimes occur in patients after multiple cycles of treatment.  An alternate dosing 
schedule for GDC-0032 with scheduled intermittent treatment breaks from GDC-0032 
may be beneficial in improving the overall tolerability of the regimen and possibly 
decrease the frequency of toxicities such as gastrointestinal (GI) toxicities or rash.  
Several cohorts with different dosing schedules of GDC-0032 at the 4-mg tablet dose will 
be tested.  Cohorts J and Q will consist of a 21-day on, 7-day off (21/7) schedule.  
Cohorts K and R will consist of a 5-day on, 2-day off (5/2) schedule.  Cohorts L and S 
will consist of a 7-day on, 7-day off (7/7) schedule.


Protocol:  GDC-0032—Genentech, Inc.
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3.2.12
Rationale for Evaluating Hormone ReceptorPositive Breast 
Cancer at 2-mg Tablets (Stage 2, Cohorts M and N)
Preliminary efficacy results from Cohorts E and F have demonstrated that some patients 
who started at the GDC-0032 6-mg capsule QD dose and then dose-reduced to 3-mg 
capsule QD have been able to maintain partial responses.  Several alternate dose 
schedules and dose levels will be tested to obtain further data on the relative tolerability 
of adding intermittent breaks to the GDC-0032 dosing schedule and of a lower 
continuous GDC-0032 dosing with endocrine therapy.  Patients in Cohorts M and N will 
be administered daily doses of 2-mg GDC-0032 in tablet formulation (equivalent to 3-mg 
capsule).  Data from this dose level will help characterize the risk/benefit profile of the 
2-mg tablet in combination with letrozole or fulvestrant.
3.2.13
Rationale for Implementing GDC-0032 in Tablet Form for 
Cohorts HX
The impact of formulation on the pharmacokinetics of GDC-0032 has been assessed in 
the multipart study of healthy volunteers, Study GP28619.  See Section 1.3.2 and the 
Investigator’s Brochure for more details.  AUC and Cmax for the 2-mg GDC-0032 tablet 
were comparable to the 3-mg capsule formulation.  A 4-mg GDC-0032 tablet dose is 
estimated to provide an AUC equivalent to a 6-mg capsule dose because of the linear, 
dose-proportional pharmacokinetics over a broad dose range demonstrated by 
GDC-0032.  Similarly, a 6-mg GDC-0032 tablet dose is estimated to be equivalent to a 
9-mg capsule dose.  See Table 1.
Table 1
Dose Conversion between GDC-0032 Capsules and Tablets
Current capsule dose
3 mg
6 mg
9 mg
Tablet dose
2 mg
4 mg
6 mg
3.2.14
Rationale for Assessing the Pharmacokinetics of GDC-0032 in 
Combination with Letrozole (Stage 2, Cohorts E and NS)
Letrozole 2.5 mg will be administered orally on a daily schedule.  Letrozole is mainly 
metabolized to a pharmacologically-inactive carbinol metabolite by CYP2A6 and 
CYP3A4 in vivo.  The carbinol metabolite is subsequently excreted by the kidney as a 
glucuronide conjugate.  GDC-0032, which has the potential to induce CYP3A4, may 
affect the pharmacokinetics of letrozole, thereby resulting in a decrease in letrozole 
exposure (refer to the Investigator’s Brochure for details regarding the nonclinical 
studies).
Samples for assessing GDC-0032 and letrozole pharmacokinetics will be collected 
following continuous concomitant daily dosing.  The PK data from the combination will 
be compared with GDC-0032 PK data from this clinical trial and published letrozole 
PK data.


Protocol:  GDC-0032—Genentech, Inc.
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The purpose of this assessment is to inform study designs of future studies with the 
combination of GDC-0032 and letrozole.
3.2.15
Rationale for Assessing the Pharmacokinetics of GDC-0032 in 
Combination with Fulvestrant (Stage 2, Cohorts F, J, K, L, and 
M; Phase II)
Fulvestrant 500 mg will be administered intramuscularly on Days 1 and 15 of Cycle 1 
and Day 1 of subsequent cycles (i.e., every 28 days).  Metabolism of fulvestrant appears 
to involve combinations of a number of possible biotransformation pathways, including 
oxidation, aromatic hydroxylation, and conjugation with glucuronic acid and/or sulphate.  
Fulvestrant has not been shown to cause clinically relevant DDIs.  Although fulvestrant 
appears to be a CYP3A4 substrate, concomitant administration with ketoconazole or 
rifampicin has not had an impact on fulvestrant PK.  Therefore, a PK interaction is not 
expected when fulvestrant and GDC-0032 are given concomitantly.
Samples for assessing GDC-0032 and fulvestrant pharmacokinetics will be collected 
following administration of the combination.
The purpose of this assessment is to provide information for the design of future studies 
with the combination of GDC-0032 and fulvestrant.
Given the low likelihood for a DDI between GDC-0032 and fulvestrant, sparse blood 
samples will be collected in the Phase II portion of the study.  The sparse sampling 
approach will allow for comparison of GDC-0032 and fulvestrant in this slightly different 
cancer patient population to historical values. 
3.2.16
Rationale for Evaluating Patients with Non-Hodgkin’s 
Lymphoma (Stage 2, Cohort T)
The goal of Cohort T is to obtain a preliminary safety assessment of GDC-0032 in 
patients with non-Hodgkin’s lymphoma.  See Section 1.4.1.2 for rationale.
3.2.17
Rationale for the Patient Population for Phase II Portion
Female patients with HER2-negative, ER-positive, locally recurrent, or metastatic breast 
cancer will be enrolled in this study.  This patient population is usually treated with 
multiple rounds of single-agent endocrine therapy prior to receiving cytotoxic 
chemotherapy.  Recently, everolimus was approved by the FDA and European 
Medicines Agency (EMA) in combination with exemestane for the treatment of advanced 
or metastatic breast cancer in patients after recurrence or progression following 
treatment with a nonsteroidal aromatase inhibitor (AI).  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 tumor shrinkage in 
this setting.


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In the Phase II portion of this study, the patient population will include patients with 
progressive disease during or after treatment with an AI for recurrent or progressive 
disease.  This will enable the evaluation of this regimen in a clinically meaningful 
population given the new indication for everolimus.
Based on nonclinical and clinical data for GDC-0032 in PIK3CA mutant breast cancer, a 
minimum of 30 patients in the Phase II portion will be required to have PIK3CA mutant 
breast cancer.  This will be important to assess the clinical activity in this specific 
diagnostic subpopulation that may be more likely to benefit from the combination of 
GDC-0032 and fulvestrant.  
3.2.18
Rationale for Assessing the Safety and Efficacy of GDC-0032 in 
Combination with Fulvestrant (Phase II Portion)
Preliminary data from Stage 2, Cohort F is promising with 3 patients in the 6-mg capsule 
cohort demonstrating greater than 30% decrease by RECIST.  However, patients in 
Stage 2, Cohort F are heterogeneous in the type and number of prior therapies.  Many of 
these patients have been treated with prior fulvestrant and have had multiple prior 
chemotherapies.  In order to better assess whether the GDC-0032 is tolerable for a 
longer duration in combination with fulvestrant and to better assess the clinical activity of 
this combination, a Phase II portion of the study is planned.
The Phase II portion will be different from Stage 2, Cohort F in that no prior fulvestrant 
will be allowed, and a maximum of one prior cytotoxic chemotherapy for the metastatic 
setting will be allowed.  This patient population will be similar to those to be tested in 
future studies.  Preliminary data on response rate and CBR will be obtained and 
compared with historical control of fulvestrant.  
In addition to a preliminary evaluation of efficacy, the Phase II portion of the study will be 
important in evaluating the long-term tolerability of GDC-0032 with fulvestrant.  
Additional safety data can be gathered because patients will be expected to be on study 
treatment for a longer duration than those in Stage 2, Cohort F. 
3.2.19
Rationale for Selection of the Recommended GDC-0032 Dose 
in Combination with Fulvestrant for the Phase II Portion
The recommended GDC-0032 dose in combination with fulvestrant for the Phase II 
portion of the trial will be 6-mg capsule QD.  This is based upon a comprehensive 
assessment of GDC-0032 nonclinical and clinical data.  In Stage 1, GDC-0032 has 
demonstrated single-agent activity in breast cancer at 5 mg QD.  In Stage 2, the 
selected single-agent dose was 9-mg capsule QD.  Data from Stage 2, Cohorts E and F 
have provided clinical data for GDC-0032 in combination with endocrine therapy.  
No DLTs have been observed in Cohort E (GDC-0032 and letrozole) or Cohort F 
(GDC-0032 and fulvestrant) at the 6-mg and 9-mg dose levels (n 6 for each dose level 
in each cohort).  Preliminary data from Stage 2, Cohort F is promising with 3 patients in 
the 6-mg capsule cohort demonstrating greater than 30% decrease by RECIST.


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The recommended Phase II dose for GDC-0032 in combination with fulvestrant is also 
based upon the target patient population.  Endocrine therapy, including fulvestrant, is 
relatively well tolerated by patients and has a relatively favorable safety profile.  Based 
on an assessment of the safety, pharmacokinetics, and clinical activity of single-agent 
GDC-0032 and combination therapy with endocrine therapy agents, the recommended 
Phase II dose of GDC-0032 in combination with fulvestrant is 6-mg capsule QD.
3.2.20
Rationale for QT/QTc Assessments
The potential of non-cardiovascular drugs to delay cardiac repolarization, which may 
cause cardiac arrhythmias such as torsade de pointes (TdP), has emerged as a major 
concern for sponsors and regulators.  Recently, two International Conference on 
Harmonisation (ICH) guidelines for nonclinical (S7B) and clinical (E14) testing have been 
developed.
Cardiovascular toxicity assessments were incorporated in nonclinical studies conducted 
with GDC-0032 on the basis of the testing strategy outlined in the ICH S6 and S7B 
guidelines.  Results from these studies suggest that GDC-0032 is unlikely to cause 
delayed cardiac repolarization, prolongation of the QT/QTc interval, or arrhythmias.  
GDC-0032 inhibited the hERG channel in a GLP functional assay with an IC50136 M, 
which is 27,000-fold higher than the predicted unbound Cmax at 3 mg, the starting dose 
in Stage 1 of this Phase I clinical trial, and is not considered to pose a cardiovascular 
risk based on Redfern et al. 2003.
Transient increases of 1318% in arterial blood pressure (systolic, diastolic, and mean 
pressures) observed in telemetry-instrumented dogs administered 0.3 and 1.0 mg/kg 
were reversed after 5 hours postdose and were not considered to be adverse.
In the 28-day GLP toxicity study in dogs, a decreased heart rate and, as a consequence, 
increased PR interval (external ECGs) was noted in animals administered 0.3 and 
1 mg/kg, respectively, on Study Day 28 but not during the recovery phase and therefore 
not considered adverse.  Furthermore, these effects were not observed in the GLP 
single-dose cardiovascular safety pharmacology study in telemetry-instrumented dogs 
that were administered the same doses.  Taken together, these observed effects on 
heart rate and PR interval in the 28-day study are considered to be minimal, reversible, 
and non-adverse.  ECGs will be done in triplicate during the study.  Furthermore, 
patients will be monitored for potential cardiovascular effects as part of standard safety 
monitoring procedures.
The QT/QTc assessment strategy for this trial was based on recommendations in the 
ICH E14 guideline and the special considerations for evaluating drug effects on the 
QT/QTc interval in cancer patients (Fingert and Varterasian 2006).  Triplicate digital 
ECGs will be collected at baseline and postdose on Day 1 and Day 15 for Stage 1 
patients.  Additional ECGs will be collected during steady-state exposure in Stage 2 
(e.g., after 2 weeks of continuous dosing).  ECGs at different timepoints will be collected 


Protocol:  GDC-0032—Genentech, Inc.
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concurrently with PK sampling to allow for an evaluation of the relationship between 
GDC-0032 exposure and changes in QT/QTc interval.  Meal intake relative to dosing 
and other factors (e.g., supine position, ECGs collected before PK sampling) will be 
standardized, as it is well established that numerous external factors such as these may 
prolong the QT/QTc interval (Bednar et al. 2001).
The timing of ECG collections was based on the PK profile of GDC-0032 in humans 
predicted from allometric scaling of nonclinical PK data and a typical small-molecule PK
profile.  The collection schedule should allow for an adequate characterization of the 
QT/QTc interval over a range of GDC-0032 concentrations.  If the observed PK profile is 
different from the predicted PK profile, up to four additional ECGs may be collected from 
each patient or the ECG measurement times may be adjusted. Likewise, measurement 
times that are not informative will be eliminated.
3.2.21
Rationale for FDG-PET Evaluation
In vitro, GDC-0032 has been shown to inhibit glucose uptake in tumor cells, and similar 
experiments are underway to confirm this effect in tumor xenografts using FDG-PET 
imaging.  The PI3K pathway has demonstrated an impact on the Glut1 transporter; thus, 
change in glucose uptake may be a valid PD marker (Shaw and Cantley 2006).  In 
addition, FDG-PET has been demonstrated to be a useful tool to identify early changes 
associated with tumor activity (Weber 2006).  Decreases in tumor FDG uptake have 
been observed in a clinical trial in which patients were treated with the PI3K-inhibitor 
GDC-0941.  Significant changes in tumor FDG uptake in patients treated with GDC-0032 
will provide evidence that this agent is able to exert biologic effects in tumor tissue and 
will aid in the selection of the dose to be used in future studies.  See Section 4.5.1.g for 
details on FDG-PET imaging and Appendix G for details regarding assessments of 
FDG-PET response. 
3.2.22
Rationale for Surrogate Pharmacodynamic Samples
Surrogate PD assays are routinely incorporated into Phase I oncology trials to determine 
whether an investigational agent can modulate the drug target in humans and to explore 
the various relationships between exposure of the agent, surrogate biomarkers, and 
other study endpoints (LoRusso et al. 2005).  Evaluation of changes in PD markers such 
as pAKT in easily accessible blood samples may provide support for the effects of 
GDC-0032 in modulating the PI3K pathway.  Evaluation of changes in circulating 
angiogenic factors may provide additional evidence for the effects of GDC-0032 in 
modulating tumor angiogenesis.  Collection of multiple samples at different GDC-0032 
exposures may allow a better understanding of the relationship between 
pharmacokinetics and pharmacodynamics.
3.2.23
Rationale for Pharmacogenetic Blood Sample Collection
Blood 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 


Protocol:  GDC-0032—Genentech, Inc.
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transporters [e.g., OATP1B1]) and genetic variants that could contribute to a potentially 
drug-related rash, diarrhea, 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 the collection of this genetic material for the 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, affecting their safety and efficacy.  For example, 
patients who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase (UGT) 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 2006).  Preliminary 
results from in vitro metabolism studies with GDC-0032 suggest that GDC-0032 is
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 will be collected from all 
patients in this study for potential pharmacogenetic analysis of genes that may affect the 
pharmacokinetics of GDC-0032 or the response to GDC-0032.
The decision to analyze the samples will be based on a review of the PK and safety 
response data.
Most recently, 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.
3.2.24
Rationale for Collection of Archival Tumor Specimens
Development of a predictive diagnostic assay that enables prospective identification of 
patients who are likely to respond to treatment with GDC-0032 would facilitate the future 
clinical development of this agent.  Both PIK3CA mutation and PTEN loss have been 
shown to be present in multiple tumor types with high frequency.  PIK3CA chromosomal 
amplification has also been described to be prevalent in several cancer types.  These 
variations are known to increase proliferative and oncogenic properties and are strong 
candidates for a predictive diagnostic marker.  Archival paraffin-embedded tissue will be 
used to assay for specific PIK3CA mutations by sequencing or quantitative reverse 
transcriptase polymerase chain reaction (qRT-PCR)based methods and by 


Protocol:  GDC-0032—Genentech, Inc.
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immunohistochemistry (IHC) for loss of PTEN expression.  DNA and/or RNA may also 
be extracted from tumor tissue to enable the identification of somatic mutations and 
transcript expression levels through technologies such as NGS-based platforms.  
PIK3CA amplification may be assayed using in situ hybridization to determine the 
number of chromosomal copies of PIK3CA in tumor cells or by molecular methods.  
Other potential predictive markers that are related to the PI3K pathway may also be 
analyzed if guided by either nonclinical or clinical data.  Examples may include tumor 
type-specific biomarkers, such as BCL2 and MYC in DLBCL and p16 in HNSCC.  
3.2.25
Rationale for Collection of Fresh Tumor Specimens
Correlation of pathway inhibition in tumor tissue would be important to 
confirm an appropriate dose and exposure for GDC-0032 for future studies.  Paired 
tumor tissue biopsies will be optional, both predose and postdose, for all patients, with 
the exception of 6 patient slots (3 patients with PIK3CA-mutant and 3 patients with 
PIK3CA-wild-type tumors) in each of Cohorts N and P, in which paired tumor biopsies 
will be mandatory.  The purpose of these mandatory biopsies is to obtain PD data at 
different doses of GDC-0032 in combination with letrozole on the PI3K (and other) 
pathways in both PIK3CA-wild-type and mutant tumors.  A minimum of 5 patients from 
Cohort X3 are required to provide fresh pre-treatment and on-treatment biopsy samples 
to assess the effects of GDC-0032 on PI3K (and other cancer-related) pathways in 
HNSCC.  The pretreatment tissue biopsy will be reviewed by a pathologist to determine 
whether the tissue is evaluable.  If the pretreatment tissue is evaluable, then a 
subsequent biopsy will be performed either during Cycle 1 or Cycle 2, approximately 
14 hours after the morning dose, depending on the cohort to which the patient is 
assigned (see Section 4.5.1.n).  Patients will be asked to consent to provide tumor 
biopsy samples.  Tumor biopsies upon progression of disease are also optional and may 
be informative in understanding the mechanisms of resistance to GDC-0032, including 
alterations in the PI3K pathway such as PIK3CA mutations.  Tissue samples will be used 
to assess PD changes in PI3K pathway (and other) markers, such as pS6 and a group 
of other downstream markers by IHC assay and the reverse-phase protein array (RPPA) 
when IHC assay is not available.  In addition, alterations of the PI3K pathway, such as 
PI3K mutation status and PTEN loss by IHC, may be examined.  DNA and/or RNA may 
also be extracted from tumor tissue to enable the identification of somatic mutations and 
transcript expression levels through technologies such as NGS.  These findings will help 
to determine changes in pathway status relative to archival tissue and any clinical 
activity observed.  If sufficient tissue is available, drug levels within tissue will also be 
measured.
3.2.26
Rationale for Collection of Blood for DNA Mutation Analysis 
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 have been developed to identify the 


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mutations (including PIK3CA) in ctDNA from plasma, and results from this analysis will 
be correlated with both fresh tumor specimens (when available) and archival tumor 
specimens.  Detection of PIK3CA or other cancer-related mutations in plasma may be 
used for disease monitoring.
3.2.27
Rationale for Collection of Blood Sample for the Detection of 
Circulating Tumor Cells
Tumor cells can be found circulating in the blood of cancer patients.  The use of 
circulating tumor cells (CTCs) as a potential surrogate biomarker of treatment efficacy 
has been examined in metastatic breast cancer, and prospective trials are ongoing to 
evaluate the clinical significance of CTCs (Cristofanilli et al. 2004; Moreno et al. 2005; 
Budd et al. 2006).  CTCs can serve as a complement to the characterization of tumor 
tissue, and there are multiple methods for isolating and characterizing these cells.  CTCs 
have been correlated with HER2 gene amplification by fluorescence in situ hybridization 
(FISH) (Fehm et al. 2002; Meng et al. 2006).  The predominance of a critical number of 
CTCs with a cancer stem cell phenotype may correlate with disease progression, but 
this is controversial.  Exploratory analyses of CTCs for other proteins and genes 
involved in the biology of metastases and acquisition of therapy resistance may be 
examined using various platforms at selected timepoints.
3.2.28
Rationale for Collection of Blood Sample for the Detection 
of Cytokine and Chemokines in the Plasma 
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).
3.2.29
Rationale for Suspension (Extemporaneous Formulation) for 
Patients with Head and Neck Squamous Cell Carcinoma
A significant proportion of patients with HNSCC have disease or undergo surgical 
procedures that make it difficult for them to swallow food, liquids, and medications.  
These patients often receive nutrition and medications through gastrostomy tubes.  To 
administer GDC-0032 to these patients, instructions will be provided to patients for 
extemporaneous preparation of a suspension form of GDC-0032 from tablets, only at 
sites where administration of the extemporaneous suspension is approved by the 
IRB/EC (see Section 4.3.2.b).  To better understand the pharmacokinetics of GDC-0032 
administered as a suspension, additional PK measurements will be obtained from 
patients in Cohort X3 (Appendix B-10).
3.2.30
Rationale for Cycle 1, Day 8 Visit for Cohort H
As of 23 October 2015, 1 case of Grade 4 hyperglycemia was reported in each of 
Cohorts H and X.  One patient enrolled on Cohort H (GDC-0032 6 mg tablet, 21 days on, 
7 days off) had Grade 4 hyperglycemia on Cycle 1 Day 15.  One patient enrolled on 
Cohort X (GDC-0032 6 mg tablet QD) had Grade 4 hyperglycemia on Cycle 1 Day 14.  


Protocol:  GDC-0032—Genentech, Inc.
88/P PMT4979g (GO00886)-A10
Both patients achieved glucose control with GDC-0032 dose interruption and 
management of hyperglycemia per protocol guidelines and were able to resume 
GDC-0032 dosing.  
Because these two cases occurred early in Cycle 1, an additional fasting blood glucose 
(FBG) check as part of a chemistry panel and clinic visit should be performed at Cycle 1, 
Day 8 for patients receiving GDC-0032 6 mg tablets (Cohort H).  This increased 
monitoring may help to identify some of the patients at an earlier timepoint who would 
otherwise develop subsequent severe hyperglycemia.  Based upon the 40-hour half-life 
of GDC-0032, testing for fasting blood glucose after 1 week of continuous dosing and 
steady-state exposure may identify patients with asymptomatic hyperglycemia (e.g. 
Grade 2 or 3 hyperglycemia) that could then be managed per protocol guidelines.  This 
additional assessment brings Cohort H in alignment with the schedule of assessments of 
other cohorts on PMT4979g that have GDC-0032 at 6 mg tablet-equivalent or higher 
doses and also have a Cycle 1 Day 8 blood glucose check.  Based upon the available 
clinical data and experience with GDC-0032, the glucose monitoring is sufficient for 
subsequent cycles.  The Sponsor believes the current schedule of glucose monitoring is 
adequate for those patients being treated at the 4-mg tablet dose level.
3.2.31
Rationale for Evaluating NHL using 4-mg Tablets (Stage 2, 
Cohort T and T2)
As of 18 March 2016, there were 5 of 8 (62.5%) patients who had events of grade 3 or 
greater neutropenia reported in Cohort T, including one case of febrile neutropenia and 
one case of neutropenic colitis that were deemed serious in a mixed non-Hodgkin’s 
lymphoma patient population.  Initial events of Grade 3 or higher neutropenia occurred 
during Cycle 1 in 4 of 5 patients with this event.  Grade 3 or higher leukopenia (including 
neutropenia) in other cohorts, including Cohort X, has been an otherwise rare event (at 6 
mg: 5/179 [2.8%] and at 4 mg: 3/197 [1.5%]), suggesting that neutropenia following 
GDC-0032 is mainly seen in patients with hematologic malignancies.  Infections and, in 
some cases, serious infections were also observed in Cohort T, including bacteremia, 
respiratory tract infection, and one episode of septic shock.  To try to reduce the 
incidence of neutropenia and infection in Cohorts T and T2 NHL patients, the dose of 
GDC-0032 will be a 4-mg tablet daily, decreased from a 6-mg tablet daily originally 
utilized in Cohort T.  This change in starting dose was implemented in an administrative 
letter to sites on 25 July 2016. Patients enrolled in Cohorts T and T2 should have a 
weekly CBC for the first two cycles and on Day 1 of each subsequent cycle or more 
frequently as clinically indicated.  In addition, new neutropenia management guidelines 
are introduced in Amendment 9 (Section 3.4.5.i).
3.2.32
Rationale for Pneumocystis Jirovecii Pneumonia Prophylaxis 
in Cohorts T and T2
In response to the recent provisional safety measure recommended by the European 
Medicines Agency (EMA) for NHL patients treated with the PI3K-delta-specific inhibitor 


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idelalisib, recommendation for Pneumocystis jirovecii pneumonia (PJP) prophylaxis is 
introduced in Amendment 9 as a precautionary measure against a possible therapeutic 
class effect. Recommendations for PJP prophylaxis for patients in Cohorts T and T2 are 
given in Section 4.4.1.1.
3.2.33
Rationale for Change in Starting Dose from 6 mg to 4 mg in 
Cohort X
The rationale for this dose change is to obtain safety and efficacy data at the 4 mg dose 
in patients with PIK3CA-mutant solid tumors in Cohort X.  In preliminary analysis of 
Cohort X, partial responses at 6 mg have been observed in different tumor types, 
including HNSCC, triple-negative breast cancer, cervical cancer, cholangiocarcinoma, 
and other tumor types.  However, potential differences in tolerability have been observed 
between Cohort X and other PMT4979g cohorts with lower doses.  Overall dose 
reduction rates in Cohort X are similar to other cohorts, but dose reductions have 
occurred earlier.  As of 12 Aug 2016, in Cohort X, 13 dose reductions in 87 
safety-evaluable patients occurred prior to Cycle 2.  In the PMT4979g Phase II cohort (4 
mg tablet equivalent dose), 2 dose reductions in 60 patients occurred prior to Cycle 2.  
Numerically higher rates of pneumonitis have been observed in mixed solid tumor 
patients in Cohort X (4 of 87 [4.6%]), compared to pooled data from breast cancer 
patients in fulvestrant (4 of 167 [2.4%]) or letrozole (2 of 114 [1.8%]) cohorts.  In order to 
optimize the benefit-risk profile in the Cohort X population, the dose in Cohort X will be 
lowered from 6 mg to 4 mg for all newly enrolling patients.  Patients already enrolled at 6 
mg may continue at that dose at the investigator’s discretion or may lower the dose to 4 
mg in consultation with the Sponsor.  In choosing the 4 mg starting dose for Cohort X, 
efficacy at this dose has been observed in other cohorts, and safety has been 
manageable.  Note that the dose and schedule for Cohort H of GDC-0032 6 mg, 21 days 
on, 7 days off, will not be changed, because Cohort H is testing an alternative schedule 
at the 6 mg dose.
3.2.34
Rationale for Collecting Tumor TypeSpecific Cancer History 
and Tumor Pathology
To better understand potential clinical factors associated with response to GDC-0032 in 
patients with different tumor types (e.g., HNSCC or cervical cancer), the results of local 
assessments of patient clinical history and tumor pathology will be collected 
retrospectively.  Examples include p16 expression and smoking status in patients with 
HNSCC and histologic classification in patients with cervical cancer.  
3.3
OUTCOME MEASURES
3.3.1
Safety Outcome Measures
The safety and tolerability of GDC-0032 will be assessed using the following primary 
safety outcome measure:

Incidence of DLTs (as defined in Section 3.1.3.a) by NCI CTCAE v4.0 grade 
and associated dose of GDC-0032


Protocol:  GDC-0032—Genentech, Inc.
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In addition, the safety will be assessed using the following secondary safety outcome 
measures:

Incidence of adverse events by NCI CTCAE v4.0 grade and associated dose 
of GDC-0032

Incidence of Grade 3 and 4 abnormalities in safety-related laboratory parameters 
and associated dose of GDC-0032
3.3.2
Pharmacokinetic Outcome Measures
The following primary PK parameters will be derived from the plasma concentration–time 
profile of GDC-0032, following administration of single and/or multiple doses, when 
appropriate as data allow:

AUCinf after single dose and AUC0-after single and multiple doses

Maximum plasma concentration (Cmax)

Minimum plasma concentration (Cmin)

Time to maximum plasma concentration (tmax)

Terminal half-life (t1/2)

Apparent clearance (CL/F) after single and multiple doses

Accumulation ratio (AR) at steady-state
The following secondary PK parameters may also be derived, when appropriate as 
data allow:

Cmax and AUC under fed and fasted conditions (for patients participating in the 
food-effect assessment)

AUC0-24hr, Cmax, tmax, and other PK parameters of midazolam, letrozole, 
and fulvestrant, when applicable

Fraction of dose excreted (fe) and renal CL (CLr)

PK-dose proportionality as assessed with Cmax and AUC

The time to achieve steady state as assessed with trough (predose) concentrations
For Phase II
A sparse sampling approach will be used to assess the plasma concentrations of 
GDC-0032 and fulvestrant following single and multiple doses.
3.3.3
Activity Outcome Measure
The following activity outcome measures will be assessed:

Best overall response, duration of objective response, and progression-free 
survival (PFS) for patients with measurable disease according to RECIST v1.1
(see Appendix C)

In Cohort T, response assessment will be based on the 2007 Revised IWG 
Response Criteria in Malignant Lymphoma (see Appendix I).


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
In Cohort T2, response assessment will be based on a modified version of the 2014 
Lugano Response Criteria in Malignant Lymphoma (see Appendix J).
3.3.4
Exploratory Outcome Measures
The following correlative biology outcome measures will be assessed:

PET response for patients with detectable FDG tumor uptake at baseline 
(see Section 4.9.9)

Change from baseline in pAKT levels and/or other pathway biomarkers in 
platelet-rich plasma (Stage 1 only)

Change in pS6 level as measured by IHC in patients with accessible tumors who 
provide consent for biopsy, and, if tissue quantity permits, change in expression or 
phosphorylation of other PI3-kinase pathway markers, and vascular markers, 
as measured by IHC and reverse phase protein array (RPPA)

DNA mutation and copy number status of tumor type- and pathway-specific 
biomarkers (e.g., PIK3CA), RNA expression analysis, and PTEN expression in 
archival tumor tissue and/or in DNA from blood and in any fresh tumor biopsy 
samples obtained

Enumeration of CTCs and assessment of PI3K and cancer-related pathway status, 
when appropriate, (e.g., PIK3CA mutation, PTEN expression, etc.) in CTCs and 
ctDNA from peripheral blood (Cohorts Q, R, S, T, and X excluded from CTC 
analysis) 

Expression of cytokines and chemokines in plasma

QT/QTc interval changes

Tumor typespecific biomarkers as appropriate; examples may include BCL2 and 
MYC in DLBCL and p16 in HNSCC.
3.4
SAFETY PLAN
See Section 5 (Assessment of Safety) for complete details of the safety evaluation for 
this study.
3.4.1
Nonclinical Toxicity with GDC-0032
The toxicology program consisted of pilot single- and repeat-dose toxicity studies in rats 
and dogs, 28-day GLP studies in rats and dogs to support up to 28 QD doses in Phase I 
trials, GLP cardiovascular, neurobehavioral, and respiratory assessments in vitro and in 
vivo (rats and dogs), and in vitro genotoxicity studies.
Nonclinical findings were consistent with the anticipated pharmacologic effects of PI3K 
inhibition and include effects on glucose metabolism, manifestations of lymphoid 
depletion in tissues, and effects on bone marrow.  Additional nonclinical findings 
included reversible effects on body weights in rats (decreased body weight gain) and in 
dogs (body weight loss), reversible microscopic formation of cysts in ovaries of rats, and 
reversible GI inflammation in dogs administered GDC-0032.  The majority of findings 


Protocol:  GDC-0032—Genentech, Inc.
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was minimal to mild, reversible, and considered not adverse.  Moreover, these findings 
are expected to be clinically monitorable and manageable in patients.  Findings from the 
nonclinical toxicology program are as follows:

Reversible effects on body weights in rats (decreased body weight gain) and in dogs 
(body weight loss) 

Dose-dependent increases in blood glucose and insulin in a single-dose glucose 
challenge test in rats and minimal increases in the 28-day pivotal rat and dog toxicity 
studies

Reversible inflammation in dogs (e.g., increased fibrinogen, absolute neutrophil and 
platelet counts) with neutrophil infiltration in the GI tract in some dogs

Reversible lymphoid depletion and decreased peripheral blood lymphocytes in rats 
and dogs 

Reversible bone marrow findings in rats characterized by decreased peripheral 
blood basophil, eosinophil, and neutrophil counts and microscopic findings of 
hypocellularity of hematopoietic tissue

Reversible formation of cyst, with or without hemorrhage, in the corpora lutea in rats  

No adverse cardiovascular, respiratory, neurobehavioral, or ophthalmic 
abnormalities were detected in vitro and in rat and dog studies

No clinically-relevant inhibition of hERG was observed in an in vitro assay

No genotoxic effects were seen in either the human chromosomal aberration study 
or the bacterial mutagenesis assay.

No significant responses in an off-target secondary pharmacology screen; 
high (1,000-fold) biochemical selectivity for PI3K-family kinases over other kinases
Based on results of the 28-day rat and dog studies, the STD10 in rats was determined to 
be 3 mg/kg PO QD (18 mg/m2) and the HNSTD in dogs was determined to be 0.3 mg/kg 
PO QD (6 mg/m2).  Considering that one-tenth of the rat STD10 in dogs, on a mg/m2
basis, was not severely toxic to dogs, the rat toxicity data formed the basis for the 
maximum recommended starting dose (MRSD) calculation. A rat-to-human BSA 
conversion factor of 0.16 and a safety factor of 10 were applied to the STD10 in rats, and 
the resulting MRSD was 0.05 mg/kg or 3 mg QD per 60-kg patient.
3.4.2
Toxicity with PI3K Inhibitors in the Clinic
There are several ongoing clinical trials evaluating PI3K inhibitors.  Experience with 
pan-Class I PI3K inhibitors to date has demonstrated that the agents are generally well 
tolerated.  Common adverse events seen in ongoing clinical trials testing PI3K inhibitors 
include fatigue, diarrhea, skin rash, altered taste, pneumonitis, and hyperglycemia.  
In general, these agents appear to be reasonably well tolerated at doses examined to 
date in the Phase I setting without consistent irreversible and/or unmonitorable toxicities.  
Certain adverse events (e.g., rash, colitis, and pneumonitis) may also occur after holding 
or stopping GDC-0032, usually within 12 weeks after stopping GDC-0032.  See the 


Protocol:  GDC-0032—Genentech, Inc.
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Investigator’s Brochure for the most current safety data across all GDC-0032 clinical 
trials, including PMT4979g.
3.4.3
Toxicities Observed with GDC-0032 in Clinical Studies
a.
Hyperglycemia
Hyperglycemia has been observed in patients who received GDC-0032 in the 
single-agent Phase I study.  Hyperglycemia has been reversible upon holding 
GDC-0032 and/or initiation of anti-hyperglycemic medication (e.g., metformin).  
Patients with diabetes requiring daily anti-hyperglycemic medication or who have a 
fasting blood glucose level 120 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. 
b.
Rash
Treatment-related rash, including cases of Grade 3 rash, has occurred in patients who
received GDC-0032.  This rash is commonly manifested as maculo-papular with or
without pruritus.  Incidence rate and severity of rash appear to be dose dependent.  The
rash has resolved upon holding of GDC-0032 and/or giving supportive therapy 
(e.g., topical or systemic steroids).  
c.
Gastrointestinal Toxicity
Nausea, vomiting, diarrhea, and stomatitis/oral mucositis, and dyspepsia have been 
observed in patients who receive GDC-0032.  Colitis was diagnosed by several methods, 
including endoscopy and abdominal imaging (computed tomography [CT] scans).  
Pathology from biopsy samples obtained from endoscopy has confirmed colitis.  Patients 
usually present with Grade 2 or Grade 3 diarrhea that has been refractory to 
antidiarrheals.  The time (from the first dose of study treatment) to onset (formal 
diagnosis of colitis) ranged from approximately 99250 days.  Patients had resolution or 
improvement of gastrointestinal toxicities upon holding study drug and/or initiating 
corticosteroid therapy.  Perforated duodenal ulcer has been observed in 2 patients (1 
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, NSAIDs, and corticosteroids, which can 
increase the risk of gastritis, peptic ulcers, or GI perforation.
Patients with active inflammatory bowel disease, such as Crohn’s disease or ulcerative 
colitis, are excluded from this study.  Patients who resume treatment after hold(s) for 
gastrointestinal toxicity should be monitored closely for sign of renewed diarrhea.
Dose delay and modification guidelines for patients who experience gastrointestinal 
toxicities (diarrhea, colitis, and stomatitis/oral mucositis) can be found in Section 3.4.5.d.


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d.
Pneumonitis
Non-infectious pneumonitis has been observed in patients treated with everolimus and 
temsirolimus, rapamycin analogues that inhibit mTOR signaling, and PI3K inhibitors.
Pneumonitis has been observed in patients treated with GDC-0032.  Symptoms 
associated with pneumonitis were reversible upon treatment with corticosteroids.  As an 
example, noninfectious pneumonitis has been observed in the single-agent Phase I 
study in a lung adenocarcinoma patient treated at the 16-mg capsule daily dose level 
1 week after discontinuing GDC-0032.  The patient was treated with corticosteroids, and 
associated symptoms resolved. 
Refer to Section 3.4.5.b for guidelines on pneumonitis management.
e.
Potential Abnormal Liver Enzymes
Some patients have experienced elevations of liver enzymes (e.g., AST or ALT).  
Patients will be monitored throughout the study treatment for changes in liver enzymes.
Dose delay and modification guidelines for patients who experience elevated liver 
enzymes can be found in Section 3.4.5.f.
f.
Potential Inflammatory or Immunosuppressant Effects
Based on data from nonclinical toxicity studies showing changes in WBC and absolute 
lymphocyte and/or neutrophil counts, patients will be required to have adequate 
hematologic function to participate in the study, and any bone marrow toxicities from 
prior therapies must be resolved before initiation of GDC-0032.  Patients will be 
monitored throughout the study treatment for changes in blood counts and signs of 
infections.
g. Neutropenia
As of 18 March 2016, there were 5 of 8 (62.5%) patients who had events of grade 3 or 
greater neutropenia reported in Cohort T, including one case of febrile neutropenia and 
one case of neutropenic colitis that were deemed serious in a mixed non-Hodgkin’s 
lymphoma patient population.  Any grade leukopenia (including neutropenia) in other 
cohorts, including Cohort X, has been an otherwise rare event (at 6 mg: 5/179 [2.8%] 
and at 4 mg: 3/197 [1.5%]), suggesting that neutropenia following GDC-0032 is mainly 
seen in patients with hematologic malignancies.  Neutropenia in patients enrolled in 
Cohort T has been reversible with dose hold and administration of granulocyte colony 
stimulating factor (G-CSF).  Patients will be monitored throughout study treatment for 
changes in blood counts.  Dose delay and modification guidelines for patients who 
experience neutropenia can be found in Section 3.4.5.i.  Infections and, in some cases, 
serious infections, including bacteremia, respiratory tract infection, and one episode of 
septic shock, were observed in Cohort T.  Patients in Cohorts T and T2 should be 
monitored closely and evaluated promptly for signs and symptoms of infection.


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h. Infections
Infections were identified as an adverse drug reaction during the primary analysis of 
Study GO29058.  At the time of the analysis, of the 416 patients in the GDC-0032 arm,
41.8% had developed infections compared with 23.9% of the 213 patients in the placebo 
arm.  Serious infections occurred in 7.5% of patients in the GDC-0032 arm compared 
with 0.9% of patients in the placebo arm, and 0.5% of patients died on account of 
infection in the GDC-0032 arm compared with no patients in the placebo arm.  Urinary 
tract infections were the most commonly reported infection; however, respiratory tract, 
gastrointestinal tract, and skin infections were also common in the GDC-0032 arm.
Dose delay and modification guidelines for patients who experience infections can be 
found in Section 3.4.5.j.
i. 
Additional Adverse Drug Reactions
The following additional adverse drug reactions were identified during the primary 
analysis of Study GO29058:

Alopecia

Fever

Weight loss
3.4.4
Safety Monitoring of GDC-0032
Safety will be evaluated through the monitoring of all serious and non-serious adverse 
events, with severity graded according to the NCI CTCAE, v4.0.  Safety assessments 
will include interval history since the previous assessment, physical examination, and 
specific laboratory studies, including serum chemistries and blood counts (see 
Appendices A-1 to A-7 and Appendix A-9 for the schedule of study assessments).  
Patients in Stages 1 and 2 of the Phase I study will be monitored weekly for safety 
during the first 9 weeks, then every 2 weeks for an additional 6 months, and every 
4 weeks thereafter until 30 days after the last dose of GDC-0032.  Patients in the 
Phase II portion will be monitored for safety per Appendix A-8.  Patients with unresolved 
adverse events thought to be related to GDC-0032 must be followed as clinically 
indicated, until the event is resolved or stabilized, another anti-cancer therapy is initiated, 
the patient is lost to follow up, or it has been determined that the study treatment or 
participation is not the cause of the adverse event.
All serious adverse events, Grade 3 or 4 adverse events, and potential DLTs will be 
reported in real time via the electronic data capture (EDC) system to the Drug Safety 
representative and Medical Monitor at Genentech. In addition, adverse events will be 
discussed at regularly scheduled teleconferences between the Medical Monitor and the 
investigators.
As with any first-in- human study, there is the potential for toxicities that cannot be 
predicted from animal studies. To mitigate potential unknown risks at least in part, 
dosing beyond 35 days will be limited to patients who are tolerating GDC-0032 treatment 


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and not exhibiting signs or symptoms of disease progression, as previously described in 
Section 3.1.  In addition, complete recovery from any prior chemotherapy, radiation 
therapy, or surgical procedures will be a requirement for study entry.  Patients with 
history of prior pelvic radiation therapy and/or female genital tract fistulae should be 
carefully monitored for local complications such as bleeding, infection or fistulae. One 
patient with cervical cancer, on-going rectovaginal fistula, and history of local radiation 
therapy developed severe localized hemorrhage on study.
The potential for phototoxicity with GDC-0032 is unknown; therefore, it is recommended 
that patients avoid prolonged sun exposure and apply protective sunscreen and lip balm 
as appropriate while on study. 
Dose escalation to the next higher level will occur following a review of safety data after 
the last patient completes Cycle 1 in each cohort as well as any safety data obtained 
from other studies with GDC-0032.
3.4.5
Management of Toxicities
The dose delay and modification instructions provided in Table 2Table 9 are intended 
to serve as recommended guidelines to allow ongoing treatment for patients 
experiencing clinical benefit without signs or symptoms of progression while ensuring 
patient safety.  In addition to these guidelines, more conservative drug interruptions or 
dose reductions for the management of adverse events are permitted at the discretion of 
the treating investigator when deemed to be in the best interest of the patient and to 
ensure patient safety.
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 events resolves to
Grade ≤1 as discussed below (e.g., stomatitis/oral mucositis, rash, diarrhea).  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 resolved.  
Investigators should follow management guidelines for toxicities as described below 
including administration of topical or systemic corticosteroids as appropriate.
a.
Management of Hyperglycemia
Hyperglycemia has been observed in patients who received GDC-0032 while 
participating in PMT4979g and other studies.  Hyperglycemia has been reversible upon 
holding GDC-0032 and/or initiating anti-hyperglycemic medication (e.g., metformin).
Patients with diabetes who require daily anti-hyperglycemic medication or who have a 
fasting blood glucose level 120 mg/dL will be excluded from the study.  HbA1c and 
fasting glucose levels will be monitored at baseline, and regular monitoring of fasting 
glucose levels will occur during the study.  Dose delay and modification guidelines for 
patients who experience hyperglycemia are presented in Table 2.


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Table 2
GDC-0032 Dose Delay and Modification Guidelines for 
Hyperglycemia
Grade of 
Hyperglycemia
GDC-0032 Dose Modification and Management Guidelines
1 or 2
Initiation of or an increase in the dose of an anti-hyperglycemic agent 
(e.g., metformin) and additional glucose monitoring will be implemented.
GDC-0032 dosing may either be held or continued per investigator 
evaluation.
3 (asymptomatic)
Hold GDC-0032.
Treat hyperglycemia 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 improves to Grade 1, may resume GDC-0032 dosing at one dose 
level lower.
3 (symptomatic),
3 (requiring 
hospitalization), 
or 4
Hold GDC-0032.
Treat hyperglycemia per standard of care, including implementation of 
additional glucose monitoring and initiation of or an increase in the dose 
of anti-hyperglycemic therapy.
If improves to Grade 1, may resume GDC-0032 dosing at one dose 
level lower.
For recurrent symptomatic Grade 3 or Grade 4 hyperglycemic event, 
GDC-0032 must be permanently discontinued.
b.
Management of Pneumonitis
Pneumonitis has been observed in patients treated with GDC-0032.  Symptoms 
associated with pneumonitis were reversible upon treatment with corticosteroids.  Dose 
delay and modification guidelines for patients who experience pneumonitis are 
presented in Table 3.
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.  
Patients will also have CT scans of the chest at every tumor assessment.  Oxygen 
saturation by pulse oximetry will be measured at every visit as part of the assessment of 
vital signs.


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Table 3
Management of 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.
Hold GDC-0032 as long as 
corticosteroids are being given.
If pneumonitis improves to 
Grade 1 and upon completion of 
any corticosteroid treatment, 
resume GDC-0032 dosing at the 
same GDC-0032 dose or one dose 
level lower per investigator 
evaluation.
For recurrent Grade 2 event, 
resume GDC-0032 dosing at one 
dose level lower.
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.
Hold GDC-0032 as long as 
corticosteroids are being given.
If pneumonitis improves to 
Grade 1 and upon completion of 
any corticosteroids, resume GDC-
0032 dosing at one dose level 
lower.
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.
Permanently discontinue 
GDC-0032.
Table modified from White et al. 2010.
CTcomputed tomography; PFT pulmonary function test.
Note:  PFTs include tests for DLCO and room air oxygen saturation at rest (pulse oximetry).
a Dose reductions per Section 4.3.3.
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).
c.
Management of Rash
Treatment-related rash is commonly manifested as maculo-papular with or without 
pruritus.  The rash has usually resolved upon holding GDC-0032 and/or giving 
supportive therapy (e.g., topical or systemic steroids).  Dose delay and modification 
guidelines for patients who experience rash are presented in Table 4.


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Table 4
GDC-0032 Dose Delay and Modification Guidelines for Rash
Grade of Rash
GDC-0032 Dose Modification and Management Guidelines
1
Continue dosing at current dose and monitor for change in severity.
Consider prescribing topical corticosteroids a.
2
Hold GDC-0032.
Treat rash with topical corticosteroids.
Consider treatment of rash with oral corticosteroids b.  Hold 
GDC-0032 as long as oral corticosteroids are being administered.
If rash improves to Grade 1and upon completion of any systemic 
corticosteroids, resume GDC-0032 at the same dose or one 
dose-level lower per investigator evaluation.
For recurrent Grade 2 rash, resume GDC-0032 at one dose level 
lower.
3
Hold GDC-0032.
Treat rash with topical corticosteroids and/or systemic corticosteroids 
(oral or intravenous).  Hold GDC-0032 as long as systemic 
corticosteroids are being administered.
Consider dermatological consultation and skin biopsy.
If rash improves to Grade 1 and upon completion of any systemic 
corticosteroids, resume GDC-0032 at one dose level lower.
4
Permanently discontinue GDC-0032.
Treat with topical corticosteroids and/or systemic corticosteroids.
Consider dermatological consultation and skin biopsy.
AEadverse event; BIDtwice daily.
Note:  AE grading is based on National Cancer Institute Common Terminology Criteria 
for Adverse Events, 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 BID.
b Suggested oral 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.).
d.
Management of Gastrointestinal Toxicity
Nausea, vomiting, dyspepsia, diarrhea, abdominal pain, stomatitis, and oral mucositis 
have been observed in patients who received GDC-0032.  Colitis was diagnosed by 
several methods, including endoscopy and abdominal imaging (CT scans).  Pathology 
from biopsies obtained from endoscopy confirmed colitis.  Patients usually present with 
Grade 2 or Grade 3 diarrhea that has been refractory to antidiarrheal agents.  The time 
to onset (from the first dose of study treatment to the formal diagnosis of colitis) ranged 
from approximately 0.5 to 8 months with a median onset of 4.7 months.  Patients had 
resolution or improvement of gastrointestinal toxicities upon holding study drug and/or 
initiating corticosteroid therapy.  Perforated duodenal ulcer was observed in 2 patients 
(1 patient at 6-mg capsule dose in combination with letrozole; another patient at 6-mg 
capsule dose in combination with fulvestrant).  Appropriate caution should be taken with 


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the administration of medications such as aspirin, NSAIDs, and corticosteroids, which 
can increase the risk of gastritis, peptic ulcers, or gastrointestinal perforation.
Patients with active inflammatory bowel disease, such as Crohn’s disease or ulcerative 
colitis, are excluded from this study.  Patients who resume GDC-0032 treatment should 
be monitored closely for signs of renewed diarrhea.
Dose delay and modification guidelines for patients who experience gastrointestinal 
toxicities (diarrhea, colitis, stomatitis, and oral mucositis) can be found in Table 5.


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Table 5
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis
Grade
GDC-0032 Dose Modification and Management
1
Manage per standard-of-care with antidiarrheal agents a (e.g., loperamide).
For Grade 1 diarrhea occurring after Cycle 2 that persists 5 days despite treatment 
with antidiarrheal agents, obtain stool culture for infectious workup b.  Infections (e.g., 
Clostridium difficile, enteric bacteria, CMV) should be treated with the appropriate 
antibiotic.
For non-infectious diarrhea, consider holding GDC-0032 and treating with a 
corticosteroid taper (2040 mg prednisone PO QD starting dose) or budesonide 9 mg 
PO QD.  Upon completion of corticosteroid treatment, resume GDC-0032 dosing at 
same dose or one dose level lower per investigator evaluation.
2
Hold GDC-0032 and initially manage with antidiarrheal agents a.  Obtain stool culture 
for infectious workup b.  Infections (e.g., Clostridium difficile, enteric bacteria, CMV) 
should be treated with the appropriate antibiotic.
For non-infectious Grade 2 diarrhea that has not improved to Grade 1 despite 
48 hours of antidiarrheal treatment or for Grade 2 colitis, treat with corticosteroid taper 
(2040 mg prednisone PO QD starting dose) or budesonide 9 mg PO QD.  Steroid 
dosage can be increased if diarrhea does not improve.
If diarrhea or colitis does not improve after 48 hours of corticosteroid treatment, a 
colonoscopy should be considered to evaluate for other causes of diarrhea (e.g., CMV 
colitis).
If Grade 2 diarrhea occurred after Cycle 2 or improved with corticosteroid treatment or 
for Grade 2 colitis, resume GDC-0032 dosing at one dose level lower upon 
improvement to Grade 1 and after completion of any corticosteroid taper.
If Grade 2 diarrhea occurred before Cycle 2 and did not require corticosteroid 
treatment, resume GDC-0032 dosing at the same dose level or one dose level lower 
per investigator evaluation upon improvement to Grade 1.
For recurrent Grade 2 diarrhea, resume GDC-0032 dosing at one dose level lower 
upon improvement to Grade 1.
3
Hold GDC-0032 dosing and initially manage with antidiarrheal agents a.  Obtain stool 
culture for infectious workup b.  Infections (e.g., Clostridium difficile, enteric bacteria, 
CMV) should be treated with the appropriate antibiotic.
For Grade 3 diarrhea or colitis, treat with systemic corticosteroids 
(IV methylprednisolone 1620 mg every 8 hours or prednisone 6080 mg PO QD 
equivalent to start).  Can increase steroid dosage if diarrhea does not improve.
Consider colonoscopy as part of further gastrointestinal workup.  If diarrhea does not 
improve after 48 hours of corticosteroid treatment, a colonoscopy should be 
considered to evaluate for other causes of diarrhea (e.g., CMV colitis).


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Table 5
GDC-0032 Dose Modification and Management Guidelines 
for Diarrhea and Colitis (cont.)
Grade
GDC-0032 Dose Modification and Management
3
If diarrhea or colitis improves to Grade 1 and upon completion of any steroid taper, 
resume GDC-0032 dosing at one dose level lower.
Patients with recurrent Grade 3 diarrhea or colitis must be permanently discontinued 
from GDC-0032.
4
Permanently discontinue GDC-0032.  Manage as per Grade 3 diarrhea guidelines.
CMV cytomegalovirus; IV intravenous; PO taken by mouth; QD once daily.
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, four times daily, until control 
achieved [maximum: 20 mg/day], then reduce dose as needed; some patients may 
achieve control with doses of 5 mg/day)

Tincture of opium (6 mg of undiluted opium tincture [10 mg/mL] four times daily).
b Non-infectious diarrhea can be diagnosed by stool culture with work-up for Clostridium 
difficile and for various enteric bacteria.  Fecal calprotectin is a possible marker for bowel 
inflammation.  Blood-based CMV polymerase chain reaction test can also be used to detect 
CMV infection.
e. 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).  Examples of mouth care include rinsing with nonalcoholic 
mouthwash, flossing after each meal, using a mild toothpaste and soft-bristled 
toothbrush, and avoiding agents that contain hydrogen peroxide, iodine, and thyme 
derivatives.  It may also be helpful to advise patients to avoid foods that are spicy, acidic, 
or salty.


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Table 6
GDC-0032 Dose Delay and Modification Guidelines for Stomatitis 
and Oral Mucositis
Grade
GDC-0032 Dose Modification and Management Guidelines
All grades
Aggressive mouth care that includes mouthwash formulations (e.g., combinations 
of local anesthetic, antihistamine, corticosteroid, antacid, anti-fungal and/or 
antibiotics) may be implemented to help manage symptoms.
Diet management (e.g., avoidance of spicy foods)
1
Monitor symptoms and initiate management (see above).  Re-evaluate within 
4872 hours.
2
Hold GDC-0032 and manage until Grade 1.
If stomatitis or mucositis improves to Grade 1, resume GDC-0032 dosing at the 
same dose or one dose level lower per investigator evaluation.
For recurrent Grade 2 stomatitis or mucositis, resume GDC-0032 dosing at one 
dose-level lower.
3
Hold GDC-0032 and manage until Grade 1.
If stomatitis or mucositis improves to Grade 1, resume GDC-0032 dosing at one 
dose-level lower.
4
Permanently discontinue GDC-0032.
f.
Management of Abnormal Liver Enzymes
Some patients have experienced elevations of liver enzymes (e.g., AST or ALT).  
Patients will be monitored throughout the study treatment for changes in liver enzymes.  
Given the potential for hepatic toxicity, all patients must have adequate liver function as 
manifested by measurements of serum bilirubin and hepatic transaminases 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 levels at 
baseline to allow safety testing to be adequately assessed in this patient group.
For new abnormal liver enzymes (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 enzymes may be a result of liver metastases, concomitant 
medications, or biliary obstruction.  Dose delay and modification for patients who 
experience abnormal liver enzymes can also follow the guidelines in Table 9 if deemed 
clinically appropriate by the investigator.
g.
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 lab values.  Upon discussion with 
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.


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h.
Potential Inflammatory or Immunosuppressant Effects
On the basis of GDC-0032 data from nonclinical toxicity studies showing changes in 
WBC and absolute lymphocyte and/or neutrophil counts, patients will be required to 
have adequate hematologic function to participate in the study, and any bone marrow 
toxicities from prior therapies must be resolved before initiation of GDC-0032.  Patients 
will be monitored throughout the study treatment for changes in blood counts and signs 
of infection.
Infection prophylaxis and recommendations for Pneumocystis prophylaxis are covered in 
Section 4.4.1.1.
i.
Management of Neutropenia
Some patients with hematologic malignancies in Cohort T have experienced grade 3 and 
higher neutropenia, including cases of febrile neutropenia and one case of neutropenic 
colitis.  Patients enrolled in Cohorts T and T2 should have a weekly CBC for the first two 
cycles and on Day 1 of each subsequent cycle or more frequently as clinically indicated.  
While the clinical experience is limited, neutropenia has responded to dose interruption 
and/or administration of daily G-CSF (filgrastim), with a median duration of 
approximately 3 days.  Dose delay and modification guidelines for patients who 
experience neutropenia are presented in Table 7.


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Table 7
Neutropenia Management Guidelines
Grade (ANC1000/mm3)
Management
1 (LLN1500)
Continue current GDC-0032 dosing.
2 (15001000)
Continue current GDC-0032 dosing.
3 (1000500)
Options:
1) Hold GDC-0032 and suggest GCSF per 
local guidelines until ANC 1000.
2) Continue GDC-0032 and administer GCSF 
until ANC 1000, then re-check CBC in 
23 days.
Monitor CBC at least weekly.
4 (500)
Stop GDC-0032 dosing until ANC 1000.
Start GCSF per local guidelines until ANC 
1000. 
Monitor CBC at least weekly.
May re-challenge at same dose after ANC 
1000 if asymptomatic Grade 4.
If symptomatic Grade 4 neutropenia (e.g. 
febrile neutropenia or active infection), or 
recurrent Grade 4 asymptomatic neutropenia, 
resume GDC-0032 at next lower dose.
If neutropenic colitis or recurrent Grade 4 
symptomatic neutropenia, may consider 
resuming at next lower dose or stopping 
treatment, depending on individualized 
assessment of benefit-risk.
ANCabsolute neutrophil count; CBCcomplete blood count; GCSFgranulocyte colony 
stimulating factor; LLNlower limit of normal.
j.
Management of Infection and Other Clinically Significant Adverse Events
Investigators and patients should be aware of the increased risk of infection with 
GDC-0032.  If a diagnosis of infection is made, appropriate treatment should be 
promptly initiated and consideration should be given to holding or discontinuing 
GDC-0032 as per the guidelines in Table 8.
See Table 8 for the dose modifications for other clinically significant adverse events.


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Table 8
GDC-0032 Dose Delay and Modification Guidelines for Other 
Clinically Significant Adverse Events
Grade
GDC-0032
3:  first event
Hold GDC-0032 until Grade 1.
Consider restarting at next lower dose.
3:  recurrent
4:  non-life-threatening
Hold GDC-0032 until Grade 1. 
Restart at next lower dose.
4:  life-threatening
Permanently discontinue GDC-0032. 
3.4.6
Safety Monitoring for Midazolam
Midazolam is a relatively fast-acting benzodiazepine with central nervous system 
(CNS)-depressant effects.  It is frequently used perioperatively for sedation, anxiolysis, 
and amnesia.  Significant potential side effects include respiratory depression, apnea, 
and airway obstruction.  The severity and frequency of these events are markedly 
increased when midazolam is combined with other CNS-depressing agents as well as in 
patients with abnormal airway anatomy, cyanotic congenital heart disease, or sepsis or 
severe pulmonary disease.  In some cases, death or hypoxic encephalopathy has 
occurred.
In this study, a single oral dose of midazolam 5 mg will be given as part of the 
assessment of potential DDIs with GDC-0032.  This dose is similar to that typically given 
in the perioperative setting.  The effects of midazolam are dependent on the dose, route 
of administration, and the presence or absence of other medications, especially those 
with CNS effects.  The time to onset of sedative effects following oral administration is 
approximately 30 minutes and recovery may take 26 hours.
The single dose of midazolam 5 mg used in this study will be given while patients are 
under medical supervision in the clinic for safety and PK assessments.  Patients will 
remain in clinic and/or another appropriate medically-supervised setting until the effects 
of midazolam have subsided and patients may be safely discharged.
3.4.7
Safety Monitoring for Letrozole
Letrozole is a nonsteroidal aromatase inhibitor indicated for first-line treatment of 
hormone receptorpositive or hormone receptorunknown, locally advanced or 
metastatic breast cancer in postmenopausal women.  Letrozole is also indicated 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.  
Discontinuations for adverse events other than progression of tumor occurred in 2% of 


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patients on letrozole.  Refer to the letrozole Package Insert or Summary of Product 
Characteristics for additional information.  
There are no expected significant overlapping toxicities between GDC-0032 and 
letrozole.  Routine safety monitoring and periodic laboratory tests for the letrozole and 
GDC-0032 combination will occur throughout the study.
3.4.8
Safety Monitoring for Fulvestrant
Fulvestrant is an estrogen receptor antagonist indicated for the treatment of hormone 
receptorpositive metastatic breast cancer in postmenopausal women with disease 
progression following anti-estrogen therapy.
In a trial with postmenopausal patients with advanced breast cancer who had disease 
recurrence on or after adjuvant endocrine therapy or progression following endocrine 
therapy for advanced disease, the most frequently reported adverse events were 
injection-site pain (11.6% of patients), nausea (9.7%), and bone pain (9.4%).  Because 
fulvestrant is administered intramuscularly, it should be used with caution in patients with 
bleeding diatheses, thrombocytopenia, or anticoagulant use.  For more details regarding 
the safety profile of fulvestrant, please refer to the fulvestrant (e.g., FASLODEX®) 
Package Insert or Summary of Product Characteristics (SmPC).
There are no expected significant overlapping toxicities between GDC-0032 and 
fulvestrant.  Routine safety monitoring and periodic laboratory tests for the fulvestrant 
and GDC-0032 combination will occur throughout the study.
3.5
DOSING CONSIDERATIONS
Dosing beyond Cycle 1 for Phase I and II patients will be allowed at the discretion of the 
investigator after a careful assessment and thorough discussion of the potential risks 
and benefits of continued treatment with the patient.  Only those patients who are 
tolerating GDC-0032 treatment and are not exhibiting signs and symptoms of disease 
progression may receive GDC-0032 beyond Cycle 1.  Patients must comply with the 
requirements of the protocol.  These patients will have the opportunity to continue study 
treatment as long as the above conditions are met.  Efforts will be made to allow patients 
to continue treatment if they are continuing to benefit, depending on the development 
status and availability of GDC-0032.  If the study is terminated however, study drug may 
not be offered after termination (see Section 4.7).
3.6
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in accordance with the U.S. Food and Drug Administration 
(FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for 
Good Clinical Practice (GCP), applicable local, state, and federal laws, as well as 
applicable country laws and regulations.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Patient Selection
Specific inclusion and exclusion criteria for Phase I (Stage 1 and Stage 2) cohorts are 
detailed in Section 4.1.2 and Section 4.1.3, respectively.  There is no limit to the number 
or type of prior regimens for Phase I patients.
4.1.2
Inclusion Criteria
Patients must meet the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years 

Phase I, Stage 1 and Stage 2, Cohorts AD, G, H, T, T2, and X:  Histologically
documented locally advanced or metastatic solid malignancy or non-Hodgkin’s 
lymphoma that has progressed or failed to respond to at least one prior regimen 
and are not candidates for regimens known to provide clinical benefit

Phase I, Stage 2, Cohorts AX will include patients with the following tumor type, 
mutational status, and cohort-specific inclusion criteria:
Cohort A:  Patients with PIK3CA-mutant breast cancer based on results from 
archival or fresh tumor tissue
Cohort B:  Patients with PIK3CA-mutant solid malignancy other than breast 
cancer, based on results from archival or fresh tumor tissue
Cohort C:  Patients with any type of solid malignancy
Cohort D:  Patients with HER2-positive breast cancer (e.g., FISH-positive, 
chromogenic in situ hybridization [CISH]-positive, IHC 3+, or HER2-positive by 
local laboratory assessment)
Cohorts E and F:  Postmenopausal patients with histologically documented 
locally advanced or metastatic hormone receptorpositive breast cancer that 
has progressed or failed to respond to at least one prior endocrine therapy in 
the adjuvant or metastatic setting.  A minimum of 10 patients per cohort will be 
required to have PIK3CA-mutant breast cancer.
Hormone receptor-positive is defined as expression of ER in 1% cells, 
or hormone receptor-positive by local laboratory or regional definition.
Postmenopausal is defined as one of the following: 
1.
Age 60 years
2.
Age 60 years and 12 months of amenorrhea plus follicle 
stimulating hormone (FSH) and plasma estradiol levels within 
postmenopausal range by local laboratory assessment; these 
patients must have discontinued gonadotropin-releasing hormone 
(GnRH) agonists at least 15 months prior to initiation of study 
treatment


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3.
Prior bilateral oophorectomy (28 days prior to first treatment on 
Day 1 of Cycle 1)
Cohort G:  Patients with solid malignancy with increased PIK3CA copy number, 
based on archival or fresh tumor tissue
Cohort H:  Patients with PIK3CA-mutant solid malignancy other than breast or 
colorectal cancer, based on results from archival or fresh tumor tissue
Must include a minimum of 5 patients with cervical cancer and a minimum 
of 20 patients with NSCLC
Cohorts J, K, L, M, N, P, Q, R, and S:  Postmenopausal patients with 
HER2-negative, hormone receptorpositive breast cancer as defined in Stage 2, 
Cohort F that has progressed or failed to respond to at least one prior 
endocrine therapy in the adjuvant or metastatic setting.  HER2-negative will be 
as defined by local clinical guidelines.
For each of these cohorts, a minimum of 10 patients per cohort will be 
required to have PIK3CA-mutant breast cancer.  Hormone 
receptorpositive defined as expression of ER in 1% cells, or hormone 
receptorpositive by local laboratory or regional definition.  HER2-negative 
will be as defined by local clinical guidelines. 
For Cohorts N and P, a minimum of 6 patients (3 patients with 
PIK3CA-mutant and 3 patients with PIK3CA-wild-type tumors) in each 
cohort must consent to undergo paired pre-treatment and on-treatment 
tumor biopsies.
As per national or local treatment guidelines, endocrine therapy 
(e.g., fulvestrant, letrozole) is recommended and treatment with 
cytotoxic chemotherapy is not necessary for patients at time of entry into the 
study.
Cohort T:  Patients with non-Hodgkin’s lymphoma, regardless of PIK3CA
mutation status
Cohort T2: Patients with DLBCL, regardless of PIK3CA mutation status
Availability of a representative tumor specimen and the corresponding 
pathology report for retrospective central confirmation of the diagnosis of 
DLBCL and for exploratory research on candidate biomarkers.
All Cohort T2 patients must consent to providing a formalin-fixed
paraffin-embedded block or a minimum of 15 freshly cut, unstained 
tumor slides (submission of 20 is strongly encouraged) from archival 
tumor tissue or a newly collected (“fresh”) tumor sample for PIK3CA
mutation testing as well as for other protocol-mandated exploratory 
assessments.  Lymph node excisions or biopsies are strongly preferred. 
If archival tissue is unavailable or unacceptable, a pretreatment 
core-needle, excisional, or incisional tumor biopsy is required. 
Cytological or fine-needle aspiration samples are not acceptable. 


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If the available biopsy was performed more than 12 months prior to 
Day 1 of Cycle 1 for patients with DLBCL or the patient received 
anti-lymphoma treatment between the time of the most recently 
available biopsy and Day 1 of Cycle 1, a core-needle biopsy is strongly 
recommended. 
Further details are provided in Section 4.5.1.v. 
Cohort X:  Patients with PIK3CA-mutant tumors based on results from archival 
or fresh tumor tissue, with tumor histology defined for the following sub-cohorts:
X1:  endometrial cancer
X2:  bladder cancer
X3:  HNSCC
1020 patients with PIK3CA mutant HNSCC, regardless of PIK3CA
copy number status, by local or central testing
1020 patients with HNSCC with amplification of the PIK3CA gene and 
no PIK3CA somatic mutations detected, by local or central testing
A minimum of 5 patients in Cohort X3 must consent to undergo paired 
pre-treatment and on-treatment tumor biopsies.
X4:  cervical cancer
X5:  gastric and gastroesophageal junction cancer
X6:  small cell lung cancer (closed)
X7:  triple-negative (HER2-negative, ER-negative, PR-negative) breast 
cancer, as defined by local guidelines
X8:  colorectal cancer, excluding KRAS mutant
X9:  squamous cell cancer, excluding any histology in Cohorts X1X8 
and X10 and NSCLC
X10:  ovarian cancer, including clear cell
X11:  PIK3CA-mutant cancer not otherwise specified in Cohorts X1X10 
and excluding breast, NSCLC, and colorectal cancer.  SCLC is allowed in 
Cohort X11.
Cohort X patients may be enrolled on the basis of local or central test 
results that indicate a PIK3CA mutation or amplification.  A copy of the 
local PIK3CA gene mutation or amplification report must be submitted for 
review by the Medical Monitor prior to enrollment.  
All Cohort X patients must consent to providing a formalin-fixed 
paraffin-embedded block or a minimum of 10 freshly cut unstained tumor 
slides (submission of 1520 is strongly encouraged) from archival tumor 
tissue or a newly collected (“fresh”) tumor sample for PIK3CA-mutation and 
copy number testing as well as for other protocol-mandated exploratory 
assessments.  When tissue is available from more than one source


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(e.g., primary tumor or metastatic sites), preference should be given to the 
tissue that was most recently collected.
Tumor tissue should be of good quality based on total and viable tumor 
content (refer to the Laboratory Manual).  Evaluation of the patient’s tumor 
sample for adequate tumor-tissue content by a central laboratory must 
occur prior to initiation of study treatment.
For Cohort X8, determination of KRAS wild-type status is required prior to 
initiation of study treatment per local institutional guidelines or central 
testing.

Evaluable or measurable disease per RECIST v1.1 (see Appendix C) for Phase I 
(Stages 1 and 2, except Cohorts T, T2, and X) and Phase II and/or the following for 
Phase I (Stages 1 and 2) only:
Patients with castrate-resistant prostate cancer with non-measurable disease 
are eligible if they have two rising prostate-specific antigen (PSA) levels 
5 ng/mL measured 2 weeks apart that meet the PSA Working Group criteria 
for progression prior to initiation of study treatment (see Appendix D), and 
otherwise are not candidates for regimens known to provide clinical benefit.
Ovarian cancer patients with non-measurable disease are eligible if they have 
progression or recurrence based on serum CA-125 levels as defined by the 
Gynecological Cancer Intergroup (GCIG) Criteria for Evaluation according to 
CA-125 (see Appendix E), and otherwise are not candidates for regimens 
known to provide clinical benefit.

Evaluable or measurable disease for Cohorts T and T2 patients with lymphoma of at 
least one bi-dimensionally measurable lesion on CT scan defined as 1.5 cm in its 
longest diameter

For Cohort X, measurable disease per RECIST v1.1 (see Appendix C)

Phase II:  Postmenopausal female patients with HER2-negative, hormone 
receptorpositive breast cancer as defined in Stage 2, Cohort F.  A minimum of 
30 patients are required to have PIK3CA-mutant breast cancer.  For Phase II, 
HER2-negative will be as defined by local clinical guidelines.
HER2 status will be identified by an IHC and/or an ISH assay as evaluated at 
the institution.

Phase II:  As per national or local treatment guidelines, endocrine therapy 
(i.e., fulvestrant) is recommended, and treatment with cytotoxic chemotherapy is not 
necessary for patients, at time of entry into the study.

ECOG performance status of 0 or 1 at screening (see Appendix F)

Life expectancy of 12 weeks

Adequate hematologic and organ function within 28 days prior to initiation of study 
treatment, defined by the following:

Granulocyte count 1500/L


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
Hemoglobin 9 g/dL

Platelet count 100,000/L (except for Cohorts T and T2 where platelet count 
75,000/L)

Fasting glucose 120 mg/dL

Total bilirubin 1.5 ULN

Patients with known Gilbert’s disease who have serum bilirubin 3 ULN may be 
enrolled.

Serum albumin 2.5 g/dL

AST and ALT 1.5 ULN with the following exception:
Patients with documented liver metastases may have AST and/or 
ALT 5.0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 if female)
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.

Documented willingness to use an effective means of contraception 
(e.g., abstinence, hormonal or double barrier method, surgically sterilized partner; if 
using hormonal means of contraception, then a second means of contraception 
must be used) for both men and women while participating in the study and for 
90 days after the last dose of GDC-0032

Willingness to provide archival tumor tissue
4.1.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Leptomeningeal disease as the only manifestation of the current malignancy

Type 1 or 2 diabetes requiring anti-hyperglycemic medication

Inability or unwillingness to swallow pills, except for patients with HNSCC 
(Cohort X3)
Patients with head and neck cancer with gastrostomy tubes are eligible to take 
GDC-0032 as a suspension, only at sites where administration of the 
extemporaneous suspension is approved by the IRB/EC.

Malabsorption syndrome or other condition that would interfere with enteral 
absorption


Protocol:  GDC-0032—Genentech, Inc.
113/P PMT4979g (GO00886)-A10

Known and untreated, or active CNS metastases (progressing or requiring 
anticonvulsants for symptomatic control)  
Patients with a history of treated CNS metastases are eligible, provided they 
meet all of the following criteria: 
Disease outside the CNS is present.
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
No history of intracranial hemorrhage or spinal cord hemorrhage 
Minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 
and recovery from significant (Grade ≥3) acute toxicity with no ongoing 
requirement for 10 mg of prednisone per day or an equivalent dose of 
other corticosteroid

Congenital long QT syndrome or QTc 500 msec

Active congestive heart failure or ventricular arrhythmia requiring medication

Uncontrolled ascites requiring weekly large-volume paracentesis for 
3 consecutive weeks prior to initiation of study treatment

Active infection requiring intravenous (IV) antibiotics 

Patients requiring any daily supplemental oxygen

Active inflammatory diseases that require immunosuppressants, including small or 
large intestine inflammation such as Crohn’s disease or ulcerative colitis
Patients currently receiving immunosuppressants (e.g., sulfasalazines) are 
considered to have active disease and are, therefore, ineligible.

Symptomatic hypercalcemia requiring continued use of bisphosphonate or 
denosumab therapy

Clinically significant history of liver disease, including viral or other 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 (examples include but are not 
limited to clinically significant non-healing wound, active bleeding, or ongoing fistula 
or active tuberculosis infection)

Significant traumatic injury within 3 weeks prior to initiation of GDC-0032

Major surgical procedure within 4 weeks prior to initiation of GDC-0032

Treatment with chemotherapy, corticosteroids, hormonal therapy (except GnRH 
agonists or antagonists for prostate cancer, or oral endocrine therapy), 


Protocol:  GDC-0032—Genentech, Inc.
114/P PMT4979g (GO00886)-A10
immunotherapy, or biologic therapy as cancer therapy within 3 weeks prior to 
initiation of study treatment.  
Note:  For Cohorts T and T2, if corticosteroid treatment is urgently required for 
lymphoma symptom control prior to the start of study treatment, up to 100 mg/day 
prednisone or equivalent can be given for 7 days, but all tumor assessments must 
be completed prior to start of corticosteroid treatment.

Oral endocrine therapy (e.g., tamoxifen, letrozole, anastrozole, exemestane) within 
2 weeks prior to initiation of study treatment.  
Note:  Patients who are receiving letrozole prior to study entry may continue 
letrozole treatment if they are enrolled into a Stage 2 letrozole combination 
cohort (Cohorts E, N, P, Q, R, and S).

Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks 
prior to initiation of GDC-0032, provided that any drug-related toxicity has 
completely resolved and prior approval is obtained from the Medical Monitor.

Prior treatment with a PI3-kinase inhibitor in which the patient experienced a 
Grade 3 drug-related adverse event or otherwise would be at increased risk for 
additional PI3K-related toxicity

For patients in Stage 2 (Phase I) and Phase II:  prior treatment with PI3-kinase 
inhibitors, except for Cohorts T and T2 (e.g., prior idelalisib is allowed for Cohorts T 
and T2)

For patients in Stage 2, Cohorts J, K, L, and M and in Phase II:  prior treatment with 
fulvestrant

For patients in Stage 2, Cohorts, J, K, L, M, N, P, Q, R, and S and patients in 
Phase II:  Prior treatment with 1 cytotoxic chemotherapy regimen in the metastatic 
setting (Prior treatment with everolimus is permitted and is not considered a 
cytotoxic chemotherapy) 

For Cohort T:  Patients with primary CNS lymphoma, acute leukemias, 
accelerated/blast-phase chronic myelogenous leukemia, CLL, Burkitt lymphoma, 
plasma cell leukemia, or non-secretory myeloma

For Cohort T2:  Patients with prior history of Richter’s transformation or allogeneic 
stem cell transplantation.  Prior autologous stem cell transplantation is allowed.

Palliative radiation to bony metastases within 2 weeks prior to initiation of 
GDC-0032

Radiation therapy (other than palliative radiation to bony metastases) as cancer 
therapy within 4 weeks prior to initiation of GDC-0032

Treatment with an investigational agent within 3 weeks or 5 half-lives prior to 
initiation of GDC-0032, whichever is shorter

Unresolved toxicity from prior therapy, except for alopecia and Grade 1 peripheral 
neuropathy

Pregnancy or lactation


Protocol:  GDC-0032—Genentech, Inc.
115/P PMT4979g (GO00886)-A10

Women of childbearing potential (including those who have had a tubal ligation) 
must have a documented negative pregnancy test within 28 days prior to initiation of 
GDC-0032.

Inability to comply with study and follow-up procedures
4.2
METHOD OF TREATMENT ASSIGNMENT
This is an open-label study.  Patients in Stage 1 will be assigned to dose levels in the 
order in which they are enrolled.  Patients in Stage 2 will be assigned by Genentech.  
Patients in Phase II will be assigned by Genentech.  Patients in Cohort X (Basket Cohort) 
will be assigned to a tumor sub-cohort (X1X11) on the basis of their tumor type by 
Genentech.  Upon completion of all screening evaluations and verification that the 
patient has met all eligibility criteria, sites will contact Genentech to confirm patient 
eligibility and to obtain a patient number, cohort and dose assignment, and confirm the 
dosing schedule. 
4.3
STUDY TREATMENT
4.3.1
Formulation and Storage
a.
GDC-0032
GDC-0032 Drug Product is provided in a capsule formulation consisting of active 
pharmaceutical ingredient (API) powder (at different quantities) and hard gelatin capsule 
shells.  The Drug Product will be initially provided as capsules of three strengths:  1 mg, 
3 mg, and 5 mg.  The 1-mg capsules are size 3 and Swedish orange, the 3-mg capsules 
are size 2 and white opaque, and the 5-mg capsules are size 2 and dark green.  The 
only excipient in GDC-0032 Drug Product is the hard gelatin capsule shell.
The Drug Product is packaged in high-density polyethylene (HDPE) bottles.  Each bottle 
is induction sealed and labeled for clinical use.
GDC-0032 capsules will be shipped to the study sites in bulk containers.  GDC-0032 
capsules should be stored at room temperature between 5986F (1530C) and should 
be protected from light.  Patients will be instructed to store study drug at room 
temperature between 5986F (1530C).
GDC-0032 is also provided for use in clinical studies as a white, film-coated, 
immediate-release tablet formulation of 2 mg strength.   GDC-0032 tablets should not be 
stored above 25C. 
Patients with gastrostomy tubes who are unable to swallow tablets may receive their 
GDC-0032 dose in the form of a suspension prepared extemporaneously from 
(GDC-0032) 2-mg tablets.  Patients will be provided with instructions for preparation of 
the suspension.  See Section 4.3.2.b.
For further details, see the Taselisib (GDC-0032) Investigator’s Brochure.


Protocol:  GDC-0032—Genentech, Inc.
116/P PMT4979g (GO00886)-A10
b.
Midazolam (Stage 2, Cohort C Only)
Refer to the midazolam Package Insert or SmPC for details on the formulation and 
storage of midazolam.
c.
Letrozole (Stage 2, Cohorts E, N, P, Q, R, and S)
Refer to the letrozole (e.g., Femara®) Package Insert or SmPC for details on the 
formulation and storage of letrozole.
d.
Fulvestrant (Stage 2, Cohorts F, J, K, L, and M; Phase II)
Fulvestrant is supplied in sterile single-patient prefilled syringes containing 50 mg/mL 
fulvestrant as a 5-mL injection.  Refer to the fulvestrant (e.g., FASLODEX®) Package 
Insert or SmPC for details on the storage of fulvestrant.
4.3.2
Dosage and Administration
The starting dose of GDC-0032 is 3 mg (capsule formulation) in the dose-escalation 
Phase I, Stage 1 portion.  Dose escalations will occur as described in Section 3.1.3.
On Day 1 of Cycle 1 for patients in Phase I, Stage 1 and Stage 2, Cohorts AG, 
GDC-0032 will be administered to patients in a clinical setting that can accommodate 
frequent blood draws over a period of up to 72 hours after the morning dose is 
administered.  See Sections 4.3.2.a and 4.3.2.b for the Stage 1 and Stage 2 dosing 
regimens, respectively.
At each study visit, after establishing patient eligibility for continued administration of
GDC-0032, a sufficient number of capsules or tablets should be dispensed to the patient 
to last only until the next visit or, at the investigator’s discretion, through one cycle.  
Patients will self-administer GDC-0032 as detailed below, except on study visit days 
when the GDC-0032 will be administered in the clinic.
Patients will receive a single dose of GDC-0032 on scheduled dosing days.  Patients will 
take GDC-0032 at the same time of day 2 hours, unless otherwise instructed.  Patients 
will be instructed as to the number and strength of capsules or tablets to take, according 
to their assigned dose level and schedule.  Patients with head and neck cancer and with 
gastrostomy tubes who are enrolled in Cohort X3 will be provided with special 
instructions on how to prepare a suspension (extemporaneous formulation) from 
GDC-0032 tablets for easier administration (see Section 4.3.2.b).  To minimize the 
number of capsules or tablets administered, doses will be rounded so that a combination 
of no more than two different strengths will be required.  The capsules should never be 
opened.  Patients will be asked to record the time and date that they take each dose in a 
medication diary.
For Stage 1, unless otherwise instructed, GDC-0032 should be taken on an empty 
stomach (i.e., approximately 1 hour before or 2 hours after a meal), except on days of 
extensive PK sampling (Days 1 and 15 of Cycle 1) when administration will be under 


Protocol:  GDC-0032—Genentech, Inc.
117/P PMT4979g (GO00886)-A10
fasted conditions.  For administration under fasted conditions, patients will fast overnight 
for at least 10 hours before dosing and 4 hours postdose and will refrain from drinking
water from 1 hour before and until 1 hour after dosing, with the exception of GDC-0032 
administration when the capsules will be swallowed whole (not chewed) with 240 mL 
(8 fluid ounces) of water.
For Stage 2 cohorts, GDC-0032 may be taken with or without food except on days on 
which there is a post-dose PK assessment where administration should be under fasted 
conditions.  There is no water restriction around the time of GDC-0032 administration 
under fasted conditions for Stage 2 cohorts.
If a patient misses a GDC-0032 dose or vomits up a capsule or tablet, he or 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 capsules or tablets to each study visit or, at the investigator’s discretion, 
at the end of each cycle, for GDC-0032 accountability.
On safety assessment days, PK samples will be collected at the same time as other 
blood tests are performed, including fasting lipid panels.  Patients will be instructed to 
hold the morning dose of GDC-0032 until after PK blood samples have been obtained.
For Cohorts HX, once fasting blood draws have been collected and GDC-0032 
administered, the patient need not continue to remain fasted for any post-dose, PK blood 
draw.
a.
Stage 1 Dosing
In Stage 1, Cycle 1 will be 35 days in length and will begin with a PK evaluation, during 
which all patients will receive a single fasting dose of GDC-0032 on Day 1 at their 
assigned dose level.  The initial dose will be followed by a 7-day washout and frequent 
PK sampling up to 72 hours to determine the single-dose PK properties of GDC-0032 in 
humans.  Urine samples will be collected up to 24 hours after the first dose to determine 
urinary elimination of GDC-0032.  Blood samples will be taken at several scheduled 
timepoints to explore the surrogate PD response after a single dose.  In Cycle 1, 
continuous GDC-0032 daily dosing will begin on Day 8 and will continue for 4 weeks
(Days 835).
Subsequent cycles will be 28 days in length (4 weeks of daily dosing with GDC-0032).
b.
Stage 2 Dosing
The dosing regimens for the Stage 2 cohorts are as follows:

Cohort A:  In Cycle 1, patients will receive a single dose of GDC-0032 on Day 1, 
and then daily doses from Day 8 to Day 35.  On Day 1 or 8 of Cycle 1, GDC-0032 
administration will be under either fasted or fed conditions for the food-effect 
assessment (i.e., fasted on Day 1 and fed on Day 8 or vice versa).  The patients will 


Protocol:  GDC-0032—Genentech, Inc.
118/P PMT4979g (GO00886)-A10
fast overnight for at least 10 hours before the morning dose.  If the patient is 
receiving a high-fat breakfast, the meal must be entirely consumed within 
30 minutes and GDC-0032 dose will be given 30 minutes after the start of the meal.  
The high-fat meal (approximately 800 to 1000 calories) will consist of approximately 
33 g protein, 58 g carbohydrate, and 75 g fat, respectively (e.g., 2 eggs fried in butter, 
2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash-brown potatoes, and 
8 ounces of whole milk).  Patients will refrain from drinking water from 1 hour before 
and until 1 hour after dosing, with the exception of 240 mL (8 fluid ounces) water 
intake required for administration of GDC-0032.  GDC-0032 capsules will 
be swallowed whole (not chewed) with water.  No additional food should be allowed 
for at least 4 hours postdose.  In addition, patients will receive a GDC-0032 dose 
under fasted conditions on Cycle 1, Day 22 for assessment of steady state 
pharmacokinetics.  Subsequent cycles will be 28 days in length (4 weeks of daily 
dosing with GDC-0032).

Cohorts B, D, and G:  In Cycle 1, patients will receive daily oral doses of GDC-0032 
on an empty stomach (i.e.,1 hour before or 2 hours after a meal) on Days 128, 
except on Days 1, 8, and 15 when patients receive GDC-0032 under fasted 
conditions.  For subsequent cycles patients will receive daily oral doses of 
GDC-0032 on Days 128.

Cohort C:  In Cycle 1, patients will receive midazolam 5 mg in hydrochloride syrup 
on Days 1 and 16.  Each midazolam dose will be administered by oral syringe, 
followed by approximately 200 mL of water to rinse the mouth and swallow.  
Midazolam will not be mixed with any liquid before ingestion.  Patients will then 
receive daily doses of GDC-0032 on Days 229.  All doses will be taken on an 
empty stomach (i.e., 1 hour before or 2 hours after a meal), except on Days 1 and 
16 when patients receive the doses under fasted conditions.  For subsequent cycles
patients will receive daily oral doses of GDC-0032 on Days 128.

Cohort E:  In Cycle 1, patients will receive daily oral doses of GDC-0032 and 
letrozole 2.5 mg orally on Days 128.  Patients will take the GDC-0032 and letrozole 
doses on an empty stomach (i.e., 1 hour before or 2 hours after a meal), except on 
Days 1 and 15 when patients will receive the doses under fasted conditions.  
For subsequent cycles patients will continue to take daily oral doses of GDC-0032 
and daily oral doses of letrozole 2.5 mg on Days 128.  On study visit days, 
GDC-0032 and letrozole will be administered in the clinic.

Cohort F:  In Cycle 1, patients will receive daily oral doses of GDC-0032 on 
Days 128.  Patients will take the GDC-0032 doses on an empty stomach 
(i.e., 1 hour before or 2 hours after a meal), except on Days 1 and 15 when patients 
will receive the doses under fasted conditions.  Fulvestrant is supplied in sterile 
single-patient prefilled syringes containing a 250 mg dose (50 mg/mL fulvestrant as 
a 5-mL injection).  Patients will receive fulvestrant 500 mg, administered 
intramuscularly in the buttocks slowly (12 minutes per injection) as two 5-mL 
injections (one in each buttock), in the clinic on Days 1 and 15 of Cycle 1.  
For subsequent cycles patients will continue to receive daily oral doses of 
GDC-0032 on Days 128 and will receive fulvestrant via intramuscular injections as 
described above in the clinic on Day 1 of each cycle.


Protocol:  GDC-0032—Genentech, Inc.
119/P PMT4979g (GO00886)-A10

Cohort H:  In Cycle 1, patients will receive daily oral doses of GDC-0032 on 
Days 121 of each 28-day cycle.  For PK testing on Cycle 1 Day 15, patients will 
receive GDC-0032 under fasted conditions in the clinic.  For subsequent cycles 
patients will receive daily oral doses of GDC-0032 on Days 121 of each cycle.  For 
PK testing on Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.

Cohort J:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in 
tablet form on Days 121.  For PK testing on Cycle 1 Day 15, patients will take 
GDC-0032 under fasted conditions in the clinic.  Fulvestrant will be supplied in 
sterile single-patient prefilled syringes containing a 250-mg dose (50 mg/mL 
fulvestrant as a 5-mL injection).  Patients will receive fulvestrant 500 mg, 
administered intramuscularly in the buttocks slowly (12 minutes per injection) as 
two 5-mL injections (one in each buttock), in the clinic on Days 1 and 15 of Cycle 1.  
For subsequent cycles patients will continue to receive daily oral doses of 
GDC-0032 on Days 121 of each cycle and will receive fulvestrant as described 
above in the clinic on Day 1 of each cycle.  For PK testing on Day 1 of Cycles 2 and 
6, GDC-0032 will be administered in the clinic.

Cohort K:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in 
tablet form on Days 15, 812, 1519, and 2226.  For PK testing on Cycle 1 
Day 15, patients will take GDC-0032 under fasted conditions in the clinic.  
Fulvestrant will be supplied in sterile single-patient prefilled syringes containing a 
250-mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will receive 
fulvestrant 500 mg, administered intramuscularly in the buttocks slowly (12 minutes 
per injection) as two 5-mL injections (one in each buttock), in the clinic on Days 1 
and 15 of Cycle 1.  For subsequent cycles patients will continue to receive daily oral 
doses of GDC-0032 on Days 15, 812, 1519, and 2226 of each cycle and will 
receive fulvestrant as described above in the clinic on Day 1 of each cycle.  For PK 
testing on Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.

Cohort L:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in 
tablet form on Days 17 and 1521.  For PK testing on Cycle 1 Day 1, patients will 
take GDC-0032 under fasted conditions in the clinic.  Fulvestrant is supplied in 
sterile single-patient prefilled syringes containing a 250-mg dose (50 mg/mL 
fulvestrant as a 5-mL injection).  Patients will receive fulvestrant 500 mg, 
administered intramuscularly in the buttocks slowly (12 minutes per injection) as 
two 5-mL injections (one in each buttock), in the clinic on Days 1 and 15 of Cycle 1.  
For subsequent cycles patients will continue to receive daily oral doses of 
GDC-0032 on Days 17 and Days 1521 of each cycle and will receive fulvestrant 
via intramuscular injections as described above in the clinic on Day 1 of each cycle. 
For PK testing on Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the 
clinic.

Cohort M:  In Cycle 1, patients will receive a daily oral dose of 2 mg GDC-0032 in 
tablet form on Days 128.  For PK testing on Cycle 1 Day 15, patients will take 
GDC-0032 under fasted conditions in the clinic.  Fulvestrant is supplied in sterile 
single-patient, prefilled syringes containing a 250-mg dose (50 mg/mL fulvestrant as 
a 5-mL injection).  Patients will receive fulvestrant 500 mg, administered 
intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL 


Protocol:  GDC-0032—Genentech, Inc.
120/P PMT4979g (GO00886)-A10
injections (one in each buttock), in the clinic on Days 1 and 15 of Cycle 1.  
For subsequent cycles, patients will continue to receive daily oral doses of 
GDC-0032 on Days 128 and will receive fulvestrant via intramuscular injections, as 
described above, in the clinic on Day 1 of each cycle.  For PK testing on Day 1 of 
Cycles 2 and 6, GDC-0032 will be administered in the clinic.
Fulvestrant dosing exceptions (Cohorts F, J, K, L, and M):  For patients with moderate 
hepatic impairment (Child-Pugh Class B), a single-agent dose of 250 mg is 
recommended on the basis of clinical data described in the fulvestrant package insert.

Cohort N:  In Cycle 1, patients will receive a daily oral dose of 2 mg GDC-0032 in 
tablet form and letrozole 2.5 mg orally on Days 128.  For PK testing on Cycle 1 
Day 15, patients will take GDC-0032 and letrozole doses under fasted conditions in 
the clinic.  For subsequent cycles, patients will continue to take daily oral doses of 
GDC-0032 and daily oral doses of letrozole 2.5 mg on Days 128.  For PK testing 
on Day 1 of Cycles 2 and 6, GDC-0032 and letrozole will be administered in the 
clinic.

Cohort P:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in 
tablet form and letrozole 2.5 mg orally on Days 128.  For PK testing on Cycle 1 
Day 15, patients will take GDC-0032 and letrozole under fasted conditions in the 
clinic.  For subsequent cycles, patients will continue to take daily oral doses of 
GDC-0032 and daily oral doses of letrozole 2.5 mg on Days 128.  For PK testing 
on Day 1 of Cycles 2 and 6, GDC-0032 and letrozole will be administered in the 
clinic.

Cohort Q:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in 
tablet form on Days 121 and letrozole 2.5 mg orally on Days 128.  For PK testing 
on Cycle 1 Day 15, patients will take GDC-0032 under fasted conditions in the clinic.  
For subsequent cycles, patients will continue to take daily oral doses of GDC-0032 
on Days 121 and daily oral doses of letrozole 2.5 mg on Days 128.  For PK 
testing on Day 1 of Cycle 2 and 6, GDC-0032 and letrozole will be administered in 
the clinic.

Cohort R:  In Cycle 1, patients will receive a daily oral dose of 4 mg GDC-0032 in 
tablet form on Days 15, 812, 1519, and 2226 and letrozole 2.5 mg orally on 
Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 and 
letrozole under fasted conditions in the clinic.  For subsequent cycles, patients will 
continue to take daily oral doses of GDC-0032 on Days 15, 812, 1519, and 
2226 of every cycle and daily oral doses of letrozole 2.5 mg on Days 128.  For PK 
testing on Day 1 of Cycle 2 and 6, GDC-0032 and letrozole will be administered in 
the clinic.

Cohort S:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in 
tablet form on Days 17 and 1521 and letrozole 2.5 mg orally on Days 128.  For 
PK testing on Cycle 1 Day 1, patients will take GDC-0032 and letrozole under fasted 
conditions in the clinic.  For subsequent cycles, patients will continue to receive daily 


Protocol:  GDC-0032—Genentech, Inc.
121/P PMT4979g (GO00886)-A10
oral doses of GDC-0032 on Days 17 and Days 1521 and daily oral doses of 
letrozole 2.5 mg orally on Days 128. For PK testing on Day 1 of Cycles 2 and 6, 
GDC-0032 and letrozole will be administered in the clinic.

Cohort T:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in 
tablet form on Days 128.  For PK testing on Cycle 1 Day 15, patients will take 
GDC-0032 under fasted conditions in the clinic.  For subsequent cycles, patients will 
continue to take oral daily doses of GDC-0032 on Days 128.  For PK testing on 
Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.

Cohort T2:  In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in 
tablet form on Days 128.  For PK testing on Cycle 1 Day 15, patients will take 
GDC-0032 under fasted conditions in the clinic.  For subsequent cycles, patients will 
continue to take oral daily doses of GDC-0032 on Days 128.  For PK testing on 
Day 1 of Cycles 2 and 6, GDC-0032 will be administered in the clinic.

Cohort X, except sub-Cohort X3 patients who are taking GDC-0032 as suspension:  
In Cycle 1, patients will receive daily oral doses of 4 mg GDC-0032 in tablet form on 
Days 128.  For PK testing on Cycle 1 Day 15, patients will take GDC-0032 under 
fasted conditions in the clinic.  For subsequent cycles, patients will continue to take 
oral daily doses of GDC-0032 on Days 128.  For PK testing on Day 1 of Cycles 2 
and 6, GDC-0032 will be administered in the clinic.  

Cohort X3:  Patients with head and neck cancer who can swallow tablets will receive 
daily oral doses of 4 mg GDC-0032 in tablet form.  For patients who cannot take 
tablets orally and have gastrostomy (G) tubes, GDC-0032 will be administered via 
G-tube as an aqueous suspension prepared extemporaneously from GDC-0032 
tablets.  Patients will be provided with special instructions on how to make a 
suspension from GDC-0032 tablets.  The suspension is prepared by placing the 
GDC-0032 tablets in water (20 mL of water per tablet) in a glass container for 
15 minutes at room temperature.  The mixture is then stirred or swirled to generate 
a suspension before administering into the G-tube.  The container should be rinsed 
with 30 mL of water, and the water from the rinse should also be administered into 
the G-tube.  This rinsing procedure should be repeated one additional time.  
Suspensions should be prepared immediately prior to dosing.  Patients or 
caregivers should wash their hands after the preparation and any utensils used to 
prepare the suspension after administration.  In Cycle 1, patients will receive daily 
doses of 4 mg GDC-0032 via G-tube on Days 128.  Patients or caregivers should 
prepare GDC-0032 suspension under observation in the clinic on Cycle 1 Days 1 
and 2.  For PK testing, patients will take GDC-0032 on Cycle 1 Days 1 and 15 under 
fasted conditions in the clinic.  For subsequent cycles, patients will continue to take 
daily doses of GDC-0032 via G-tube on Days 128.  For PK testing on Day 1 of 
Cycles 2 and 6, GDC-0032 will be administered in the clinic.  See Appendix B-10 for 
additional PK testing for Cohort X3 to test the pharmacokinetics of GDC-0032 
administered as a suspension.


Protocol:  GDC-0032—Genentech, Inc.
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c.
Phase II Dosing
In Cycle 1, patients will receive daily oral doses of GDC-0032 on Days 128.  Patients 
will take the GDC-0032 doses on an empty stomach (i.e., 1 hour before or 2 hours after 
a meal), except on Days 1 and 15 when patients will receive the doses under fasted 
conditions.  Fulvestrant will be supplied in sterile single-patient prefilled syringes 
containing a 250-mg dose (50 mg/mL fulvestrant as a 5-mL injection).  Patients will 
receive fulvestrant 500 mg, administered intramuscularly in the buttocks slowly 
(12 minutes per injection) as two 5-mL injections (one in each buttock), in the clinic on 
Days 1 and 15 of Cycle 1.  For subsequent cycles patients will continue to receive daily 
oral doses of GDC-0032 on Days 128 and will receive fulvestrant as described above in 
the clinic on Day 1 of each cycle.
For patients with moderate hepatic impairment (Child-Pugh Class B), a single-agent dose 
of fulvestrant 250 mg is recommended based upon clinical data described in the fulvestrant 
package insert.
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF and the physician should be notified immediately.
4.3.3
Dose Modification
a.
Dose Modifications for Cycle 1 in Stage 1 and Stage 2, Cohorts E and F
Patients who experience a DLT during the DLT assessment window (Days 135; 
see Section 3.1.3) must have GDC-0032 dosing suspended.  GDC-0032 will be 
permanently discontinued, except when the DLT is reversible and monitorable and the 
risk-benefit ratio suggests a reasonable rationale for the patient to continue in the study, 
with approval by the Medical Monitor.  In such cases, if the DLT resolves to at least the 
baseline grade within 28 days, GDC-0032 dosing may resume at one dose level lower 
(as detailed in Table 9).  If more than the allowed number of doses of study drugs 
(see Section 3.1.3 for Stage 1, Section 3.1.4e for Stage 2, Cohort E, and Section 3.1.4f 
for Stage 2, Cohort F) are missed during this period for reasons other than a DLT, the 
patient will be replaced in that cohort.  Continuation of study treatment for such patients 
may occur after an assessment of future compliance and discussion between the 
investigator and the Medical Monitor.  No dose reductions are allowed for letrozole 
(Stage 2, Cohort E) or for fulvestrant (Stage 2, Cohort F).
b.
Dose Modifications for Stage 2 Cohorts AD and GX, and for 
Cycles 2 in Stage 1 and Stage 2, Cohorts E and F
After the DLT assessment window (Stage 1 and Stage 2, Cohorts E and F) and during 
the continuation phase of the study (Stage 2, Cohorts AD, and GX), patients may 
temporarily suspend GDC-0032 dosing for up to 28 days if they experience a GDC-0032 
drug-related toxicity or an unanticipated medical event not associated with study 
treatment toxicity or with disease progression.  Depending on the nature and the severity 


Protocol:  GDC-0032—Genentech, Inc.
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of the GDC-0032 related toxicity, patients may resume dosing at the same dose or one 
dose level lower (as detailed in Table 9 and management guidelines in Section 3.4.5). 
Initiation and/or increase of anti-hyperglycemic therapy in response to hyperglycemia 
may be allowed without requiring a dose reduction of GDC-0032, in consultation with the 
investigator and with the approval of the Medical Monitor.


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Table 9
Dose Modifications for GDC-0032 in Stage 2, Cohorts AD and GX, and for Cycles 2 and Greater in 
Stage 1 and Stage 2, Cohorts E and F
GDC-0032
Cohorts
AD and G
(Capsules)
Cohorts
E and F
(Capsules)
Cohort H b
(Tablets)
Cohorts J
and Q c
(Tablets)
Cohorts K
and R d
(Tablets)
Cohorts L
and S e
(Tablets)
Cohorts M 
and N
(Tablets)
Cohorts P, T, 
T2, X
(Tablets)
Starting dose
9 mg QD
6 mg QD
6 mg QD
(21 days on/
7 days off)
4 mg QD
(21 days on/
7 days off)
4 mg QD 
(5 days on/ 2 
days off)
4 mg QD
(7 days on/
7 days off)
2 mg QD
4 mg QD
First reduction
6 mg QD
3 mg QD
4 mg QD
(21 days on/
7 days off)
2 mg QD
(21 days on/
7 days off)
2 mg QD (5 
days on/ 2 
days off)
2 mg QD
(7 days on/
7 days off)
2 mg QOD a
2 mg QD
Second reduction
3 mg QD
3 mg QOD a
2 mg QD
(21 days on/
7 days off)
2 mg QOD a
2 mg QD
(3 days on/
4 days off) a
2 mg QD
(Days 1, 3, 5, 
7, 15, 17, 19, 
and 21) a
2 mg QOD a
Third reduction
3 mg QOD a
─
2 mg QOD a
─
─
─
QDonce daily; QODevery other day.
a If the patient continues to experience specified drug related adverse events after dose reduction, the treatment should be discontinued.
b For Cohort H (21 day-on, 7-day off schedule), GDC-0032 will be administered on Days 121 of the 28-day cycle.  For the third dose reduction, 
dosing will be converted to 2 mg QOD of the entire 28-day cycle.
c For Cohorts J and Q (21-day on, 7-day off schedule), GDC-0032 will be administered on Days 121 of the 28-day cycle.  For the second dose 
reduction, dosing will be converted to 2 mg QOD of the entire 28-day cycle.
d For Cohorts K and R (5-day on, 2-day off schedule), GDC-0032 will be administered on Days 15, 812, 1519, 2226 of the 28-day cycle.  For 
the second dose reduction, dosing will be 3 days on/4 days off.
e For Cohorts L and S (7-day on, 7-day off schedule), GDC-0032 will be administered on Days 17 and Days 1521 of each 28-day cycle.  For the 
second dose reduction, dosing of GDC-0032 will be on the days specified.


Protocol:  GDC-0032—Genentech, Inc.
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Patients may temporarily suspend dosing with letrozole (Stage 2, Cohorts E, N, P, Q, R, 
and S) or fulvestrant (Stage 2, Cohorts F, J, K, L, and M) for up to 28 days if they 
experience endocrine therapy-related toxicity or an unanticipated medical event not 
associated with study treatment toxicity or with disease progression. Letrozole or 
fulvestrant doses do not necessarily need to be held for GDC-0032-related adverse 
events.  No dose reductions are allowed for letrozole (Stage 2, Cohorts E, N, P, Q, R, 
and S) or for fulvestrant (Stage 2, Cohorts F, J, K, L, and M).  For Stage 2, Cohorts E, F, 
J, K, L, M, N, P, Q, R, and S, GDC-0032 can be continued if letrozole or fulvestrant has 
been discontinued.
Patients may suspend dosing for greater than 28 days if the risk-benefit ratio suggests a 
reasonable rationale for the patient to continue in the study, with approval by the Medical 
Monitor.
It is not expected that patients in Stage 2, Cohorts A-G receiving capsules will need to 
switch to tablets.  However, in the unlikely event that a patient would need to do so, then 
the patient would switch to the equivalent expected exposure in tablets (0.67 times the 
amount in capsules).  For example, a patient being treated at the 9-mg capsule dose 
would switch to a 6-mg tablet dose.  A patient at the 6-mg capsule dose would switch to 
a 4-mg tablet dose.  A patient at the 3-mg capsule dose would switch to the 2-mg tablet 
dose.
c.
Dose Modifications for Phase II
Patients may temporarily suspend GDC-0032 dosing for up to 28 days if they experience 
a GDC-0032-related toxicity or an unanticipated medical event not associated with study 
treatment toxicity or with disease progression.  Patients may suspend dosing for greater 
than 28 days upon consultation with the Medical Monitor and may resume dosing after a 
positive risk-benefit assessment for continuing on study.  Depending on the nature and 
the severity of the GDC-0032-related toxicity, patients may resume dosing at the same 
dose or one dose level lower (as detailed in Table 10 and management guidelines in 
Section 3.4.5).  Initiation and/or increase of anti-hyperglycemic therapy in response to 
hyperglycemia may be allowed without requiring a dose reduction of GDC-0032. 
Table 10 Dose Modifications for Phase II
GDC-0032 Capsules
Starting dose
6 mg
First reduction
3 mg
Second reduction
3 mg QOD a
QODevery other day.
a If the patient continues to experience specified drug-related adverse 
events after dose reduction, the treatment should be discontinued.


Protocol:  GDC-0032—Genentech, Inc.
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Patients may temporarily suspend dosing with fulvestrant for up to 28 days if they 
experience endocrine therapy-related toxicity or an unanticipated medical event not 
associated with study treatment toxicity or with disease progression.  Fulvestrant doses 
do not need to be held for GDC-0032-related adverse events.  No dose reductions are 
allowed for fulvestrant.  GDC-0032 can be continued if fulvestrant has been discontinued 
after investigator assessment of risk/benefit.
Patients may suspend dosing for greater than 28 days if the risk-benefit ratio suggests a 
reasonable rationale for the patient to continue in the study, with approval by the Medical 
Monitor.
It is not expected that patients in Phase II currently taking capsules will need to switch to 
tablets.  However, in the unlikely event that a patient would need to do so, then the 
patient would switch to the equivalent expected exposure in tablets (0.67 times the 
amount in capsules).  A patient at the 6-mg capsule dose would switch to the 4-mg tablet 
dose.  A patient at the 3-mg capsule dose would switch to the 2-mg tablet dose.
4.4
CONCOMITANT AND EXCLUDED THERAPIES
4.4.1
Concomitant Therapy
Concomitant therapy includes any prescription medications or over-the-counter 
preparations, herbal remedies, and supplements used by a patient from 7 days before 
screening to the end of study.
Patients who experience toxicities should be treated symptomatically as clinically 
indicated.  Patients treated with anti-seizure medications should have levels monitored 
regularly.
Patients who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy as specified in the eligibility criteria (see Sections 4.1.2 and 4.1.3) 
should continue their use.  All concomitant medications should be recorded on the 
appropriate eCRF.
Anti-emetics and antidiarrheal medications should not be administered prophylactically 
before initial treatment with study drug.  At the discretion of the investigator, prophylactic 
anti-emetic and antidiarrheal medication(s) may be used as per standard clinical practice 
before subsequent doses of study drug.
Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study.
4.4.1.1
Infection Prophylaxis 
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial, or 
Pneumocystis infections is permitted and should be instituted per institutional practice.  
Infection prophylaxis for PJP is recommended for patients with NHL enrolled in Cohorts 


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T and T2 while on treatment and continuing for 2-6 months after discontinuing GDC-
0032.  The Medical Monitor should be notified if these infections are observed.  The 
potential for drug-drug interactions should be considered (e.g., azoles for fungal 
prophylaxis). 
4.4.2
Excluded Therapy and Foods
Use of the following foods and therapies is prohibited for 7 days prior to Day 1 dosing 
and during the study, unless otherwise specified here or in Section 4.1.3:

Proton-pump inhibitors (for patients in Stage 2, Cohorts A and C only)

H2-histamine receptor antagonists within 10 hours prior to and 2 hours after a 
GDC-0032 dose (for patients in Stage 2, Cohorts A and C only)

Antacids within 4 hours before a GDC-0032 dose (for patients in Stage 2, Cohorts A 
and C only)

Antacid restrictions may be modified for individual patients on the basis of real-time 
PK data and with agreement by the Medical Monitor.

Any concomitant therapy intended for the treatment of cancer, whether 
FDA-approved or experimental, including chemotherapy, radiotherapy, 
immunotherapy, biologic therapy, herbal therapy, or hormonal therapy (other than 
letrozole for Stage 2, Cohorts E, N, P, Q, R, and S, and leuprolide for prostate 
cancer).

GnRH agonists or antagonists for ovarian suppression

Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed.

Radiotherapy for unequivocal progressive disease will be as follows:  Patients who 
have demonstrated control of their systemic disease (defined as having received 
clinical benefit [i.e., a partial response (PR), complete response (CR), or stable 
disease (SD) for 3 months]) but who have developed brain metastases that are 
treatable with radiation will be allowed to continue to receive therapy with GDC-0032 
on study until they either experience systemic progression of their disease and/or 
further progression in the brain (based on investigator assessments).  Patients must 
not miss more than one cycle due to radiation treatment and must have an ECOG 
performance status of 0, 1, or 2 to continue study treatment.  After Cycle 1 (Stage 1; 
Stage 2, Cohorts E and F) or for all cycles for all other patients, certain forms of 
radiation therapy may be considered for pain palliation or isolated (e.g., single lesion) 
progressive disease if patients are deriving benefit, with agreement by the Medical 
Monitor; study treatment (e.g., GDC-0032, fulvestrant, letrozole) may be suspended 
during radiation therapy with agreement by the Medical Monitor.

Quinidine or other anti-arrhythmic agents

Initiation or increased dose of hematopoietic colony-stimulating factors 
(e.g., granulocyte colony-stimulating factors [G-CSF; filgrastim], 
granulocyte/macrophage colony-stimulating factor [GM-CSF; sargramostim], 
pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) from 7 days before 


Protocol:  GDC-0032—Genentech, Inc.
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Cycle 1 Day 1 until completion of the DLT Assessment Window in the absence of 
DLT (Stage 1 and dose-escalation portion of Cohorts E and F in Stage 2).

After the DLT Assessment window has been completed (or after DLT has been 
observed), colony-stimulating factors may be administered per standard 
clinical practice.
Patients who require the use of any of these agents will be discontinued from treatment 
with GDC-0032 and followed for safety outcomes for 30 days after their last dose of 
GDC-0032, or until they receive another anti-cancer therapy, whichever occurs first.
Based on in vitro data suggesting that GDC-0032 is metabolized by CYP3A4, the 
following drugs should be avoided.  If use of one of these drugs is necessary, the risks 
and benefits should be discussed with the medical monitor prior to its concomitant use 
with GDC-0032:

Strong/moderate CYP3A4 inhibitors:  atazanavir, ritonavir, indinavir, nelfinavir, 
saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, 
itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, 
fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or 
grapefruit supplements

Strong/moderate CYP3A4 inducers:  rifampin, carbamazepine, phenytoin, 
oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin 
(St. Johns Wort), and cyproterone
The investigator will contact the Medical Monitor if questions arise regarding medications 
not listed above for strong CYP3A4 inhibitors and inducers.
4.5
STUDY ASSESSMENTS
Patients will be closely monitored for safety and tolerability throughout the study.  
All assessments must be performed and documented for each patient.  
See Appendices A-1 to A-7 and B-1 to B-14 for the schedule of assessments for the 
Phase I portion of the study.  See Appendices A-8 and B-14 for the schedule of 
assessments for the Phase II portion of the study.  Patients continuing treatment 
beyond LPI 6 months will undergo a reduced set of assessments, as outlined in 
Appendix A-9.
4.5.1
Definitions of Study Assessments
As of Amendment 10, patients continuing on GDC-0032 beyond LPI 6 months will 
continue to undergo assessments described in Sections 4.5.1.b, 4.5.1.c, and local 
assessments described in Section 4.5.1.d. The requirement for assessments described in 
Sections 4.5.1.e through 4.5.1.v and the central assessments described in
Section 4.5.1.d will be removed.  All assessments, including those similar to those 
described in Section 4.5.1.d, may continue as per local standards of care.


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a.
Medical History and Demographic Data
Medical history includes clinically significant diseases within the last 5 years, surgeries, 
cancer history (including tumor characteristics), prior cancer therapies and procedures, 
and all medications used by the patient within 7 days before the screening visit 
(including prescription, over-the-counter, and herbal/homeopathic remedies and 
therapies).
Demographic data includes age, sex, and self-reported race/ethnicity.
b.
Vital Signs
Vital signs will include measurements of heart rate, respiratory rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and oral or tympanic
temperature.  Oxygen saturation will be assessed by pulse oximetry after patient has 
been in a seated position for 5 minutes.
c.
Physical Examination
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat (HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Changes from baseline abnormalities should 
be recorded at each subsequent physical examination.  New or worsened abnormalities 
should be recorded as adverse events if appropriate. 
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
d.
Laboratory Assessments
Local laboratory assessment will include the following:

Hematology:  CBC, including RBC count, hemoglobin, hematocrit, reticulocyte count, 
WBC count with differential (neutrophils, bands, eosinophils, basophils, lymphocytes, 
monocytes, and other cells), and platelet count

Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, 
potassium, magnesium, bicarbonate, calcium, phosphorus, total protein, albumin, 
serum bilirubin, alkaline phosphatase, glucose, AST, and ALT

Fasting glucose

Fasting insulin (at screening)

Glycosylated hemoglobin (HbA1C)

Fasting lipid profile:  total cholesterol, high-density lipoprotein (HDL), low-density 
lipoprotein (LDL), triglycerides, amylase, and lipase

Coagulation:  aPTT (or PTT) and INR

Serum fibrinogen

Urinalysis:  specific gravity, pH, glucose, protein, ketones, and blood


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
Serum or urine pregnancy test:  for women of childbearing potential, 
including premenopausal women who have had a tubal ligation
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  The following assessments will be performed at a central laboratory or at 
Genentech:

Flow cytometry for lymphocyte subsets (CD19, CD3, CD4, CD8, CD16, and CD56) 
by fluorescence-activated cell sorting (FACS)

Blood samples for PK analysis (see Section 4.5.1.h and Appendices B-1 to B-14)

Urine samples for PK analysis (Stage 1 only; see Section 4.5.1.h and Appendix B-1)

Blood samples for PD analysis (Stage 1 only; see Section 4.5.1.j and Appendix B-1)

Blood samples for analysis of circulating tumor cells (see Section 4.5.1.k)

Blood samples for DNA sequencing to identify PI3K- and cancer-related mutations 
in ctDNA (see Section 4.5.1.l)

Archival tumor tissue sample for evaluation of PIK3CA mutation status and other 
testing (see Section 4.5.1.m)

Fresh tumor tissue samples for markers (optional [and mandatory in Cohorts N, P, 
and X3 for select patients]; see Section 4.5.1.n)

Pharmacogenetic blood sample (see Section 4.5.1.o)

Blood sample for analysis of cytokines and chemokines (see Section 4.5.1.s)

For Phase II:  On days of study drug administration, predose blood samples for local 
laboratory assessments should be obtained within 96 hours.  All other laboratory 
samples should be drawn on the day of study drug administration according to the 
schedule of assessments.
e.
Tumor and Response Evaluation
All measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation (at the end of every even-numbered cycle).  Response 
assessments will be made by the investigator on the basis of physical examinations, 
imaging studies, laboratory results and bone marrow examinations (if appropriate).  For 
solid tumor cohorts, image-based evaluation using RECIST v1.1 (see Appendix C) will 
be performed.  For Cohort T, the 2007 Revised IWG Response Criteria for Malignant 
Lymphoma (see Appendix I) will be applied.  For Cohort T2, a modified version of the 
2014 Lugano Response Criteria for Malignant Lymphoma (see Appendix J) will be 
applied.  Bone scans and brain scans (CT or MRI) will also be performed if clinically 
indicated.  The same radiographic procedure used to define measurable lesions at 
baseline must be used throughout the study for each patient.  Imaging should include 
CT scans of the chest, abdomen, and pelvis.  CT scans of the neck should be included if 
clinically indicated.  At the investigator’s discretion, imaging scans may be repeated at 
any time if progressive disease is suspected.  In patients for whom a CT scan is 


Protocol:  GDC-0032—Genentech, Inc.
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contraindicated due to a CT IV contrast allergy, a CT of the chest without contrast and 
MRI of the abdomen and pelvis with contrast are recommended.
An assessment of PSA levels will be included for patients who have prostate cancer with 
non-measurable disease (see Appendix D).
An assessment of CA-125 levels will be included for patients who have ovarian cancer 
with non-measurable disease (see Appendix E).
An assessment of other tumor markers such as carcinoembryonic antigen (CEA), 
CA19-9, and -fetoprotein (AFP) will be included if the marker is elevated at baseline 
and has been followed in the patient.
Patients with Non-Hodgkin’s Lymphoma in Cohort T
Screening and follow-up tumor assessments must include CT scans of the chest,
abdomen, and pelvis (with oral/IV contrast unless contraindicated).  CT scans of the 
neck should be included if clinically indicated.  If a CT scan of the neck is obtained 
during screening, then it should continue to be performed throughout the study.  
CT scans of the brain are not required.  FDG-PET, or combined PET-CT, should be
performed at screening.  If the lymphoma is FDG-avid, FDG-PET, or combined PET-CT,
should continue to be performed throughout the study.  Response will be assessed by 
the investigator on the basis of PET and CT scans using the Cheson 2007 criteria 
(Appendix I).  Assessment of B symptoms, LDH, and peripheral blood counts should be 
performed at screening and with each tumor assessment.  Assessment of the bone 
marrow should include both an evaluation of the bone marrow (i.e., biopsy) for 
morphology and an aspirate and are required at screening and at the end of Cycle 4, or 
earlier as per the standard of care. If the bone marrow is involved at screening and still 
involved at Cycle 4, a subsequent bone marrow examination is required only to confirm
a CR.  At the investigator’s discretion, CT or PET scans may be repeated at any time if 
progressive disease is suspected.
Patients with DLBCL in Cohort T2
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Response will be assessed by the investigator on 
the basis of PET and CT scans, using a modified version of the Lugano 2014 criteria 
(Appendix J).  In this study, the Lugano 2014 criteria for a PET-CT-based CR have been 
slightly modified to require normal bone marrow for patients with bone marrow 
involvement at screening.  Additionally, designation of PET-CT-based PR requires that 
CT-based response criteria for a CR or PR be met in addition to the PET-CT-based 
response criteria for a PR (see Appendix J).  Sites will be asked to enter three 
assessments:  Lugano CT response, Lugano PET response, and modified Lugano 
response.  


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Additional Response Assessments for Phase II
A technetium bone scan will be performed at screening (up to 28 days prior to Day 1 
Cycle 1) to evaluate for the presence of bone metastases.  In addition, bone disease 
identified on bone imaging should be evaluated radiographically by X-ray, CT scan, or 
MRI.  Bone scans should be repeated in the event of clinical suspicion of progression of 
existing bone lesions, the development of new bone lesions, and in the assessment of a 
CR, if any disease was evident at screening.  For patients with bone-only disease not 
visible on the CT or MRI scans being performed as part of the tumor assessments, a 
bone scan should be repeated at the end of 12, 24, and 32 weeks and every 12 weeks 
thereafter (7 days for flexibility in the event of isotope shortage) and when clinically 
indicated.  The shorter 8-week interval between Weeks 24 and 32 has been included in 
order to align the bone scans with other tumor assessments for patient convenience.  
Any changes in bone imaging should be evaluated radiographically by X-ray, CT scan, 
or MRI to ascertain the presence of bone destruction versus a healing reaction.
In the event that it is not feasible to perform a bone scan or it is anticipated that it will not 
be feasible to perform bone scans throughout the study, F-18 sodium fluoride (18F NaF) 
PET scans may be substituted.  In this case, an 18F NaF PET scan must be performed at 
screening and, in patients with bone-only disease not visible on the CT or MRI scans 
being performed as part of the tumor assessments, must be repeated at every tumor 
assessment.
The same imaging modality (bone scan or 18NaF scan) should be used throughout the 
study.  See Appendix H for additional guidance in the event that bone scans are not 
available because of an isotope shortage.  If any shortages in access to technetium are 
expected, contact the Sponsor or the Imaging Core Facility immediately.
f.
QT/QTc and Cardiac Function Evaluations
To assess the impact of GDC-0032 on the QT/QTc interval as well as other 
ECG parameters, resting digital 12-lead ECGs will be recorded pretreatment 
(before dosing on Day 1 of Cycle 1) and as detailed in Appendices A-1 through A-8
(triple measurements at each timepoint) in Cycle 1.  In Phase I, resting triplicate digital 
ECGs will also be recorded for safety assessments on Day 1 of Cycles 26 and on 
Day 1 of every even-numbered cycles thereafter, as directed in Appendices A-1 
through A-7.  In Phase II, resting triplicate digital ECGs will also be recorded for safety 
assessments as directed in Appendix A-8.  Triplicate digital ECG recordings will be 
obtained within approximately 25 minutes of each other at each specified timepoint. 
The average of the 3 readings will be used to determine ECG intervals (e.g., PR, QT). 
ECGs for each patient should be obtained from the same machine whenever possible. 
To minimize variability, it is important that patients be in a resting position for 
≥10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 


Protocol:  GDC-0032—Genentech, Inc.
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resting period and during ECG recording. ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws.
The triplicate ECGs need to be completed within 30 min of the specified PK sample 
(i.e., PK sample needs to be time-matched to ECG).
If QTc prolongation (500 msec) is noted, the ECG should be repeated until normalized 
or stable, underlying causes such as electrolyte imbalances evaluated, an unscheduled 
PK sample should be obtained (if one was not scheduled at the time of prolongation), 
and the Medical Monitor should be notified.
g.
FDG-PET Imaging
FDG-PET imaging will be required starting with patients enrolled in Cohorts 2 in 
Stage 1 and for all patients enrolled in Stage 2 (Cohorts AG, L, M, N, Q, R, and S) but 
will be optional for patients in Cohorts 1 and 2 of Stage 1 (performed only if patients 
provide specific consent).  FDG-PET imaging will not be performed for the Phase II 
study.  If the baseline FDG-PET imaging for a patient shows no detectable tumor FDG 
uptake, additional FDG-PET imaging will not be required for that patient.  Similarly, if 
there are no significant changes in FDG-PET in Cycle 1, then the FDG-PET imaging in 
Cycle 2 should not be obtained.
Patients will have the baseline imaging pretreatment (within 14 days prior to dosing 
on Day 1 of Cycle 1) and will have repeat imaging during the last week of Cycle 1 
(e.g., between Days 2935 for a 35-day cycle), and at the end of Cycle 2 (between 
Days 2228). FDG-PET imaging should be performed approximately 14 hours after 
dosing with GDC-0032.  Timing and days of FDG-PET imaging may change on the basis 
of PK and PD data analyzed during the study.  FDG-PET imaging may be collected for 
review by a central facility and by Genentech.  
Instructions on preparing patients for FDG-PET are provided in the imaging manual.  
See Appendix G for additional details on assessments of FDG-PET.  See Appendix G 
for additional details on assessments of FDG-PET imaging.
h.
Pharmacokinetic Evaluations
See Appendices B-1 to B-14 for the schedule of PK sample collection.  Samples will be 
collected predose and at various timepoints postdose in Cycle 1.  Additional samples will 
be collected predose at the start of subsequent cycles (Cycles 2), as detailed in the 
Appendices B-1 to B-14.  The plasma isolated from each blood sample will be split into 
two aliquots:  a primary sample and a back-up sample.  Instructions for sample 
processing and shipping will be provided by a central laboratory. 
Urine samples will be collected predose and 06 hours and 624 hours after dosing on 
Day 1 in Stage 1 only (see Appendix B-1).  Instructions for sample processing and 
shipping will be provided by a central laboratory.


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i.
Food–Effect Assessment
This assessment will examine the effects of food on GDC-0032 exposure.  A preliminary 
assessment of the effect of food on GDC-0032 pharmacokinetics will be implemented in 
Stage 2, Cohort A.  Additional PK samples will be collected from patients following 
GDC-0032 dosing under fasted or fed conditions.  See Appendix B-2 for additional 
details on drug administration and PK sampling for the food effect assessment. 
Data from this assessment will be used to guide dosing requirements in subsequent 
clinical trials with GDC-0032.  Details about high-fat meals will be provided in the study 
reference manual.
j.
Surrogate Pharmacodynamics
Blood samples for biomarker evaluation will be collected before the first dose and at 
several timepoints postdose in Cycle 1 in Stage 1 only and will be processed to obtain 
platelet-rich plasma for determination of changes in surrogate PD markers (pAKT and 
possibly others).  Instructions for sample processing and shipping will be provided by a 
central laboratory.  See Appendix B-1 for the schedule of blood PD assessments in 
Stage 1 patients.
k.
Blood for Identifying Biomarkers in Circulating Tumor Cells
Blood samples for DNA sequencing to identify PI3K-specific mutations and other 
cancer-related mutations in CTCs will be collected from all patients (except Cohorts Q, R,
S, T, and X) pretreatment, during Cycles 1 and 3, at the study completion visit, and also 
at the clinic visit subsequent to a confirmed partial or complete tumor response (per 
RECIST) for any patient as directed in Appendices A-1 through A-8.  Instructions for 
sample processing and shipping will be provided by the central laboratory.  See 
Appendices A-1 to A-8 for the schedule of assessments.
l.
Blood for Identifying Cancer-Related Mutations in Circulating Tumor 
DNA from Plasma
Blood samples for DNA sequencing to identify PI3K-mutations and other cancer-related 
mutations (e.g., ESR1) in ctDNA will be collected from all patients as directed in 
Appendices A-1 through A-8.  Instructions for sample processing and shipping will be 
provided by the central laboratory.  See Appendices A-1 to A-8 for the schedule of 
assessments.
m. Evaluation of PIK3CA Mutation Status
All potential patients will be asked to provide archival tumor tissue (either paraffin blocks 
or 15 unstained slides) for mutation testing to occur.  For Cohort X (basket study), tissue 
must be deemed evaluable, as defined in the Laboratory Manual, by central confirmation 
prior to study enrollment.  For Cohort X, if 10 slides are available, the Medical Monitor 
must be consulted.  For Cohort X, if the patient already has a PIK3CA mutation status 
report from the Foundation One clinical sequencing assay from Foundation Medicine, 
the Medical Monitor may be consulted.  If archival tissue is not available, patients may 


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undergo a tumor biopsy for mutational testing to determine eligibility provided the biopsy 
can be obtained with minimal risk and discomfort to the patient and the patient consents 
to the procedure.  Detailed instructions will be provided in a separate manual. 
Screening assessments should be performed after confirmation of PIK3CA mutation 
status for relevant Stage 2 and some Phase II patients.  Patients with identified PIK3CA 
mutations will also need to fulfill all other eligibility criteria to enroll in the study.
There are three mutation hotspots in the PIK3CA gene:  E542K and E545K in exon 9 
and H1047R in exon 20; these mutations represent > 80% of all PIK3CA mutations
described.  The frequency of PIK3CA mutations in breast cancers has been estimated at 
30%-40%. A Taqman qPCR assay or another appropriate assay (e.g., next-generation 
sequencing [NGS]) will be used for mutation detection.  Roche Diagnostics has 
developed a qPCR assay kit using Taqman technologies to detect mutations in the 
three hotspots of the PIK3CA gene and one rare mutation, E545D, also found in exon 9.  
Assays from all samples will be run on the Roche Diagnostics cobas 4800 instruments 
and mutation calls made using the manufacturer’s specified protocols.  Following 
histopathologic review, samples with 20% tumor content will be enriched for tumor 
content by macro- or micro-dissection.  PIK3CA testing may be performed at outside 
facilities to allow the patient to be enrolled, provided that the results are submitted to the 
sponsor for review before the patient is enrolled; archival tumor tissue will need to be 
provided for confirmation by central testing.
Additional studies of PI3-kinaserelated proteins and PTEN protein expression by IHC 
may be performed on tissue samples.  Additional studies on expression of other 
PI3K-related proteins may be performed.  Other exploratory studies of gene expression, 
DNA mutations, protein, or DNA markers of PI3K pathway activation may also be 
conducted on these samples by Genentech or the central laboratory.  Tissue blocks from 
archival biopsies will be returned to the archival facility from which they were originally 
received.
n.
Fresh Tumor Tissue and Other Sample Collection
Optional paired (pre-treatment and post-treatment) tumor biopsy samples for biomarker 
assessments will be obtained from patients in Phase I (Stages 1 and 2) and Phase II 
who specifically consent to this procedure.  In addition, paired tumor biopsy samples are 
mandatory for six patient slots (3 patients with PIK3CA-wild-type and 3 patients with 
PIK3CA-mutant tumors) in each of Cohorts N and P, and five patient slots in Cohort X3.  
Patients selected for biopsy should have safe and accessible tumor tissue biopsy sites.  
Tumor tissue biopsy samples will be obtained prior to starting GDC-0032 treatment.  The 
pretreatment tissue biopsy will be reviewed by a pathologist to determine whether the 
tissue is evaluable.  If the pretreatment tissue is evaluable, a subsequent biopsy will be 
performed on the day specified below, approximately 14 hours after the morning dose.  
If there is only one lesion for both the biopsy and imaging scans, then the biopsy should 
be performed either immediately after or 1 week prior to FDG-PET or other imaging 


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scans.  If two different lesions are being biopsied and scanned, then the second lesion 
may be biopsied anytime between Days 15 and 21.  The timing of the biopsy after 
dosing may be adjusted on the basis of PK data obtained during the trial.  Tumor 
biopsies upon progression of disease are also optional.
For the following cohorts with a 5-day on 2-day off GDC-0032 dosing schedule, the 
optional on-treatment biopsy sample should be obtained between Days 15 and 19 of 
Cycle 1:

Cohorts K and R
For the following cohorts, the optional or mandatory on-treatment biopsy sample should 
be obtained between Days 15 and 21 of Cycle 1:

Cohort H

Cohorts J, L, M (fulvestrant combination cohorts)

Cohorts N, P, Q, S (letrozole combination cohorts)

Cohorts T, T2 (lymphoma)

Cohort X (Basket)
For Phase II, the optional on-treatment biopsy sample should be obtained between 
Days 1 and 15 of Cycle 2.
For a patient enrolled in a mandatory paired tumor biopsy slot in Cohort N, P, or X3, if 
either the pre- or on-treatment biopsy tissue quality is deemed unevaluable by the 
Central Laboratory, the patient may remain enrolled in the study, but an additional 
patient may be enrolled to complete the cohort.
In addition, if a patient undergoes a medically indicated procedure any time during the 
course of the study that has the likelihood of yielding tissue, fluids, or ascites, any 
remaining samples or a portion of the sample not necessary for medical diagnosis may 
be obtained for exploratory analysis.  Patients must have provided specific consent to 
obtain optional discarded samples from routine care.
o.
Pharmacogenetic Blood Sample
A blood sample will be collected from all eligible patients before initiation of GDC-0032 
treatment on Day 1 for potential pharmacogenetic analysis of genes that may affect the 
pharmacokinetics of GDC-0032 (e.g., drug-metabolizing enzymes and membrane 
transporters) and genetic variants that could contribute to a potential drug-related 
adverse event (including but not limited to HLA).  Preliminary results from in vitro 
metabolism studies suggest that GDC-0032 may be a substrate for multiple enzymes 
and transporters.  Genotyping patients for variants in these genes may provide important 
information about their roles in the metabolism and disposition of GDC-0032.  
Instructions for sample processing and shipping will be provided.  The decision to 
analyze the samples will be based on a review of the PK and safety data.


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p.
Effect of GDC-0032 on the Pharmacokinetics of Midazolam 
(a CYP3A4 Substrate)
This assessment will examine the effects of GDC-0032 on midazolam exposure in 
Stage 2, Cohort C patients by comparing midazolam plasma exposures (Cmax and/or 
AUC24hr) without GDC-0032 (Day 1) and after 15 daily doses of GDC-0032 (Day 16).  
See Appendix B-4 for additional details on drug administration and PK sampling. 
Data from this assessment will be used to guide combination therapies and concomitant 
medications in subsequent clinical trials with GDC-0032.
q.
Assessment of the Pharmacokinetics of GDC-0032 in Combination with 
Letrozole or Fulvestrant
The pharmacokinetics of GDC-0032 and letrozole or fulvestrant following concomitant 
administration will be assessed in Stage 2, Cohorts E, N, P, Q, R, and S (letrozole) 
and F, J, K, L, and M (fulvestrant).  The pharmacokinetics of GDC-0032 and fulvestrant 
will also be assessed in the Phase II portion.  Data will be compared to the GDC-0032 
PK data collected in this study and historical letrozole or fulvestrant PK data, including 
plasma exposures, as measured by Cmax and/or AUC24hr, on Day 15 of Cycle 1.  See 
Appendices B-5, B-6, B-8, B-9, B-12, and B-14 and Figure 5 for additional details on 
drug administration and PK sampling.
Data from this assessment will be used to guide the design of future GDC-0032 studies 
in combination with letrozole and/or fulvestrant. 
r.
Evaluation of PIK3CA Copy Number Status
Screening assessments should be performed after confirmation of increased PIK3CA
copy number for Stage 2, Cohort G patients.  Patients with identified amplification of the 
PIK3CA gene will also need to fulfill all other eligibility criteria to enroll in the study.  
PIK3CA amplification testing may be performed at outside facilities provided that the 
results are submitted to the Sponsor for review before patient enrollment; tumor tissue 
will need to be provided for confirmation by central testing.  Refer to Section 4.8.h for
acceptable methodologies.
s.
Blood for Analyzing Cytokines and Chemokines from Plasma
Blood samples to assess cytokine and chemokine expression in the plasma will be 
assessed in Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (as detailed in 
Appendix A-7).  Blood samples will also be collected from patients in the Phase II portion 
(as detailed in Appendix A-8).  Instructions for sample processing and shipping will be 
provided by the central laboratory. 
t.
Samples for Optional Exploratory Research
All specimens left over from testing, including body fluids, solid tissues, and derivatives 
thereof (e.g., DNA, RNA, proteins, peptides), may be used for exploratory research.  The 
analysis of residual specimens will facilitate the rational design of new pharmaceutical 


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agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Any leftover samples may be used for exploratory research, provided the patient has 
specifically consented to this optional research testing.  The residual specimens will be 
used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
u. Progression Biopsy Collection
Tumor tissue sample may be collected at the time of progression for exploratory 
research on non-inherited biomarkers and for DNA and/or RNA extraction to enable 
NGS for exploratory research (including, but not limited to, cancer-related genes and 
biomarkers associated with common molecular pathways).  Any leftover material will be 
kept for future research purposes. 
NGS may be performed by a clinical cancer genomic profiling laboratory 
(e.g., Foundation Medicine). If performed by Foundation Medicine, the investigator can 
obtain results from the samples collected at the time of disease progression in the form 
of an NGS report, which is available upon request directly from Foundation 
Medicine. The investigator may share and discuss the results with the patient, unless 
the patient chooses otherwise. The Foundation Medicine NGS assay has not been 
cleared or approved by health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.  
v.
Cohort T2 DLBCL Tumor Tissue Collection
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis: archival or fresh tumor tissue samples and 
the corresponding pathology report for retrospective central confirmation of the diagnosis 
of DLBCL, and for exploratory research on candidate biomarkers.
Lymph node resections or biopsies are strongly recommended.  The specimen must 
contain adequate evaluable tumor cells (≥ 20% for excisional biopsy and ≥ 50% for core 
biopsy).  Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  If a 
tissue block is not available, 15−20 serial, freshly cut, unstained slides accompanied by 
a punch biopsy may be sent.  If fewer than 15−20 unstained serial slides are available, 
the study site should consult the Sponsor (or delegate) regarding the acceptability of a 
fewer number of slides.


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If archival tissue is unavailable, a pretreatment core-needle, excisional, or incisional 
tumor biopsy is required.  Cytological or fine-needle aspiration samples are not 
acceptable.
If the available biopsy was performed more than 12 months prior to Day 1 of Cycle 1, or 
the patient received anti-lymphoma treatment between the time of the most recent 
available biopsy and Day 1 of Cycle 1, a core-needle biopsy is strongly recommended.
The sample should be shipped according to instructions provided in the laboratory 
manual.  The remainder of the tissue blocks will be returned to the local pathology 
laboratory, according to country-specific procedures.
Proposed non-inherited biomarkers to be assessed from tumor tissue may include 
lymphoma-related genetic changes (DNA) and gene expression (mRNA) and protein 
expression, [PDL-1, HLA-1, CD8, and other biomarkers of T-cell subpopulations, 
biomarkers of other immune cells (such as macrophages), cytokines, drug transporters, 
and genes related to regulation of apoptosis].
4.5.2
Screening and Pretreatment Assessments
Screening tests and evaluations will be performed within the 28 days preceding Cycle 1, 
Day 1 (defined as the day of the first dose of GDC-0032), unless otherwise specified.  
Results of screening evaluations must be reviewed to confirm that patients meet all 
eligibility criteria before the first dose of GDC-0032.  Written informed consent may be 
obtained up to 28 days before Cycle 1, Day 1 and before performing any study-specific 
screening tests or evaluations.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent but within the time required for screening 
may be used for the study rather than repeating these tests.  Informed Consent Forms 
(ICFs) for patients who are not subsequently enrolled will be maintained at the study site.
Pretreatment assessments should be performed only after patient eligibility has been 
established and informed consents have been signed, and any time prior to the first 
dose of GDC-0032 at Cycle 1, Day 1 (unless otherwise specified in Section 4.5.1).
See the Study Flowchart provided in Appendices A-1 to A-5, A-7, and A-8 for the 
schedule of screening and pretreatment assessments.
4.5.3
Assessments during Treatment
All visits must occur within the time windows specified.  If a visit is scheduled for 
a holiday, then dosing may be postponed to the soonest following date with subsequent 
dosing continuing on a 28-day dosing schedule.  Assessments scheduled on the day of 
study drug administration (Day 1) of each cycle should be performed prior to study drug 
dosing, unless otherwise noted.


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Please see the Study Flowchart provided in Appendices A-1 to A-8 and B-1 to B-14 for 
the schedule of treatment period assessments.  Following the initiation of treatment, 
patients should be assessed for tumor lysis per local guidelines.  Patients continuing 
treatment beyond LPI 6 months will undergo a reduced set of assessments, as outlined 
in Appendix A-9.
4.5.4
Study Completion/Early Termination Visit
Patients who complete the study (defined as completing 5 years of treatment) or
discontinue from the study early will be asked to return to the clinic within 30 days 
(2 weeks) after the last dose of GDC-0032 for a visit.  The visit at which the response 
assessment shows progressive disease may be used as the early termination visit.  If a 
patient discontinues from the study for reasons other than progressive disease 
(e.g., symptomatic deterioration) and without having a tumor assessment, the patient 
should have a tumor response assessment at the early termination visit.  Patients with 
unresolved adverse events thought to be related to GDC-0032 must be followed as 
clinically indicated, until the event is resolved or stabilized, another anti-cancer therapy is 
initiated, the patient is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the adverse event.
The end of the study is defined as the date on which the last patient has their last
visit (LPLV).
Please see the Study Flowchart provided in Appendices A-6 to A-9 for assessments to 
be performed at the study completion/early termination visit.
4.5.5
Follow-Up Assessments
Patients with unresolved adverse events thought to be related to GDC-0032 must be 
followed as clinically indicated, until the event is resolved or stabilized, another 
anti-cancer therapy is initiated, the patient is lost to follow up, or it has been determined 
that the study treatment or participation is not the cause of the adverse event. 
For patients enrolled in Phase I, Stage 2, Cohorts HX and the Phase II portion of the 
study, survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
withdrawal of consent, or study termination by Genentech.  All patients will be followed 
for survival information unless the patient requests to be withdrawn from study survival 
follow-up.  The request must be documented in the source file and signed by the 
investigator.  If the patient withdraws from the study treatment but not from study 
follow-up, the study staff may use a public information source (such as county records) 
to obtain information about survival status only.
4.6
PATIENT DISCONTINUATION
Patients may withdraw or be withdrawn from the study at any time.  Any patient who 
discontinues treatment should be encouraged to return to the study site for a treatment 


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completion/early termination evaluation (see Section 4.5.4).  The primary reason for 
discontinuation must be recorded on the appropriate eCRF.
Patients must be withdrawn from study treatment if they experience any of the following:

Disease progression (defined using RECIST v 1.1; see Appendix C)

In Cohort T: Disease progression (defined using the 2007 IWG Revised Response 
Criteria for Malignant Lymphoma; see Appendix I)

In Cohort T2:  Disease progression (defined using the 2014 Lugano Response 
Criteria for Malignant Lymphoma; see Appendix J)

Use of another anti-cancer therapy (see Section 4.4)
Other reasons for patient discontinuation may include, but are not limited to, the 
following:

In general, patients experiencing a DLT (see Section 3.1.3.a for DLT definition) 
during the DLT assessment window should discontinue from the study.  However, 
under certain circumstances where the adverse event is reversible, monitorable, 
and the risk/benefit suggests a reasonable rationale to continue on the study, 
patients may continue with consultation with the medical monitor.

Excessive pill burden, defined as 2 or more patients in a cohort who are unable to 
take 90% of their doses at a dose level that requires a minimum of seven capsules 
or tablets to be taken per dose 

Change in patient eligibility

Non-compliance with protocol-specified study visits and procedures

Investigator decision based on the patient’s best interest

Patient decision
The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study and for reasons of noncompliance (e.g., missed doses, visits) or 
pregnancy or if the investigator determines it is in the best interest of the patient.
See Section 4.5.4 and Appendix A-6, A-7, and A-8 for assessments that are to be 
performed for patients who prematurely withdraw from the study during the treatment 
period.
Treatment Post-Progression
Under special circumstances, when it is believed that the patient may clinically benefit 
from continued therapy with GDC-0032, dosing beyond progression may be considered 
if it is judged by the investigator, in consultation with the Sponsor, to be in the best 
interest of the patient.  Only patients who have experienced some clinical benefit as 
assessed by the investigator will be eligible for continued treatment.  Considered 
patients must remain “on study” and cannot have initiated any other anti-cancer therapy.  


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All such cases will require approval of the Sponsor before continuing study drug 
treatment within this protocol.
STUDY DISCONTINUATION
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.

Data recording is inaccurate or incomplete.
Genentech will notify the investigator if Genentech decides to discontinue the study.
Genentech has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the ICH guideline for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
4.7
POST-TRIAL ACCESS
Genentech does not intend to provide GDC-0032 or other study interventions to patients 
after the conclusion of the study or any earlier withdrawal.  Genentech will evaluate 
whether to continue providing GDC-0032 in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following Web 
site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.8
ASSAY METHODS
a.
Mutational Analysis for PIK3CA
Mutations in the PIK3CA gene have been estimated at a prevalence of 30%40% in 
breast cancers.  A Taqman quantitative PCR (qPCR) assay or another appropriate 
assay, such as NGS, will be used for mutation detection.  Roche Diagnostics has 
developed a qPCR assay kit to detect mutations in common hotspots of the 
PIK3CA gene.  Samples may be run on the Roche Diagnostics cobas 4800 instruments 
and mutation calls using appropriate cutoffs and automated software.  Following 
histopathologic review, samples with 20% tumor content will be enriched for tumor 
content by macro- or micro-dissection.  Somatic mutations in the PIK3CA gene are 
found in approximately 30% of breast cancers and occur most commonly in exons 9 


Protocol:  GDC-0032—Genentech, Inc.
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and 20 in the codons encoding amino acids E542, E545, and H1047.  Real time PCR 
assays that amplify exons 9 and 20 of PIK3CA offer a sensitive and quantitative method 
to detect mutations from archival tumor material.  DNA will be extracted from tumor 
samples and subjected to quantitative real-time PCR (qRT-PCR) assays that detect the 
wild-type allele, as well as assays for nucleotide substitutions that include but are not 
limited to the following amino acid changes: E542 (K), E545 (A, G, or K), and 
H1047 (L, R, Y).  Assays from samples will be run on ABI7900 Real Time PCR 
instruments and mutation calls made using appropriate cutoffs and automated software.
b.
PTEN Testing
PTEN status will be examined by immunohistochemistry using a protocol that has been 
validated for specificity using several available cell line controls.  Archival tumor material 
will be scored only if appropriate staining is observed in internal control stromal or 
normal (non-tumor) tissue elements.  PTEN status may also be examined by qRT-PCR 
assay for mRNA levels, by use of NGS platform or chromosomal loss by use of in situ 
hybridization techniques (e.g., FISH or chromogenic in situ hybridization [CISH]).
c.
Circulating Tumor Cell and Circulating Tumor DNA Analyses
CTC analysis will be performed on whole blood using the Cellsearch, Biocept, Cellective 
and/or other CTC enumeration and molecular profiling platforms.  In addition, 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.
d.
mRNA and miRNA Expression Profiling
In cases where there is sufficient archival tissue to isolate RNA, gene expression of a 
panel of genes and microRNAs including, but not limited to, cancer biology and/or PI3K 
signaling, will be performed using qRT-PCR assays conducted on the Fluidigm Biomark 
or equivalent platform, such as NanoString, or by use of NGS platforms (RNAseq).  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.
e.
Plasma and Urine PK Samples
Plasma PK samples for GDC-0032 will be analyzed using a validated LC/MS/MS 
method and the urine PK samples will be analyzed using a separate non-validated 
LC/MS/MS method at a Genentech-designated laboratory.  After the plasma and urine 
samples are analyzed, any remaining samples may be used for optional exploratory 
research.
f.
Blood PD Assays
Blood samples for PD measurement will be separated to yield the platelet-rich plasma 
(PRP) and the platelet-poor plasma (PPP).  Pathway biomarkers, such as pAKT S473, 
will be measured in PRP by modified MSD (Meso Scale Discovery, Gaithersburg, 


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Maryland) based-assays.  Circulating angiogenesis factors will be measured by 
immunoassays in PPP.
g.
PD Biomarker Assays in Tumor Tissues
PI3-kinase pathway biomarkers will be tested in the fresh tumor biopsy samples by IHC 
and, if tissue quantity permits, change in expression or phosphorylation status 
of additional pathway biomarkers will be measured by the reverse phase protein array 
(RPPA), or other technologies.  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 ~100 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. 
h.
Copy Number Analysis of PIK3CA Gene
The level of amplification of the PIK3CA gene should be determined using DNA based 
technologies, either cytogenetically using chromosomal ISH with labeled probes 
spanning the PIK3CA locus or using NGS platforms.  For cytogenetic assays, detection 
may be either fluorescence-based (FISH assay) or CISH-based detection. 
Chromosomal ploidy changes that involve the entire chromosome may be assessed by 
ISH for a chromosome 3 centromeric probe (CEP3). Refer to the laboratory manual 
for definition of PIK3CA amplification.
i.
Chemokine and Cytokine Analyses
Assays to assess the expression of soluble, systemic cytokines and chemokines from 
the plasma of patients will be carried out using an ELISA-based or similar methodology.
j.
KRAS Mutation Testing
KRAS-mutation testing applies only to patients enrolled in the KRAS wild-type colorectal 
cancer Basket-Cohort X8.  KRAS mutations may be tested at a Genentech-designated 
Central Reference Laboratory or per institutional guidelines.  If a 
nonGenentech-designated laboratory is used for KRAS-mutation testing, 
documentation of the test procedures and results must be included as source 
documentation.  KRAS-mutation testing may be performed with the Qiagen Therascreen 
KRAS RGQ PCR-based assay or other appropriate technologies.  Only patients whose 
tumors test negative for a KRAS mutation (i.e., KRAS wild-type) will be eligible for 
enrollment in this study cohort, if other eligibility criteria are met.  Tumor samples may be 
obtained from the primary cancer or any metastatic site.
k. Next-Generation Sequencing
NGS provides a powerful approach to determine the alterations of somatic mutations in 
key cancer genes with broad mutation coverage. Panels have been developed to 


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characterize the most frequently mutated oncogenes and tumor suppressors in various 
cancer types.
4.9
STATISTICAL METHODS
The final analysis will be based on patient data collected through patient discontinuation 
or study discontinuation, whichever occurs first.  All analyses will be based on the 
safety-evaluable population, defined as all patients who receive at least one dose of
GDC-0032, letrozole, or fulvestrant.  All summaries will be presented according to the 
assigned dose level and cohort.
4.9.1
Analysis of the Conduct of the Study
Enrollment, major protocol violations, and reasons for discontinuations from the study 
will be summarized by dose level and cohort.
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, type 
of malignancy, duration of malignancy, site of metastatic disease, and baseline ECOG 
performance status, will be summarized using means, standard deviations, medians, 
and ranges for continuous variables, and proportions for categorical variables.  
All summaries will be presented overall and by assigned dose level.
4.9.2
Safety Analyses
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, and changes in vital signs.  All patients who receive any amount of 
GDC-0032 will be included in the safety analyses.  
GDC-0032 exposure, including the proportion of patients with dose modifications, will be 
summarized by assigned dose level and cohort.
All collected adverse event data will be listed by study site, patient number, and cycle.  
All adverse events occurring on or after treatment on Day 1 will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 toxicity grade.  
In addition, all serious adverse events, including deaths will be listed separately and 
summarized.  
QT/QTc data will be analyzed using the E14 guidelines and may include analyses of 
central tendency, categorical analyses, analysis of the relationship between drug 
exposure and QT/QTc interval changes, and morphologic analyses of ECG waveforms.
4.9.3
Pharmacokinetic Analyses
Individual plasma GDC-0032 concentration vs. time data and summary statistics will be 
tabulated by dose level and schedule.  Individual and mean (SD) plasma concentration 
versus time profiles will be plotted.


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The plasma GDC-0032 pharmacokinetic data obtained after a single dose (Day 1) and at 
steady state (Day 15) will be analyzed using noncompartmental methods to estimate 
PK parameters, which include but are not limited to AUC0-and/or AUC0-inf, Cmax, Cmin, 
tmax, t1/2, CL/F, accumulation (AR), renal excretion fraction (fe), urinary CL (CLr).  
Additional PK parameters may be determined as data allow.  Estimates for these 
parameters and summary statistics (mean, standard deviation, coefficient of variation, 
median, minimum, and maximum) will be tabulated by dose level and schedule. 
For Phase II, GDC-0032 and fulvestrant plasma concentrations will be tabulated from 
individual patients and presented with appropriate summary statistics (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum).
4.9.4
Food-Effect Analyses
For patients participating in the food–effect assessment in Stage 2, Cohort A, the effects 
of food versus fasting states on Cmax, tmax, and AUC0-24 of GDC-0032 will be examined 
based on intra-subject comparison.  Estimates of these parameters and summary 
statistics will be tabulated.  The food effect on the pharmacokinetics of GDC-0032 will be 
estimated as the ratio of geometric mean values of Cmax and AUC0-24, and the 
corresponding 90% confidence intervals (CIs) will be constructed.
4.9.5
Analyses of Effect of GDC-0032 on the Pharmacokinetics of 
Midazolam
For patients participating in Stage 2, Cohort C, the effects of GDC-0032 on Cmax, tmax, 
and AUC0-24 of midazolam will be examined based on intra-subject comparison.  
Estimates of these parameters and summary statistics will be tabulated.  The effect of 
GDC-0032 on the pharmacokinetics of midazolam will be estimated as the ratio of 
geometric mean values of Cmax and AUC0-24 and the corresponding 90% CIs will be 
constructed.
4.9.6
Analyses of the Pharmacokinetics of GDC-0032 in Combination 
with Letrozole
For patients participating in Stage 2, Cohorts E, N, P, Q, R, and S the pharmacokinetics 
of GDC-0032 and letrozole, as measured by Cmax, tmax, and AUC0-24, will be estimated 
and the summary statistics will be tabulated.
4.9.7
Analyses of the Pharmacokinetics of GDC-0032 in Combination 
with Fulvestrant
For patients participating in Stage 2, Cohorts F, J, K, L, and M, and Phase II, the 
pharmacokinetics of GDC-0032 and fulvestrant, as measured by Cmax, tmax, and AUC0-24, 
will be estimated and the summary statistics will be tabulated.


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4.9.8
Activity Analyses
a.
Tumor Assessment Data
Objective overall response will be summarized for safety-evaluable patients with 
baseline measurable disease by dose level and schedule.  Duration of response and 
PFS will be summarized for all safety evaluable patients by dose level and schedule.
Objective overall response in patients with measurable disease is defined as a complete 
or partial response, as determined by investigator assessment using RECIST v1.1
(see Appendix C) and confirmed by one consecutive assessment 4 weeks after initial 
documentation.  Response for lymphoma patients (Cohort T) will be assessed using the 
2007 IWG Revised Response Criteria for Malignant Lymphoma (Appendix I).  Response 
for DLBCL patients (Cohort T2) will be assessed using a modified version of the 2014 
Lugano Response Criteria for Malignant Lymphoma (Appendix J).  Patients with 
measurable disease at baseline who do not meet this criterion will be considered 
non-responders.
In patients with disease that is evaluable but not measurable by RECIST v1.1, response 
will be assessed either quantitatively, in the case of patients with elevated tumor 
markers (PSA or CA-125; see Appendices D and E), or descriptively (e.g., resolution of 
bone scan findings, decrease in tumor-related pain symptoms).  Any patient with 
insufficient data to determine response will be classified as a non-responder.  
Among patients with an objective overall response, duration of response will be defined 
as the time from the initial complete or partial response to the time of disease 
progression or death, whichever occurs first.  If a patient has not experienced disease 
progression or death, duration of response will be censored at the day of the last tumor 
assessment showing no disease progression.  
PFS will be defined as the time from the first day of GDC-0032, fulvestrant, or letrozole
treatment until documented disease progression, or death on study (defined as death 
within 30 days of last study drug administration), whichever occurs first.  For patients 
who do not have documented progressive disease or death on study, PFS will be 
censored at the day of the last tumor assessment showing no disease progression.  If a 
patient has no post-baseline tumor assessment, PFS will be censored at the day of the 
first dose of study drug administration.  PFS will be summarized using the Kaplan-Meier 
method.
The 6-month clinical benefit will be defined as a confirmed complete response, 
confirmed partial response, or without disease progression for 6 months per 
RECIST v1.1.
Among patients with clinical benefit, duration of clinical benefit will be defined as the time 
from the first day of GDC-0032 treatment until documented disease progression, or 
death on study, whichever occurs first.  If a patient has not experienced disease 


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progression or death, duration of clinical response will be censored at the day of the last 
tumor assessment showing no disease progression.  
Analysis methods for the expansion cohorts will include a summary of adverse events, 
an estimation of objective overall response rate (ORR) and its corresponding 95% 
Pearson-Clopper exact confidence interval.
4.9.9
Exploratory Analyses
a.
Pharmacodynamic Analyses
PD analyses will include imaging studies and assessments of PD biomarkers in both 
tumor tissue and blood.
The effect of GDC-0032 on FDG-PET will be assessed on the basis of the maximum 
standardized uptake value (SUVmax) of up to five tumor regions of interest (ROIs).  
The tumor ROIs will be identified for each patient from pretreatment imaging.  
Determination of PET response will be based on the modified definitions of the 
European Organisation for Research on the Treatment of Cancer (EORTC; 
Young et al. 1999).  The percent change in the SUVmax will be quantified.  In the event of 
more than one ROI, the overall percent change in SUVmax will be based on the arithmetic 
mean (mSUVmax).  The selected ROIs should overlap with RECIST target or non-target 
lesions identified at baseline and have FDG uptake.  FDG-PET response rates will be 
calculated and, where sample sizes warrant, exact 95% confidence intervals for the 
above response rates will be presented using the Pearson-Clopper method.  FDG-PET 
imaging will be independently read and analyzed by a central reviewer and by 
Genentech for SUV changes.  Other parameters, such as SUVmean, may also be 
analyzed.  Given the exploratory nature of these analyses, results of FDG-PET imaging 
will not be used to determine disease status during treatment with GDC-0032.
The PD effect of GDC-0032 in blood cells will be assessed through changes from 
baseline in pAKT levels and other pathway biomarker levels in platelet-rich plasma in 
Stage 1.  The relationship of GDC-0032 exposure with magnitude of effect on pAKT and 
other biomarker levels may be described.
Tumor biopsy samples will be tested for the expression of multiple phospho-proteins in 
cell signaling pathways, including the PI3K pathway.  Inhibition of the PI3K pathway is 
defined as 60% inhibition of two or more phospho-proteins in the same pathway 
compared to baseline in a particular patient.  The percentage of patients with significant 
PI3K pathway inhibition will be assessed.  The degree of inhibition of various pathway 
markers in each patient and their relationship to PK, safety, and tumor response will be 
explored.
Changes in PD biomarkers will be listed by dose, cohort, and response status.  
Additional PK and PD analyses will be conducted as appropriate.


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b.
Expression and Mutational Analyses on Cancer-Related Proteins 
and Genes
Association of PD and anti-tumor activity and PI3K mutation status, PI3K amplification, 
degree of loss of PTEN expression, and/or other cancer-related mutations in archival
tissue and fresh tumor tissue (for patients who elect to provide biopsy samples) may be 
analyzed.  Mutations in ctDNA and CTCs may also be assessed.
c.
Pharmacogenomic Analysis
In the event that PK analyses become difficult to interpret, gene mutations may 
be assayed using multiplex PCR, allele-specific PCR, direct sequencing, or other 
appropriate method.  PK parameters, including dose-normalized AUC and Cmax, would 
be compared between genotypes and, where possible, predicted phenotypes.
4.9.10
Determination of Sample Size
A total of approximately 623723 patients are expected to be enrolled in this study.  
In the single-agent dose-escalation portion of this study (Stage 1 of Phase I), 34 patients 
have been enrolled.  Approximately 529629 patients are expected to be enrolled in 
Stage 2 of Phase I, including with Amendment 8, 6 additional patients each in Cohorts N 
and P; 20 patients each in Cohorts Q, R, and S; 10 lymphoma patients in Cohort T; 
1020 DLBCL patients in Cohort T2; 1020 patients in each sub-cohort of the basket 
Cohort X (X1-X10); 2040 patients in sub-Cohort X3; and 50 patients in sub-Cohort X11 
with PIK3CA-mutant tumor types not covered in X1-X10.  Phase II has fully enrolled with 
a total of 60 patients.
a.
Stage 1:  Dose Escalation
The sample size for Stage 1 is based on the dose-escalation rules described in the study 
design section of this protocol (see Section 3.1.3).  The sample size for this trial is not 
based on explicit power or type I error considerations.
Table 11 describes the probabilities of dose escalation with different underlying rates of 
DLT and the performance of 3 3 dose-escalation schemas when certain assumptions 
hold for the study drug.  As GDC-0032 has not been studied in humans before, it is not 
known whether these assumptions hold for this study.


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Table 11 Probability for the Dose-Escalation Rules with Different 
Underlying Rates of Dose-Limiting Toxicity
Underlying Rate of 
Dose-Limiting Toxicity
Probability That Dose 
Escalation Proceeds
0.10
0.91
0.20
0.71
0.33
0.43
0.40
0.31
0.50
0.17
0.60
0.08
The following assumptions were made to generate Table 11:

The observed number of patients experiencing a DLT follows a binomial distribution.

Given a true rate of DLT, the probability of observing a DLT is the same for 
each patient.

The probability that dose escalation proceeds is the probability of observing either of 
the following in the current dose cohort:  (a) none of the first 3 patients in the cohort 
experiences a DLT, or (b) 1 of the first 3 patients in the cohort experiences a DLT, 
the cohort is expanded to include another 3 patients, and none of the additional 
patients experiences a DLT.
The final sample size for Stage 1 of this trial will be determined by the dose-escalation 
rules described in Section 3.1.3.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such adverse event in a given cohort of 6 patients is 46.9%, 
26.5%, and 5.8%, respectively.
b.
Stage 2:  Expansion Cohorts 
To better characterize the safety of single-agent GDC-0032 administered at the 
recommended dose for future studies, approximately 82 patients will be enrolled and 
treated with single-agent GDC-0032 in Stage 2, Cohorts AD and G.  For a given 
adverse event with a true rate of 10%, 5%, or 1% the probability of observing at least 
one such adverse event in 82 patients from the single-agent GDC-0032 expansion 
cohorts (Stage 2, Cohorts AD and G) is 99.9%, 98.5%, and 56.1%, respectively.
Cohorts AD and GH of Stage 2 encompass distinct patient populations that may have 
differing safety profiles.  For example, Cohort D includes HER2-positive metastatic 
breast cancer patients, whereas Cohort G includes patients with solid tumors that have 
increased PIK3CA copy number.


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Increasing the size of Cohorts A and B to 20 patients will provide more robust safety 
data in the patient populations tested.  For a given adverse event with a true rate of 10%, 
5%, or 1%, the probability of observing at least one such adverse event in 20 patients is 
87.8%, 64.1%, and 18.2%, respectively.  Cohort H will also provide more robust safety 
data on a different single-agent schedule of GDC-0032 being given on a 21-day on, 
7-day off (21/7) schedule.  For a given adverse event with a true rate of 10%, 5%, or 
1%, the probability of observing at least one such adverse event in an expanded cohort 
of 40 patients is 98.6%, 87.1%, and 33.1%, respectively.
To better characterize the safety of the combination of GDC-0032 with either letrozole 
(Stage 2, Cohort E) or with fulvestrant (Stage 2, Cohort F), approximately 2728 patients 
will be enrolled in each of these expansion cohorts.  This number includes the possibility 
that two dose levels will be tested as described in Sections 3.1.4.e and 3.1.4.f with 
20 patients enrolled at the selected dose level.
Promising anti-tumor activity has been observed at the 6-mg QD capsule dose level of 
GDC-0032 in combination with letrozole (Cohort E) and in combination with fulvestrant 
(Cohort F).  Several alternate dose schedules will be evaluated to obtain additional data 
on the relative tolerability of adding intermittent breaks to the GDC-0032 dosing 
schedule or lower doses of GDC-0032 in combination with either fulvestrant (Cohorts J, 
K, L, M) or letrozole (Cohorts N, P, Q, R, and S).
Approximately 20 patients will be enrolled into Stage 2, Cohort J to evaluate an 
alternative dose schedule of GDC-0032 4-mg QD tablet dose level with a 21-day on, 
7-day off (21/7) schedule in combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort K to evaluate an 
alternative dose schedule of GDC-0032 4-mg QD tablet dose level with a 5-day on, 
2-day off (5/2) schedule in combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort L to evaluate an 
alternative dose schedule of GDC-0032 4-mg QD tablet dose level with a 7-day on, 
7-day off (7/7) schedule in combination with fulvestrant.
Approximately 20 patients will be enrolled into Stage 2, Cohort M to evaluate an 
alternative dose level of GDC-0032 2-mg QD tablet dose level in combination with 
fulvestrant.
Approximately 26 patients will be enrolled into Stage 2, Cohort N to evaluate an 
alternative dose level of GDC-0032 2-mg QD tablet dose level in combination with 
letrozole.  This includes six patient slots (three with PIK3CA-mutant and three with 
PIK3CA-wild-type tumors) in which paired pre- and on-treatment tumor biopsies are 
required.


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Approximately 26 patients will be enrolled into Stage 2, Cohort P to evaluate an 
alternative dose level of GDC-0032 4-mg QD tablet dose level in combination with 
letrozole in a less heavily pretreated population as compared with Stage 2, Cohort E.  
This includes six patient slots (three with PIK3CA-mutant and three with PIK3CA-wild-
type tumors) in which paired pre- and on-treatment tumor biopsies are required.
For the 12 slots in Cohorts N and P in which paired pre- and on-treatment tumor 
biopsies are required, if a patient enrolls in the study and either the pre- or the 
on-treatment biopsy tissue quality is deemed unevaluable by the Central Laboratory, the 
patient may continue on treatment, but additional patients may be enrolled to complete 
the cohort (at the Sponsor’s discretion).  The paired tumor biopsies support the 
exploratory objective of assessing GDC-0032 PD effects on the PI3K (and other) 
pathways.  Therefore, a limited number of patients (3 patients with PIK3CA-mutant and 
3 patients with PIK3CA-wild type tumors in each cohort) was chosen to provide a 
preliminary PD assessment.
Approximately 20 patients will be enrolled into Stage 2, Cohort Q to evaluate an 
alternative dose schedule of GDC-0032 4-mg tablet dose level with a 21-day on, 
7-day off (21/7) schedule in combination with letrozole.
Approximately 20 patients will be enrolled into Stage 2, Cohort R to evaluate an 
alternative dose schedule of GDC-0032 4-mg QD tablet dose level with a 5-day on, 
2-day off (5/2) schedule in combination with letrozole.
Approximately 20 patients will be enrolled into Stage 2, Cohort S to evaluate an 
alternative dose schedule of GDC-0032 4 mg QD tablet dose level with a 7-day on, 
7-day off (7/7) schedule in combination with letrozole.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such adverse event in an expanded cohort of 20 patients is 
87.8%, 64.1%, and 18.2%, respectively. This is especially important in characterizing an 
adverse event such as pneumonitis that may occur at a low frequency.  It is important to 
understand the safety profile of GDC-0032 in combination with letrozole as this regimen 
may be tested in future studies for patients with early hormone receptorpositive breast 
cancer, an indication with a unique risk-benefit profile.  The combination of GDC-0032 
and fulvestrant may be tested in future studies as an early-line therapy for patients with 
advanced hormone receptorpositive breast cancer.
In Cohort T, to characterize the safety and tolerability of single-agent GDC-0032 for 
patients with lymphoma, approximately 10 patients will be enrolled, irrespective of their 
tumor’s PIK3CA-mutation status.  For a given adverse event with a true rate of 10%, 
5%, or 1%, the probability of observing at least one such adverse event in an expanded 
cohort of 10 patients is 65.1%, 40.1%, and 9.6%, respectively.


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In Cohort T2, to characterize the safety and tolerability of single-agent GDC-0032 for 
patients with DLBCL, approximately 1020 patients will be enrolled, irrespective of their 
tumor’s PIK3CA-mutation status.  If less than 2 responders (CR or PR, confirmed or 
unconfirmed) are observed from the first 10 patients with DLBCL, enrollment will be 
suspended for Cohort T2; if 2 or more responders are observed from the first 10 patients, 
another 10 patients may be enrolled into the cohort.  However, if clinical benefit is 
observed for the first 10 patients with DLBCL in Cohort T2 (e.g., a majority of patients 
demonstrate SD at Week 8 although there are less than 2 responders), then further 
enrollment of 10 additional patients may be allowed for this cohort, depending on the 
decision made by the Sponsor.  Assessment for expansion of Cohort T2 will be made on 
a rolling basis, depending on when responses are observed.  In addition, a decision 
about further enrollment of additional patients beyond 20 will be made by the Sponsor if 
clinical benefit is observed (e.g., 4 PR in 20 patients). 
In Cohort X (sub-Cohorts X1X10), to provide preliminary efficacy and safety data of 
single agent GDC-0032 in a diverse population of patients with PIK3CA-mutant cancer, 
the following rule will be applied to each of the sub-cohorts:  if less than 2 responders 
(CR or PR, confirmed or unconfirmed) are observed from the first 10 patients with 
PIK3CA-mutant cancer, enrollment will be suspended for that indication; if 2 or more 
responders are observed from the first 10 patients, another 10 patients will be enrolled 
into the cohort.  However, if clinical benefit is observed for the first 10 patients with 
PIK3CA-mutant cancer in the cohort (e.g., a majority of patients demonstrate SD at 
Week 8 although there are less than 2 responders), then further enrollment of 
10 additional patients may be allowed for this cohort, depending on the decision made 
by Genentech.  Assessment for expansion of a given sub-cohort will be made on a 
rolling basis, depending on when responses are observed.  These expansion rules will 
also be applied for the 10-20 patients with HNSCC with amplification of the PIK3CA 
gene number and no PIK3CA somatic mutations detected in Cohort X3.  In addition, if a 
given indication is expanded to 20, a decision about further enrollment of additional 
patients beyond 20 (up to a maximum of 40 for any given indication, e.g., 
PIK3CA-mutant HNSCC) will be made by the Sponsor if clinical benefit is observed (e.g., 
4 PR in 20 patients).
A positive PIK3CA-mutation or amplification status from local testing will be centrally 
confirmed for patients in Cohort X.  If a patient enrolls as per a positive local test result 
and a mutation or amplification is not detected per central testing, the patient will be 
allowed to continue in the study, and additional patients may be enrolled to meet 
enrollment goals of patients with PIK3CA-mutant or amplified tumors.
With the assumption of an expected true response rate of 30% or higher, there is at 
most a 15% chance of observing less than 2 responses in 10 patients, which is the false 
negative rate.  If the true response rate increases to 40%, the false negative rate 
decreases to 5%.  Alternately, with the assumption of a response rate of 5% or less, 
there is at most a 9% chance of observing 2 or more responses in 10 patients, which is 


Protocol:  GDC-0032—Genentech, Inc.
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the false positive rate.  If the response rate decreases to 4%, the false positive rate 
decreases to 6%.
Assuming a preferable response rate was observed (20% responders) at Week 8 in 
Cohort T2 and X and 10 additional patients were enrolled, with an observed response 
rate of 20%, a sample size of 20 patients within a given indication (i.e., 
sub-Cohorts X1X10) would result in an 80% Pearson-Clopper exact CI of 9% to 36%, 
excluding a response rate of 8%. Assuming that the observed responder rate is 20% 
with 20 patients in a sub-cohort of Cohort X, and that an additional 20 patients were 
enrolled, the resulting sample size of 40 patients within a given indication would result in 
an 80% Pearson-Clopper exact CI of 12% to 30%, which is narrower than when the 
sample size is 20, thus providing more confidence in the observed response rate. The 
precision of the estimation under different observed response rates is illustrated in 
Table 12, through 80% Pearson-Clopper exact CIs.
Table 12 Confidence Intervals under Different Response Rates
80% Pearson-
Clopper Exact CIs 
(%)
Sample Size
Response Rate (%)
10
20
30
40
50
5
027
118
115
113
212
10
134
324
421
419
518
15
339
630
727
825
924
20
545
936
1132
1230
1329
25
850
1341
1538
1636
1735
30
1255
1747
1943
2041
2140
CI confidence interval.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such adverse event in an expanded cohort of 20 patients is 
87.8%, 64.2%, and 18.2%, respectively; in an expanded cohort of 40 patients the 
probability is 98.5%, 87.1%, and 33.1%, respectively.  Table 13 describes the 80% 
Pearson-Clopper CI under different AE rates with 10-50 patients.


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Table 13 Confidence Intervals under Different Underlying Adverse Event 
Rates
80% Pearson-
Clopper Exact CIs 
(%)
Sample Size  
Underlying Adverse 
Event Rate (%)
10
20
30
40
50
1
022
012
09
07
06
5
027
118
115
113
212
10
134
324
421
419
518
CIconfidence interval.
In sub-Cohort X11, approximately 50 patients will be enrolled with PIK3CA-mutant 
tumors not otherwise specified in sub-Cohorts X1X10 and excluding breast cancer, 
NSCLC, and colorectal cancer.  With 50 patients, the probability of observing at least 
one such adverse event with a true rate of 10%, 5%, or 1% will be 99.5%, 92.3%, and 
39.5%, respectively.
c.
Phase II
The Phase II portion of the trial will evaluate safety and provide a preliminary evaluation 
of efficacy of the combination of GDC-0032 and fulvestrant as measured by ORR and 
CBR.  The study is designed to estimate the ORR and the CBR with reasonable 
precision to contrast the results of this study with historical data from studies with 
fulvestrant in a similar patient population, which have ORR of 7%10% and CBR rate of 
32%46% (Chia et al. 2008; Di Leo et al. 2010).  CBR allows for evaluation of bone-only 
disease patients while ORR does not.  Based upon previous literature, bone-only 
disease is approximately 30% of patients (Chia et al. 2008; Di Leo et al. 2010).
The Phase II portion of this trial will be able to detect a large benefit of the combination 
of GDC-0032 and fulvestrant, in terms of ORR.  For example, an observed ORR of 
≥30% in 21 patients with PIK3CA mutant tumors (assuming 30% of the 30 patients will 
have non-measurable bone only disease) will have a 95% confidence interval of (14.6%, 
57.0%), excluding an ORR of 10%.  Similarly, an observed CBR of 67% in 30 patients 
will have a 95% confidence interval of (47.2%, 82.7%), excluding a CBR of 46%.
4.10
DATA QUALITY ASSURANCE
The data will be collected via Electronic Data Capture (EDC) using eCRFs.  The site will 
be responsible for data entry into the EDC system.  In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system.  The CRO will be responsible for the data 
management of this trial, including quality checking of the data.


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Genentech will perform oversight of the data management of this trial.  Genentech will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Central Laboratory data and other electronic data will be sent 
directly to Genentech, using Genentech’s standard procedures to handle and process 
the electronic transfer of these data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail.  System backups for data stored at 
Genentech and records retention for the study data will be consistent with Genentech’s 
standard procedures.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study drug(s).
Genentech or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements.
Genentech or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
agencies and competent authorities by telephone or fax within 7 calendar days after 
being notified of the event. Genentech or its designee will report other relevant SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and central IRBs/ECs (except in the United 
States where investigators are responsible for reporting to their IRBs per local 
requirements) by a written safety report within 15 calendar days of notification.  
5.1.1
Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution.
This includes the following:

AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with cancer that were 
not present prior to the AE reporting period (see Section 5.2.1)

Complications that occur as a result of protocol-mandated interventions
(e.g., invasive procedures such as biopsies)


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
AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g. invasive procedures such as biopsies, 
medication washout, or no treatment run-in). 

Preexisting medical conditions (other than cancer), judged by the investigator to 
have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period
5.1.2
Serious Adverse Events
An SAE is any AE that is any of the following:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)

Requires or prolongs inpatient hospitalization

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)

A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s)

Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs.
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves 
as the guide for defining regulatory reporting obligations.
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the eCRF.
Serious adverse events are required to be reported by the investigator to Genentech 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.1.3
Protocol-Defined Events of Special Interest/Non-Serious 
Expedited Adverse Events
The following events are events of special interest and will need to be reported to the 
Sponsor expeditiously (i.e., within 24 hours after learning of the event; see Section 5.4.2
for reporting instructions), irrespective of regulatory seriousness criteria:

DLTs occurring during the DLT assessment window 

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 5.3.1)

Suspected transmission of an infectious agent by the study drug
5.2
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs and SAEs (as defined in 
Section 5.1) are recorded on the eCRF and reported to the Sponsor in accordance with 
protocol instructions. 
5.2.1
Adverse Event Reporting Period
After informed consent, but prior to initiation of study medications, only SAEs caused by 
a protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in).
After initiation of study medication, all AEs and SAEs regardless of attribution will be 
collected until 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is later (see Section 5.5).  After this period, 
investigators should report only SAEs that are felt to be related to prior study treatment 
(see Section 5.6).
5.2.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning for eliciting AE information at all 
patient evaluation timepoints should be adopted.  Examples of non-directive questions 
include:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?” 


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5.2.3
Assessment of Severity and Causality of Adverse Events
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will 
be recorded in the patient’s medical record and on the Adverse Event eCRF.
For each AE and SAE recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity, and 
causality.
Table 14 provides guidance for grading AE severity and Table 15 provides guidance for 
assessing the causal relationship to the investigational product(s).
The AE grading (severity) scale found in the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 will be used for assessing 
AE severity (see Table 14).
Table 14 Adverse Event Grading (Severity) Scale
Grade
Severity
Alternate Description a
1
Mild (apply event-specific 
NCI CTCAE grading criteria)
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated
2
Moderate (apply event-specific 
NCI CTCAE grading criteria)
Minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental 
ADLb
3
Severe (apply event-specific 
NCI CTCAE grading criteria)
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self 
care ADLc
4
Very severe, life threatening, 
or disabling (apply event-specific 
NCI CTCAE grading criteria)
Life-threatening consequences; 
urgent intervention indicated
5
Death related to AE
ADL activities of daily living; AE adverse event; CTCAE Common Terminology Criteria for 
Adverse Events; NCI National Cancer Institute.
The NCI CTCAE v4.0 can be found at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
Note:  Regardless of severity, some events may also meet regulatory seriousness criteria.  
Refer to definition of a serious AE (see Section 5.1.2).
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported 
AE is not in the NCI CTCAE listing.
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.


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To ensure consistency of causality assessments, investigators should apply the 
following general guidelines:
Table 15 Causal Attribution Guidance
Is the AE/SAE suspected to be caused by the investigational product based on facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily explained 
by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to the investigational product; and/or the AE 
abates or resolves upon discontinuation of the investigational product or dose 
reduction and, if applicable, reappears upon re-challenge.
Investigators should apply facts, evidence, or rationales based on scientific principles 
and clinical judgment to support a causal/contributory association with an 
investigational product.
NO
AEs will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the AE has an etiology other than the investigational product 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
administration of the investigational product (e.g., cancer diagnosed 2 days after 
first dose of study drug).
Note: The investigator’s assessment of causality for individual AE reports is part of the 
study documentation process. Regardless of the “Yes” or “No” causality assessment 
for individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. Attribution of 
SAEs will be reviewed on an ongoing basis, and may be changed as additional 
clinical data emerges (e.g., reversibility of AE, new clinical findings in patient 
with AE, effects of retreatment, AEs in other patients).
AEadverse event; SAEserious adverse event.
In addition to assessing causality with respect to study drug, investigators should also 
assess whether other factors (e.g., disease under study, concurrent illness, concomitant 
medication, or study procedure) may have caused the event, using similar guidance.
5.3
PROCEDURES FOR RECORDING ADVERSE EVENTS
5.3.1
Recording Adverse Events on the eCRF
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the eCRF.  Avoid colloquialisms and abbreviations.
There is one Adverse Event eCRF for recording AEs or SAEs. 
Only one medical concept should be recorded in the event field on the Adverse Event 
eCRF.


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a.
Diagnosis versus Signs and Symptoms
If known, a diagnosis should be recorded on the 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 as an AE or SAE on the eCRF.  If a diagnosis 
is subsequently established, it should be reported as follow-up information.
b.
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF. 
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF.  For example, 
if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the eCRF.
c.
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution between patient 
evaluation timepoints.  Such AEs should only be recorded once in the eCRF unless their 
severity changes.  If a persistent AE becomes more or less severe it should be recorded 
on a new AE eCRF with the same AE description but with the new severity recorded.
If a change in intensity of the AE qualifies the event as an SAE per the seriousness 
criteria in Section 5.1.2, the event should be recorded as a separate event on the 
Adverse Event eCRF and reported to the Sponsor per the SAE reporting procedure 
outlined in Section 5.4.2.
A recurrent AE is one that occurs and resolves between patient evaluation timepoints 
and subsequently recurs.  All recurrent AEs should be recorded separately on an 
Adverse Event eCRF.
d.
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, 
further diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5the ULN associated with cholecystitis), only 
the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF.


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If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  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 as AEs or SAEs on the eCRF, unless their severity, 
seriousness, or etiology changes.
Abnormal Liver Enzymes
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 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 5.3.1).
e.
Deaths
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1) 
that are attributed by the investigator solely to progression of cancer will be recorded 
only on the Study Discontinuation eCRF.  All other on-study deaths, regardless of 
attribution, will be recorded on an Adverse Event eCRF and expeditiously reported to the 
Sponsor.
When recording a death, 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.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Unexplained Death” on the Adverse Event eCRF.
f.
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the General Medical History and Baseline Conditions 
eCRF.
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on an Adverse Event eCRF, it is important to convey the concept 


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that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
g.
Worsening of Cancer
Worsening and/or progression of cancer (including new sites of metastasis) should not
be recorded as an AE or SAE.  These data will be captured as efficacy assessment data 
only.
Signs and symptoms clearly associated with the disease under study should not be 
reported as AEs unless they are any one of the following: 

Newly emergent (i.e., not previously observed in the patient) 

Judged by the investigator to be unusually severe or accelerated 

Judged by the investigator to represent exacerbation of disease-related signs and 
symptoms caused directly by the study drug
If there is reasonable uncertainty about an AE being caused by disease progression, it 
should be reported as an AE or SAE as appropriate.
h.
Hospitalization, Prolonged Hospitalization or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to:

Perform an efficacy measurement for the study

Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed

Receive scheduled therapy for the target disease of the study
i.
Pregnancy
If a female patient becomes pregnant while receiving investigational therapy or within 
90 days after the last dose of investigational product, a Pregnancy Report eCRF should 
be completed and submitted electronically via the EDC system to Genentech’s Drug 
Safety Department or its designee within 24 hours of learning of the pregnancy.  
Pregnancy should not be recorded on the Adverse Event eCRF.  In the event the EDC 
system is unavailable, a completed paper Pregnancy CRF and Pregnancy fax 
coversheet should be completed and faxed to Genentech’s Drug Safety Department or 
its designee at the fax numbers listed in Section 5.4.2.  Once the EDC system is 
available, all information will need to be entered and submitted using the EDC system.
Abortion, whether therapeutic or spontaneous, should always be classified as serious 
(as the Sponsor considers these medically significant), recorded on an Adverse Event 


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eCRF, and expeditiously reported to the Sponsor.  After the study period, such events 
should still be reported expeditiously to the Sponsor. 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to the investigational product should be classified as serious 
and recorded on an Adverse Event eCRF and expeditiously reported to the Sponsor 
during the study period.  After the study period, such events should still be reported 
expeditiously to the Sponsor recorded and reported as an SAE.
In the event the EDC system is unavailable, a paper Pregnancy Report form and 
Pregnancy Fax Coversheet should be completed and faxed to Genentech’s Drug Safety 
Department or its designee at the fax numbers listed in Section 5.4.2.
j.
Overdose
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
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 Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).
5.4
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS AND PROTOCOL-DEFINED EVENTS OF 
SPECIAL INTEREST
5.4.1
Reporting Requirements for Fatal/Life-Threatening Serious 
Adverse Events Related to Investigational Product
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on an Adverse Event eCRF 
within 24 hours as described in Section 5.4.2.
Medical Monitor Contact Information:
Medical Monitor:
, M.D.
Telephone No.:
Alternate Telephone No.: +1 (888) 835-2555


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5.4.2
Reporting Requirements for All 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 Adverse Event eCRF and submit the report via the EDC 
system.  A report will be generated and sent to the Sponsor’s Safety Risk Management 
department by the EDC system.
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), using the fax number provided 
below.  If international fax is not available, the CRF may be sent via email to the address 
below.  Once the EDC system is available, all information will need to be entered and 
submitted via the EDC system.
Fax No.:  +44 122 337 4102
Email: 
EMEAASIASafetyCentral.SM@ppdi.com
Relevant follow-up information should be submitted to Genentech’s Safety Risk 
Management Department or its designee as soon as it becomes available and/or upon 
request.
5.5
TYPE AND DURATION OF FOLLOW UP OF PATIENTS AFTER
ADVERSE EVENTS
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, another anti-cancer therapy is initiated, the patient is lost to follow up, or it 
has been determined that the study treatment or participation is not the cause of the 
AE/SAE.  Resolution of AEs and SAEs (with dates) should be documented on the 
appropriate Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification (SDV) during the study period.
For some SAEs, the Sponsor or its designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).
5.6
POST-STUDY ADVERSE EVENTS
At the last scheduled visit, the investigator should instruct each patient to report to the 
investigator any subsequent SAEs that the patient’s personal physician believes could 
be related to prior study treatment.
The investigator should notify the study Sponsor of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if felt to be 


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related to prior study treatment.  The Sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a patient that participated in this study.  The 
investigator should report these events to Genentech Drug Safety on the study Adverse 
Event eCRF.  If the study Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Genentech Drug Safety via phone at 1-888-835-2555.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
Genentech 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, Genentech will 
assess the expectedness of these events using the following reference document:

Taselisib (GDC-0032) Investigator's Brochure

SmPC for fulvestrant, letrozole, or midazolam
Genentech 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 Genentech as needed.
6.
INVESTIGATOR REQUIREMENTS
6.1
STUDY INITIATION
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative:

U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator

The names of any subinvestigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations.

Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators

Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572 

Federalwide Assurance number or IRB statement of compliance


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
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval)

A copy of the IRB/EC-approved Informed Consent Form

Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form.

Current laboratory certification of the laboratory performing the analysis (if other 
than a Genentech-approved central laboratory), as well as current references 
ranges for all laboratory tests

A Clinical Research Agreement signed and dated by the study site

Investigator Brochure Receipt signed and dated by the Principal Investigator

Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable), IRB/EC approval letters, 
and pertinent correspondence

A Protocol Acceptance Form signed and dated by the Principal Investigator

Country-specific documents, as required
6.2
STUDY COMPLETION
The following data and materials are required by Genentech before a study can be 
considered complete or terminated:

Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period

All laboratory certifications for laboratories performing the analysis (is other than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests

eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator

Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms)

Copies of protocol amendments and IRB/EC approval/notification, if appropriate

A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable)

All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, U.S. FDA Form 1572 for each site)

A signed and dated Protocol Amendment Acceptance Form(s) (if applicable)

Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572 (applicable for 1 year after the 
last patient has completed the study)


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7.
ETHICAL CONSIDERATIONS
7.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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 (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
7.2
INFORMED CONSENT FORM
Genentech’s Sample Informed Consent Form (and sample Child’s Assent, if applicable) 
will be provided to each site.  Genentech or its designee must review and approve any 
proposed deviations from the Sample Informed Consent Form [and Child’s Assent, if 
applicable] or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/EC submission.  Patients must be re-consented to the 
most current version of the Consent Forms during their participation in the study.  
The final IRB/EC-approved Consent Forms must be provided to Genentech for 
regulatory purposes.
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language.
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time.
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate.
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to Genentech for 
regulatory purposes.


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If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/IEC review and approval may not be required per 
study site policies.
In the United States, each Informed Consent Form may also include authorization 
allowing the institution, investigator, subinvestigator and the Sponsor(s) to use and 
disclose Personal Health information in compliance with the HIPAA of 1996.
Signed and dated Informed Consent Forms must remain in each patient’s study file and 
must be available for verification by study monitors at any time.
Optional Research Informed Consent
If archival tissue and/or plasma/serum collection for optional research is approved by the 
IRB/IEC, the Consent Form entitled “Sample Optional Research Informed Consent 
Form,” will be provided by Genentech to each study site.  This form gives patients the 
option to authorize the collection and use of these samples and personal health 
information for additional research purposes.  Signing of this separate consent form is 
not required for enrollment in the trial but is required prior to any optional research 
sample collection.  All procedures outlined above for review, approval, processing, and 
use of Consent Forms also apply to this optional research form.
7.3
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD 
OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator for review and approval before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients or
others.
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, assessed to be related to study treatment, and are unexpected.  Investigators 
may receive written IND safety reports or other safety-related communications from 
Genentech.  Investigators are responsible for ensuring that such reports are reviewed 


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and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s Study File.
7.4
CONFIDENTIALITY
Genentech maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data 
and used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided 
upon request.
7.5
FINANCIAL DISCLOSURE
Investigators will provide Genentech with sufficient, accurate financial information in 
accordance with local regulations to allow Genentech 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.


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8.
DATA COLLECTION AND MANAGEMENT
8.1
DATA QUALITY ASSURANCE
Genentech will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
Genentech will produce an EDC Study Specification document that describes the quality 
checking to be performed on the data.  Central laboratory data or other electronic data 
will be sent directly to Genentech, using the Genentech’s standard procedures to handle 
and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
8.2
STUDY MONITORING REQUIREMENTS
Site visits will be conducted by an authorized Genentech representative to inspect study 
data, patients’ medical records, and eCRFs.  The Principal Investigator will permit 
Genentech monitors/representatives and collaborators, the U.S. FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health 
authorities to inspect facilities and records relevant to this study.
8.3
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using the Medidata Solutions (New York, NY) RAVEEDC 
system.  Sites will receive training for appropriate eCRF completion.  eCRFs will be 
submitted electronically to Genentech and should be handled in accordance with 
instructions from Genentech.
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator.
In addition, at the end of the study, the investigator will receive patient data for his or her 
site in a readable format on a compact disc that must be kept with the study records.
8.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification (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. 


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Source documents are where 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 diaries or 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 the pharmacy, laboratories, and medico-technical departments involved in a 
clinical trial.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed.
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor 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 regulatory authorities.
8.5
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 FDA requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical 
research purposes) would be one that (1) allows data entry only by authorized 
individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation.
In collaboration with the study monitor, Genentech’s Quality Assurance group may assist 
in assessing whether electronic records generated from computerized medical record 
systems used at investigational sites can serve as source documents for the purposes of 
this protocol.
If a site’s computerized medical record system is not adequately validated 
for the purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified.
8.6
STUDY MEDICATION ACCOUNTABILITY
In the United States, only GDC-0032 will be provided by Genentech; sites will procure 
fulvestrant, letrozole, and midazolam, and these drugs will be reimbursed by Genentech.  
In non-U.S. countries, all study drugs required for completion of this study will be 
provided by Genentech.  The recipient will acknowledge receipt of the drug by returning 


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the appropriate documentation form indicating shipment content and condition.  
Damaged supplies will be replaced.
Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log or 
comparable document.
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Genentech with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented.
Genentech must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site.
8.7
DISCLOSURE OF DATA
Patient medical information obtained by this study is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate.
8.8
RETENTION OF RECORDS
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for Good Clinical 
Practice (GCP) (see Section 4.9 of the Guideline) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including eCRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after the last 
marketing application approval in an ICH region or after at least 2 years have elapsed 
since formal discontinuation of clinical development of the investigational product.  
All state and local laws for retention of records also apply. 
No records should be disposed of without the written approval of Genentech.  Written 
notification should be provided to Genentech for transfer of any records to another party 
or moving them to another location.


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For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the U.S. 
FDA IND regulations and the relevant national and local health authorities, whichever is 
longer.
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to Genentech and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by Genentech or an authorized representative for inspection 
of study data, patients’ medical records, and eCRFs.  The investigator will permit 
national and local health authorities, Genentech monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by Genentech, Inc.  Study centers in the United States, Canada, 
and Europe will participate in this study to enroll approximately 611711 patients.  
Data will be recorded via an EDC system from Medidata Solutions, Inc. (New York, NY), 
using electronic Case Report Forms (eCRFs; see Section 8.3).  An independent review 
facility (IRF) will be used for interpretation and central review of FDG-PET imaging in 
accordance with guidelines that will be detailed in an IRF charter; an imaging manual will 
be provided to study sites.  A central ECG facility will be used for blinded ECG reading 
and interpretation; an ECG manual will be provided to study sites.  A central laboratory 
will be used to manage PK, PD, and tissue samples.


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9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, Genentech is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals.  Genentech will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 7.4 for more details).  
For more information, refer to the Roche (Genentech) Global Policy on Sharing of 
Clinical Trials Data at the following website:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, Genentech aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, Genentech aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to Genentech prior to 
submission for publication or presentation.  This allows Genentech to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the investigator.
In accordance with standard editorial and ethical practice, Genentech will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Genentech personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of Genentech, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by Genentech.  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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Protocol:  GDC-0032—Genentech, Inc.
181/P PMT4979g (GO00886)-A10
Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined 
phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen 
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Shaw RJ, Cantley LC.  Ras, PI(3)K and mTOR signalling controls tumor cell growth. 
Nature 2006;441:424.
Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian 
cancer. Nat Genet 1999;21:99102.
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Protocol:  GDC-0032—Genentech, Inc.
182/P PMT4979g (GO00886)-A10
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Protocol:  GDC-0032—Genentech, Inc.
183/P PMT4979g (GO00886)-A10
Appendix A-1
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 1
Assessment
Screening a Pretreatment b PK Evaluation Period
Cycle 1
Cycle Day (Window)
14 to 1
1
2
3
4
8 (1)
15 (1)
16 (1)
22 (1)
29 (1)
Informed consent(s) (28 to 1 days)
x
Medical history and demographic data c
x
Complete physical examination d
x
x
Limited physical examination e
x
x
x
x
Weight and height (height at screening only)
x
x
x
x
x
x
Vital signs f
x
x g
x
x
x
x
x
x
ECOG performance status (see Appendix F)
x
x
12-Lead electrocardiogram h
x
x
x
x
x
Tumor assessment i
x
CBC with differential and platelet count j
x
x
x
x
x
Fasting serum or plasma chemistry k
x
x
x
x
x
Glycosylated hemoglobin (HBA1c)
x
Fasting insulin and glucose l
x
x
x
x
x
x
Fasting lipid profile and amylase m
x
x
x
x
Coagulation (INR and aPTT/PTT)
x
Serum fibrinogen
x
x
Urinalysis (laboratory) n
x
Pregnancy test o
x
Flow cytometry (FACS) p
x
FDG-PET imaging q
x
x


Appendix A-1
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 1 (cont.)
Protocol:  GDC-0032—Genentech, Inc.
184/P PMT4979g (GO00886)-A10
Assessment
Screening a Pretreatment b PK Evaluation Period
Cycle 1
Cycle Day (Window)
14 to 1
1
2
3
4
8 (1)
15 (1)
16 (1)
22 (1)
29 (1)
Blood sample for CTCs r
x
x
Blood sample for ctDNA s
x
Optional fresh tumor tissue biopsy t
x
x
Urine PK collection u
x
x
Plasma PK and PD samples v
x
x
x
x
x
x
x
x
x
Archival tumor tissue w
x
Pharmacogenetic blood sample (CYP450 
genotyping) v
x
GDC-0032 dosing x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
Concomitant medications
x y
x
x
x
x
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PDpharmacodynamic; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors version 1.1.
a Perform within 14 days prior to Day 1, with the exception of informed consent and the baseline tumor assessment, which may be obtained up to 
28 days prior to Day 1.  Assessments performed as standard of care before within the time frame required may be used for screening.
b May be performed any time during screening after a patient is determined to be eligible for the study and prior to Day 1 of Cycle 1.
c Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
d A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also include 
the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
e Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 


Appendix A-1
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 1 (cont.)
Protocol:  GDC-0032—Genentech, Inc.
185/P PMT4979g (GO00886)-A10
f
Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.
g Obtain vital signs predose and 2, 4, and 8 hours postdose.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECG at screening.  Perform triplicate 12-lead 
electronic ECGs measurements on Days 1 and 15 of Cycle 1 (predose, and 4, 8, and 24 hours postdose).  A 30-minutes window is acceptable 
for all timepoints.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed or stabilized, evaluate for causes of 
QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.
i
Assess all sites of disease per RECIST v1.1 at screening.  Include PSA, CA-125, CEA, CA19-9, and/or AFP tests, if appropriate.  The same 
imaging method and serum marker tests used at screening must be used throughout the study.  A documented standard of care assessment 
performed within 28 days before Day 1 may be used for screening.  See Section 4.5.1.d and Appendices C, D, and E.
j
CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.  The Cycle 1 Day 8 CBC may be obtained up to 24 hours in advance.
k 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.
l
Collect fasting insulin and glucose sample per schedule provided in Appendix B-1.  Glucose levels may be obtained by fingerstick.
m Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.
n Includes specific gravity, pH, glucose, protein, ketones, and blood.
o Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
p Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
q Optional for patients in Cohort 1 in Stage 1 (perform only if patients sign the optional consent).  Required for all other patients (Cohorts 2 in 
Stage 1).  Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, 
Day 1) and at the end of Cycle 1 (between Days 2935).  Perform imaging 14 hours after GDC-0032 dose.
r
Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.
s Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient.
t
Obtain fresh tumor tissue from those patients in Stage 1 who sign the optional Research Informed Consent Form.  Perform biopsy before 
initiation of GDC-0032 (up to 28 days prior to Cycle 1, Day 1).  The pretreatment tissue biopsy will be reviewed by a pathologist to determine 
whether or not the tissue is evaluable.  If the pretreatment tissue is evaluable, then a subsequent biopsy will be performed between Days 15 and 
21 of Cycle 1, approximately 14 hours after the morning dose.  If there is only one lesion for both the biopsy and imaging scans, perform the 


Appendix A-1
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 1 (cont.)
Protocol:  GDC-0032—Genentech, Inc.
186/P PMT4979g (GO00886)-A10
biopsy immediately after the scan or at least 1 week prior to FDG-PET imaging or other scans.  If two different lesions are being biopsied 
and scanned, then the second lesion may be biopsied anytime between Days 15 and 21.
u Urine samples will be collected predose and 06 hours and 624 hours after dosing on Day 1 of Cycle 1.
v Obtain PK/PD and pharmacogenetic samples according to the schedule provided in Appendix B-1; PK blood samples should be prepared to 
obtain plasma.  Exploratory PK/PD analyses will be run on any leftover samples if the patient specifically consents to this optional testing.  
The pharmacogenetic blood sample may be obtained on Cycle 1 Day 1 prior to dosing.
w Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study.
x See Section 4.3.2 for instructions on dosing under fasted conditions (Days 1 and 8).  On clinic visit days, administer the dose of GDC-0032 in 
the clinic.  On Day 8, dispense a sufficient number of capsules to the patient to last only until the next visit or, at the investigator’s discretion, 
until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and diary completion (see Section 4.3.2).  Dispense diary and review 
at subsequent visits and perform GDC-0032 accountability.
y Record all medications used by patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements).


Protocol:  GDC-0032—Genentech, Inc.
187/P PMT4979g (GO00886)-A10
Appendix A-2
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort A
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
2
8 (1)
9 (1)
15 (1)
22(1)
23 (1)
29(1)
Informed consent(s) (28 to 1 days)
x
Medical history and demographic data c
x
Complete physical examination d
x
x
Limited physical examination e
x
x
x
x
Weight and height (height at screening only)
x
x
x
x
x
x
Vital signs f
x
x g
x
x
x
x
x
x
x
ECOG performance status (see Appendix F)
x
x
12-Lead electrocardiogram h
x
x
x
x
Tumor assessment i
x
CBC with differential and platelet count j
x
x
x
x
x
Fasting serum or plasma chemistry k
x
x
x
x
x
Glycosylated hemoglobin (HBA1c)
x
Fasting insulin and glucose l
x
x
x
x
Fasting lipid profile and amylase m
x
x
x
x
Coagulation (INR and aPTT/PTT)
x
Serum fibrinogen
x
x
Urinalysis (laboratory) n
x
Pregnancy test o
x
Flow cytometry (FACS) p
x
FDG-PET imaging q
x
x


Appendix A-2
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort A (cont.)
Protocol:  GDC-0032—Genentech, Inc.
188/P PMT4979g (GO00886)-A10
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
2
8 (1)
9 (1)
15 (1)
22(1)
23 (1)
29(1)
Blood sample for CTCs r
x
x
Blood sample for ctDNA s
x
Optional fresh tumor tissue biopsy t
x
x
Plasma PK samples u
x
x
x
x
x
x
Archival tumor tissue v
x
Pharmacogenetic blood sample (CYP450 
genotyping) u
x
GDC-0032 dosing w
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
Concomitant medications
x x
x
x
x
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors version 1.1.
a Perform within 14 days prior to Day 1, with the exception of informed consent and the baseline tumor assessment, which may be obtained up to 
28 days prior to Day 1.  Assessments performed as standard of care before within the time frame required may be used for screening.
b May be performed any time during screening after a patient is determined to be eligible for the study and prior to Day 1 of Cycle 1.
c Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
d A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
e Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
f
Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.


Appendix A-2
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort A (cont.)
Protocol:  GDC-0032—Genentech, Inc.
189/P PMT4979g (GO00886)-A10
g Obtain vital signs predose and 2, 4, and 8 hours postdose.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECG at screening.  Perform triplicate 12-lead 
electronic ECGs measurements on Days 1 and 22 of Cycle 1 (predose, and 4, 8, and 24 hours postdose).  A 30-minutes window is acceptable 
for all timepoints.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed or stabilized, evaluate for causes of 
QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.
i
Assess all sites of disease per RECIST v1.1 at screening.  Include PSA, CA-125, CEA, CA19-9, and/or AFP tests, if appropriate.  The same 
imaging method and serum marker tests used at screening must be used throughout the study.  A documented standard of care assessment 
performed within 28 days before Day 1 may be used for screening.  See Section 4.5.1.d and Appendices C, D, and E.
j
CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.  The Cycle 1 Day 8 CBC may be obtained up to 24 hours in advance.
k Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
l
Collect fasting insulin and glucose sample per schedule provided in Appendix B-2.  Glucose levels may be obtained by fingerstick.
m Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.
n Includes specific gravity, pH, glucose, protein, ketones, and blood.
o Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
p Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
q Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, Day 1) and 
during the last week of Cycle 1.  Perform imaging approximately 14 hours after GDC-0032 dose.
r
Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient. 
s Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient.  Pretreatment samples may be obtained on Day 1 before dosing.
t
Obtain paired fresh tumor tissue from those patients who sign the optional Research Informed Consent Form.  Perform biopsy before initiation of 
GDC-0032 (up to 28 days prior to Cycle 1, Day 1).  The pretreatment tissue biopsy will be reviewed by a pathologist to determine whether or not 
the tissue is evaluable.  If the pretreatment tissue is evaluable, then a subsequent biopsy will be performed between Days 15 and 21 of Cycle 1, 
approximately 14 hours after the morning dose.  If there is only one lesion for both the biopsy and imaging scans, perform the biopsy 
immediately after the scan or at least 1 week prior to FDG-PET imaging or other scans.  If two different lesions are being biopsied and scanned, 
then the second lesion may be biopsied anytime between Days 15 and 21.


Appendix A-2
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort A (cont.)
Protocol:  GDC-0032—Genentech, Inc.
190/P PMT4979g (GO00886)-A10
u Obtain PK and pharmacogenetic samples according to the schedule provided in Appendix B-2; PK blood samples should be prepared to obtain 
plasma. Exploratory PK analyses will be run on any leftover samples if the patient specifically consents to this optional testing.  
The pharmacogenetic blood sample may be obtained on Cycle 1 Day 1 prior to dosing.
v Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study.
w See Section 4.3.2 for instructions on dosing under fasted (Day 22) or fed conditions (Day 1 or 8).  On clinic visit days, administer the dose of 
GDC-0032 in the clinic.  On Day 8, dispense a sufficient number of capsules to the patient to last only until the next visit or, at the investigator’s 
discretion, until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and diary completion (see Section 4.3.2).  Dispense diary 
and review at subsequent visits and perform GDC-0032 accountability.
x Record all medications used by patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements).


Protocol:  GDC-0032—Genentech, Inc.
191/P PMT4979g (GO00886)-A10
Appendix A-3
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts B, D, and G
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
8 (1)
15 (1)
16 (1)
22 (1)
Informed consent(s) (28 to 1 days)
x
Medical history and demographic data c
x
Complete physical examination d
x
x
Limited physical examination e
x
x
x
Weight and height (height at screening only)
x
x
x
x
x
Vital signs f
x
x g
x
x
x
x
ECOG performance status (see Appendix F)
x
x
12-Lead electrocardiogram h
x
x
x
Tumor assessment i
x
CBC with differential and platelet count j
x
x
x
x
Fasting serum or plasma chemistry k
x
x
x
x
Glycosylated hemoglobin (HBA1c)
x
Fasting insulin and glucose l
x
x
x
x
Fasting lipid profile and amylase m
x
x
x
Coagulation (INR and aPTT)
x
Serum fibrinogen
x
x
Urinalysis (laboratory) n
x
Pregnancy test o
x
Flow cytometry (FACS) p
x
FDG-PET imaging q
x
x


Appendix A-3
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts B, D, and G (cont.)
Protocol:  GDC-0032—Genentech, Inc.
192/P PMT4979g (GO00886)-A10
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
8 (1)
15 (1)
16 (1)
22 (1)
Blood sample for CTCs r
x
x
Blood sample for ctDNA s
x
Optional fresh tumor tissue biopsy t
x
x
Plasma PK samples u
x
x
x
x
Archival tumor tissue v
x
Pharmacogenetic blood sample (CYP450 genotyping) u
x
GDC-0032 dosing w
x
x
x
x
Adverse events
x
x
x
x
x
Concomitant medications
x x
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors, version 1.1.
a Perform within 14 days prior to Day 1, with the exception of informed consent and the baseline tumor assessment, which may be obtained up to 
28 days prior to Day 1.  Assessments performed as standard of care before within the time frame required may be used for screening.
b May be performed any time during screening after a patient is determined to be eligible for the study and prior to Day 1 of Cycle 1.
c Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
d A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological,
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
e Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
f
Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.


Appendix A-3
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts B, D, and G (cont.)
Protocol:  GDC-0032—Genentech, Inc.
193/P PMT4979g (GO00886)-A10
g Obtain vital signs predose only.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECG at screening.  Perform triplicate 12-lead 
electronic ECGs measurements on Days 1 and 15 of Cycle 1 (predose and 3 hours postdose).  A 30-minutes window is acceptable for all 
timepoints.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed or stabilized, evaluate for causes of 
QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.
i
Assess all sites of disease per RECIST v1.1 at screening.  Include PSA, CA-125, CEA, CA19-9, and/or AFP tests, if appropriate.  The same 
imaging method and serum marker tests used at screening must be used throughout the study.  A documented standard of care assessment 
performed within 28 days before Day 1 may be used for screening.  See Section 4.5.1.d and Appendices C, D, and E.
j
CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.
k Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total 
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
l
Collect fasting insulin and glucose sample per schedule provided in Appendix B-3.  Glucose levels may be obtained by fingerstick.
m Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.
n Includes specific gravity, pH, glucose, protein, ketones, and blood.
o Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
p Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
q Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, Day 1) and 
during the last week of Cycle 1.  Perform imaging 14 hours after GDC-0032 dose.
r
Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.
s Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient.  Pretreatment samples may be obtained on Day 1 before dosing.
t
Obtain paired fresh tumor tissue from those patients who sign the optional Research Informed Consent Form.  Perform biopsy before initiation of 
GDC-0032 (up to 28 days prior to Cycle 1, Day 1).  The pretreatment tissue biopsy will be reviewed by a pathologist to determine whether or not 
the tissue is evaluable.  If the pretreatment tissue is evaluable, then a subsequent biopsy will be performed between Days 15 and 21 of Cycle 1, 
approximately 14 hours after the morning dose.  If there is only one lesion for both the biopsy and imaging scans, perform the biopsy 
immediately after the scan or at least 1 week prior to FDG-PET imaging or other scans.  If two different lesions are being biopsied and scanned, 
then the second lesion may be biopsied anytime between Days 15 and 21.


Appendix A-3
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts B, D, and G (cont.)
Protocol:  GDC-0032—Genentech, Inc.
194/P PMT4979g (GO00886)-A10
u Obtain PK and pharmacogenetic samples according to the schedule provided in Appendix B-3; PK blood samples should be prepared to obtain 
plasma.  Exploratory PK analyses will be run on any leftover samples if the patient specifically consents to this optional testing.  
The pharmacogenetic blood sample may be obtained on Cycle 1 Day 1 prior to dosing.
v Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study.
w On clinic visit days, administer the dose of GDC-0032 in the clinic.  On Day 1, dispense a sufficient number of capsules or tablets to the patient 
to last only until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and 
diary completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform GDC-0032 accountability.
x Record all medications used by patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements).


Protocol:  GDC-0032—Genentech, Inc.
195/P PMT4979g (GO00886)-A10
Appendix A-4
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort C
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
2
9 (1)
16 (1)
17 (1)
23 (1)
Informed consent(s) (28 to 1 days)
x
Medical history and demographic data c
x
Complete physical examination d
x
x
Limited physical examination e
x
x
x
Weight and height (height at screening only)
x
x
x
x
x
Vital signs f
x
x g
x
x
x
x
x
ECOG performance status (see Appendix F)
x
x
12-Lead electrocardiogram h
x
x
x
x
x
Tumor assessment i
x
CBC with differential and platelet count j
x
x
x
x
Fasting serum or plasma chemistry k
x
x
x
x
Glycosylated hemoglobin (HBA1c)
x
Fasting insulin and glucose l
x
x
x
Fasting lipid profile and amylase m
x
x
x
Coagulation (INR and aPTT)
x
Serum fibrinogen
x
x
Urinalysis (laboratory) n
x
Pregnancy test o
x
Flow cytometry (FACS) p
x
FDG-PET imaging q
x
x


Appendix A-4
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort C (cont.)
Protocol:  GDC-0032—Genentech, Inc.
196/P PMT4979g (GO00886)-A10
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
2
9 (1)
16 (1)
17 (1)
23 (1)
Blood sample for CTCs r
x
x
Blood sample for ctDNA s
x
Optional fresh tumor tissue biopsy t
x
x
Plasma PK samples u
x
x
x
x
Archival tumor tissue v
x
Pharmacogenetic blood sample (CYP450 genotyping) u
x
GDC-0032 dosing w
x
x
x
x
Midazolam dosing
x
x
Adverse events
x
x
x
x
x
x
Concomitant medications
x x
x
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors version 1.1.
a Perform within 14 days prior to Day 1, with the exception of informed consent and the baseline tumor assessment, which may be obtained up to 
28 days prior to Day 1.  Assessments performed as standard of care within the time frame required may be used for screening.
b May be performed any time during screening after a patient is determined to be eligible for the study and prior to Day 1 of Cycle 1.
c Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
d A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
e Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 


Appendix A-4
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort C (cont.)
Protocol:  GDC-0032—Genentech, Inc.
197/P PMT4979g (GO00886)-A10
f
Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.
g Obtain vital signs predose and 2, 4, and 8 hours postdose.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECG at screening.  Perform triplicate 12-lead 
electronic ECGs measurements on Days 1 and 16 of Cycle 1 (predose, and 4, 8, and 24 hours postdose).  A 30-minutes window is acceptable 
for all timepoints.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed or stabilized, evaluate for causes of 
QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.
i
Assess all sites of disease per RECIST v1.1 at screening.  Include PSA, CA-125, CEA, CA19-9, and/or AFP tests, if appropriate.  The same 
imaging method and serum marker tests used at screening must be used throughout the study.  A documented standard of care assessment 
performed within 28 days before Day 1 may be used for screening.  See Section 4.5.1.d and Appendices C, D, and E.
j
CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.
k Fasting (10-hour fast) serum of plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
l
Collect fasting insulin and glucose sample per schedule provided in Appendices B-4.  Glucose levels may be obtained by fingerstick.
m Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.
n Includes specific gravity, pH, glucose, protein, ketones, and blood.
o Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
p Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
q Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, Day 1) and 
during the last week of Cycle 1.  Perform imaging 14 hours after GDC-0032 dose.
r
Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.
s Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient.  Pretreatment samples may be obtained on Day 1 before dosing.


Appendix A-4
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohort C (cont.)
Protocol:  GDC-0032—Genentech, Inc.
198/P PMT4979g (GO00886)-A10
t
Obtain fresh tumor tissue from those patients who sign the optional Research Informed Consent Form.  Perform biopsy before initiation of 
GDC-0032 (up to 28 days prior to Cycle 1, Day 1).  The pretreatment tissue biopsy will be reviewed by a pathologist to determine whether or not 
the tissue is evaluable.  If the pretreatment tissue is evaluable, then a subsequent biopsy will be performed between Days 15 and 21 of Cycle 1, 
approximately 14 hours after the morning dose.  If there is only one lesion for both the biopsy and imaging scans, perform the biopsy 
immediately after the scan or at least 1 week prior to FDG-PET imaging or other scans.  If two different lesions are being biopsied and scanned, 
then the second lesion may be biopsied anytime between Days 15 and 21.
u Obtain PK and pharmacogenetic samples according to the schedule provided in Appendices B-4; PK blood samples should be prepared to 
obtain plasma.  Exploratory PK analyses will be run on any leftover samples if the patient specifically consents to this optional testing.  
The pharmacogenetic blood sample may be obtained on Cycle 1 Day 1 prior to dosing.
v Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study.
w On clinic visit days, administer the dose of GDC-0032 in the clinic.  On Day 2, dispense a sufficient number of capsules to the patient to last only 
until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and diary 
completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform GDC-0032 accountability.
x Record all medications used by patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements).


Protocol:  GDC-0032—Genentech, Inc.
199/P PMT4979g (GO00886)-A10
Appendix A-5
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts E and F
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
8 (1)
15 (1)
16 (1)
22 (1)
Informed consent(s) (28 to 1 days)
x
Medical history and demographic data c
x
Complete physical examination d
x
x
Limited physical examination e
x
x
x
Weight and height (height at screening only)
x
x
x
x
x
Vital signs f
x
x
x
x g
x
x
ECOG performance status (see Appendix F)
x
x
12-Lead electrocardiogram h
x
x
x
x
Tumor assessment i
x
CBC with differential and platelet count j
x
x
x
x
Fasting serum or plasma chemistry k
x
x
x
x
Glycosylated hemoglobin (HBA1c)
x
Fasting insulin and glucose l
x
x
x
x
Fasting lipid profile and amylase m
x
x
x
Coagulation (INR and aPTT)
x
Serum fibrinogen
x
x
Urinalysis (laboratory) n
x
Pregnancy test o
x
Flow cytometry (FACS) p
x
FDG-PET imaging q
x
x


Appendix A-5
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts E and F (cont.)
Protocol:  GDC-0032—Genentech, Inc.
200/P PMT4979g (GO00886)-A10
Assessment
Screening a
Pretreatment b
Cycle 1
Cycle Day (Window)
14 to 1
1
8 (1)
15 (1)
16 (1)
22 (1)
Blood sample for CTCs r
x
x
Blood sample for ctDNA s
x
Optional fresh tumor tissue biopsy t
x
x
Plasma PK samples u
x
x
x
x
Archival tumor tissue v
x
Pharmacogenetic blood sample (CYP450 genotyping) u
x
GDC-0032 dosing w
x
x
x
x
Letrozole dosing (Cohort E only) x
x
x
x
x
Fulvestrant dosing (Cohort F only) y
x
x
Adverse events
x
x
x
x
x
Concomitant medications
x z
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors version 1.1.
a Perform within 14 days prior to Day 1, with the exception of informed consent and the baseline tumor assessment, which may be obtained up to 
28 days prior to Day 1.  Assessments performed as standard of care before within the time frame required may be used for screening.
b May be performed any time during screening after a patient is determined to be eligible for the study and prior to Day 1 of Cycle 1.
c Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
d A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
e Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate.


Appendix A-5
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts E and F (cont.)
Protocol:  GDC-0032—Genentech, Inc.
201/P PMT4979g (GO00886)-A10
f
Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.
g Obtain vital signs predose and 2, 4, and 8 hours postdose.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECG at screening.  Perform triplicate 12-lead 
electronic ECGs measurements on Day 1 (predose and 3 hours postdose) and Day 15 of Cycle 1 (predose, and 4, 8, and 24 hours postdose).  
A 30-minutes window is acceptable for all timepoints.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed 
or stabilized, evaluate for causes of QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.
i
Assess all sites of disease per RECIST v1.1 at screening.  Include PSA, CA-125, CEA, CA19-9, and/or AFP tests, if appropriate.  The same 
imaging method and serum marker tests used at screening must be used throughout the study.  A documented standard of care assessment 
performed within 28 days before Day 1 may be used for screening.  See Section 4.5.1.d and Appendices C, D, and E.
j
CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.
k Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total 
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
l
Collect fasting insulin and glucose sample per schedule provided in Appendices B-5 and B-6.  Glucose levels may be obtained by fingerstick.
m Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.
n Includes specific gravity, pH, glucose, protein, ketones, and blood.
o Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
p Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
q Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, Day 1) and at 
during the last week of Cycle 1. Perform imaging 14 hours after GDC-0032 dose.
r
Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.
s Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient.  Pretreatment samples may be obtained on Day 1 before dosing.


Appendix A-5
Study Flowchart:  Screening and Cycle 1 Assessments for Stage 2, Cohorts E and F (cont.)
Protocol:  GDC-0032—Genentech, Inc.
202/P PMT4979g (GO00886)-A10
t
Obtain fresh tumor tissue from those patients who sign the optional Research Informed Consent Form.  Perform biopsy before initiation of 
GDC-0032 (up to 28 days prior to Cycle 1, Day 1).  The pretreatment tissue biopsy will be reviewed by a pathologist to determine whether or not 
the tissue is evaluable.  If the pretreatment tissue is evaluable, then a subsequent biopsy will be performed between Days 15 and 21 of Cycle 1, 
approximately 14 hours after the morning dose.  If there is only one lesion for both the biopsy and imaging scans, perform the biopsy 
immediately after the scan or at least 1 week prior to FDG-PET imaging or other scans.  If two different lesions are being biopsied and scanned, 
then the second lesion may be biopsied anytime between Days 15 and 21.
u Obtain PK and pharmacogenetic samples according to the schedule provided in Appendices B-5 and B-6; PK blood samples should be prepared 
to obtain plasma.  Exploratory PK analyses will be run on any leftover samples if the patient specifically consents to this optional testing.  
The pharmacogenetic blood sample may be obtained on Cycle 1 Day 1 prior to dosing. 
v Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study.
w On clinic visit days, administer the dose of GDC-0032 in the clinic.  On Day 1, dispense a sufficient number of capsules to the patient to last only 
until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and diary 
completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform GDC-0032 accountability.
x Cohort E only:  On clinic visit days, administer the dose of letrozole in the clinic.  On Day 1, dispense a sufficient number of letrozole capsules to 
the patient to last only until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on letrozole dosing 
procedures and diary completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform letrozole accountability.
y Cohort F only:  Administer the dose of fulvestrant in the clinic.
z Record all medications used by patient within 7 days before screening (including prescription, over-the-counter, herbal remedies, and 
supplements).


Protocol:  GDC-0032—Genentech, Inc.
203/P PMT4979g (GO00886)-A10
Appendix A-6
Study Flowchart:  Assessments for Continuation of Treatment beyond Cycle 1
(Stage 1; Stage 2, Cohorts AG)
Assessment
Cycle 2
Cycles 36
Cycles 7
Odd-Numbered Cycles
Cycles 7
Even-Numbered Cycles
Study Completion/ 
Early Termination a
Cycle Day
1b
8
15
1
15
1
1
Visit Window (Day[s])
1
1
1
1
1
3
3
2 Weeks
Complete physical examination c
x
x
x
x
Limited physical examination d
x
x
x
x
Weight
x
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
x
ECOG performance status (see 
Appendix F)
x
x
x
x
x
12-Lead electrocardiogram f
x
x
x
Tumor assessment g
x
x
x
x
CBC with differential and platelet count h
x
x
x
x
x
x
x
x
Fasting serum or plasma chemistry i
x
x
x
x
x
x
x
x
Fasting insulin and glucose j
x
x
x
x
x
Fasting lipid profile and amylase k
x
x
x
x
Serum fibrinogen
x
x
x
x
Flow cytometry (FACS) l
x
x
x
x
FDG-PET imaging m
x
Plasma PK samples n
x
x
x
x
x
Blood sample for CTCs o
x
x
Blood sample for ctDNA p
x
x


Appendix A-6
Study Flowchart:  Assessments for Continuation of Treatment beyond Cycle 1
(Stage 1; Stage 2, Cohorts AG) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
204/P PMT4979g (GO00886)-A10
Assessment
Cycle 2
Cycles 36
Cycles 7
Odd-Numbered Cycles
Cycles 7
Even-Numbered Cycles
Study Completion/ 
Early Termination a
Cycle Day
1b
8
15
1
15
1
1
Visit Window (Day[s])
1
1
1
1
1
3
3
2 Weeks
Optional fresh tumor tissue biopsy q
x
GDC-0032 dosing r
x
x
x
x
x
x
x
Letrozole dosing (Cohort E only) s
x
x
x
x
x
x
x
Fulvestrant dosing (Cohort F only) t
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x u
Concomitant medications
x
x
x
x
x
x
x
x
aPTTactivated partial thromboplastin time; CA-125cancer antigen 125; CTCs circulating tumor cells; ctDNAcirculating tumor DNA; 
DLT dose-limiting toxicity; FACSfluorescence-activated cell sorter; FDG-PET 18fluorodeoxyglucose positron emission tomography; 
INRinternational normalized ratio; PKpharmacokinetic; PSAprostate-specific antigen; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors version 1.1.
Notes:  All assessments should be performed before dosing unless otherwise noted.  Some assessments may be done outside the window 
indicated to accommodate holidays and unforeseen scheduling issues, depending on the assessment, and ongoing safety issues with the trial and 
with the patient, after approval by the Medical Monitor.
a The Study Completion/Early Termination Visit should be performed within 30 days (2 weeks) after the last dose of GDC-0032.
b The end of Cycle 1 visit is the same as the Cycle 2, Day 1 visit.  All assessments will be performed and results should be reviewed before dosing 
for Cycle 2.
c A complete physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
d Changes from baseline abnormalities should be recorded at each subsequent limited, symptom-directed, physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate. 
e Vital signs will include measurements of heart rate, respiratory rate, and systolic and diastolic blood pressure while the patient is in a seated 
position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after patient has been in a seated position for 5 minutes.


Appendix A-6
Study Flowchart:  Assessments for Continuation of Treatment beyond Cycle 1
(Stage 1; Stage 2, Cohorts AG) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
205/P PMT4979g (GO00886)-A10
f
Perform triplicate digital 12-lead ECG after administration of GDC-0032 at the specified visits.  On Cycle 2, Day 1, also perform triplicate digital 
12-lead ECG prior to administration of GDC-0032.  If QTc prolongation (500 msec) is noted, repeat ECG until the prolongation is reversed or 
stabilized, evaluate for causes of QT prolongation such as electrolyte imbalances, and notify the Medical Monitor.  ECGs must be submitted to 
the diagnostic facility for central review.
g Assess all sites of disease per RECIST v1.1 at the end of Cycle 2 (between Days 2228) and at the end of each even-numbered cycle thereafter 
(i.e., every 8 weeks; between Days 2228).  For patients in the study for 24 cycles, imaging may be performed every 12 weeks.  Perform 
assessments before dosing at the next scheduled cycle.  Include PSA or CA-125 tests, if appropriate.  The same imaging method and serum 
marker tests used at screening must be used throughout the study.  See Section 4.5.1.d and Appendices C, D, and E.  If a patient undergoes an 
interim tumor evaluation to confirm a partial response (i.e., between 57 weeks after previous tumor assessment), the next scheduled tumor 
assessment may be skipped.
h CBC includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.
i
Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
j
Collect fasting insulin and glucose samples per schedule provided in Appendices B-1 to B-6.  Glucose levels may be obtained by fingerstick.
k Fasting lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, amylase, and lipase.  
The assessment may be performed up to 1 week prior to Day 1 of each cycle (i.e., between Days 2228 of the previous cycle) in order for the 
test results to be available for the scheduled visit.
l
Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56).
m Optional for patients in Cohort 1 in Stage 1 (perform only if patients sign the optional consent).  Required for all other patients, starting with 
patients enrolled in Cohort 2 in Stage 1 and for all patients enrolled in Stage 2.  Perform imaging at the end of Cycle 2 (between Days 2228), 
14 hours after GDC-0032 dose.  If the Cycle 1 PET imaging shows no significant changes in tumor FDG uptake from screening, then the 
FDG-PET imaging in Cycle 2 should not be obtained.
n PK samples should be obtained according to the schedule provided in Appendices B-1 to B-6.
o Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.
p Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, at the study discontinuation visit, and 
at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) subsequent to confirmed partial or complete tumor responses and/or at 
progressive disease (per RECIST) for any patient. Pretreatment samples may be obtained on Day 1 before dosing.
q Obtain optional fresh tumor tissue upon disease progression from those patients who sign the optional Research Informed Consent Form.


Appendix A-6
Study Flowchart:  Assessments for Continuation of Treatment beyond Cycle 1
(Stage 1; Stage 2, Cohorts AG) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
206/P PMT4979g (GO00886)-A10
r
On clinic visit days, administer the dose of GDC-0032 in the clinic.  On Day 1, dispense a sufficient number of capsules or tablets to the patient 
to last only until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on GDC-0032 dosing procedures and 
diary completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform GDC-0032 accountability.
s Cohort E only:  On clinic visit days, administer the dose of letrozole in the clinic.  On Day 1, dispense a sufficient number of letrozole capsules to 
the patient to last only until the next visit or, at the investigator’s discretion, until the next cycle.  Instruct the patient on letrozole dosing 
procedures and diary completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform letrozole accountability.
t
Cohort F only:  Administer the dose of fulvestrant in the clinic.
u Patients with unresolved adverse events thought to be related to GDC-0032 must be followed as clinically indicated, until the event is resolved or 
stabilized, another anti-cancer therapy is initiated, the patient is lost to follow up, or it has been determined that the study treatment or 
participation is not the cause of the adverse event.


Protocol:  GDC-0032—Genentech, Inc.
207/P PMT4979g (GO00886)-A10
Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before 
LPI 6 months
Assessment
Screening Pretreatment
Cycle 1
Cycle 2
Cycles 
3 
Treatment 
Completion a
(within 
30 Days after 
Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
8
(2 
days)
15 
(2 
days)
1 
(2 days)
15
(2 
days)
1
(3 
days)
Informed consent
x
Medical history and demographic 
data b
x
Concomitant medications c
x
x
x aa
x
x
x
x
x
Adverse events d
x
x aa
x
x
x
x
x
x
B symptoms (Cohorts T and T2)
x
x
x
x
x
Vital signs e
x
x
x aa
x
x
x
x
x
Complete physical examination, 
weight f
x
x
Limited physical examination, 
weight g
x
x
x
x
x
ECOG performance status
x
x
x
x
Triplicate 12-lead ECG h
x
x
x
x
Tumor (or response) assessment i
x
End of Cycles 2, 4, 6, and 8 and every 3 cycles 
(12 weeks) thereafter
x


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
208/P PMT4979g (GO00886)-A10
Assessment
Screening Pretreatment
Cycle 1
Cycle 2
Cycles 
3 
Treatment 
Completion a
(within 
30 Days after 
Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
8
(2 
days)
15 
(2 
days)
1 
(2 days)
15
(2 
days)
1
(3 
days)
Bone scan (Cohorts J, K, L, M, N, P, 
Q, R, and S) j
x
End of Cycles 3, 6, and 8, and every 3 cycles 
(12 weeks) thereafter
Bone marrow aspiration and biopsy 
(Cohorts T and T2)
x
As indicated with tumor assessment only if marrow 
involvement is present at screening bb
Pregnancy test k
x
CBC with differential and platelets l
x
x
x dd
x
x
x
x
x
Fasting serum or plasma 
chemistry m
x
x
x aa
x
x
x
x
x
LDH (Cohorts T and T2)
x
x
x
x
x
HbA1C
x
Coagulation (INR, aPTT)
x
Fasting lipid profile n
x
x
x
x
Urinalysis o
x
Pharmacogenetics sample
x
FDG-PET (Cohorts L, M, N, Q, R, 
and S) z
x
x
x
Archival tumor tissue p
x


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
209/P PMT4979g (GO00886)-A10
Assessment
Screening Pretreatment
Cycle 1
Cycle 2
Cycles 
3 
Treatment 
Completion a
(within 
30 Days after 
Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
8
(2 
days)
15 
(2 
days)
1 
(2 days)
15
(2 
days)
1
(3 
days)
Optional fresh tumor biopsy q
x
x
x
Mandatory PD tumor biopsy 
(Cohorts N and P)
x
x
Confirmation of receipt of adequate 
tissue for PIK3CA assessment 
(Cohort X)
x
Tumor tissue specimen (Cohort 
T2) cc
x
Confirmation of KRAS wild-type 
status for Cohort X8
x
Tissue sample at disease 
progression *
Tissue taken anytime following disease progression
Blood sample for ctDNA r
x
x
x
Blood sample for CTC (Cohorts 
HP) s
x
x
x
x
Chemokine and cytokine blood 
sample t
x
x
x
Flow cytometry u
x
x
x


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
210/P PMT4979g (GO00886)-A10
Assessment
Screening Pretreatment
Cycle 1
Cycle 2
Cycles 
3 
Treatment 
Completion a
(within 
30 Days after 
Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
8
(2 
days)
15 
(2 
days)
1 
(2 days)
15
(2 
days)
1
(3 
days)
Pharmacokinetics sample
See Appendices B-7 to B-14 for 
Cohorts H, J, K, L, M, N, P, Q, R, S, T, 
T2, and X
Fulvestrant administration (Cohorts 
J, K, L, and M) v
x
x
x
x
Letrozole administration (Cohorts N, 
P, Q, R, and S) y
x
x
x
GDC-0032 administration in the 
clinic w
x
x
x
x
x
Follow-up assessment for survival x
x
aPTTactivated partial thromboplastin time; BUNblood urea nitrogen; CBCcomplete blood count; C1D1Cycle 1 Day 1; CT computed
tomography; CTCcirculating tumor cells; Dday; ECGelectrocardiogram; ECOGEastern Cooperative Oncology Group; EOT end of 
treatment; FFPEformalin-fixed paraffin-embedded; INRinternational normalized ratio; MRImagnetic resonance image; PDpharmacodynamic; 
RBCred blood cell; WBCwhite blood cell.
Note:  i) Screening Labs must be valid within 28 days prior to C1D1. ii) Assessments scheduled on the day of study drug administration in the clinic 
(e.g., Cycle 2 Day 1) should be performed prior to study drug administration, unless otherwise noted.  Results should be reviewed prior to the 
administration of the study drug treatments.  iii) Discontinuation of GDC-0032 treatment, i.e., EOT (GDC-0032), after LPI 6 months 
(approximately 31 December 2018) will also constitute discontinuation from the study. iv) Patients continuing treatment beyond LPI 6 
months will undergo a reduced set of assessments, as outlined in Appendix A-9.
a The visit at which disease progression is recorded may serve as the treatment completion visit.


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
211/P PMT4979g (GO00886)-A10
b Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity.
c Concomitant medications include prescription medication, over-the-counter preparations, herbal/homeopathic remedies, and therapies used 
within 7 days prior to screening visit and investigational and anti-cancer therapies used within 28 days prior to Cycle 1 Day 1.
d Record adverse events during the study and for 30 days after the last dose of study drug or study discontinuation/termination, whichever is later.  
Follow any serious adverse events and treatment-related adverse events that are ongoing at treatment completion until the event resolves or 
stabilizes, patient is lost to follow-up, new anti-tumor treatment is initiated, patient withdraws consent, or it is determined that study treatment or 
participation is not the cause of the adverse event.
e Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic blood pressure while the patient is in a seated position, 
and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after the patient has been in a seated position for 5 minutes.
f
Complete physical examination should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems and measurement of weight.
g Limited physical examination, including measurement of weight, should be performed to assess and record changes from baseline abnormalities.  
New or worsened abnormalities should be recorded as adverse events if appropriate.  For patients on study for 24 cycles, limited physical 
exam may be performed every other cycle.
h Submit all ECGs to the diagnostic facility for central review.  Perform triplicate digital 12-lead ECGs at screening, on Cycle 1 Day 15 (pre-dose) 
and Cycle 2 Day 1 (pre-dose) for Cohorts H, J, K, M, N, P, Q, R, T, and X.  For Cohorts L and S, perform triplicate digital 12-lead ECGs at 
screening only.  The triplicate ECGs need to be completed within 30 min of the specified PK sample (i.e., ECGs needs to be time-matched to 
pre-dose PK sample on Cycle 1 Day 15 and Cycle 2 Day 1).  Triplicate digital ECG recordings will be obtained within approximately 2−5 minutes 
at each specified timepoint.  The average of the 3 readings will be used to determine ECG intervals (e.g., PR, QT).  ECGs for each patient 
should be obtained from the same machine whenever possible.  To minimize variability, it is important that patients be in a resting position for 
10 minutes prior to each ECG evaluation.  Body position should be consistently maintained for each ECG evaluation to prevent changes in 
heart rate.  Environmental distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting period and during 
ECG recording.  ECGs should be performed prior to any scheduled vital sign measurements and blood draws.  If QTc prolongation (500 msec) 
is noted, repeat ECG until the prolongation is reversed or stabilized, evaluate for causes of QT prolongation such as electrolyte imbalances, and 
notify the Medical Monitor.  Perform ECG at the treatment completion visit, and when clinically indicated.
i
Assess all sites of disease per RECIST v1.1 or the Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma 
(Cohort T) at screening (28 days prior to Cycle 1 Day 1), the end of Cycles 2, 4, 6, and 8 (between Days 2228), and at the end of every 
3 cycles thereafter (i.e., every 12 weeks between Days 2228).  Cohort T2 will use the Lugano Response Criteria, as detailed in Appendix J.  
Perform assessments before dosing at the next scheduled cycle. The same imaging method and serum marker tests used at screening must be 
used throughout the study.


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
212/P PMT4979g (GO00886)-A10
j
Perform a technetium bone scan at screening to rule out bone metastases.  In addition, bone disease identified on bone imaging should be 
evaluated radiographically by CT scan, MRI, or X-ray.  In patients without bone-only disease, bone scans should be repeated in the event of 
clinical suspicion of progression of existing bone lesions, the development of new bone lesions, and in the assessment of a complete response, 
if any disease was evident at screening.  Any changes in bone imaging should be evaluated radiographically by CT scan, MRI, or X-ray to 
ascertain the presence of bone destruction versus a healing reaction.  For patients with bone-only disease not visible on the CT or MRI scans 
being performed as part of the tumor assessments, bone scans should be repeated at the end of Cycles 3, 6, and 8, and every three cycles 
(12 weeks) thereafter (1 week for flexibility in the event of isotope shortage).  Any changes in bone imaging should be evaluated 
radiographically by CT scan, MRI, or X-ray to ascertain the presence of bone destruction versus a healing reaction.  In the event that it is not 
feasible to perform a bone scan or it is anticipated that it will not be feasible to perform bone scans throughout the study, 18F NaF PET scans 
may be substituted, with the Sponsor’s approval.  The same modality used at screening should be used throughout the study.
k Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
l
includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.  Patients enrolled in Cohorts T and T2 should have a weekly CBC for the first two 
cycles and then on Day 1 of each subsequent cycle or more frequently as clinically indicated.  
m Fasting (10 hours) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total 
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
n Fasting (10 hours) lipid profile should be performed at screening, Day 1 of Cycles 1, 3, and every 3 cycles thereafter and includes total 
cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, amylase, and lipase. 
o Specific gravity, pH, glucose, protein, ketones, and blood.
p Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study; except in Cohort X, 
archival tissue must be submitted and deemed evaluable prior to enrollment in Cohort X.
q Obtain fresh tumor tissue from patients who have signed the optional Research Informed Consent Form or who are enrolled in a mandatory 
tumor biopsy slot in Cohorts N, P, and X3.  Perform biopsy before initiation of GDC-0032 (up to 28 days prior to Cycle 1 Day 1).  For Cohorts K 
and R (5-day on, 2-day off schedule), the on-treatment biopsy will occur between Cycle 1 Day 15 and Cycle 1 Day 19, approximately 14 hours 
after the morning dose of GDC-0032.  For other cohorts (H, J, L, M, N, P, Q, S, T, T2, and X), the on-treatment biopsy will occur between 
Cycle 1 Day 15 and Cycle 1 Day 21, approximately 14 hours after the morning dose of GDC-0032.
* Obtain fresh tumor biopsy upon disease progression from those who sign the optional Research Informed Consent Form.
r
Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 5 Day 1, at the study 
discontinuation visit, and at clinic visits on Day 1 of every odd numbered cycle (e.g., C7D1) for any patient.  Pretreatment samples may be 
obtained on Day 1 before dosing.


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
213/P PMT4979g (GO00886)-A10
s Blood will be collected for CTC analysis for Cohorts H, J, K, L, M, N, and P prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at 
the study discontinuation visit, and at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease 
(per RECIST) for any patient.
t
Obtain blood sample for plasma cytokine and chemokine analysis.  Samples must be collected before dosing on Cycle 1 Day 1, Cycle 1 Day 15, 
and at the treatment completion visit.
u Obtain a blood sample for flow cytometry for lymphocyte subsets by FACS (CD19, CD3, CD4, CD8, CD16, and CD56) prior to dosing on Cycle 1 
Day 1, Cycle 3 Day 1, and at the study discontinuation visit.
v Fulvestrant will be administered in the clinic as two intramuscular injections of 250 mg each on Days 1 and 15 of Cycle 1 and Day 1 of each 
subsequent 28-day cycle.
w GDC-0032 will be taken orally once daily beginning on Cycle 1 Day 1.  For Cohorts H and J, GDC-0032 will be taken on Days 121 of each 28-
day cycle.  For Cohort K, GDC-0032 will be taken on Days 15, 812, 1519, and 2226 of each 28-day cycle.  For Cohort L, GDC-0032 will be 
taken on Days 17 and 1521 of each 28-day cycle.  GDC-0032 will be administered in the clinic at each scheduled clinic visit, after the predose 
assessments and procedures, and at home on all non-clinic visit days.  A sufficient number of study drug tablets to last until the next visit, or, at 
the investigator’s discretion, to last until the next administration of fulvestrant.  Extra tablets may be dispensed if there is a reasonable possibility 
that the patient’s next visit may be delayed (e.g., because of inclement weather or distance between the patient’s home and study center).  
Patients will also receive a medication diary.  Instruct patient to record the time and date each treatment dose is taken in the diary and to return 
all unused tablets at each study visit.  Collect and review medication diary and unused tablets and assess compliance at each subsequent visit.  
At the completion visit, do not dispense any additional study drug tablets or provide a new medication diary.
x All patients who discontinue from the treatment phase will be followed for survival information and subsequent anti-cancer therapies unless the 
patient requests to be withdrawn from study survival follow-up.  Survival follow-up information will be collected via telephone calls, patient’s 
medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study termination by 
Genentech.
y On Day 1 of each cycle, dispense a sufficient number of letrozole capsules to the patient to last only until the next visit or, at the investigator’s 
discretion, until the next cycle.  Instruct the patient on letrozole dosing procedures and diary completion (see Section 4.3.2).  Dispense diary and 
review at subsequent visits and perform letrozole accountability.  
z Perform FDG-PET imaging pretreatment (unless performed as a standard of care assessment and within 14 days prior to Cycle 1, Day 1) and 
during the last week of Cycle 1.  Perform Cycle 1 imaging 14 hours after GDC-0032 dose. Perform imaging at the end of Cycle 2 (between 
Days 22 and 28), 14 hours after GDC-0032 dose.  If the Cycle 1 PET imaging shows no significant changes in tumor FDG uptake from 
screening, then the FDG-PET imaging in Cycle 2 should not be obtained.
aa Cycle 1, Day 8 office visit for patients in Cohort H at 6-mg tablet dose only.


Appendix A-7
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11) before LPI 6 
months (cont.)
Protocol:  GDC-0032—Genentech, Inc.
214/P PMT4979g (GO00886)-A10
bb For patients with bone marrow involvement at screening, a repeat assessment will be performed at least once if there is radiologic evidence of a 
complete response or if clinically indicated (e.g., if there is clinical suspicion of progressive disease in the bone marrow with no radiologic 
evidence of progression).
cc Availability of adequate archival or freshly biopsied tumor tissue samples should be confirmed at screening (see Section 4.5.1 for details).
dd Cohorts T and T2 only.


Protocol:  GDC-0032—Genentech, Inc.
215/P PMT4979g (GO00886)-A10
Appendix A-8
Study Flowchart:  Phase II Portion of the Study
Assessment
Screening
Pretreatment
Cycle 1
Cycle 2
Cycles 3 
Treatment 
Completion a
(within 30 Days 
after Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
15 
(2 days)
1 
(2 days)
15
(2 days)
1
(3 days)
Informed consent
x
Medical history and demographic 
data b
x
Concomitant medications c
x
x
x
x
x
x
x
Adverse events d
x
x
x
x
x
x
x
Vital signs e
x
x
x
x
x
x
x
Complete physical examination, 
weight f
x
x
Limited physical examination, weight g
x
x
x
x
x
ECOG performance status
x
x
x
x
Triplicate 12-lead ECG h
x
x
x
Tumor assessment i
x
End of Cycles 2, 4, 6, and 8 and every 3 cycles 
(12 weeks) thereafter
x
Bone scan j
x
End of Cycles 3, 6, and 8, and every 3 cycles 
(12 weeks) thereafter
Pregnancy test k
x
CBC with differential and platelets l
x
x
x
x
x
x
x
Fasting serum or plasma chemistry m
x
x
x
x
x
x
x


Appendix A-8
Study Flowchart:  Phase II Portion of the Study (cont.)
Protocol:  GDC-0032—Genentech, Inc.
216/P PMT4979g (GO00886)-A10
Assessment
Screening
Pretreatment
Cycle 1
Cycle 2
Cycles 3 
Treatment 
Completion a
(within 30 Days 
after Last Dose)
Follow-
Up
Cycle Day (Window)
28 days 
prior to 
C1D1
28 days prior 
to C1D1
1
15 
(2 days)
1 
(2 days)
15
(2 days)
1
(3 days)
HbAIC
x
Coagulation (INR, aPTT)
x
Fasting lipid profile n
x
x
x
x
Urinalysis o
x
Archival tumor tissue p
x
Optional fresh tumor biopsy q
x
x
x
Blood sample for ctDNA r
x
x
x
x
Blood sample for CTC s
x
x
x
x
Chemokine and cytokine blood 
sample t
x
x
x
Pharmacogenetics sample
x
Pharmacokinetics sample
See Appendix B-14
Fulvestrant administration u
x
x
x
x
GDC-0032 administration in the clinic 
v
x
x
x
x
x
Follow-up assessment for survival w
x
aPTTactivated partial thromboplastin time; BUNblood urea nitrogen; CBCcomplete blood count; C1D1Cycle 1 Day 1; CT computed 
tomography; CTCcirculating tumor cells; Dday; ECGelectrocardiogram; ECOG Eastern Cooperative Oncology Group; FFPEformalin-fixed 
paraffin-embedded; INRinternational normalized ratio; MRImagnetic resonance image; RBCred blood cell; WBCwhite blood cell.


Appendix A-8
Study Flowchart:  Phase II Portion of the Study (cont.)
Protocol:  GDC-0032—Genentech, Inc.
217/P PMT4979g (GO00886)-A10
Note:  Assessments scheduled on the day of study drug administration in the clinic (e.g., Cycle 2 Day 1) should be performed prior to study drug 
administration, unless otherwise noted.  Results should be reviewed prior to the administration of the study drug treatments.  
a The visit at which disease progression is recorded may serve as the treatment completion visit.
b Medical history includes clinically significant diseases within the last 5 years, surgeries, cancer history (including tumor characteristics), 
prior cancer therapies, and procedures.  Demographic data includes age, sex, and self-reported race/ethnicity. 
c Concomitant medications include prescription medication, over-the-counter preparations, herbal/homeopathic remedies, and therapies used 
within 7 days prior to screening visit and investigational and anti-cancer therapies used within 28 days prior to Cycle 1 Day 1.
d Record adverse events during the study and for 30 days after the last dose of study drug or study discontinuation/termination, whichever is later.  
Follow any serious adverse events and treatment-related adverse events that are ongoing at treatment completion until the event resolves or 
stabilizes, patient is lost to follow-up, new anti-tumor treatment is initiated, patient withdraws consent, or it is determined that study treatment or 
participation is not the cause of the adverse event.
e Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic blood pressure while the patient is in a seated position, 
and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after the patient has been in a seated position for 5 minutes.
f
Complete physical examination should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, dermatological,
musculoskeletal, respiratory, gastrointestinal, and neurological systems and measurement of weight.  
g Limited physical examination, including measurement of weight, should be performed to assess and record changes from baseline abnormalities.  
New or worsened abnormalities should be recorded as adverse events if appropriate.
h Triplicate digital ECG recordings will be obtained within approximately 2−5 minutes at each specified timepoint.  The average of the 3 readings 
will be used to determine ECG intervals (e.g., PR, QT).  ECGs for each patient should be obtained from the same machine whenever possible.  
To minimize variability, it is important that patients be in a resting position for 10 minutes prior to each ECG evaluation.  Body position should 
be consistently maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG recording.  ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws.  The triplicate ECGs need to be completed with 30 minutes of the specified PK sample 
(i.e., PK sample needs to be time-matched to ECG).  Perform ECGs on Cycle 3 Day 1 and every 3 cycles thereafter (e.g., Day 1 of Cycles 6, 9, 
etc.), at the treatment completion visit, and when clinically indicated.
i
Assess all sites of disease per RECIST v1.1 at screening (28 days prior to Cycle 1 Day 1), the end of Cycles 2, 4, 6, and 8 (between 
Days 2228), and at the end of every 3 cycles thereafter (i.e., every 12 weeks between Days 2228).  Perform assessments before dosing at the 
next scheduled cycle.  The same imaging method and serum marker tests used at screening must be used throughout the study. 


Appendix A-8
Study Flowchart:  Phase II Portion of the Study (cont.)
Protocol:  GDC-0032—Genentech, Inc.
218/P PMT4979g (GO00886)-A10
j
Perform a technetium bone scan at screening to rule out bone metastases.  In addition, bone disease identified on bone imaging should be 
evaluated radiographically by CT scan, MRI, or X-ray.  In patients without bone-only disease, bone scans should be repeated in the event of 
clinical suspicion of progression of existing bone lesions, the development of new bone lesions, and in the assessment of a complete response, 
if any disease was evident at screening.  Any changes in bone imaging should be evaluated radiographically by CT scan, MRI, or X-ray to 
ascertain the presence of bone destruction versus a healing reaction.  For patients with bone-only disease not visible on the CT or MRI scans 
being performed as part of the tumor assessments, bone scans should be repeated at the end of Cycles 3, 6, and 8, and every three cycles 
(12 weeks) thereafter (1 week for flexibility in the event of isotope shortage).  Any changes in bone imaging should be evaluated 
radiographically by CT scan, MRI, or X-ray to ascertain the presence of bone destruction versus a healing reaction.  In the event that it is not 
feasible to perform a bone scan or it is anticipated that it will not be feasible to perform bone scans throughout the study, 18F NaF PET scans 
may be substituted, with the Sponsor’s approval.  The same modality used at screening should be used throughout the study.
k Serum or urine pregnancy test for women of childbearing potential, including premenopausal women who have had a tubal ligation.
l
includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, eosinophils, basophils, 
lymphocytes, monocytes, and other cells), and platelet count.
m Fasting (10-hour fast) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, phosphorus, total
protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
n Fasting (10 hours) lipid profile should be performed at screening, Day 1 of Cycles 1, 3, and every 3 cycles thereafter and includes total 
cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, amylase, and lipase. 
o Specific gravity, pH, glucose, protein, ketones, and blood.
p Archival tissue from any prior tumor excision or biopsy performed at any time during the course of the patient’s illness will be requested from the 
pathology department of origin.  Archival tissue availability will not affect the time a patient may start or enroll into the study. 
q Obtain fresh tumor tissue from patients who have signed the optional Research Informed Consent Form.  Perform biopsy before initiation of 
GDC-0032 (up to 28 days prior to Cycle 1 Day 1).  The on-treatment biopsy will occur between Cycle 2 Day 1 and Cycle 2 Day 15, approximately 
14 hours after the morning dose of GDC-0032.  Obtain optional fresh tumor tissue upon disease progression from those patients who sign the 
optional Research Informed Consent Form.
r
Blood will be collected for ctDNA analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 5 Day 1, at the study 
discontinuation visit, and at clinic visits on Day 1 of every odd numbered cycle (e.g., Cycle 7 Day 1) subsequent to confirmed partial or complete 
tumor response and/or at progressive disease (per RECIST) for any patient.  Pretreatment samples may be obtained on Day 1 before dosing. 
s Blood will be collected for CTC analysis prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, at the study discontinuation visit, and 
at the clinic visit subsequent to the first confirmed partial or complete tumor response or progressive disease (per RECIST) for any patient.  
t
Obtain blood sample for plasma cytokine and chemokine analysis.  Samples must be collected before dosing on Cycle 1 Day 1, Cycle 1 Day 15, 
and at the treatment completion visit.


Appendix A-8
Study Flowchart:  Phase II Portion of the Study (cont.)
Protocol:  GDC-0032—Genentech, Inc.
219/P PMT4979g (GO00886)-A10
u Fulvestrant will be administered in the clinic as two intramuscular injections of 250 mg each on Days 1 and 15 of Cycle 1 and Day 1 of each 
subsequent 28-day cycle.
v GDC-0032 will be taken orally once daily beginning on Cycle 1 Day 1.  GDC-0032 will be administered in the clinic at each scheduled clinic visit, 
after the predose assessments and procedures, and at home on all non-clinic visit days.  A sufficient number of study drug tablets to last until the 
next visit, or, at the investigator’s discretion, to last until the next administration of fulvestrant.  Extra tablets may be dispensed if there is a 
reasonable possibility that the patient’s next visit may be delayed (e.g., because of inclement weather or distance between the patient’s home 
and study center).  Patients will also receive a medication diary.  Instruct patient to record the time and date each treatment dose is taken in the 
diary and to return all unused capsules at each study visit.  Collect and review medication diary and unused capsules and assess compliance at 
each subsequent visit.  At the completion visit, do not dispense any additional study drug capsules or provide a new medication diary.
w All patients who discontinue from the treatment phase will be followed for survival information and subsequent anti-cancer therapies unless the 
patient requests to be withdrawn from study survival follow-up.  Survival follow-up information will be collected via telephone calls, patient’s 
medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study termination by 
Genentech.


Protocol:  GDC-0032—Genentech, Inc.
220/P PMT4979g (GO00886)-A10
Appendix A-9
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11)
after LPI 6 Months (Patients Deriving Benefit from GDC-0032)
Assessment
Day 1 (3 days) of Each 
Treatment Cycle
Treatment Completion a
(within 30 Days after Last 
Dose)
Follow-Up
Concomitant medications b
x
x
Adverse events c
x
x
x
Vital signs d
x
x
Complete physical examination, weight e
x
Limited physical examination, weight f
x
ECOG performance status
x
x
Monitoring for disease progression
Perform per institutional 
standards
CBC with differential and platelets g
x
x
Fasting serum or plasma chemistry h
x
x
Fasting lipid profile i
x
x
Fulvestrant administration (Cohorts J, K, L,
and M) j
x
Letrozole administration (Cohorts N, P, Q, R, 
and S) k
x
GDC-0032 administration in the clinic l
x
aPTT activated partial thromboplastin time; BUN blood urea nitrogen; CBC complete blood count; C1D1 Cycle 1 Day 1; 
CT computed tomography; CTC circulating tumor cells; D day; ECG electrocardiogram; ECOG Eastern Cooperative 
Oncology Group; FFPE formalin-fixed paraffin-embedded; INR international normalized ratio; MRI magnetic resonance 
image; PD pharmacodynamic; RBC red blood cell; WBC white blood cell.


Protocol:  GDC-0032—Genentech, Inc.
221/P PMT4979g (GO00886)-A10
Appendix A-9
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11)
after LPI 6 Months (Patients Deriving Benefit from GDC-0032) (cont.)
Notes:  Assessments scheduled on the day of study drug administration in the clinic (e.g., Cycle 2 Day 1) should be performed 
prior to study drug administration, unless otherwise noted.  Results should be reviewed prior to the administration of the 
study drug treatments.
Survival follow-up will be halted as of LPI 6 months.  
a The visit at which disease progression occurs may serve as the treatment completion visit.
b Concomitant medications include prescription medication, over-the-counter preparations, herbal/homeopathic remedies, and 
therapies used within 7 days prior to screening visit and investigational and anti-cancer therapies used within 28 days 
prior to Cycle 1 Day 1.
c
Record adverse events during the study and for 30 days after the last dose of study drug or study 
discontinuation/termination, whichever is later.  Follow any serious adverse events and treatment-related adverse events 
that are ongoing at treatment completion until the event resolves or stabilizes, patient is lost to follow-up, new anti-tumor 
treatment is initiated, patient withdraws consent, or it is determined that study treatment or participation is not the cause 
of the adverse event.
d Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic blood pressure while the patient 
is in a seated position, and oral or tympanic temperature.  Oxygen saturation by pulse oximetry after the patient has been 
in a seated position for 5 minutes.
e
Complete physical examination should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems and measurement of weight.
f
Limited physical examination, including measurement of weight, should be performed to assess and record changes from 
baseline abnormalities.  New or worsened abnormalities should be recorded as adverse events if appropriate.  For patients 
on study for 24 cycles, limited physical exam may be performed every other cycle.
g Includes RBC count, hemoglobin, hematocrit, reticulocyte count, WBC count with differential (neutrophils, bands, 
eosinophils, basophils, lymphocytes, monocytes, and other cells), and platelet count.  Patients enrolled in Cohorts T and T2 
should have a weekly CBC for the first two cycles and then on Day 1 of each subsequent cycle or more frequently as 
clinically indicated.  
h Fasting (10 hours) serum or plasma chemistry:  BUN, creatinine, sodium, potassium, magnesium, bicarbonate, calcium, 
phosphorus, total protein, albumin, serum bilirubin, alkaline phosphatase, glucose, AST, and ALT.
i
Fasting (10 hours) lipid profile should be performed at screening, Day 1 of Cycles 1, 3, and every 3 cycles thereafter and 
includes total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, amylase, and lipase. 


Protocol:  GDC-0032—Genentech, Inc.
222/P PMT4979g (GO00886)-A10
Appendix A-9
Study Flowchart:  Stage 2, Cohorts H, J, K, L, M, N, P, Q, R, S, T, T2, and X (X1X11)
after LPI 6 Months (Patients Deriving Benefit from GDC-0032) (cont)
j
Fulvestrant will be administered in the clinic as two intramuscular injections of 250 mg each on Days 1 and 15 of Cycle 1 
and Day 1 of each subsequent 28-day cycle.
k On Day 1 of each cycle, dispense a sufficient number of letrozole capsules to the patient to last only until the next visit or, 
at the investigator’s discretion, until the next cycle.  Instruct the patient on letrozole dosing procedures and diary 
completion (see Section 4.3.2).  Dispense diary and review at subsequent visits and perform letrozole accountability.  
l
GDC-0032 will be taken orally once daily beginning on Cycle 1 Day 1.  For Cohorts H and J, GDC-0032 will be taken on 
Days 121 of each 28-day cycle.  For Cohort K, GDC-0032 will be taken on Days 15, 812, 1519, and 2226 of each 28-
day cycle.  For Cohort L, GDC-0032 will be taken on Days 17 and 1521 of each 28-day cycle.  GDC-0032 will be 
administered in the clinic at each scheduled clinic visit, after the predose assessments and procedures, and at home on all 
non-clinic visit days.  A sufficient number of study drug tablets to last until the next visit, or, at the investigator’s 
discretion, to last until the next administration of fulvestrant.  Extra tablets may be dispensed if there is a reasonable 
possibility that the patient’s next visit may be delayed (e.g., because of inclement weather or distance between the patient’s 
home and study center).  Patients will also receive a medication diary.  Instruct patient to record the time and date each 
treatment dose is taken in the diary and to return all unused tablets at each study visit.  Collect and review medication 
diary and unused tablets and assess compliance at each subsequent visit.  At the completion visit, do not dispense any 
additional study drug tablets or provide a new medication diary.




Protocol:  GDC-0032—Genentech, Inc.
224/P PMT4979g (GO00886)-A10
Appendix B-1
Pharmacokinetic, Surrogate Pharmacodynamic, and CYP450 
Genotyping Flowchart for Patients in Stage 1 (cont.)
Cycle and Day
Timepoint(s)
Assessment/Procedure
Draw Sequence
Cycle 1, Day 15
(1 day) 
(cont’d)
3 hours postdose
GDC-0032 PK 
1
GDC-0032 PD
2
4 hours postdose
GDC-0032 PK 
1
8 hours postdose
GDC-0032 PK
1
GDC-0032 PD
2
Cycle1, Day 16 
(1 day)
24 hours postdose (2 hours)
GDC-0032 PK c
1
Cycle 1, Day 22
(1 day)
Predose a
GDC-0032 PK
1
GDC-0032 PD 
2
Insulin and glucose b
3
2 hours postdose
Insulin and glucose b
1
Cycle 1, Day 29
(1 day)
Predose a
GDC-0032 PK
1
Insulin and glucose b
2
2 hours postdose
Insulin and glucose b
1
Cycles 26, 
Day 1
(1 day)
Predose a
GDC-0032 PK
1
Insulin and glucose b
2
2 hours postdose
Insulin and glucose b
1
Cycles 7, Day 1
(3 days)
Predose a
GDC-0032 PK 
1
Insulin and glucose b
2
2 hours postdose
Insulin and glucose b
1
Study 
Completion/ 
Early 
Termination Visit
GDC-0032 PK 
1
Insulin and glucose b
2
PDpharmacodynamic; PK pharmacokinetic.
Notes:  Except where noted, all sample draw times are 10 minutes.  For the PK samples, the 
plasma will be split into two equal aliquots:  a primary sample and a backup sample. 
Unless otherwise instructed, GDC-0032 should be taken on an empty stomach 
(i.e., approximately 1 hour before or 2 hours after a meal), except on days of extensive PK 
sampling (Days 1 and 15 of Cycle 1) when administration will be under fasted conditions.  For 
administration under fasted conditions, patients will fast overnight for at least 10 hours before 
dosing and 4 hours postdose and will refrain from drinking water from 1 hour before and until 
1 hour after dosing, with the exception of GDC-0032 administration when the capsules will be 
swallowed whole (not chewed) with 240 mL (8 fluid ounces) of water.  On the day of GDC-0032
dosing in the clinic, patients will receive a standard meal at 4 hours postdose.
a The blood samples will optimally be obtained within 5 minutes prior to dosing but may be 
obtained up to 2 hours prior to dosing.
b Obtain samples for glucose and insulin only from patients in fasted state.  Do not obtain 
samples from patients who receive a standard meal before dosing.  Glucose levels may be 
obtained by fingerstick.
c
The PK draw is scheduled prior to the morning dose.






Appendix B-2
Pharmacokinetic, Insulin and Glucose, and CYP450 Genotyping 
Flowchart for Stage 2, Cohort A (Effect of Food on GDC-0032 
Pharmacokinetics in Patients with PIK3CA-Mutant Breast 
Cancers) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
227/P PMT4979g (GO00886)-A10
swallowed whole (not chewed) with 240 mL (8 fluid ounces) of water.  On the day of 
GDC-0032 dosing in the clinic, patients will receive a standard meal at 4 hours postdose.  
Unless otherwise instructed, all other doses will be taken on an empty stomach (approximately 
1 hour before or 2 hours after a meal).
b The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
c Samples for glucose and insulin should only be obtained from patients in a fasted state.  
For patients who receive a standard meal before dosing, do not obtain samples.
d The PK draw is scheduled prior to the morning dose. 
e Patients should be in a fasted state (fasted predose for 10 hours and 4 hours postdose).  
The postdose sample is not required for patients not being dosed that day.




Appendix B-3
Pharmacokinetic, Insulin and Glucose, and CYP450 Genotyping 
Flowchart for Stage 2, Cohort B (Patients with PIK3CA-Mutant 
Solid Tumors), Cohort D (Patients with HER2-Positive Breast 
Cancers), and Cohort G (Patients with PIK3CA-Amplified Solid 
Tumors) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
229/P PMT4979g (GO00886)-A10
a The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
b Samples for glucose and insulin should only be obtained from patients in a fasted state (fasted 
predose for 10 hours and 4 hours postdose).  For patients who receive a standard meal 
before dosing, do not obtain samples.




Appendix B-4
Pharmacokinetic, Insulin and Glucose, and CYP450 Genotyping 
Flowchart for Stage 2, Cohort C (Effect of GDC-0032 on 
Midazolam in Patients with Solid Tumors) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
231/P PMT4979g (GO00886)-A10
Study Visit
Timepoint(s)
Assessment/Procedure
Draw 
Sequence
Cycles 26, 
Day 1
(1 day)
Predose a
GDC-0032 PK
1
Insulin and glucose b
2
Cycles 7, 
Day 1
(3 days)
Predose a
GDC-0032 PK
1
Insulin and glucose b
2
Study 
Completion/Early 
Termination Visit
GDC-0032 PK
1
Insulin and glucose b
2
PK pharmacokinetic.
Notes:  Except where noted, all sample draw times are 10 minutes.  For the PK samples, the 
plasma will be split into two equal aliquots:  a primary sample and a back-up sample.
Unless otherwise instructed, GDC-0032 should be taken on an empty stomach 
(i.e., approximately 1 hour before or 2 hours after a meal), except on days of extensive PK 
sampling (Days 1 and 8 of Cycle 1) and on study days with scheduled fasting insulin and glucose 
measures when administration will be under fasted conditions.  For administration under fasted 
conditions, patients will fast overnight for at least 10 hours before dosing and 4 hours postdose 
and will refrain from drinking water from 1 hour before and until 1 hour after dosing, with the 
exception of GDC-0032 (and midazolam) administration when the doses will be swallowed whole 
(not chewed) with approximately 240 mL (8 fluid ounces) of water.  On the day of GDC-0032 
dosing in the clinic, patients will receive a standard meal at 4 hours postdose.
a The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
b Samples for glucose and insulin should only be obtained from patients in a fasted state (fasted 
predose for 10 hours and 4 hours postdose).  For patients who receive a standard meal 
before dosing, do not obtain samples.
c The blood draw is scheduled prior to the morning dose.




Appendix B-5
Pharmacokinetic, Insulin and Glucose, and CYP450 Genotyping 
Flowchart for Stage 2, Cohort E (GDC-0032 in Combination with 
Letrozole in Patients with Hormone Receptor-Positive Breast 
Cancer) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
233/P PMT4979g (GO00886)-A10
Study Visit
Timepoint(s)
Assessment/Procedure
Draw 
Sequence
Day 1
(3 days)
Letrozole PK
2
Insulin and glucose b
3
Study 
Completion/Early 
Termination Visit
GDC-0032 PK
1
Letrozole PK
2
Insulin and glucose b
3
PK pharmacokinetic.
Notes:  Except where noted, all sample draw times are 10 minutes.  For the PK samples, the 
plasma will be split into two equal aliquots:  a primary sample and a back-up sample.
Unless otherwise instructed, GDC-0032 should be taken on an empty stomach 
(i.e., approximately 1 hour before or 2 hours after a meal), except on days with scheduled fasting 
insulin and glucose measures when administration will be under fasted conditions.  For 
administration under fasted conditions, patients will fast overnight for at least 10 hours before 
dosing and 4 hours postdose and will refrain from drinking water from 1 hour before and until 
1 hour after dosing, with the exception of GDC-0032 administration when the doses will be 
swallowed whole (not chewed) with approximately 240 mL (8 fluid ounces) of water.  On the day 
of GDC-0032 dosing in the clinic, patients will receive a standard meal at 4 hours postdose.
a The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
b Samples for glucose and insulin should only be obtained from patients in a fasted state (fasted 
predose for 10 hours and 4 hours postdose).  For patients who receive a standard meal 
before dosing, do not obtain samples.
c
The PK draw is scheduled prior to the morning dose.




Appendix B-6
Pharmacokinetic, Insulin and Glucose, and CYP450 Genotyping 
Flowchart for Stage 2, Cohort F (GDC-0032 in Combination with 
Fulvestrant in Patients with Hormone Receptor-Positive Breast 
Cancer) (cont.)
Protocol:  GDC-0032—Genentech, Inc.
235/P PMT4979g (GO00886)-A10
PK pharmacokinetic.
Notes:  Except where noted, all sample draw times are 10 minutes.  For the PK samples, the 
plasma will be split into two equal aliquots:  a primary sample and a back-up sample.
Unless otherwise instructed, GDC-0032 should be taken on an empty stomach 
(i.e., approximately 1 hour before or 2 hours after a meal), except on days with scheduled fasting 
insulin and glucose measures when administration will be under fasted conditions.  For 
administration under fasted conditions, patients will fast overnight for at least 10 hours before 
dosing and 4 hours postdose and will refrain from drinking water from 1 hour before and until 
1 hour after dosing, with the exception of GDC-0032 administration when the doses will be 
swallowed whole (not chewed) with approximately 240 mL (8 fluid ounces) of water.  On the day 
of GDC-0032 dosing in the clinic, patients will receive a standard meal at 4 hours postdose.
a The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
b Samples for glucose and insulin should only be obtained from patients in a fasted state (fasted 
predose for 10 hours and 4 hours postdose).  For patients who receive a standard meal 
before dosing, do not obtain samples.
c The PK draw is scheduled prior to the morning dose.


Protocol:  GDC-0032—Genentech, Inc.
236/P PMT4979g (GO00886)-A10
Appendix B-7
Pharmacokinetic Sample Collection:  Phase I, Stage 2, Cohorts H
and X Patients
Study Visit
Time
Event
Cycle 1, Day 15
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032
3 hours (60 minutes) 
postGDC-0032 administration.
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032
Cycle 6, Day 1
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032
Note:  See Appendix B-10 for PK sample collection for Cohort X3 patients with head and neck 
cancers who are taking GDC-0032 as suspension.


Protocol:  GDC-0032—Genentech, Inc.
237/P PMT4979g (GO00886)-A10
Appendix B-8
Pharmacokinetic Sample Collection:  Phase I, Stage 2,
Cohorts J, K, and M Patients
Study Visit
Time
Event
Cycle 1, Day 15
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for 
fulvestrant
Predose plasma sample for 
GDC-0032
3 hours (60 min)  postGDC-0032 
administration.
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for 
fulvestrant
Predose plasma sample for 
GDC-0032
Cycle 6, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for 
fulvestrant
Predose plasma sample for 
GDC-0032


Protocol:  GDC-0032—Genentech, Inc.
238/P PMT4979g (GO00886)-A10
Appendix B-9
Pharmacokinetic Sample Collection:  Phase I, Stage 2, Cohorts N, 
P, Q, and R Patients
Study Visit
Time
Event
Cycle 1, Day 15
04 hours prior to letrozole and 
GDC-0032 administration
Predose plasma sample for letrozole
Predose plasma sample for GDC-0032
3 hours (60 minutes) 
postGDC-0032 administration.
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to letrozole and 
GDC-0032 administration
Predose plasma sample for letrozole
Predose plasma sample for GDC-0032
Cycle 6, Day 1
04 hours prior to letrozole and 
GDC-0032 administration
Predose plasma sample for letrozole
Predose plasma sample for GDC-0032


Protocol:  GDC-0032—Genentech, Inc.
239/P PMT4979g (GO00886)-A10
Appendix B-10
Pharmacokinetic Sample Collection:  Phase I, Stage 2, Cohort X3 
(Head and Neck Cancer) Patients Taking GDC-0032 as 
Suspension
Cycle and Day
Timepoint(s)
Assessment/Procedure
Cycle 1, Day 1
Pre-dose a
Plasma sample for GDC-0032
0
Administer dose
0.5 hour post-dose (5 min)
Plasma sample for GDC-0032
1 hour post-dose (5 min)
Plasma sample for GDC-0032
2 hours post-dose
Plasma sample for GDC-0032
3 hours post-dose
Plasma sample for GDC-0032
4 hours post-dose
Plasma sample for GDC-0032
8 hours post-dose
Plasma sample for GDC-0032
Cycle 1, Day 2
24 hours post-dose b (2 hours) b
Plasma sample for GDC-0032
Cycle 1, Day 15
(1 day)
Pre-dose a
Plasma sample for GDC-0032
0
Administer dose
0.5 hour post-dose (5 min)
Plasma sample for GDC-0032
1 hour post-dose (5 min)
Plasma sample for GDC-0032
2 hours post-dose
Plasma sample for GDC-0032
3 hours post-dose
Plasma sample for GDC-0032
4 hours post-dose
Plasma sample for GDC-0032
8 hours post-dose
Plasma sample for GDC-0032
Cycle 1, Day 16
(1 day)
24 hours post-dose (2 hours) b
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to GDC-0032 
administration
Pre-dose plasma sample for 
GDC-0032
Cycle 6, Day 1
04 hours prior to GDC-0032 
administration
Pre-dose plasma sample for 
GDC-0032
a The blood samples should optimally be obtained within 5 minutes prior to dosing, but may be 
obtained up to 2 hours prior to dosing.
b The PK draw is scheduled prior to the morning dose. 
Note: Except where noted otherwise, all sample draw times are 10 minutes.


Protocol:  GDC-0032—Genentech, Inc.
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Appendix B-11
Pharmacokinetic Sample Collection:  Phase I, Stage 2,
Cohort L Patients
Study Visit
Time
Event
Cycle 1, Day 1
3 hours (60 min)  postGDC-0032 
administration
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for 
fulvestrant
Cycle 6, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for 
fulvestrant


Protocol:  GDC-0032—Genentech, Inc.
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Appendix B-12
Pharmacokinetic Sample Collection:  Phase I, Stage 2,
Cohort S Patients
Study Visit
Time
Event
Cycle 1, Day 1
3 hours (60 min)  postGDC-0032 
administration
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to letrozole and 
GDC-0032 administration
Predose plasma sample for letrozole
Cycle 6, Day 1
04 hours prior to letrozole and 
GDC-0032 administration
Predose plasma sample for letrozole


Protocol:  GDC-0032—Genentech, Inc.
242/P PMT4979g (GO00886)-A10
Appendix B-13
Pharmacokinetic Sample Collection:  Phase I, Stage 2, Cohorts T 
and T2 Patients
Study Visit
Time
Event
Cycle 1, Day 15
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032
3 hours (60 minutes) 
postGDC-0032 administration.
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032
Cycle 6, Day 1
04 hours prior to GDC-0032 
administration
Predose plasma sample for 
GDC-0032


Protocol:  GDC-0032—Genentech, Inc.
243/P PMT4979g (GO00886)-A10
Appendix B-14
Pharmacokinetic Sample Collection:  Phase II Patients
Study Visit
Time
Event
Cycle 1, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for fulvestrant
Predose plasma sample for GDC-0032
Cycle 1, Day 
15
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for fulvestrant
Predose plasma sample for GDC-0032
4 hours (30 minutes) 
postGDC-0032 administration.
Plasma sample for GDC-0032
Cycle 2, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for fulvestrant
Predose plasma sample for GDC-0032
Cycle 6, Day 1
04 hours prior to fulvestrant and 
GDC-0032 administration
Predose plasma sample for fulvestrant
Predose plasma sample for GDC-0032


Protocol:  GDC-0032—Genentech, Inc.
244/P PMT4979g (GO00886)-A10
Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
version 1.1,1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.
a. Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b. Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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


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


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
247/P PMT4979g (GO00886)-A10
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
Baseline Documentation of Target and Non-Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed.


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
248/P PMT4979g (GO00886)-A10
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
Response Criteria
a. Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  Disappearance of all target lesions

Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline

In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.

The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b. Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
249/P PMT4979g (GO00886)-A10
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However,
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.
c. Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol.

Complete response (CR):  Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level

All lymph nodes must be non-pathological in size (10 mm short axis).


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
250/P PMT4979g (GO00886)-A10

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

Progressive disease (PD):  Unequivocal progression of existing non-target lesions

The appearance of one or more new lesions is also considered progression.
d. Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there is
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial. 
Bone-Only Disease:  Since bone lesions are not considered measurable, patients with 
bone-only disease will be evaluated for progression only.  Progression is defined as the 
appearance of new lytic lesions or other new bone destruction thought to be related to 
cancer by X-ray, CT scan or MRI, or a bone event requiring intervention (surgery) if not 
associated with trauma or other obvious cause.  Changes in bone scan or 18F NaF PET 


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
251/P PMT4979g (GO00886)-A10
scan should not be used to define progression.  Any changes in bone imaging should be 
evaluated radiographically by X-ray, CT scan, or MRI to ascertain the presence of bone 
destruction versus a healing reaction.  The appearance of new lesions on bone scan or 
18F NaF PET scan may constitute progressive disease if associated with clinical 
symptoms suggestive of disease progression.  The occurrence of a pathologic fracture 
at a site previously recognized for bone disease may constitute progressive disease if 
not associated with trauma or other obvious cause.  Bone pain requiring radiation will 
constitute progressive disease.  Increase in pain at a site of previously recognized bone 
disease may constitute progressive disease if it is persistent and not associated with 
other obvious cause.
e. New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a 
CT scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
Evaluation of Response
a. Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
252/P PMT4979g (GO00886)-A10
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
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since 
stable disease is increasingly used as an endpoint for assessment of efficacy in 
some trials; thus, assigning “stable disease” when no lesions can be measured is 
not advised.
b. Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular 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.  This would be most likely to happen 


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
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253/P PMT4979g (GO00886)-A10
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and during the study only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
254/P PMT4979g (GO00886)-A10
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at First 
Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
PR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
c. Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 


Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication (cont.)
Protocol:  GDC-0032—Genentech, Inc.
255/P PMT4979g (GO00886)-A10
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Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


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Appendix D
Criteria for PSA Response and Progression for Prostate Cancer 
Patients
Adapted from Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for 
phase II clinical trials in androgen-independent prostate cancer: recommendations from the 
Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461–7.
PSA Response Criteria 
A PSA response is defined as a PSA decline of 50%, which must be confirmed by a 
second PSA value 4 weeks later. The baseline PSA should be a measurement within 
2 weeks before starting therapy. PSA response commences on the date of the first 50% 
decline in PSA.
Criteria for Definition of PSA Progression
PSA Progression
An increasing PSA may be the only marker of presumed progressive 
disease. In patients whose PSA has not decreased, progressive disease is defined as 
a 50% increase over baseline (on study), provided that the increase in the absolute 
PSA level is 5 ng/mL and that it is confirmed by a second value. There is no limit on 
the time that elapses between the first documentation of progression and the 
confirmatory value. In patients whose PSA has decreased, progressive disease occurs 
when PSA increases by 50% over the nadir, provided that the increase is 5 ng/mL 
and is confirmed.
Time to PSA Progression
PSA progression may occur before clinical progression. The start of the time to PSA 
progression is the day treatment is initiated. The date of PSA progression is the date of 
the first PSA measurement that fulfills the criteria for PSA progression.


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Appendix E
Response Criteria for Patients with Ovarian Cancer Who Have 
Evaluable but Non-Measurable Disease
Patients with evaluable but non-measurable disease are eligible for this 
study. Their response will be evaluated according to changes in CA-125 and clinical 
or radiologic observations as described below. Baseline CA-125 is the 
last measurement prior to starting treatment. Response or progressive disease must 
be confirmed no less than 48 weeks following initial response.
Complete response is defined by both of the following:

A decrease in CA-125 to within the institutional normal limits and 40 IU/mL

No clinical or radiologic evidence of disease
Partial response is defined by both of the following:

A > 50% decrease in CA-125 from baseline 

No clinical or radiologic evidence of new lesions
Stable disease is defined as both the following: 

Any change in CA-125 that does not meet the criteria for complete or partial 
response or for progressive disease

No clinical or radiologic evidence of new lesions
Progressive disease is defined by either of the following:

Per the Gynecologic Cancer Intergroup (GCIG) Criteria for Evaluation of 
Progression according to CA-125 (November 2005), progression or recurrence 
based on serum CA 125 levels will be defined on the basis of a progressive serial 
elevation of serum CA 125, according to the following criteria:
A.
Patients with elevated CA-125 pretreatment and normalization of CA-125 must 
show evidence of CA-125 2ULN on two occasions at least 1 week apart, or
B.
Patients with elevated CA-125 pretreatment, which never normalizes must 
show evidence of CA-125 2the nadir value on two occasions at least 
1 week apart, or
C.
Patients with CA-125 in the normal range pretreatment must show evidence of 
CA-125 2 ULN on two occasions at least 1 week apart.

Clinical or radiologic evidence of new lesions


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


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Appendix G
Assessment of FDG-PET Responses
FDG-PET assessments will be used to address one of the exploratory objectives of the 
study.  The outcome measure for this objective will be based on the maximum standard 
uptake value (SUVmax) of up to five regions of interest (ROIs).  The tumor ROIs will be 
identified for each patient on pretreatment PET imaging and must correspond to a 
subset of the target lesions for analysis of the patient’s pretreatment CT scans per 
RECIST.  Additional criteria for selection of ROI on PET imaging will be provided in the 
Imaging Review Charter.
Determination of PET response will be according to modified European Organization for 
Research on the Treatment of Cancer (EORTC) definitions (Young et al. 1999).  
Specifically, the SUVmax of each ROI on the on-treatment scans will be compared with its 
SUVmax on the corresponding pretreatment scan and the percent change will be 
determined.  In the event of more than one ROI, the overall percent change in SUVmax
will be the arithmetic mean of the percent changes in SUVmax for each of the ROIs 
(mSUVmax).
PET responses will be defined as follows:

Progressive disease (PET-PD):  percent increase of 20% in mSUVmax
or the development of a new lesion with an SUVmax above background and not 
explained by another cause (e.g., infection)

Stable disease (PET-SD):  percent increase of 20% in mSUVmax or a percent 
decrease of 20% in mSUVmax

Partial response (PET-PR):  percent decrease of 20% in mSUVmax

Complete response (PET-CR):  SUVmax indistinguishable from background in 
all ROIs (i.e., complete disappearance of all PET lesions)
Other methods of analyzing and interpreting the PET imaging data may also be explored.
FDG-PET Imaging
All PET imaging are to be obtained using a combined PET/CT scanner.  The image 
acquisition system must remain consistent throughout all scans for the same patient.  
Whole-body PET images should extend from the orbital meatus to the proximal femurs.  
Technical details of the PET scans will be described in an imaging charter.
Plasma PK and PD samples that are scheduled on visits when PET imaging are 
performed should be obtained before each PET imaging.  Blood glucose levels will be 
obtained immediately prior to FDG-PET imaging.  The times of each of these tests and 
the time of the most recent study drug dose will be recorded on the appropriate eCRFs.  
All FDG-PET imaging will be collected for evaluation by a central review facility and by 
Genentech.


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Appendix H
Instructions for Scans in the Event of Isotope Shortage
Over the last 20 years there have be intermittent, severe shortages of Tc-99m 
generators.  The most recent one occurred in 2009/2010 when the two reactors 
supplying the majority of generators (Chalk River Reactor, Canada, and High Flux 
Reactor, The Netherlands) were repeatedly down for maintenance and repairs.  
Both reactors are now functioning and there are currently no shortages expected.
Throughout that last shortage, added flexibility in the bone scan imaging schedule of 
7 days has been found sufficient to maintain imaging of clinical trial patients (at times 
by scheduling them in the evenings or at the weekend).
In the event that it is not feasible to perform a bone scan or it is anticipated that it will not 
be feasible to perform bone scans throughout the study, F-18 sodium fluoride (18F NaF) 
PET scans may be substituted, with the approval of the Sponsor.  In this case, an 
18F NaF PET scan must be performed at screening and, in patients with bone-only 
disease visible only by 18F NaF PET scan, must be repeated at end of Cycles 3, 6, 8, 
and every 3 cycles thereafter.
If any challenges in the continued bone scan imaging of patients on this protocol is 
suspected or anticipated the Sponsor or the Imaging Core Facility should be contacted 
immediately.


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Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s 
Lymphoma Cohort T
SELECTION OF TARGET LESIONS
Up to six of the largest dominant nodes or tumor masses should be selected according 
to all of the following (ideally a minimum of three lesions should be chosen):

Clearly measurable in at least two perpendicular dimensions 

If possible, they should be from disparate regions of the body. 

Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 

Extranodal lesions within the liver or spleen must be at least 1.0 cm in two 
perpendicular dimensions.  
SELECTION OF NON-TARGET LESIONS  
Non-target lesions will be qualitatively assessed at each subsequent time point. All of the 
sites of disease present at baseline and not classified as target lesions will be classified 
as non-target lesions, including any measurable lesions that were not chosen as target 
lesions. Examples of non-target lesions include: 

All bone lesions, irrespective of the modality used to assess them 

Lymphangitis of the skin or lung 

Cystic lesions 

Splenomegaly and hepatomegaly 

Irradiated lesions 

Measurable lesions beyond the maximum number of six chosen as target lesions 

Groups of lesions that are small and numerous 

Pleural/pericardial effusions and/or ascites 

For this study, a significant increase in existing pleural effusions, ascites, or other 
fluid collections will be considered sufficient evidence of progression and will not 
require cytological proof of malignancy. Effusions, ascites, or other fluid collections 
will be followed as non-target lesions. 
Existing effusions/ascites:  Effusions, ascites, or other fluid collections will be 
followed as non-target lesions. At each time point, radiologists will check for the 
presence or absence of effusions/ascites. If there is a significant volume 
increase in the absence of a benign etiology, progression can be assessed. 
New effusions/ascites:  Significant new effusions, ascites, or other fluid 
collections that are radiographically suggestive of malignancy should be 
recorded as new lesions. 


Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s
Lymphoma Cohort T (cont.)
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REPORTING CONVENTIONS
UNABLE TO EVALUATE (UE) LESION CATEGORY
This category is reserved for target and non-target lesions that are deemed unevaluable 
because 1) subsequent (post-baseline) examinations had not been performed, 2) lesions 
could not be evaluated due to poor radiographic technique or poorly defined margins, or 
3) lesions identified at baseline were not at a subsequent timepoint.
Examples of UE lesions are a lung lesion in the hilum obstructing the bronchus and 
causing atelectasis of the lobe, or a hypodense liver lesion that becomes surrounded by 
fatty infiltration. In both examples, the boundaries of the lesion can be difficult to 
distinguish. Every effort should be made to assign measurements to lesions that develop 
less distinct margins because they become much smaller. Another example is the 
instance when lesions identified at baseline were not imaged at a subsequent timepoint. 
Lesions that cannot be measured or evaluated will be classified for that timepoint as UE.
If a target lesion is classified as UE post-baseline, the sum of the products of the 
diameters (SPD)/area (whichever applies) of the target lesions cannot accurately be 
determined for that timepoint, a response of complete response (CR), partial response 
(PR), or stable disease (SD) cannot be assigned for that timepoint and the response 
assessment will be UE unless unequivocal progression is determined on the basis of 
non-target or new lesions or the evaluable target lesions.
Progressive disease (PD) can be determined without evaluation of all sites of disease 
based on the greatest tumor dimension (GTD), area, or SPD for target lesions, 
evaluation of unequivocal progression in non-target lesions, or observation of a new 
lesion within the available radiographic or clinical assessments.
TOO SMALL TO MEASURE (TSTM) LESION CATEGORY
Any target lesion findings identified on baseline images, which at a subsequent timepoint 
decreases in size to < 5 mm in any dimension, should be categorized as TSTM. The 
lesion, node, or mass should be assigned measurements of 5 mm × 5 mm (for the GTD 
and the short axis) on the source document for the purpose of calculating the area. If 
that lesion increases in size to ≥ 5 mm in any dimension afterwards, its true size (GTD 
and short axis) should be recorded. The purpose of the assigned value for the 
measurement is the acknowledgment that small findings are not accurately measured.


Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s
Lymphoma Cohort T (cont.)
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Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s
Lymphoma Cohort T (cont.)
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COMPLETE REMISSION
1. Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present prior to therapy
2a. Typically 18fluorodeoxyglucose (FDG)-avid lymphoma:  In patients with no pre-
treatment positron emission tomography (PET) scan or when the PET scan was positive 
before therapy, a post-treatment residual mass of any size is permitted as long as it is 
PET negative.
2b. Variably FDG-avid lymphomas/FDG avidity unknown:  In patients without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, all lymph nodes and 
nodal masses must have regressed on CT to normal size (1.5 cm in their greatest 
transverse diameter for nodes 1.5 cm before therapy).  Previously involved nodes that 
were 1.11.5 cm in their long axis and 1.0 cm in their short axis before treatment must 
have decreased to 1.0 cm in their short axis after treatment.
3. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination and 
should be considered normal size by imaging studies, and nodules related to lymphoma 
should disappear.  However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma.
4. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (20 mm unilateral core).  If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry.  A sample 
that is negative by immunohistochemistry but demonstrating a small population of clonal 
lymphocytes by flow cytometry will be considered a complete remission until data 
become available demonstrating a clear difference in patient outcome.
PARTIAL REMISSION
1. 50% decrease in SPD of up to six of the largest dominant nodes or nodal masses.  
These nodes or masses should be selected according to the following:  a) they should 
be clearly measurable in at least two perpendicular dimensions; b) if possible, they 
should be from disparate regions of the body; c) they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved. 


Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s
Lymphoma Cohort T (cont.)
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2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single 
nodules, in the greatest transverse diameter. 
4. With the exceptions of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a partial remission if the 
sample was positive prior to treatment.  However, if positive, the cell type should be 
specified (e.g., large-cell lymphoma or small neoplastic B cells).  Patients who achieve a 
complete remission by the above criteria but who have persistent morphologic bone 
marrow involvement will be considered partial responders.
6. No new sites of disease should be observed (e.g., nodes 1.5 cm in any axis). 
7. Typically FDG-avid lymphoma:  For patients with no pre-treatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown:  For patients without a pre-
treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria should be 
used. 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with one or at most two residual masses that have regressed by 50% on CT; 
those with more than two residual lesions are unlikely to be PET negative and should be 
considered partial responders.
STABLE DISEASE
1. Failing to attain the criteria needed for complete remission or partial remission but not 
fulfilling those for progressive disease (see below) 
2. Typically FGD-avid lymphomas:  The PET should be positive at prior sites of disease 
with no new areas of involvement on the post-treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown:  For patients without a pre-
treatment PET scan or if the pre-treatment PET was negative, there must be no change 
in the size of the previous lesions on the post-treatment CT scan. 


Appendix I
Modified Response and Progression CriteriaNon-Hodgkin’s
Lymphoma Cohort T (cont.)
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RELAPSED DISEASE (AFTER COMPLETE REMISSION) OR PROGRESSIVE 
DISEASE (FOR PATIENTS WITH PARTIAL REMISSION OR STABLE 
DISEASE)
Lymph nodes should be considered abnormal if the long axis is 1.5 cm, regardless of 
the short axis.  If a lymph node has a long axis of 1.11.5 cm, it should be considered 
abnormal only if its short axis is 1.0. Lymph nodes 1.0 cm by 1.0 cm will not be 
considered as abnormal for relapse or progressive disease.
1. Appearance of any new lesion 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size; increased FDG uptake in a previously 
unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes or in a 
single involved node or the size of other lesions (e.g., splenic or hepatic nodules).  To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by 50% and to a size of 1.5 1.5 cm or 1.5 cm in the long 
axis.
3. At least a 50% increase in the longest diameter of any single previously identified 
node 1 cm in its short axis. 
4. Lesions should be PET positive if observed in a typical FDG avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (1.5 cm in its long axis by CT). 
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease.  For these recommendations, the spleen is considered nodal disease.
Adapted from Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for 
malignant lymphoma. J Clin Oncol 2007;25:579−86.


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Appendix J
Lugano Response Criteria for DLBCL Cohort T2 
In this study, a PET-CTbased complete response requires normal bone marrow by morphology for patients with bone marrow 
involvement at baseline.  If indeterminate by morphology, immunohistochemistry should be negative. Additionally, the designation of 
PET-CTbased PR requires that CT-based response criteria for a CR or PR be met in addition to the PET-CTbased response criteria 
for a PR.  This modified response should be entered in addition to the Lugano PET-CTBased and CTBased Responses defined in 
the table below.  


Appendix J
Lugano Response Criteria for DLBCL Cohort T2 (cont.)
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Appendix J
Lugano Response Criteria for DLBCL Cohort T2 (cont.)
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Appendix J
Lugano Response Criteria for DLBCL Cohort T2 (cont.)
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Appendix J
Lugano Response Criteria for DLBCL Cohort T2 (cont.)
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5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LDi = longest 
transverse diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi 
and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for 
multiple lesions.


Appendix J
Lugano Response Criteria for DLBCL Cohort T2 (cont.)
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a 
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials
involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment).  Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in two diameters.  Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation.  Non-measured lesions: Any disease not selected as measured; dominant disease and truly 
assessable disease should be considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.  In 
Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of 
chemotherapy or myeloid growth factors).
b PET 5PS: 1 = no uptake above background; 2 = uptake ≤mediastinum; 3 = uptake > mediastinum but ≤liver; 4 = uptake moderately > liver; 
5uptake markedly higher than liver and/or new lesions; X = new areas of uptake unlikely to be related to lymphoma.