Clinical trial NCT04680273
Conditions: Healthy Volunteers
Sponsor: Genentech, Inc.
Start date: 2021-01-07; Completion date: 2021-04-12
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is an open-label, single-center, two part study in healthy female subjects of non-childbearing potential to investigate the absorption, metabolism, and excretion of \[14C\]-GDC-9545 (Part 1), the absolute bioavailability of formulations F12 and F18 (i.e., GDC-9545/F12 capsule, 30 mg and GDC-9545/F18 capsule, 30 mg) and relative bioavailability of GDC-9545 oral capsule F18 to the F12 formulation (Part 2). It is planned that Part 1 will begin prior to Part 2 of the study, and that the two parts of the study will partially overlap.

Detailed description:

Arms: arm 1: Participants will be enrolled to receive a single dose of Carbon-14 labelled \[14C\]-GDC-9545. arm 2: Participants will be randomly allocated to one of two treatment sequences (BCD for this arm). In each treatment period, participants will receive a single dose of GDC-9545 in the fasted state in each of three treatment periods. The three treatment periods will be separated by a treatment-free washout between each study drug administration. arm 3: Participants will be randomly allocated to one of two treatment sequences (BDC for this arm). In each treatment period, participants will receive a single dose of GDC-9545 in the fasted state in each of three treatment periods. The three treatment periods will be separated by a treatment-free washout between each study drug administration.
Interventions: intervention 1: [14C]-GDC-9545 intervention 2: GDC-9545 Solution for Infusion intervention 3: GDC-9545/F12 Capsule intervention 4: GDC-9545/F18 Capsule
Intervention descriptions: intervention 1: Participants will receive a single oral dose of \[14C\]-GDC-9545 capsule, 30 milligrams (mg) (not more than \[NMT\] 4.6 megabecquerel \[MBq\]; 124 microcurie \[μCi\]) with approximately 240 millilitres (mL) water in the fasted state. intervention 2: Treatment B: 30 mg GDC-9545 as a solution for infusion, 3 mg/mL administered intravenously (IV) in 10 mL as an infusion over 30 minutes. intervention 3: Treatment C: GDC-9545/F12 capsule, 30 mg, administered orally with approximately 240 mL water. intervention 4: Treatment D: GDC-9545/F18 capsule, 30 mg, administered orally with approximately 240 mL water.

Protocol documents:
Prot_000.pdf: 
 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an Investigator, 
potential Investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
GDC-9545—Genentech, Inc. 
Protocol GP42662 (QSC204283), Version 4 
PROTOCOL 
TITLE: 
A PHASE I, SINGLE CENTER, OPEN-LABEL, 
PARTIALLY RANDOMIZED, TWO PART STUDY 
TO INVESTIGATE THE ABSORPTION, 
METABOLISM, AND EXCRETION OF 
[14C]-GDC-9545 FOLLOWING A SINGLE ORAL 
DOSE (PART 1) AND TO EVALUATE THE 
ABSOLUTE BIOAVAILABILITY OF ORAL 
CAPSULE FORMULATIONS OF GDC-9545 F12 
AND F18 AND THE RELATIVE BIOAVAILABILITY 
OF F18 COMPARED TO F12 (PART 2) IN 
HEALTHY FEMALE SUBJECTS OF 
NON-CHILDBEARING POTENTIAL 
PROTOCOL NUMBER: GP42662 (QSC204283) 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-004650-29 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04680273 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
CLINICAL 
PHARMACOLOGY: 
MS, PharmD 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
18 Feb 2021 


 
 
GDC-9545—Genentech, Inc. 
2/Protocol GP42662 (QSC204283), Version 4 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 8 
PROTOCOL ACCEPTANCE FORM .................................................................... 9 
PROTOCOL SYNOPSIS .................................................................................... 10 
1. 
BACKGROUND .......................................................................................... 20 
1.1 
Background on Breast Cancer ............................................... 20 
1.2 
Background on GDC-9545 .................................................... 20 
1.2.1 
Toxicology and Safety Pharmacology ................................... 20 
1.2.2 
Clinical Summary ................................................................... 21 
1.2.2.1 
Safety .................................................................................... 22 
 
 23 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 26 
1.3.1 
Study Rationale ..................................................................... 27 
1.3.2 
Risk-Benefit Assessment ....................................................... 27 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 28 
2.1 
Mass Balance, Pharmacokinetic and Metabolite 
Profiling and Identification Objectives (Primary 
and Secondary Study Objectives) ......................................... 28 
2.1.1 
Part 1 ..................................................................................... 28 
2.1.2 
Part 2 ..................................................................................... 29 
2.2 
Safety Objective (Secondary Study Objective) ...................... 30 
3. 
STUDY DESIGN ......................................................................................... 30 
3.1 
Description of the Study......................................................... 30 
3.1.1 
Part 1 ..................................................................................... 30 
3.1.2 
Part 2 ..................................................................................... 32 
3.2 
End of Study and Length of Study ......................................... 34 
3.3 
Rationale for Study Design .................................................... 34 
3.3.1 
Rationale for Subject Population ........................................... 34 
3.3.2 
Rationale for [14C]-GDC-9545 and GDC-9545 
Doses and Schedule ............................................................. 36 
3.3.2.1 
Part 1 ..................................................................................... 36 
3.3.2.2 
Part 2 ..................................................................................... 37 


 
 
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3.3.3 
Rationale for PK Sampling Schedule ..................................... 37 
4. 
MATERIALS AND METHODS .................................................................... 37 
4.1 
Subjects ................................................................................. 37 
4.1.1 
Inclusion Criteria .................................................................... 38 
4.1.2 
Exclusion Criteria ................................................................... 39 
4.2 
Method of Treatment Assignment and Blinding ..................... 41 
4.2.1 
Part 1 ..................................................................................... 41 
4.2.2 
Part 2 ..................................................................................... 41 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 42 
4.3.1 
Study Treatment Formulations and Packaging ...................... 42 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 43 
4.3.2.1 
[14C]-GDC-9545 and GDC-9545 ............................................ 43 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 44 
4.3.3.1 
Retention of Study Drug Samples ......................................... 45 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 45 
4.4.1 
Permitted Therapy ................................................................. 45 
4.4.2 
Prohibited Therapy ................................................................ 45 
4.4.3 
Prohibited Food and Drink ..................................................... 46 
4.4.4 
Additional Restrictions ........................................................... 46 
4.5 
Study Assessments ............................................................... 47 
4.5.1 
Informed Consent Forms and Screening Log ........................ 47 
4.5.2 
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 48 
4.5.3 
Physical Examinations ........................................................... 48 
4.5.4 
Vital Signs .............................................................................. 49 
4.5.5 
Laboratory and Other Biological ............................................ 49 
4.5.5.1 
Safety Laboratory Assessments ............................................ 49 
4.5.5.2 
Mass Balance, Pharmacokinetic and Metabolite 
Profiling and Identification Assessments ............................... 50 
4.5.6 
Electrocardiograms ................................................................ 52 


 
 
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4.6 
Treatment, Subject, Study, and Site 
Discontinuation ...................................................................... 53 
4.6.1 
Stopping Criteria .................................................................... 53 
4.6.2 
Subject Discontinuation from the Study ................................. 54 
4.6.3 
Study Discontinuation ............................................................ 55 
4.6.4 
Site Discontinuation ............................................................... 56 
5. 
ASSESSMENT OF SAFETY ....................................................................... 56 
5.1 
Safety Plan ............................................................................ 56 
5.1.1 
Risks Associated with GDC-9545 .......................................... 56 
5.1.2 
Risks Associated with Radiation ............................................ 57 
5.1.3 
COVID-19 Related Risks and Risk Mitigation 
Measures ............................................................................... 57 
5.1.3.1 
IMP-Related Risk ................................................................... 58 
5.1.3.2 
General COVID-19-Related Risk Mitigation 
Measures ............................................................................... 58 
5.1.4 
General Risks ........................................................................ 58 
5.2 
Safety Parameters and Definitions ........................................ 58 
5.2.1 
Adverse Events ..................................................................... 59 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 59 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 60 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 61 
5.3.1 
Adverse Event Reporting Period ........................................... 61 
5.3.2 
Eliciting Adverse Event Information ....................................... 61 
5.3.3 
Assessment of Severity of Adverse Events ........................... 61 
5.3.4 
Assessment of Causality of Adverse Events ......................... 62 
5.3.5 
Procedures for Recording Adverse Events ............................ 63 
5.3.5.1 
Infusion-Related Reactions .................................................... 63 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 63 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 64 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 64 
5.3.5.5 
Abnormal Laboratory Values ................................................. 64 


 
 
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5.3.5.6 
Abnormal Vital Sign Values ................................................... 65 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 66 
5.3.5.8 
Deaths ................................................................................... 66 
5.3.5.9 
Preexisting Medical Conditions .............................................. 66 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 67 
5.3.5.11 
Cases of Accidental Overdose or Medication 
Error....................................................................................... 67 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 68 
5.4.1 
Emergency Medical Contacts ................................................ 69 
5.4.2 
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest ........................... 69 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 69 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 70 
5.4.3 
Reporting Requirements for Pregnancies .............................. 70 
5.4.3.1 
Pregnancies in Female Subjects ........................................... 70 
5.4.3.2 
Abortions ............................................................................... 70 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 71 
5.5 
Follow-Up of Subjects after Adverse Events .......................... 71 
5.5.1 
Investigator Follow-Up ........................................................... 71 
5.5.2 
Sponsor Follow-Up ................................................................ 71 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 71 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees .......................................................... 72 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 73 
6.1 
Determination of Sample Size ............................................... 73 
6.2 
Summaries of Conduct of Study ............................................ 74 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 74 
6.4 
Mass Balance Analyses (Part 1 Only) ................................... 74 
6.5 
Pharmacokinetic Analyses ..................................................... 75 
6.6 
Metabolite Profiling and Identification Analyses ..................... 76 
6.7 
Safety Analyses ..................................................................... 76 


 
 
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6.8 
Interim Analyses .................................................................... 77 
6.8.1 
Planned Interim Analysis ....................................................... 77 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 78 
7.1 
Data Quality Assurance ......................................................... 78 
7.2 
Electronic Case Report Forms ............................................... 78 
7.3 
Source Data Documentation .................................................. 79 
7.4 
Use of Computerized Systems .............................................. 79 
7.5 
Retention of Records ............................................................. 79 
8. 
ETHICAL CONSIDERATIONS .................................................................... 80 
8.1 
Compliance with Laws and Regulations ................................ 80 
8.2 
Informed Consent .................................................................. 80 
8.3 
Ethics Committee .................................................................. 81 
8.4 
Administration of Radiation .................................................... 82 
8.5 
Confidentiality ........................................................................ 82 
8.6 
Financial Disclosure .............................................................. 82 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 83 
9.1 
Study Documentation ............................................................ 83 
9.2 
Protocol Deviations ................................................................ 83 
9.3 
Site Inspections ..................................................................... 83 
9.4 
Administrative Structure......................................................... 83 
9.5 
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 84 
9.6 
Protocol Amendments ........................................................... 85 
10. REFERENCES ........................................................................................... 86 
 
 
LIST OF TABLES 
 
 
 ...................................................................... 25 
 
 
 ...................................................................... 25 
 
 
 ...................................................................... 25 


 
 
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Table 4 
Part 2 Treatment Sequences ...................................................... 41 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 62 
Table 6 
Causal Attribution Guidance ....................................................... 63 
 
 
LIST OF FIGURES 
 
 
 ..................... 26 
 
 
 .................... 26 
Figure 3 
Overview of Part 1 Design .......................................................... 32 
Figure 4 
Overview of Part 2 Design .......................................................... 34 
 
 
LIST OF APPENDICES 
Appendix 1 
 Part 1 Schedule of Activities ...................................................... 87 
Appendix 2 
 Part 2 Schedule of Activities ...................................................... 92 
Appendix 3 
 Part 1 Schedule of Pharmacokinetic Samples ........................... 97 
Appendix 4 
 Part 2 Schedule of Pharmacokinetic Samples ......................... 103 




GDC-9545—Genentech, Inc. 
9/Protocol GP42662 (QSC204283), Version 4 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE I, SINGLE CENTER, OPEN-LABEL, 
PARTIALLY RANDOMIZED, TWO PART STUDY TO 
INVESTIGATE THE ABSORPTION, METABOLISM, 
AND EXCRETION OF [14C]-GDC-9545 FOLLOWING 
A SINGLE ORAL DOSE (PART 1) AND TO 
EVALUATE THE ABSOLUTE BIOAVAILABILITY OF 
ORAL CAPSULE FORMULATIONS OF GDC-9545 
F12 AND F18 AND THE RELATIVE 
BIOAVAILABILITY OF F18 COMPARED TO F12 
(PART 2) IN HEALTHY FEMALE SUBJECTS OF 
NON-CHILDBEARING POTENTIAL 
PROTOCOL NUMBER: GP42662 (QSC204283) 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-004650-29 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04680273 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
CLINICAL 
PHARMACOLOGY: 
MS, PharmD 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
MS, Pharm D, 
, 
 
 
 
 
 
 
 
 
Sponsor Representative’s Signature 
 
Date 
Please retain the signed original of this form for your study files.   
 
2/19/2021


 
GDC-9545—Genentech, Inc. 
10/Protocol GP42662 (QSC204283), Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A Phase I, Single Center, Open-Label, Partially Randomized, 
Two Part Study to Investigate the Absorption, Metabolism, and 
Excretion of [14C]-GDC-9545 following a Single Oral Dose 
(Part 1) and to Evaluate the Absolute Bioavailability of Oral 
Capsule Formulations of GDC-9545 F12 and F18 and the 
Relative Bioavailability of F18 Compared to F12 (Part 2) in 
Healthy Female Subjects of Non-childbearing Potential 
PROTOCOL NUMBER: 
GP42662 (QSC204283) 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-004650-29 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT04680273 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
PHASE: 
I 
INDICATION: 
Not applicable 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
Part 1 of this study will evaluate the absorption, metabolism, excretion, pharmacokinetics and 
safety of GDC-9545 in healthy volunteers.  Part 2 of this study will evaluate the absolute and 
relative bioavailability, and safety of GDC-9545 in healthy volunteers.  Specific objectives and 
corresponding endpoints for the study are outlined below. 
 
Objectives 
Endpoints 
Primary 
Part 1: To determine the mass 
balance and routes of 
elimination of [14C]-GDC-9545 
following a single oral dose of 
[14C]-GDC-9545 capsule, 30 mg 
containing not more than (NMT) 
4.6 megabecquerel (MBq; 
124 microcurie [µCi]) 
Mass balance recovery of 
total radioactivity (TR) in all 
excreta (urine and feces): 
CumAe and CumFe 
Determination of routes 
and rates of elimination of 
[14C]-GDC-9545 by Ae, 
CumAe, Fe and CumFe by 
interval for all excreta 
(urine and feces) 
Part 1: To assess the 
pharmacokinetics (PK) of 
GDC-9545 and total drug-
derived material in plasma 
following a single oral dose of 
[14C]-GDC-9545 capsule, 30 mg 
(NMT 4.6 MBq [124 µCi]) 
Calculation of PK 
parameters as appropriate 
for GDC-9545 (plasma 
only) and TR (plasma and 
whole blood) 
Assessment of the 
concentrations of TR in 
whole blood and plasma  
Evaluation of whole 
blood:plasma 
concentration ratios for TR 


 
GDC-9545—Genentech, Inc. 
11/Protocol GP42662 (QSC204283), Version 4 
Part 2: To determine the 
absolute bioavailability of an 
oral GDC-9545/F12 capsule, 
30 mg and an oral 
GDC-9545/F18 capsule, 30 mg 
Absolute bioavailability 
assessment based on the 
PK parameter AUC0-inf for 
GDC-9545 
Part 2: To determine the 
relative bioavailability of 
GDC-9545/F18 capsule, 30 mg 
compared to the 
GDC-9545/F12 capsule, 30 mg 
Relative bioavailability 
assessment based on the 
PK parameters Cmax and 
AUC0-inf for GDC-9545 
Secondary 
Part 1: To characterize and 
identify metabolites of 
[14C]-GDC-9545 in plasma, 
urine, and feces 
Characterization of 
abundant metabolites by 
liquid chromatography-high 
resolution mass 
spectrometry 
Part 2: To characterize the PK 
of GDC-9545 following oral and 
intravenous (IV) administration 
Calculation of PK 
parameters as appropriate 
for GDC-9545 in plasma 
only 
Part 1 and Part 2: To evaluate 
the safety and tolerability of 
single doses of GDC-9545 
Incidence and severity of 
adverse events 
Incidence of abnormalities 
in laboratory safety tests, 
12-lead ECGs and vital 
sign measurements 
Metabolite profiling and identification will be reported separately from the Clinical Study Report 
as a standalone document. 
Study Design 
Description of Study 
This is an open-label, single-center, two part study in heathy female subjects of 
non-childbearing potential to investigate the absorption, metabolism, and excretion of 
[14C]-GDC-9545 (Part 1), the absolute bioavailability of formulations Roformis Number 
RO7197597/F12-01 (F12) and Roformis Number RO7197597/F18-01 (F18) (i.e., 
GDC-9545/F12 capsule, 30 mg and GDC-9545/F18 capsule, 30 mg), and relative bioavailability 
of GDC-9545 oral capsule F18 to the F12 formulation (Part 2). 
Part 1 
Part 1 is an open-label, single-treatment design.  It is planned to enroll 6 subjects to ensure data 
in a minimum of 4 evaluable subjects.  An evaluable subject for Part 1 of the study is defined as 
a subject who has provided mass balance and PK samples for up to 480 hours (up to Day 21) 
or until they have met the mass balance discharge criteria (i.e., cumulative recovery of 
radioactivity exceeds 90% of the administered dose; OR radioactivity in urine and feces is less 
than 1% of the administered dose over a 24 hour period on 2 consecutive PK sample collection 
days, as determined by quick counts). 
Each subject will receive a single oral dose of [14C]-GDC-9545 capsule, 30 mg (NMT 4.6 MBq 
[124 µCi]) with approximately 240 mL water in the fasted state (Treatment A). 
Subjects will undergo preliminary screening procedures for the study up to 28 days (Day -28 to 
Day -2) before [14C]-GDC-9545 administration on Day 1.  Subjects will be admitted in the 
morning on the day prior to [14C]-GDC-9545 administration (Day -1) and will be dosed in the 
morning of Day 1 following an overnight fast of a minimum of 10 hours.  
Urine and feces samples for measurement of TR will be collected pre-dose and at intervals until 
study completion including after discharge, if needed.  
Blood samples for measurement of plasma GDC-9545 and TR in plasma and whole blood will 
be collected pre-dose and at intervals until study completion including after discharge, if 
needed.  


 
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Safety and tolerability will be monitored by clinical and laboratory assessments at intervals 
throughout the study. 
It is planned that subjects will remain resident in the clinical unit until 480 hours post-dose 
(Day 21) when they will be discharged from the clinical unit. 
Part 2 
Part 2 is a randomized, open-label, three-treatment, two-sequence crossover design conducted 
over three periods.  It is planned to enroll 10 subjects to ensure data in a minimum of 
8 evaluable subjects.  An evaluable subject for Part 2 of the study is defined as a subject who 
has received an investigational medicinal product (IMP) and has sufficient drug concentration 
measurements up to 168 hours after dosing for evaluation of defined PK parameters for each 
treatment, and have completed all planned safety assessments up to 168 hours after dosing for 
each treatment.  
Subjects will be randomly allocated to one of two treatment sequences (BCD and BDC). In each 
treatment period, subjects will receive a single 30 mg dose of GDC-9545 in the fasted state.  
GDC-9545 will be administered as one of three possible formulations according to the 
randomization schedule: 
• 
Treatment B: 30 mg GDC-9545 as a Solution for Infusion, 3 mg/mL administered 
intravenously in 10 mL as an infusion over 30 minutes 
• 
Treatment C: GDC-9545/F12 capsule, 30 mg, administered with approximately 240 mL 
water 
• 
Treatment D: GDC-9545/F18 capsule, 30 mg, administered with approximately 240 mL 
water 
Subjects will undergo preliminary screening procedures for the study up to 28 days (Day -28 to 
Day -2) before GDC-9545 administration on Day 1 of Period 1.  Subjects will be admitted in the 
morning on the day prior to the first GDC-9545 administration (Day -1 of Period 1).  Subjects will 
be resident in the clinical unit from the morning of Day -1 in Period 1 until Day 8 in Period 3 
(i.e., for 28 to 29 consecutive nights that will cover all 3 treatment periods).   
For each treatment period, subjects will be dosed in the morning of Day 1 following an overnight 
fast of a minimum of 10 hours. 
For Treatment B, to assess tolerability of the IV administration, the first subject will be dosed as 
a sentinel; then, at least 4 hours later, the second subject will be dosed only if there are no 
acute safety findings for the first subject. If the first two subjects tolerated the IV dose, in the 
opinion of the Principal Investigator and Medical Monitor, the remaining subjects will be dosed. 
The third subject will be dosed at least 20 hours after the second subject (i.e., at least 24 hours 
after the first subject). All subsequent dosing of the IV formulation will be staggered by at least 
15 minutes. 
Blood samples for measurement of plasma GDC-9545 will be collected pre-dose and at 
intervals until Day 8 of each period.  
Safety and tolerability will be monitored by clinical and laboratory assessments at intervals 
throughout the study. 
There will be a minimum washout of 10 days between each IMP administration and a follow-up 
call will take place 13 to 15 days post-final dose. 
Number of Subjects 
For Part 1, it is planned to enroll 6 subjects to ensure data in a minimum of 4 evaluable 
subjects.  For Part 2, it is planned to enroll 10 subjects to ensure data in a minimum of 
8 evaluable subjects.  No replacement subjects are to be used in Part 1 of this study.  Up to 
4 replacement subjects are permitted in Part 2 of this study to ensure there are 8 evaluable 
subjects. 
Target Population 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
• 
Able and willing to comply with the study restrictions and to give written informed consent 
before any study procedure.   


 
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• 
Healthy female subjects of non-childbearing potential that are non-pregnant, non-lactating 
females, who are either postmenopausal or surgically sterile, aged 30 to 65 years, inclusive, 
at time of signing Informed Consent Form (ICF) 
• 
Postmenopausal females are defined as: 
• 
Age >60 years; 
• 
Age ≤60 years and amenorrhea ≥12 months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression. Estradiol levels and/or 
follicle-stimulating hormone (FSH) levels in the postmenopausal range; 
• 
Surgically sterile females for at least 90 days prior to screening are defined as: 
• 
Bilateral salpingectomy; 
• 
Hysterectomy; 
• 
Bilateral oophorectomy; 
• 
For all subjects, the pregnancy test result must be negative at screening and admission 
(Day -1 for Part 1 and Day -1 of Period 1 for Part 2) 
• 
A body mass index (BMI) between 18.5 and 32.0 kg/m2, inclusive, at screening 
• 
Ability to comply with the study protocol 
• 
Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per 
day) (Part 1 only) 
• 
Female subjects of non-childbearing potential do not need to use any methods of 
contraception.   
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
• 
Women of childbearing potential, women who are pregnant or breastfeeding. 
• 
All women must have a negative highly sensitive serum pregnancy test result at 
screening and a negative highly sensitive urine pregnancy test at admission. 
• 
Subjects who have received any IMP in a clinical research study within the 90 days prior to 
Day 1 (Part 1) or Day 1 of Period 1 (Part 2) 
• 
History of serious adverse reaction or serious hypersensitivity to any drug or allergy to the 
study drug formulation excipients 
• 
Subjects who are, or are immediate family members of, a study site or Sponsor employee 
• 
Subjects who have previously been administered IMP in this study.  Subjects who have 
taken part in Part 1 are not permitted to take part in Part 2. 
• 
Evidence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 
i.e., the virus that causes Coronavirus Disease 2019 [COVID-19]) infection 
• 
Positive for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or human 
immunodeficiency virus (HIV) antibody at screening 
• 
History of any drug or alcohol abuse in the past 2 years 
• 
Regular alcohol consumption >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 
40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) 
• 
A confirmed positive alcohol breath test at screening or admission 
• 
Current smokers and those who have smoked within the last 12 months.  A confirmed 
breath carbon monoxide reading of greater than 10 ppm at screening or admission.  
• 
Current users of e-cigarettes and nicotine replacement products and those who have used 
these products within the last 12 months  
• 
Confirmed positive drugs of abuse test result at screening or admission 
• 
Radiation exposure, including that from the present study, excluding background radiation 
but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 
12 months or 10 mSv in the last 5 years.  No occupationally exposed worker, as defined in 
the Ionising Radiation Regulations 2017, shall participate in the study (Part 1 only) 


 
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• 
Subjects who do not have suitable veins for multiple venipunctures/cannulation as 
assessed by the Investigator or delegate at screening 
• 
Clinically significant abnormal clinical chemistry, hematology, coagulation or urinalysis as 
judged by the Investigator.  Subjects with Gilbert’s Syndrome are allowed 
• 
Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance (CLcr) of <70 mL/min using the Cockcroft-Gault equation  
• 
History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic 
respiratory or gastrointestinal (GI) disease (especially peptic ulceration, GI bleeding, 
ulcerative colitis, Crohn’s Disease or Irritable Bowel Syndrome), neurological or psychiatric 
disorder, as judged by the Investigator 
• 
Presence or history of clinically significant allergy requiring treatment, as judged by the 
Investigator.  Hay fever is allowed unless it is active 
• 
Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of 
blood 
• 
Subjects who are taking, or have taken, any medication (e.g., prescription drugs, 
over-the-counter drugs, hormone replacement therapy [HRT], vaccines, topical 
medications, herbal or homeopathic remedies, nutritional supplements), other than up to 4 g 
of paracetamol per day, in the 14 days before IMP administration.  Exceptions may apply on 
a case by case basis, if considered not to interfere with the objectives of the study, as 
determined by the Investigator. 
• 
Subjects who are taking, or have taken, oral antibiotics within 4 weeks or IV antibiotics 
within 8 weeks prior to admission. 
• 
Subjects who are taking, or have taken, any medications/products known to alter drug 
absorption, metabolism, or elimination processes, including St. John’s wort, within 30 days 
prior to admission. 
• 
History of GI surgery (with the exception of appendectomy unless it was performed within 
the previous 12 months) (Part 1 only) 
• 
Acute diarrhea or constipation in the 7 days before the predicted Day 1.  If screening 
occurs >7 days before the Day 1, this criterion will be determined on Day 1.  Diarrhea will 
be defined as the passage of liquid feces and/or a stool frequency of greater than 3 times 
per day.  Constipation will be defined as a failure to open the bowels for 3 days (Part 1 only) 
• 
Malabsorption syndrome or other condition that would interfere with enteral absorption 
• 
History or presence of an abnormal ECG that is clinically significant in the Investigator's 
opinion, including complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction 
• 
QT interval corrected through use of Fridericia's formula (QTcF)  440 msec demonstrated 
by at least two ECGs  30 minutes apart 
• 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular 
hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by 
diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT 
syndrome 
• 
Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 bpm prior to 
enrollment 
• 
Current treatment with medications that are well known to prolong the QT interval 
• 
Absolute neutrophil count <1.3  109/L (1300/L)  
• 
Failure to satisfy the Investigator of fitness to participate for any other reason 


 
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End of Study 
The end of this study is defined as the date when the last subject, last visit (LSLV), occurs or 
the date at which the last data point required for statistical analysis (i.e., mass balance, PK 
and/or metabolite profiling and identification data for Part 1 and PK data for Part 2) or safety 
follow-up is received from the last subject, whichever occurs later.  The end of the study is 
expected to occur approximately 9 weeks after the last subject is enrolled in Part 2. 
Length of Study 
The total length of Part 1 of the study, from screening of the first subject to the end of the study, 
is expected to be approximately 10 weeks. The total length of Part 2 of the study, from 
screening of the first subject to the end of the study, is expected to be approximately 9 weeks. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Part 1  
A single oral dose of [14C]-RO7197597 Capsule, 30 mg (NMT 4.6 MBq [124 µCi]), which is 
referred to as [14C]-GDC-9545 capsule in this protocol (Treatment A) 
Part 2  
A single dose of 30 mg GDC-9545 in each of three treatment periods; the following formulations 
will be administered: 
• 
Treatment B: RO7197597 Solution for Infusion, 3 mg/mL, (referred to as GDC-9545 
Solution for Infusion in this protocol) administered in a 10 mL volume intravenously over 
30 minutes (as an infusion) 
• 
Treatment C: Hard Capsules GDC-9545, 30 mg (referred to as GDC-9545/F12 capsule in 
this protocol), administered orally 
• 
Treatment D: Hard Capsules GDC-9545, 30 mg F18 (referred to as GDC-9545/F18 capsule 
in this protocol), administered orally 
Statistical Methods 
Primary Analysis 
Mass balance Analyses (Part 1 only) 
The following mass balance parameters will be calculated from urine and feces separately and 
total (urine and feces combined):  
• 
Aeu: amount of TR excreted in urine 
• 
CumAeu: cumulative amount of TR excreted in urine 
• 
Feu: amount of TR excreted in urine expressed as a percentage of the radioactive dose 
administered 
• 
CumFeu: cumulative amount of TR excreted in urine expressed as a percentage of the 
radioactive dose administered 
• 
Aef: amount of TR eliminated in feces 
• 
CumAef: cumulative amount of TR eliminated in feces 
• 
Fef: amount of TR eliminated in feces expressed as a percentage of the radioactive dose 
administered 
• 
CumFef: cumulative amount of TR eliminated in feces expressed as a percentage of the 
radioactive dose administered 
• 
Aetotal: amount of TR excreted in urine and feces combined 
• 
CumAetotal: cumulative amount of TR excreted in urine and feces combined 
• 
Fetotal: amount of TR excreted in urine and feces combined expressed as a percentage of 
the radioactive dose administered 
• 
CumFetotal: cumulative amount of TR excreted in urine and feces combined expressed as a 
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Pharmacokinetic Analyses 
The PK of GDC-9545 in plasma and TR in whole blood and plasma will be summarized by 
estimating the following parameters (as appropriate for data collected): 
• 
Cmax: maximum observed concentration 
• 
tmax: time of maximum observed concentration 
• 
AUC0-t: area under the curve from time 0 to the time of last measurable concentration 
• 
AUC0-inf: area under the curve from time 0 extrapolated to infinity 
• 
λZ: first order rate constant associated with the terminal (log-linear) portion of the curve 
• 
t1/2: terminal elimination half-life 
• 
CL: total body clearance calculated after a single IV administration (for GDC-9545 only; 
Part 2 IV dose only) 
• 
CL/F: total body clearance calculated after a single extravascular administration where F 
(fraction of dose bioavailable) is unknown (for GDC-9545 only; oral doses only) 
• 
Vz: volume of distribution based on the terminal phase calculated using AUC0-inf after a 
single IV administration (for GDC-9545 only; Part 2 IV dose only) 
• 
Vz/F: apparent volume of distribution (for GDC-9545 only; oral doses only) 
• 
Ratio between whole blood and plasma concentrations for TR (Part 1 only) 
• 
Ratio between whole blood and plasma AUC0-inf values for TR (Part 1 only) 
• 
F: Absolute bioavailability calculated using AUC0-inf (for GDC-9545 only; oral doses in Part 2 
only) 
• 
Frel Cmax: Relative bioavailability based on Cmax (for GDC-9545 only; GDC-9545/F18 
capsule, 30 mg in Part 2 only) 
• 
Frel AUC0-t: Relative bioavailability based on AUC0-t (for GDC-9545 only; GDC-9545/F18 
capsule, 30 mg in Part 2 only) 
• 
Frel AUC0-inf: Relative bioavailability based on AUC0-inf (for GDC-9545 only; GDC-9545/F18 
capsule, 30 mg in Part 2 only) 
The absolute bioavailability of GDC-9545/F12 capsule and GDC-9545/F18 capsule will be 
calculated using the AUC0-inf values obtained after oral and IV administration of GDC-9545. The 
mixed-effect analysis of variance model will be used for absolute bioavailability determination. 
The model will include formulation and period as fixed effects and a random subject effect. 
To evaluate the relative bioavailability of GDC-9545 as GDC-9545/F18 capsule compared to 
GDC-9545/F12 capsule, the PK parameters Cmax and AUC0-inf for GDC-9545 will be analyzed.  
The mixed-effect analysis of variance model for the two-period crossover design will be used for 
formulation comparison.  The model will include formulation and period as fixed effects and 
random subject effect (i.e., assuming a compound symmetry covariance structure).  
Log-transformed Cmax, AUC0-t, and AUC0-inf values will be evaluated to estimate ratios of 
geometric mean values and the corresponding 90% confidence intervals (CIs) (test: 
GDC-9545/F18 capsule, reference: GDC-9545/F12 capsule; or test: GDC-9545/F12 capsule, 
reference: GDC-9545 Solution for Infusion; or test: GDC-9545/F18 capsule, reference: 
GDC-9545 Solution for Infusion). 
Determination of Sample Size   
For Part 1, it is planned to enroll 6 subjects to ensure data in a minimum of 4 evaluable 
subjects.  For Part 2, it is planned to enroll 10 subjects to ensure data in a minimum of 
8 evaluable subjects.  No replacement subjects are to be used in Part 1 of this study.  Up to 
4 replacement subjects are permitted in Part 2 of this study to ensure there are 8 evaluable 
subjects. 
The study is exploratory, and no formal sample size calculation has been made.  Based on 
experience from previous studies of a similar design, a sample size of 6 subjects for Part 1 and 
10 subjects for Part 2 is considered appropriate to meet the objectives of the study. 
Interim Analyses 
No interim analyses are planned for Part 1.  


 
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The following in-study decision will be made during Part 2 of this study: 
• 
Progression from sentinel group to main group where sentinel dosing is used for 
Treatment B 
For Treatment B, to assess tolerability of the IV administration, the first subject will be dosed as 
a sentinel; then, at least 4 hours later, the second subject will be dosed only if there are no 
acute safety findings for the first subject. If the first two subjects tolerated the IV dose, in the 
opinion of the Principal Investigator and Medical Monitor, the remaining subjects will be dosed. 
The third subject will be dosed at least 20 hours after the second subject (i.e., at least 24 hours 
after the first subject). All subsequent dosing of the IV formulation will be staggered by at least 
15 minutes. 
The decision to proceed with the main group will be made by the Investigator, based on safety 
data until up to 24 hours post-dose for the two sentinel subjects.  The Investigator will inform the 
sponsor of any safety concerns.  
The decision to proceed to the next dose level will be based on safety and tolerability data.  The 
following data are required: 
• 
Adverse events  
• 
ECGs 
• 
Vital signs 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
14C 
carbon-14 
ALT 
alanine aminotransferase 
APTT 
activated partial thromboplastin time 
ARSAC 
Administration of Radioactive Substances Advisory 
Committee 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
CI 
confidence interval 
CLcr 
creatinine clearance 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CV% 
coefficient of variation 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
ER 
estrogen receptor 
ESR1 
estrogen receptor 1 
FDA 
Food and Drug Administration 
F12 
Roformis Number RO7197597/F12-01 
F18 
Roformis Number RO7197597/F18-01 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 


 
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Abbreviation 
Definition 
IND 
Investigational New Drug (Application) 
INR 
international normalized ratio 
ISF 
Investigator Site File 
IV 
intravenous 
LBD 
ligand-binding domain 
LHRH 
luteinizing hormone-releasing hormone 
LSLV 
last subject, last visit 
MBq 
megabecquerel 
µCi 
microcurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NMT 
not more than 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic(s) 
PLD 
phospholipidosis 
PT 
prothrombin time 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
RBC 
red blood cell 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SUSAR 
suspected unexpected serious adverse reaction 
TR 
total radioactivity 
ULN 
upper limit of normal 
WBC 
white blood cell 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON BREAST CANCER 
Breast cancer is the most commonly diagnosed cancer in women, with an estimated 
global incidence of 2,088,849 new cases and 626,679 deaths reported in 2018 (Bray et 
al. 2018).  Approximately 80% of all breast cancers express estrogen receptor (ER) and 
the vast majority of these cancers are dependent on the ER for tumor growth and 
progression.  Modulation of estrogen activity and/or synthesis is the mainstay of 
therapeutic approaches in women with ER+ breast cancer.  However, despite the 
effectiveness of available endocrine therapies such as ER antagonists (e.g., tamoxifen), 
aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane), and full ER 
antagonists/degraders (e.g., fulvestrant), many patients ultimately relapse or develop 
resistance to these agents and therefore require further treatment for optimal disease 
control. 
1.2 
BACKGROUND ON GDC-9545 
GDC-9545 (RO7197597) is a potent, orally bioavailable, small-molecule therapeutic 
agent that is being developed for the treatment of patients with ER+ breast cancer.  
GDC-9545 antagonizes the effects of estrogens via competitive binding to the 
ligand-binding domain (LBD) of both wild-type and mutant ER with nanomolar potency.  
Upon binding, GDC-9545 induces an inactive conformation to the ER LBD, as measured 
by displacement of co-activator peptides.  In addition to its direct antagonist properties, 
the mechanism of action of GDC-9545 includes reducing levels of ERα protein through 
proteasome-mediated degradation.  Degradation of ER is hypothesized to enable full 
suppression of ER signaling, which is not achieved by first generation ER therapeutics 
such as tamoxifen, which display partial agonism.  GDC-9545 potently inhibits the 
proliferation of multiple ER+ breast cancer cell lines in vitro, including cells engineered to 
express clinically relevant mutations in ER. 
GDC-9545 exhibited dose-dependent anti-tumor activity in xenograft models of ER+ 
breast cancer, including in a patient-derived xenograft model that harbors an estrogen 
receptor 1 (ESR1) mutation (ER.Y537S).  The efficacious dose range was 0.1 to 
10 mg/kg/day, and all doses were well tolerated.  Fulvestrant, when dosed according to 
a clinically relevant dosing scheme, was less efficacious than GDC-9545 in the 
assessed xenograft models.  Thus, GDC-9545 demonstrated robust nonclinical activity 
in ER+ breast cancer models of ESR1-wildtype- and ESR1-mutation-bearing disease. 
Refer to the GDC-9545 Investigator's Brochure (IB) for full details on nonclinical and 
clinical studies. 
1.2.1 
Toxicology and Safety Pharmacology 
Doses used in the pivotal 4- and 26-week toxicity studies were appropriate based on 
evidence of dose-limiting (monkeys) or potentially dose-limiting (rats) toxicities, and 
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therapeutic exposures.  Adverse organ effects identified in both pivotal toxicity studies 
were dose-responsive, largely confined to the kidney and liver, and monitorable in the 
clinic using standard laboratory assessments.  Liver findings were partially to completely 
reversible, while nephropathy observed at 30 mg/kg in rats after 26 weeks of dosing did 
not reverse.  The findings in reproductive organs in both species are consistent with the 
anti-estrogenic mode of action of GDC-9545 and were partially reversible in both 
species.  
In both rats and monkeys, there was a dose-dependent phospholipidosis (PLD) 
observed in numerous organs, including in the retinal pigmented epithelium of the eye 
and choroid plexus epithelium at 30 mg/kg in rats.  In rats, PLD was not noted at 
3 mg/kg, but increased in incidence and severity with increasing dose.  In monkeys, 
dose-dependent PLD was present at all doses but was limited to minimal changes in the 
liver and lymph nodes at 7 mg/kg, the lowest dose tested.  In the 26-week chronic 
toxicity studies, the severity and incidence of PLD observed via light microscopy were 
reduced in some organs for both rats and monkeys suggesting partial reversibility in 
some organs after a 16-week recovery period. 
For the 26-week toxicity study in rats, dose levels of 3, 10, and 30 mg/kg/day resulted in 
area under the concentration-time curve (AUC)-based exposure factor that were 1x, 4x, 
and 13x relative to the 30 mg clinical dose with 30 mg/kg/day being considered the 
severely toxic dose for 10% of animals.  For the 26-week toxicity study in monkeys, dose 
levels of 7, 20, and 60 mg/kg/day resulted in AUC-based exposure factors that were 
0.4x, 0.9x, and 2.5x relative to the 30 mg clinical dose with 20 mg/kg/day being 
considered the highest non-severely toxic dose. 
GDC-9545 was not mutagenic in the bacterial mutagenesis assay, did not induce an 
increase in micronucleus formation in human lymphocytes in in vitro studies and was not 
phototoxic in an in vitro mammalian cell-based assay. 
Results from the nonclinical toxicity and safety pharmacology studies completed to date 
provide a robust characterization of the toxicity profile of GDC-9545 to support 
administration to patients with ER+ breast cancer in ongoing clinical trials. 
1.2.2 
Clinical Summary 
As of the data cutoff of 31 Jan 2020, GDC-9545 has been administered in two Phase I 
clinical studies, GO39932 and GO40987, and one clinical pharmacology trial, a relative 
bioavailability study, GP42006, is ongoing to evaluate the tablet and capsule 
formulations.  
Study GO39932 is a first-in-human Phase Ia/Ib, multicenter, open-label study evaluating 
the safety, pharmacokinetics (PK), and activity of GDC-9545 alone (at doses of 10 to 
250 mg) or in combination (doses of 100 mg GDC-9545) with palbociclib and/or 


 
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luteinizing hormone-releasing hormone (LHRH) agonist in patients with ER+ (human 
epidermal growth factor receptor 2 [HER2]-) breast cancer.  
Study GO40987 is a Phase I, open-label, multicenter, preoperative study to assess 
changes in Ki67 levels and to evaluate the pharmacodynamics, PK, safety, and biologic 
activity of GDC-9545 in patients with Stage I to III operable ER+ (HER2-) untreated 
breast cancer. 
GDC-9545 administered at 30 mg once daily is also being evaluated in a Phase III trial in 
metastatic breast cancer in combination with palbociclib (BO41843; NCT04546009), in a 
Phase II trial in untreated ER+ HER2- early breast cancer, in combination with 
palbociclib (WO42133; NCT04436744) and in a Phase II trial in previously treated ER+ 
HER2- metastatic breast cancer (WO42312; NCT04576455). 
1.2.2.1 
Safety 
The single agent dose escalation portion of Study GO39932 enrolled 29 patients (dose 
levels of 10, 30, 90 and 250 mg).  No dose-limiting toxicities, serious adverse events, or 
adverse events of special interest were reported and a maximum tolerated dose was not 
determined.  Initially 100 mg and 250 mg (±LHRH agonist) GDC-9545 doses were 
chosen for single-agent dose expansion, and an escalation cohort combined 100 mg 
GDC-9545 with 125 mg palbociclib.  
 
 
 
 
.  Enrollment was completed for the 100 mg 
single agent expansion and 100 mg in combination with palbociclib expansion; at the 
time of the data cutoff (31 Jan 2020), enrollment was ongoing in the 30 mg GDC-9545 
expansion cohort. 
As of the data cutoff of 31 Jan 2020, within the dose escalation and dose expansion 
stages combined, a total of 87 patients have been treated with single-agent GDC-9545 
(±LHRH agonist) including 22 patients within the GDC-9545 30 mg cohort.  Forty-eight 
patients have been treated with 100 mg GDC-9545 in combination with 125 mg 
palbociclib (±LHRH agonist), and one patient participated in cardiac Cohort C1 (100 mg 
GDC-9545 in combination with 125 mg palbociclib). 
GDC-9545 is tolerated well as single−agent at all dose levels (10 mg to 250 mg) and in 
combination at 100 mg with palbociclib. 
Of the 87 patients treated with single-agent GDC-9545 at doses ranging from 10 to 
250 mg, regardless of attribution to study drug, adverse events occurring in 10% or more 
patients were: fatigue, back pain, nausea, arthralgia, cough, diarrhea, constipation, and 
pain in extremity.  Grade ≥3 adverse events irrespective of causality occurring in 2 or 
more patients were: diarrhea, decreased appetite, and fatigue. 


 
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In the single agent cohorts, 7 patients (8%) experienced 8 serious events including: 
pleural effusion, pulmonary embolism, duodenal ulcer perforation, appendiceal abscess, 
small intestinal obstruction, fatigue, migraine, and paresthesia.  All serious adverse 
events were considered unrelated to GDC-9545 by the Investigators, except fatigue, 
which was also considered related to progressive disease.  One patient died due to a 
serious adverse event of duodenal ulcer perforation that was considered unrelated to 
GDC-9545 by the Investigator. 
Of the 48 patients treated with 100 mg GDC-9545 in combination with palbociclib, 
8 patients (17%) experienced 9 serious adverse events including: dyspnea, urinary tract 
infection, electrocardiogram QT prolonged, deep vein thrombosis, thrombocytopenia and 
fatal breast cancer progression (in one patient each), and neutropenia (3 patients); only 
Grade 3 QT prolonged was considered related to GDC-9545 by the Investigator. 
In Study GO40987, patients received GDC-9545 daily for approximately 14 days at one 
of three treatment cohorts (10, 30, and 100 mg).  
As of the data cutoff date of 31 Jan 2020, a total of 30 postmenopausal women with 
Stage I to III operable ER+ (HER2-) untreated breast cancer were treated with single-
agent GDC-9545 at doses ranging from 10 to 100 mg in Study GO40987.  Adverse 
events reported in ≥10% of patients irrespective of attribution to study drug were: 
nausea, procedural pain and hot flush, asthenia and arthralgia.  In this study, one patient 
experienced serious adverse event of breast abscess (Grade 3), following surgery, in the 
GDC-9545 10 mg dose group.  However, it was not related to study treatment.  No other 
Grade ≥3 adverse events or serious adverse events irrespective of causality, 
thromboembolic events, or issues with wound healing have been reported. 
Therefore, overall GDC-9545 was well tolerated at all dose levels in patients with early 
breast cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The study population rationale and the dose rationale for the study drugs are discussed 
in Sections 3.3.1 and 3.3.2, respectively. 


 
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1.3.1 
Study Rationale 
GDC-9545 is being investigated for the treatment of ER+ breast cancer, using a capsule 
formulation.  The efficacy of GDC-9545 is currently being assessed in breast cancer 
patients and as of the data cutoff of 31 Jan 2020, clinical benefit rate was reported in 
71 (60%) of 119 patients overall (in Study GO39932).  Additionally, GDC-9545 is being 
progressed into Phase III studies in metastatic breast cancer patients.   
To support the regulatory clinical pharmacology package for GDC-9545, a radiolabeled 
human mass-balance study (absorption, distribution, metabolism and elimination) is 
required to characterize the overall disposition and biotransformation of GDC-9545.  
Part 1 of this study is being conducted to investigate the mass balance recovery and 
metabolic profiling and identification for orally administered carbon-14 ([14C])-GDC-9545.  
The study will use oral administration to determine the metabolite profile of GDC-9545, 
as this is the intended therapeutic route. 
Part 2 of this study is being conducted to investigate the absolute and relative 
bioavailability of two GDC-9545 oral capsules, in order to aid formulation optimization for 
the development of a capsule formulation that will be successfully administered to 
patients. Formulation Roformis Number RO7197597/F12-01 (F12) is a 30 mg 
 capsule formulation manufactured using standard 
excipients and a 
. For Formulation Roformis Number 
RO7197597/F18-01 (F18), the encapsulation process of Formulation F12 was further 
improved and a 
 was selected as the manufacturing 
technology. 
 
1.3.2 
Risk-Benefit Assessment 
There will be no therapeutic benefit for the volunteers participating in the study.  The 
development of a product to improve the treatment of ER+ breast cancer will be of 
benefit to the wider community/patients with such symptoms. 
The risks of participation are primarily those associated with adverse reactions to the 
study drug, although there may also be some discomfort from collection of blood 
samples and other study procedures.  The tolerability profile of GDC-9545 from 
administration of single agent daily doses up to 250 mg to ER+ breast cancer patients 
has been characterized from previous clinical studies.  There have been few adverse 
drug reactions following GDC-9545 dosing in previous clinical studies in patients. With 
the exception of one event of fatigue (which was also considered related to progressive 
disease), no serious adverse drug reactions have been reported in the single agent 
studies. No specific safety concerns have been identified about the use of 30 mg 
GDC-9545 in healthy volunteers in this study.  
Because an intravenous (IV) dose of GDC-9545 has not been previously administered in 
a clinical study, a sentinel dosing design will be used for Treatment B in Part 2, i.e., the 


 
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second subject administered Treatment B will be dosed at least 4 hours after the first 
subject, and the third subject will be dosed at least 20 hours after the second subject 
(i.e., at least 24 hours after the first subject). This will allow assessment of the tolerability 
of the IV administration in the first two subjects prior to dosing the remaining subjects. 
Potential risks identified in the IB include hepatotoxicity, venous thromboembolic events, 
renal dysfunction, bradycardia and QT prolongation, which will be monitored by safety 
laboratory and electrocardiogram (ECG) assessments as applicable.  Potential 
gastrointestinal (GI) toxicities will be monitored through adverse event monitoring.  
Potential drug-drug interactions with other medications are addressed by restrictions on 
concomitant medication use.  Potential risks to a developing fetus from GDC-9545 
exposure in utero, changes in female reproductive organs and menopausal symptoms 
and male/female infertility are addressed by exclusion of males and females of 
childbearing potential from this study. Risks associated with GDC-9545 are further 
discussed in Section 5.1.1. 
Risks associated with radiation and Coronavirus Disease 2019 (COVID-19) associated 
risks are discussed in Sections 5.1.2 and 5.1.3, respectively, and general risks 
associated with the conduct of the study are discussed in Section 5.1.4.  However, these 
risks are considered to be small and therefore acceptable. 
Overall, no significant safety concerns have been identified about the use of 30 mg 
GDC-9545 or [14C]-GDC-9545 in healthy volunteers.  All volunteers will be resident in the 
clinic and remain under medical supervision following study drug administration and will 
undergo a standard battery of safety assessments.  Hence, the risks to participants in 
this study are considered acceptable. 
2. 
OBJECTIVES AND ENDPOINTS 
Part 1 of this study will evaluate the absorption, metabolism, excretion, PK and safety of 
GDC-9545 in healthy volunteers.  Part 2 of this study will evaluate the absolute and 
relative bioavailability, and safety of GDC-9545 in healthy volunteers.  Specific 
objectives and corresponding endpoints for both parts of the study are outlined below.  
2.1 
MASS BALANCE, PHARMACOKINETIC AND METABOLITE 
PROFILING AND IDENTIFICATION OBJECTIVES (PRIMARY 
AND SECONDARY STUDY OBJECTIVES) 
2.1.1 
Part 1 
The primary mass balance and PK objectives for Part 1 of this study are as follows: 
• 
To determine the mass balance and routes of elimination of [14C]-GDC-9545 
following a single oral dose of [14C]-GDC-9545 capsule, 30 mg containing not more 
than (NMT) 4.6 megabecquerel (MBq; 124 microcurie [µCi]) on the basis of the 
following endpoints: 


 
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– 
Mass balance recovery of total radioactivity (TR) in all excreta (urine and 
feces): CumAe and CumFe 
– 
Determination of routes and rates of elimination of [14C]-GDC-9545 by Ae, 
CumAe, Fe and CumFe by interval for all excreta (urine and feces) 
• 
To assess the PK of GDC-9545 and total drug-derived material in plasma following 
a single oral dose of [14C]-GDC-9545 capsule, 30 mg (NMT 4.6 MBq [124 µCi]) on 
the basis of the following endpoints: 
– 
Calculation of PK parameters as appropriate for GDC-9545 (plasma only) and 
TR (plasma and whole blood) 
– 
Assessment of the concentrations of TR in whole blood and plasma  
– 
Evaluation of whole blood:plasma concentration ratios for TR 
The secondary metabolite profiling and identification objective for Part 1 of this study is 
as follows: 
• 
To characterize and identify metabolites of [14C]-GDC-9545 in plasma, urine, and 
feces on the basis of the following endpoint: 
– 
Characterization of abundant metabolites by liquid chromatography-high 
resolution mass spectrometry 
Metabolite profiling and identification will be reported separately from the Clinical Study 
Report as a standalone document. 
 
2.1.2 
Part 2 
The primary PK objectives for Part 2 of this study are as follows: 
• 
To determine the absolute bioavailability of an oral GDC-9545/F12 capsule, 30 mg 
and an oral GDC-9545/F18 capsule, 30 mg on the basis of the following endpoints: 
– 
Absolute bioavailability assessment based on the PK parameter AUC0-inf for 
GDC-9545  
• 
To determine the relative bioavailability of GDC-9545/F18 capsule, 30 mg compared 
to the GDC-9545/F12 capsule, 30 mg on the basis of the following endpoint: 
– 
Relative bioavailability assessment based on the PK parameters Cmax and 
AUC0-inf for GDC-9545  
The secondary PK objectives for Part 2 of this study are as follows: 
• 
To characterize the PK of GDC-9545 following oral and IV administration on the 
basis of the following endpoint: 
– 
Calculation of PK parameters as appropriate for GDC-9545 in plasma only 
 


 
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2.2 
SAFETY OBJECTIVE (SECONDARY STUDY OBJECTIVE) 
The safety (secondary) objective for both Parts 1 and 2 of this study is to evaluate the 
safety and tolerability of single doses of GDC-9545 on the basis of the following 
endpoints: 
• 
Incidence and severity of adverse events 
• 
Incidence of abnormalities in laboratory safety tests, 12-lead ECGs and vital sign 
measurements 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label, single-center, two part study in heathy female subjects of 
non-childbearing potential to investigate the absorption, metabolism, and excretion of 
[14C]-GDC-9545 (Part 1), the absolute bioavailability of formulations F12 and F18 (i.e., 
GDC-9545/F12 capsule, 30 mg and GDC-9545/F18 capsule, 30 mg) and relative 
bioavailability of GDC-9545 oral capsule F18 to the F12 formulation (Part 2). 
Subjects who do not meet the criteria for participation in this study (screen failure) may 
qualify for 1 re-screening opportunity (for a total of 2 screenings per participant) at the 
Investigator's discretion.  Subjects must re-sign the consent form prior to re-screening.  
The Investigator will record reasons for screen failure in the screening log (see 
Section 4.5.1). 
It is planned that Part 1 will begin prior to Part 2 of the study, and that the two parts of 
the study will partially overlap. 
3.1.1 
Part 1 
Part 1 is an open-label, single-treatment design.  It is planned to enroll 6 subjects to 
ensure data in a minimum of 4 evaluable subjects.  An evaluable subject for Part 1 of the 
study is defined as a subject who has provided mass balance and PK samples for up to 
480 hours (up to Day 21) or until they have met the mass balance discharge criteria (i.e., 
cumulative recovery of radioactivity exceeds 90% of the administered dose; OR 
radioactivity in urine and feces is less than 1% of the administered dose over a 24 hour 
period on 2 consecutive PK sample collection days, as determined by quick counts). 
Each subject will receive a single oral dose of [14C]-GDC-9545 capsule, 30 mg (NMT 
4.6 MBq [124 µCi]) with approximately 240 mL water in the fasted state (Treatment A). 
Subjects will undergo preliminary screening procedures for the study up to 28 days 
(Day -28 to Day -2) before [14C]-GDC-9545 administration on Day 1.  Subjects will be 
admitted in the morning on the day prior to [14C]-GDC-9545 administration (Day -1) and 
will be dosed in the morning of Day 1 following an overnight fast of a minimum of 
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Urine and feces samples for measurement of TR will be collected pre-dose and at 
intervals until study completion including after discharge, if needed.  
Blood samples for measurement of plasma GDC-9545 and TR in plasma and whole 
blood will be collected pre-dose and at intervals until study completion including after 
discharge, if needed.  
Safety and tolerability will be monitored by clinical and laboratory assessments at 
intervals throughout the study. 
It is planned that subjects will remain resident in the clinical unit until 480 hours 
post-dose (Day 21) when they will be discharged from the clinical unit. 
It is planned that subjects will be released as a group when all subjects have achieved 
the following mass balance discharge criteria: 
• 
Cumulative recovery of radioactivity exceeds 90% of the administered dose; OR 
• 
Radioactivity in urine and feces is less than 1% of the administered dose over a 
24 hour period on 2 consecutive PK sample collection days, as determined by quick 
counts 
This may result in the subjects being discharged as a group prior to completion of the 
planned residency period.  Once the mass balance discharge criteria have been 
achieved, collection of all samples (blood, urine, and feces) may be stopped and the 
subjects will undergo discharge assessments.  If the mass balance discharge criteria 
have not been met by all subjects by Day 21, subjects will be discharged from the 
clinical unit and those who have not met the discharge criteria will return for outpatient 
visits every 7 days for a 24-hour sample collection interval (i.e., subjects will be resident 
in the clinical unit for 24 hours during each return visit) until the mass balance discharge 
criteria are met (the maximum number of 24-hour return visits will not exceed 3).  
Discharged subjects may be asked to return for these visits if samples are needed 
post-discharge, prior to study completion.  During the period of weekly collection, mass 
balance cumulative recovery will be estimated by means of interpolation. 
If additional residency is not considered appropriate or necessary, then home collections 
of urine and/or feces may be requested at the discretion of the Investigator for individual 
subjects. 
The total duration of Part 1 of the study for each enrolled subject (screening through to 
end of study) will be approximately 10 weeks, divided as follows: 
• 
Screening: up to 28 days before the first dose of study drug. 
• 
A single treatment period, with admission on Day -1 and discharge from the clinical 
unit on or before Day 21  


 
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• 
If mass balance discharge criteria have not been met by Day 21: return visits every 
7 days for a 24-hour sample collection interval until the radioactivity recovery criteria 
are met (maximum number of 24-hour outpatient visits will not exceed 3). 
Discharged subjects may be asked to return for these visits if samples are needed 
post-discharge, prior to study completion.   
Figure 3 presents an overview of the study design for Part 1.  A schedule of activities is 
provided in Appendix 1. 
Figure 3 Overview of Part 1 Design 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 21a  
a Subjects may be discharged as a group earlier if the mass balance discharge criteria have been 
achieved.  If the criteria have not been met by Day 21, subjects will be discharged from the 
clinical unit and those who have not met the discharge criteria will return for outpatient visits 
every 7 days for a 24-hour sample collection interval until the mass balance discharge criteria are 
met (the maximum number of 24-hour return visits will not exceed 3).  Discharged subjects may 
be asked to return for these visits if samples are needed post-discharge, prior to study 
completion.  If additional residency is not considered appropriate or necessary, then home 
collections of urine and/or feces may be requested at the discretion of the Investigator for 
individual subjects. 
 
3.1.2 
Part 2 
Part 2 is a randomized, open-label, three-treatment, two-sequence crossover design 
conducted over three periods.  It is planned to enroll 10 subjects to ensure data in a 
minimum of 8 evaluable subjects.  An evaluable subject for Part 2 of the study is defined 
as a subject who has received an investigational medicinal product (IMP) and has 
sufficient drug concentration measurements up to 168 hours after dosing for evaluation 
of defined PK parameters for each treatment, and have completed all planned safety 
assessments up to 168 hours after dosing for each treatment.  
Subjects will be randomly allocated to one of two treatment sequences (BCD and BDC; 
see Section 4.2.2). In each treatment period, subjects will receive a single 30 mg dose of 
GDC-9545 in the fasted state.  GDC-9545 will be administered as one of three possible 
formulations according to the randomization schedule: 
• 
Treatment B: 30 mg GDC-9545 as a Solution for Infusion, 3 mg/mL administered 
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• 
Treatment C: GDC-9545/F12 capsule, 30 mg, administered with approximately 
240 mL water 
• 
Treatment D: GDC-9545/F18 capsule, 30 mg, administered with approximately 
240 mL water 
Subjects will undergo preliminary screening procedures for the study up to 28 days 
(Day -28 to Day -2) before GDC-9545 administration on Day 1 of Period 1.  Subjects will 
be admitted in the morning on the day prior to the first GDC-9545 administration (Day -1 
of Period 1).  Subjects will be resident in the clinical unit from the morning of Day -1 in 
Period 1 until Day 8 in Period 3 (i.e., for 28 to 29 consecutive nights that will cover all 
3 treatment periods). 
For each treatment period, subjects will be dosed in the morning of Day 1 following an 
overnight fast of a minimum of 10 hours. 
For Treatment B, to assess tolerability of the IV administration, the first subject will be 
dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if 
there are no acute safety findings for the first subject. If the first two subjects tolerated 
the IV dose, in the opinion of the Principal Investigator and Medical Monitor per the 
criteria in Section 6.8.1, the remaining subjects will be dosed. The third subject will be 
dosed at least 20 hours after the second subject (i.e., at least 24 hours after the first 
subject). All subsequent dosing of the IV formulation will be staggered by at least 
15 minutes. 
Blood samples for measurement of plasma GDC-9545 will be collected pre-dose and at 
intervals until Day 8 of each period.  
Safety and tolerability will be monitored by clinical and laboratory assessments at 
intervals throughout the study. 
The total duration of Part 2 of the study for each enrolled subject (screening through to 
end of study) will be approximately 9 weeks, divided as follows: 
• 
Screening: up to 28 days before the first dose of study drug. 
• 
Three treatment periods, separated by a treatment-free washout so there are at 
least 10 days between each of the three study drug administrations.  
• 
Safety follow-up call: 13 to 15 days after the last dose of study drug. 
Figure 4 presents an overview of the study design for Part 2.  A schedule of activities is 
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Figure 4 Overview of Part 2 Design 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 (Period 1 only) 
 
Dose 
Day 1 (Periods 1, 2 and 3)a 
 
Discharge 
Day 8 (Period 3 only) 
 
Follow-Up Call 
13 to 15 days post-final dose 
a Subjects will receive Treatments B, C and D in Periods 1, 2 and 3 in a randomized manner.  
There will be a minimum washout of 10 days between each IMP administration. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last subject, last visit (LSLV), 
occurs or the date at which the last data point required for statistical analysis (i.e., mass 
balance, PK and/or metabolite profiling and identification data for Part 1 and PK data for 
Part 2) or safety follow-up is received from the last subject, whichever occurs later.  The 
end of the study is expected to occur approximately 9 weeks after the last subject is 
enrolled in Part 2. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of Part 1 of the study, from screening of the first subject to the end of the 
study, is expected to be approximately 10 weeks. The total length of Part 2 of the study, 
from screening of the first subject to the end of the study, is expected to be 
approximately 9 weeks. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Subject Population 
Healthy volunteers, instead of a patient population, have been chosen for this study in 
order to safely assess the absorption, metabolism, excretion, PK and safety properties of 
GDC-9545.   
As this is a Phase I study assessing the absorption, metabolism, excretion, PK, relative 
bioavailability and safety of GDC-9545, the most relevant population is healthy 
volunteers, as recommended by the U.S. Food and Drug Administration (FDA, (2002) 
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without a history of alcohol or drug abuse or regular co-medication are proposed to avoid 
interaction on drug metabolism and to avoid non-compliance. 
The target patient population for GDC-9545 is female ER+ breast cancer patients; 
therefore, it is necessary to assess the absorption, metabolism, excretion, PK and safety 
properties of GDC-9545 in female subjects. Based on the anti-estrogenic 
pharmacological activity of GDC-9545, administration during pregnancy is expected to 
have an adverse effect and poses a risk to the human fetus, including birth defects and 
miscarriage.  Additionally, only female subjects are to be enrolled owing to there being 
no previous clinical information on safety in males. Therefore, only female subjects of 
non-childbearing potential will be allowed to participate in the study. 
We acknowledge the Administration of Radioactive Substances Advisory Committee 
(ARSAC) Notes for Guidance recommend that wherever possible, healthy subjects 
selected for research projects should be aged over 50 years (2020).  However, the 
current study is designed to generate data for supporting the investigation of the human 
absorption, metabolism and excretion of a drug, as well as generating samples for 
metabolite profiling and structural identification. 
There are two main reasons for generating these data within a clinical development 
program.  The first is to provide human metabolite data that can be used to interpret the 
metabolism profiles seen in the preclinical species employed in the longer term toxicity 
studies, to ensure that there is adequate toxicology coverage for the safe development 
of the drug in patients.  The second is to provide data to understand how the drug is 
processed in physiologically normal subjects, because understanding the routes of 
metabolism and elimination in a healthy population generates the appropriate data to 
guide the clinical pharmacology package required to fulfil the regulatory requirements of 
a New Drug Application.  
In order to address these two main aims of an absorption, metabolism and excretion 
study, investigation of the drug under development is required in a population with 
normal physiological function, as it is recognized that certain physiological processes 
e.g., renal function, deteriorate with age and therefore it is preferable to use as healthy 
population as possible, to mitigate against factors which may make interpretation of the 
data difficult.  Also, healthy subjects as a trial population are ideal since they have a 
relatively stable physiological, biochemical and hormonal status, which removes any 
disease-related variations and variations due to concomitant medications. 
Additionally, healthy volunteers are considered more suitable for this study than for the 
following reasons: 
• 
Patients would not be expected to derive clinically meaningful benefit from 
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• 
Patients participating in this study would need to discontinue standard-of-care 
therapy so that the study could achieve its objective of assessing the absorption, 
metabolism, excretion, PK profile safety and tolerability of GDC-9545  
• 
Healthy volunteers are expected to have the best systemic reserve to respond to 
any unexpected reactions to GDC-9545, such as hypersensitivity reactions 
Based on the above considerations and target population, healthy female subjects of 
non-childbearing potential (i.e., surgically sterilized or post-menopausal), aged ≥30 and 
≤65 years are considered suitable for this study. 
3.3.2 
Rationale for [14C]-GDC-9545 and GDC-9545 Doses and 
Schedule 
The planned therapeutic dose for GDC-9545 (which is currently being evaluated in a 
Phase III trial in metastatic breast cancer patients) is 30 mg once daily; therefore, 30 mg 
is the chosen dose for both Parts 1 and 2 of this study.  Single doses of GDC-9545 up to 
250 mg have been administered in previous Phase I clinical studies (in ER+ breast 
cancer patients), and have been found to be well tolerated. 
GDC-9545 will be given in the fasted state in order to avoid the potential for a food 
effect. 
This is an open-label study, because the parameters (i.e., mass balance recovery of TR 
in urine and feces, TR concentrations in plasma and whole blood, and GDC-9545 
concentrations in plasma) on which the primary endpoints are based are considered to 
be objective measures. 
3.3.2.1 
Part 1 
In order to assess the absorption, metabolism and excretion of GDC-9545, a single oral 
dose of [14C]-GDC-9545 capsule, 30 mg [NMT 4.6 MBq [124 µCi]) in Part 1. 
The dose of radioactivity has been determined following review of nonclinical 
quantitative whole body autoradiography data and the consequential human dosimetry 
prediction.  The effective dose will be 0.7 millisievert (mSv) and will fall within 
International Commission on Radiological Protection (1992) Guidelines for Category IIa 
studies (0.1 to 1 mSv).  The dose of radioactivity will be no more than 4.6 MBq 
(124 µCi). 
To ensure that the [14C] drug product(s) does not exceed the limit for radioactive dose 
approved by ARSAC, the target specific activity of the drug substance will be set at 90% 
of 90% of the threshold radioactive dosing limit.  This will allow for tolerances in the 
manufacturing processes for both drug substance and drug product thereby providing 
continued assurance for compliance with the ARSAC approved limit for drug product 
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3.3.2.2 
Part 2 
In order to assess the relative and absolute bioavailability of different oral formulations of 
GDC-9545, a single IV administration of 30 mg GDC-9545 as a Solution for Infusion, 
3 mg/mL will be administered (as an infusion) for Treatment B and single oral doses of 
capsule formulations F12 and F18 (i.e., GDC-9545/F12 capsule, 30 mg and 
GDC-9545/F18 capsule, 30 mg) will be administered for Treatments C and D, 
respectively. 
An IV dose of 30 mg was selected to be equal to the oral dose in order to prevent any 
difficulties in comparison of the IV and oral dose that may arise if there is non-linearity in 
the PK. Simulations for the IV dose of 30 mg in 10 mL infused over 30 minutes using the 
population PK model and the physiologically based PK model for GDC-9545 predicted 
peak concentrations that were within the range of concentrations observed previously in 
clinic (the highest Cmax observed previously being 1650 ng/mL at steady-state following 
administration of 250 mg GDC-9545 once daily). 
For Treatment B, to assess tolerability of the IV administration, the first subject will be 
dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if 
there are no acute safety findings for the first subject. If the first two subjects tolerated 
the IV dose, in the opinion of the Principal Investigator and Medical Monitor per the 
criteria in Section 6.8.1, the remaining subjects will be dosed. The third subject will be 
dosed at least 20 hours after the second subject (i.e., at least 24 hours after the first 
subject). All subsequent dosing of the IV formulation will be staggered by at least 15 
minutes. 
A crossover design was chosen for Part 2 for Treatments C and D because it utilizes 
within-subject, as well as between-subject, comparisons and is consequently more 
efficient than a standard parallel group design.  As each subject acts as their own 
control, the impact of confounding factors is also minimized.  Subjects were randomized 
between treatment sequences BCD and BDC to minimize allocation and selection bias. 
3.3.3 
Rationale for PK Sampling Schedule  
The PK sampling schedule has been selected on the basis of data from previous studies 
in which single doses of GDC-9545 have been administered to patients.  The frequent 
sampling schedule that follows the single doses of GDC-9545 is designed to capture 
data at a sufficient number of time points to provide a detailed profile of the absorption, 
distribution, and elimination of this drug, including time to maximum observed 
concentration (tmax) and terminal half-life (t1/2). 
4. 
MATERIALS AND METHODS  
4.1 
SUBJECTS 
Approximately 16 (6 in Part 1 and 10 in Part 2) healthy female volunteers of 
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No replacement subjects are to be used in Part 1 of this study.  Up to 4 replacement 
subjects are permitted in Part 2 of this study to ensure there are 8 evaluable subjects; a 
maximum of 6 subjects in Part 1 and 14 subjects in Part 2 may be dosed. 
Subjects will be recruited from the Quotient Sciences panel or by direct advertising to the 
public.  Quotient Sciences (the Clinical Research Unit) must have a full medical history 
from each subject’s General Practitioner as follows: 
• 
Within the last 24 months prior to enrollment in the study for all volunteers who have 
previously participated in a clinical research study at Quotient Sciences.  
• 
Within the last 12 months prior to enrollment in the study for all new volunteers. 
Before subjects are admitted to the clinic, The Over Volunteering Prevention System will 
be checked to ensure that each subject has not been dosed in a study within 90 days of 
the planned Day 1 (Part 1) or Day 1 of Period 1 (Part 2) of this study. 
4.1.1 
Inclusion Criteria 
Subjects must meet the following criteria for study entry: 
1. 
Able and willing to comply with the study restrictions and to give written informed 
consent before any study procedure.   
2. 
Healthy female subjects of non-childbearing potential that are non-pregnant, 
non-lactating females, who are either postmenopausal or surgically sterile, aged 
30 to 65 years, inclusive, at time of signing the Informed Consent Form (ICF) 
• 
Postmenopausal females are defined as: 
o Age >60 years; 
o Age ≤60 years and amenorrhea ≥12 months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression. Estradiol 
levels and/or follicle-stimulating hormone (FSH) levels in the 
postmenopausal range; 
• 
Surgically sterile females for at least 90 days prior to screening are defined as: 
o Bilateral salpingectomy; 
o Hysterectomy; 
o Bilateral oophorectomy; 
• 
For all subjects, the pregnancy test result must be negative at screening and 
admission (Day -1 for Part 1 and Day -1 of Period 1 for Part 2) 
3. 
A body mass index (BMI) between 18.5 and 32.0 kg/m2, inclusive, at screening 
4. 
Ability to comply with the study protocol 
5. 
Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 
stools per day) (Part 1 only) 


 
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• 
Female subjects of non-childbearing potential do not need to use any methods of 
contraception.   
For both study parts, inclusion criterion 2 from the list above will be re-assessed at 
admission/pre-dose of Part 1 and admission/pre-dose of Part 2 Period 1. 
 
4.1.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. 
Women of childbearing potential, women who are pregnant or breastfeeding. 
– 
All women must have a negative highly sensitive serum pregnancy test result at 
screening and a negative highly sensitive urine pregnancy test at admission. 
2. 
Subjects who have received any IMP in a clinical research study within the 90 days 
prior to Day 1 (Part 1) or Day 1 of Period 1 (Part 2) 
3. 
History of serious adverse reaction or serious hypersensitivity to any drug or allergy 
to the study drug formulation excipients 
4. 
Subjects who are, or are immediate family members of, a study site or Sponsor 
employee 
5. 
Subjects who have previously been administered IMP in this study.  Subjects who 
have taken part in Part 1 are not permitted to take part in Part 2. 
6. 
Evidence of current severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2; i.e., the virus that causes COVID-19) infection 
7. 
Positive for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or 
human immunodeficiency virus (HIV) antibody at screening 
8. 
History of any drug or alcohol abuse in the past 2 years 
9. 
Regular alcohol consumption >14 units per week (1 unit = ½ pint beer, or a 25 mL 
shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) 
10. A confirmed positive alcohol breath test at screening or admission 
11. Current smokers and those who have smoked within the last 12 months.  A 
confirmed breath carbon monoxide reading of greater than 10 ppm at screening or 
admission.  
12. Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months  
13. Confirmed positive drugs of abuse test result at screening or admission 
14. Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic x-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years.  No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017, shall 
participate in the study (Part 1 only) 
15. Subjects who do not have suitable veins for multiple venipunctures/cannulation as 
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16. Clinically significant abnormal clinical chemistry, hematology, coagulation or 
urinalysis as judged by the Investigator (laboratory parameters are listed in 
Appendices 1 and 2).  Subjects with Gilbert’s Syndrome are allowed 
17. Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance (CLcr) of <70 mL/min using the Cockcroft-Gault equation  
18. History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic 
respiratory or GI disease (especially peptic ulceration, GI bleeding, ulcerative colitis, 
Crohn’s Disease or Irritable Bowel Syndrome), neurological or psychiatric disorder, 
as judged by the Investigator 
19. Presence or history of clinically significant allergy requiring treatment, as judged by 
the Investigator.  Hay fever is allowed unless it is active 
20. Donation of blood or plasma within the previous 3 months or loss of greater than 
400 mL of blood 
21. Subjects who are taking, or have taken, any medication (e.g., prescription drugs, 
over-the-counter drugs, hormone replacement therapy [HRT], vaccines, topical 
medications, herbal or homeopathic remedies, nutritional supplements), other than 
up to 4 g of paracetamol per day, in the 14 days before IMP administration.  
Exceptions may apply on a case by case basis, if considered not to interfere with 
the objectives of the study, as determined by the Investigator. 
22. Subjects who are taking, or have taken, oral antibiotics within 4 weeks or IV 
antibiotics within 8 weeks prior to admission. 
23. Subjects who are taking, or have taken, any medications/products known to alter 
drug absorption, metabolism, or elimination processes, including St. John’s wort, 
within 30 days prior to admission. 
24. History of GI surgery (with the exception of appendectomy unless it was performed 
within the previous 12 months) (Part 1 only) 
25. Acute diarrhea or constipation in the 7 days before the predicted Day 1.  If screening 
occurs >7 days before the Day 1, this criterion will be determined on Day 1.  
Diarrhea will be defined as the passage of liquid feces and/or a stool frequency of 
greater than 3 times per day.  Constipation will be defined as a failure to open the 
bowels for 3 days (Part 1 only) 
26. Malabsorption syndrome or other condition that would interfere with 
enteral absorption 
27. History or presence of an abnormal ECG that is clinically significant in the 
Investigator's opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block, or evidence of prior myocardial infarction 
28. QT interval corrected through use of Fridericia's formula (QTcF)  440 msec 
demonstrated by at least two ECGs  30 minutes apart 
29. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
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(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome 
30. Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 bpm prior to 
enrollment 
31. Current treatment with medications that are well known to prolong the QT interval 
32. Absolute neutrophil count <1.3  109/L (1300/L)  
33. Failure to satisfy the Investigator of fitness to participate for any other reason 
For Part 1, exclusion criteria 1, 6, 10, 11, 13, 16, 20, 21, 25, 27, 28, 29, 30, 31, 32 and 
33 from the list above will be re-assessed at admission/pre-dose. 
For Part 2, exclusion criteria 1, 6, 10, 11, 13, 16, 20, 21, 27, 28, 29, 30, 31, 32 and 33 
from the list above will be re-assessed at admission/pre-dose in Period 1. 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This study is open-label; no blinding is required. 
4.2.1 
Part 1 
Part 1 is non-randomized; therefore, a randomization schedule will not be produced.  A 
treatment allocation will be produced prior to dosing with IMP, which will dictate the order 
in which each subject is administered the treatment.  The treatment allocation will be 
retained in the Investigator Site File (ISF). 
Eligible subjects will be assigned a unique identification number on the morning of 
dosing (Day 1) according to the code 
 to 
 for Part 1, using the lowest number 
available. 
4.2.2 
Part 2 
Using a computer-generated randomization schedule, subject numbers will be allocated 
to one of two treatment sequences (Table 4) in Part 2.  The allocation will be balanced 
with 5 subjects assigned to each of the treatment sequences. 
Table 4 
Part 2 Treatment Sequences 
Treatment Sequence 
Period 1 
Period 2 
Period 3 
BCD 
Treatment B 
Treatment C 
Treatment D 
BDC 
Treatment B 
Treatment D 
Treatment C 
B; Treatment B = 30 mg GDC-9545 as a Solution for Infusion, 3 mg/mL administered 
intravenously in 10 mL as an infusion over 30 minutes 
C; Treatment C = GDC-9545/F12 capsule, 30 mg, administered with approximately 240 mL water 
D; Treatment D = GDC-9545/F18 capsule, 30 mg, administered with approximately 240 mL water 
 
Eligible subjects will be assigned a unique identification number on the morning of 
dosing in Period 1 according to the code 
 to 
 for Part 2, using the lowest number 


 
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available.  Replacement subjects will be allocated subject numbers 
 to 
, where 
the last 2 digits are the same as those of the original subject (e.g., if Subject 
 
withdraws the replacement will have Subject Number 
).  Replacement subjects will 
be assigned to the same treatment sequence as the subject they replaced and will 
receive any treatments that the replaced subject did not receive in addition to any 
treatments that are required to make the required comparison of interest. 
A treatment allocation list will be produced prior to dosing using the randomization 
schedule and will be retained in the ISF. 
The original randomization schedule and proof of quality control procedures will be held 
by the Data Sciences department at Quotient Sciences until the study is archived, at 
which time the randomization materials will be retained in the ISF. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The IMP for Part 1 of this study is: 
• 
For Treatment A: [14C]-RO7197597 Capsule, 30 mg (NMT 4.6 MBq [124 µCi]), which 
is referred to as [14C]-GDC-9545 capsule in this protocol 
The IMPs for Part 2 of this study are:  
• 
For Treatment B: RO7197597 Solution for Infusion, 3 mg/mL, (referred to as 
GDC-9545 Solution for Infusion in this protocol) 
• 
For Treatment C: Hard Capsules GDC-9545, 30 mg (referred to as GDC-9545/F12 
capsule in this protocol) 
• 
For Treatment D: Hard Capsules GDC-9545, 30 mg F18 (referred to as 
GDC-9545/F18 capsule in this protocol) 
4.3.1 
Study Treatment Formulations and Packaging 
For Part 1, the [14C]-GDC-9545 will be supplied by Pharmaron UK Ltd, Rushden, 
Northamptonshire, UK (Pharmaron) as a powder. 
For Part 2, the GDC-9545 active pharmaceutical ingredient will be supplied by the 
Sponsor.   
In Part 1, the radiolabeled Treatment A, [14C]-GDC-9545 capsule, 30 mg (NMT 4.6 MBq 
[124 µCi]), will be manufactured by Quotient Sciences as capsules for oral 
administration.  
In Part 2, two oral capsule formulations will be investigated (GDC-9545/F12 capsule, 
30 mg and GDC-9545/F18 capsule, 30 mg); both formulations will be manufactured by 
the Sponsor and will be supplied as 30 mg capsules. 


 
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In Part 2, for the purposes of assessment of the absolute bioavailability of the oral 
formulations, an IV formulation (GDC-9545 as a Solution for Infusion, 3 mg/mL) will also 
be administered; this will be manufactured by Quotient Sciences. 
For information on the formulation and handling of [14C]-GDC-9545 and GDC-
9545, see the Investigational Medicinal Product Dossier. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Sections 3.1.1 and 3.1.2 for Parts 1 and 2 of 
the study, respectively. 
Refer to the dosing instructions for detailed instructions on drug preparation, storage, 
and administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.3.5.11. 
Guidelines for treatment interruption or discontinuation for subjects who experience 
adverse events are provided in Section 4.6. 
4.3.2.1 
[14C]-GDC-9545 and GDC-9545 
In Part 1, each subject will receive a single oral dose of [14C]-GDC-9545 capsule, 30 mg 
(NMT 4.6 MBq [124 µCi]) (Treatment A).  The test formulation will be swallowed whole 
with approximately 240 mL water following an overnight fast of a minimum of 10 hours. 
In Part 2, each subject will be randomized to receive a single dose of 30 mg GDC-9545 
in each of three treatment periods; the following formulations will be administered: 
• 
Treatment B: GDC-9545 Solution for Infusion, 3 mg/mL  
• 
Treatment C: GDC-9545/F12 capsule, 30 mg  
• 
Treatment D: GDC-9545/F18 capsule, 30 mg   
Treatment B will be administered in a 10 mL volume intravenously over 30 minutes (as 
an infusion) following an overnight fast of a minimum of 10 hours. 
To assess tolerability of the IV administration, the first subject will be dosed as a 
sentinel; then, at least 4 hours later, the second subject will be dosed only if there are no 
acute safety findings for the first subject. If the first two subjects tolerated the IV dose, in 
the opinion of the Principal Investigator and Medical Monitor per the criteria in 
Section 6.8.1, the remaining subjects will be dosed. The third subject will be dosed at 
least 20 hours after the second subject (i.e., at least 24 hours after the first subject). All 
subsequent dosing of the IV formulation will be staggered by at least 15 minutes. To 
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of the IV administration will not be considered as a protocol deviation provided that the 
full planned dose is administered as these minor discrepancies should not have a 
significant impact on the overall study objectives.  
The planned administration time will be 30 minutes; the actual IV administration start and 
stop time will be recorded in the source.  
• 
The IV administration will finish within ± 3 minutes of the nominal time point 
Treatments C and D will be swallowed whole with approximately 240 mL water following 
an overnight fast of a minimum of 10 hours. 
There will be a minimum washout of 10 days between each IMP administration. 
[14C]-GDC-9545 and GDC-9545 doses are expressed as the free base equivalent. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
Quotient Sciences will manufacture the [14C]-GDC-9545 capsules and the GDC-9545 
Solution for Infusion.  The Sponsor will manufacture the GDC-9545/F12 and 
GDC-9545/F18 capsules.  The study site (i.e., Investigator or other authorized personnel 
[e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each subject, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that subjects are 
provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of GDC-9545 
capsules.  The study site will acknowledge receipt of GDC-9545 capsules supplied by 
the Sponsor to confirm the shipment condition and content.  Any damaged shipments 
will be replaced.  The Investigator or designee must confirm that appropriate 
temperature conditions have been maintained during transit for all IMPs received and 
that any discrepancies have been reported and resolved before use of the IMPs.  All 
IMPs must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions, with access limited 
to the Investigator and authorized staff. 
Only subjects enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the Pharmaceutical Development and Control Strategy Report, dosing 
instructions and/or the GDC-9545 IB for information on IMP handling, including 
preparation and storage, and accountability.  
4.3.3.1 
Retention of Study Drug Samples 
According to Title 21, Part 320 of the U.S. Code of Federal Regulations, reserve 
samples of the clinical supplies used in a bioavailability or bioequivalence study must be 
retained by the organization that conducted the study and stored under conditions that 
will maintain the integrity, identity, strength, quality and purity of the samples.  The 
samples for retention will be randomly selected by the Investigator or by a representative 
of the Investigator.  All samples must be retained at the study site for a period of at least 
5 years following the date on which the application or supplemental application is 
approved by the U.S. FDA.  If such application is not approved, all samples must be 
retained for at least 5 years following the date of completion of any bioavailability or 
bioequivalence study from which the reserve samples were obtained. 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, HRT, vaccines, topical medications, herbal or homeopathic 
remedies, nutritional supplements) used by a subject in addition to protocol-mandated 
treatment from 14 days before IMP administration until discharge from the study.   
All such medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Subjects are permitted to use the following therapies during the study: 
• 
Up to 4 g of paracetamol per day  
• 
Medications to treat adverse events 
If any medication is required, the name, strength, frequency of dosing and reason for its 
use will be documented in the subject's source data. 
 
4.4.2 
Prohibited Therapy 
Subjects should not take any medication (e.g., prescription drugs, over the counter 
drugs, HRT, vaccines, topical medications, herbal or homeopathic remedies, nutritional 
supplements), with the exception of up to 4 grams of paracetamol per day, from 14 days 
before IMP administration until discharge from the study unless the Investigator has 
given prior consent.  The following categories of medication are specifically prohibited:  


 
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• 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 90 days prior to initiation of study treatment and during study treatment. 
• 
Subjects may not take oral antibiotics within 4 weeks or IV antibiotics within 8 weeks 
prior to admission until discharge from the study, with the exception of any 
medications that are required to treat adverse events. 
• 
Subjects will not have received any medications/products known to alter drug 
absorption, metabolism, or elimination processes, including St. John’s wort, within 
30 days prior to admission until discharge from the study. 
 
4.4.3 
Prohibited Food and Drink  
Use of the following foods and drinks is prohibited as described below: 
• 
Consumption of liquids or foods containing grapefruit, cranberry, caffeine or other 
xanthines from 24 hours prior to admission until discharge from the clinical unit. 
• 
Consumption of food containing poppy seeds for 48 hours prior to screening and for 
48 hours prior to admission until discharge from the clinical unit. 
 
4.4.4 
Additional Restrictions  
For Part 1, subjects must not consume anything likely to disturb GI transit (e.g., spicy or 
high-fat meals such as curry or fish and chips or foods of a high-fiber content such as 
All-Bran) for 24 hours prior to admission until discharge from the study. 
For both study parts, subjects must not consume alcohol during the 24 hours prior to 
screening and the 24 hours prior to admission until discharge from the clinical unit. 
Subjects must not take part in any unaccustomed strenuous exercise from the 72 hours 
before the screening visit and then from 72 hours prior to admission until discharge from 
the clinical unit.  
Subjects must not donate blood or plasma (outside of this study), from clinical unit 
admission, throughout the study duration, and for at least 90 days following last dose of 
study medication. 
No food or fluids other than water will be allowed from 8 hours prior to each study visit 
until after study laboratory samples are obtained.   
In each study period, subjects will be provided with a light snack on the evening of 
Day -1 and no food will be allowed until 4 hours after dosing. 
Lunch will be provided at approximately 4 hours post-dose, an evening meal at 
approximately 10 hours post-dose and an evening snack at approximately 14 hours 
post-dose. 
On subsequent days, meals will be provided at appropriate times.  Meals will be similar 
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Subjects will be allowed water up to 1 hour before the scheduled dosing time and will be 
provided with 240 mL of water at 1 hour post-dose.  Water will be allowed ad libitum 
after 1 hour post-dose.  Decaffeinated fluids will be allowed ad libitum from lunch time on 
the day of dosing. 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1 for 
Part 1 and in Appendix 2 for Part 2.  All activities should be performed and documented 
for each subject.   
There are times where the protocol requires more than one procedure to be completed 
at the same time point.  In these instances, the following will apply to post-dose time 
points: 
• 
PK samples should take priority over other procedures scheduled at the same time 
point  
• 
ECGs should be taken prior to vital signs when both measurements are scheduled 
at the same time point  
• 
Other assessments, e.g., physical examinations etc., will be performed within the 
required time windows 
As guidance, the preferred order of assessments is: 
ECGs 
 
Vitals 
 
PK blood 
sampling 
(nominal 
time) 
 
Other assessments 
e.g., physical 
examinations 
 
All assessments will be timed and performed relative to the start of dosing. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled subjects and for subjects who are not subsequently enrolled 
will be maintained at the study site. 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit.  A physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation.  Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies in the local area.  Subjects will then be given the opportunity to ask 
questions and will be informed of their right to withdraw from the study without prejudice.  
After this explanation and before entering the study, the subject will voluntarily sign an 
ICF.  Until written consent has been obtained from the subject, no study specific 
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information sheet, participants will be re consented to the most current version of the 
ICF(s) where appropriate. 
All screening evaluations must be completed and reviewed to confirm that subjects meet 
all eligibility criteria before enrollment.  The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Although only women of non-childbearing potential will be enrolled, and so the risk of 
pregnancy is very low, the risk associated with exposure to ionizing radiation to women 
who may be pregnant, will be discussed with female subjects.  They will be tested using 
a highly sensitive pregnancy screening kit prior to each study period.  Any subject found 
to be pregnant, or in whom pregnancy cannot reasonably be excluded, will be withdrawn 
from the study. 
If the start of the study is delayed for any reason so that the interval between screening 
and first dose exceeds 28 days, all or part of the screening procedures may be repeated 
at the discretion of the Investigator. 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (i.e., subject has not been randomized/has not been treated); the 
reason for failure must be temporary and expected to resolve.  If re-screened, the 
subject must be re-consented. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, HRT, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the subject within 14 days prior 
to initiation of study treatment will be recorded.   
Demographic data will include age, sex, and self-reported race/ethnicity.  Height and 
weight will be recorded at screening. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.  Any 
abnormality identified at baseline should be recorded on the Medical History. 
Limited, symptom-directed physical examinations should be performed at specified 
timepoints and as clinically indicated.  Changes from baseline abnormalities should be 


 
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recorded in subject notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs  
Vital signs will include measurements of pulse rate, and systolic and diastolic blood 
pressure while the subject is in a supine position for 5 minutes, and oral temperature.   
The acceptable deviations from the nominal vital signs measurements time points are: 
• 
The pre-dose vital signs measurements will be taken ≤2 hours before dosing. 
• 
Post-dose vital signs measurements will be taken ± 15 minutes from the nominal 
post-dose time points. 
• 
Discharge vital signs measurements will be taken ± 1 hour from the nominal time 
point. 
Record abnormalities observed at baseline on the Medical History.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
4.5.5 
Laboratory and Other Biological  
When a subject withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the subject specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.5. 
For sampling procedures, storage conditions, and shipment instructions, see the Clinical 
Sample Processing Manual. 
4.5.5.1 
Safety Laboratory Assessments 
Samples for the following laboratory tests will be sent to The Doctors Laboratory for 
analysis: 
• 
Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, 
hematocrit (packed cell volume), mean cell hemoglobin, mean cell hemoglobin 
concentration, mean cell volume, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes) 
• 
Chemistry panel (serum):magnesium, sodium, potassium, chloride, glucose, fasting 
glucose, urea, creatinine, creatine kinase, total protein, albumin, phosphate 
(inorganic), calcium, total bilirubin, direct bilirubin (only if total is elevated), alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma glutamyl transferase (GGT), and bicarbonate  


 
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• 
Coagulation: international normalized ratio (INR), activated partial thromboplastin 
time (APTT), thrombin time and prothrombin time (PT) 
• 
Virology: HBsAg, HCV Antibody, HIV Antibody at screening 
• 
Estradiol and FSH (post-menopausal female subjects only) 
• 
Pregnancy test 
– 
All women will have a highly sensitive serum pregnancy test at screening and a 
highly sensitive urine pregnancy test at admission. 
• 
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood, bilirubin, 
leukocytes, nitrites, urobilinogen) and urine drug screen samples will be analyzed by 
dipstick at the clinic.  Microbiology and/or microscopic urinalysis examination, at the 
discretion of the Investigator based on urinalysis results (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) 
• 
The urine drug screen will test for the following: amphetamines, barbiturates, 
benzodiazepines, cocaine, marijuana/cannabis, methadone, 
methamphetamine/ecstasy, morphine/opiates, phencyclidine, and tricyclic 
anti-depressants.   
Scheduled blood samples for safety laboratory tests will be taken following an 8-hour 
fast.  The acceptable deviation from the nominal time points are as follows: 
• 
The pre-dose samples will be taken ≤2 hours before dosing 
• 
Post-dose samples will be taken ± 1 hour from the nominal sampling time 
CLcr will be calculated at screening by The Doctors Laboratory using the 
Cockcroft-Gault equation and body weight for eligibility purposes: 
CLcr (mL/min) = (140-age [years]) x (body weight [kg]) (× 1.04) 
 
serum creatinine (µmol/L) 
Alcohol breath tests and carbon monoxide breath tests will be performed at the clinic.  A 
positive alcohol breath test will exclude that subject from dosing during that admission.  
A carbon monoxide result of greater than 10 ppm will exclude the subject from the study. 
4.5.5.2 
Mass Balance, Pharmacokinetic and Metabolite Profiling and 
Identification Assessments 
Samples for the following laboratory tests will be sent to Covance for analysis: 
• 
Plasma samples for PK analysis of GDC-9545 
Samples for the following laboratory tests will be sent to Pharmaron for analysis: 
• 
Plasma, whole blood, urine and feces samples for analysis of TR (Part 1 only) 
• 
Other accidental sources of elimination for analysis of TR (Part 1 only) 


 
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Samples for the following laboratory tests will be sent to the Sponsor for analysis: 
• 
Plasma, urine and feces samples for metabolite profiling and identification (Part 1 
only) 
Consent will be collected from the subjects for use of these samples for the purposes of 
the proposed study. 
In Part 1, a single urine sample will be taken at pre-dose (or the first void of the day) for 
the mass balance analysis.  Where a sample is not provided, this will not be considered 
a deviation.  All individual urine voids will be collected and shipped to Pharmaron for TR 
analysis, according to Quotient Sciences’ standard operating procedures, unless 
indicated otherwise by the Sponsor. 
In Part 1, the pre-dose fecal sample will be taken in the 24 hours period before dosing 
(between admission and pre-dose).  If a pre-dose fecal sample cannot be obtained, the 
subject will still be dosed.  Where a sample is not provided, this will not be considered a 
deviation. Samples will be shipped to Pharmaron for the analysis of TR. 
During Part 1 of the study, other accidental sources of elimination will be collected as 
voided (e.g., emesis).  Samples will be shipped to Pharmaron for the analysis of TR. 
Venous blood samples will be withdrawn via an indwelling cannula or by venipuncture 
(see Appendices 3 and 4 for detailed schedules for Parts 1 and 2, respectively).  The 
acceptable deviations from the nominal PK and metabolite profiling and identification 
blood sampling times are as follows: 
• 
The pre-dose samples will be taken ≤1 hour before dosing 
• 
0.25 to 0.5 hours post-dose samples will be taken within ± 2 minutes of the nominal 
post-dose sampling time 
• 
0.58 to 1 hour post-dose samples will be taken within ± 5 minutes of the nominal 
post-dose sampling time  
• 
1.5 to 8 hours post-dose samples will be taken within ± 15 minutes of the nominal 
post-dose sampling time 
• 
12 to 24 hours post-dose samples will be taken within ± 30 minutes of the nominal 
post-dose sampling time  
• 
48 to 480 hours post-dose samples will be taken within ± 4 hours of the nominal 
post-dose sampling time  
• 
648 to 984 hours post-dose samples will be taken within ± 1 day of the nominal 
post-dose sampling time  
For Treatment B, PK samples will be timed and performed relative to the start of the IV 
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The total blood volume for each subject will not exceed 550 mL in a 4-week period.  The 
first 0.5 mL of blood withdrawn via cannula will be discarded. 
Residual PK samples will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed. 
4.5.6 
Electrocardiograms  
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1 for Part 1 and Appendix 2 for Part 2).  The 
acceptable deviations from the nominal ECG measurement time points are: 
• 
The pre-dose ECG measurements will be taken ≤2 hours before dosing 
• 
Post-dose ECG measurements will be taken ± 15 minutes from the nominal 
post-dose time point.  
• 
Discharge ECG measurements will be taken ± 1 hour from the nominal time point.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the subject has been resting in a supine position for at least 5 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal, whenever feasible.  Circumstances that may induce changes in heart 
rate, including environmental distractions (e.g., television, radio, conversation), should 
be avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the Investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the subject's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF: heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF based 
on the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory. 
If at a particular post-dose timepoint the mean QTcF is  500 msec and/or 60 msec 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs taken 30 minutes apart.  The Medical Monitor should be notified.  
Standard-of-care treatment may be instituted per the discretion of the Investigator.  If a 
PK sample is not scheduled for that timepoint, an unscheduled PK sample should be 
obtained.  A decision on study drug discontinuation should be made, as described in 
Section 4.6.1.  The Investigator should also evaluate the subject for potential concurrent 


 
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risk factors (e.g., electrolyte abnormalities, co-medications known to prolong the QT 
interval, severe bradycardia). 
4.6 
TREATMENT, SUBJECT, STUDY, AND SITE 
DISCONTINUATION 
4.6.1 
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met:  
• 
A serious adverse reaction (i.e., a serious adverse event considered at least 
possibly related to the IMP administration) in one subject. 
• 
Severe non-serious adverse reactions (i.e., severe non-serious adverse event 
considered as, at least possibly related to the IMP administration) in two subjects in 
the same cohort, independent of within or not within the same system organ class. 
Relatedness will be determined by the Investigator.  
If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment.  The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt. 
In addition, subjects must permanently discontinue study treatment if they experience 
any of the following: 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the subject's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the subject 
• 
Pregnancy 
• 
Concurrent illness that would adversely affect subject safety or data integrity or 
requirement for prohibited medication 
• 
Experiencing a serious or severe adverse event including but not limited to: 
– 
corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or increase in 
QTcF interval of >60 msec from baseline (confirmed following a repeat ECG) 
– 
ALT concentration >3 × the upper limit of the reference range (confirmed 
following a repeat ALT blood test) 
• 
Evidence of current SARS-CoV-2 infection   
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  


 
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For a subject who withdraws because of an IMP-related adverse event, every effort will 
be made to ensure the subject completes follow-up procedures.  Any subject withdrawn 
or discontinuing the study prematurely because of an IMP-related adverse event or 
termination of the study will be considered to have completed the study, and will not be 
replaced.  
Subjects who withdraw from Part 1 of the study will not be replaced. 
For Part 2 only, subjects who discontinue study treatment may be replaced at the 
discretion of the Sponsor and the Investigator to ensure a minimum of 8 evaluable 
subjects.  An evaluable subject for Part 2 of the study is defined as a subject who has 
received an IMP and has sufficient drug concentration measurements up to 168 hours 
after dosing for evaluation of defined PK parameters for each treatment, and have 
completed all planned safety assessments up to 168 hours after dosing for each 
treatment. 
4.6.2 
Subject Discontinuation from the Study 
Subjects have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the Investigator has the right to withdraw a subject from the study at any 
time. 
Reasons for subject discontinuation from the study may include, but are not limited to, 
the following: 
• 
Subject withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
Loss to follow-up 
• 
Subject non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator or Sponsor 
 
Every effort should be made to obtain a reason for subject discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a subject requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the Investigator.   
For a subject who withdraws because of an IMP-related adverse event, every effort will 
be made to ensure the subject completes follow-up procedures.  Any subject withdrawn 
or discontinuing the study prematurely because of an IMP-related adverse event or 
termination of the study will be considered to have completed the study, and will not be 
replaced.  
Subjects who withdraw from Part 1 of the study will not be replaced. 


 
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For Part 2 only, subjects who discontinue study treatment may be replaced at the 
discretion of the Sponsor and the Investigator to ensure a minimum of 8 evaluable 
subjects.  An evaluable subject for Part 2 of the study is defined as a subject who has 
received an IMP and has sufficient drug concentration measurements up to 168 hours 
after dosing for evaluation of defined PK parameters for each treatment, and have 
completed all planned safety assessments up to 168 hours after dosing for each 
treatment. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
• 
Subject enrollment is unsatisfactory 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the Sponsor and Investigator without consultation with the MHRA, 
EC, ARSAC Practitioner or ARSAC.  The ARSAC Practitioner and ARSAC (if ARSAC 
research application has been submitted or approved) must be notified promptly, in 
writing, that the study will no longer be taking place.  Notification of early termination 
should also be provided to the EC and MHRA within 15 days, clearly explaining the 
reasons for the termination. 
If the study is abandoned prior to commencement of any protocol activities, the 
Investigator or Sponsor must notify the EC, MHRA, ARSAC Practitioner and ARSAC (if 
ARSAC research application has been submitted or approved) in writing outlining the 
reasons for abandonment of the trial. 
New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer acceptable 
for subjects participating in the study may also mean termination of the study prior to 
dosing.  
Once exposure to dosing has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study.  
• 
The occurrence of serious or severe adverse event(s), if considered to be related to 
the IMP, on the dosing day. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 


 
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If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis demonstrates that the assumptions have changed and that the 
overall balance is no longer acceptable.  In these circumstances, termination can only 
take place with the agreement of the Investigator and Sponsor.  The MHRA, EC, ARSAC 
Practitioner and ARSAC will be informed of study termination. 
If it becomes necessary to consider termination of the study on the dosing day, dosing 
may be suspended pending discussion between the Investigator, Sponsor and ARSAC 
Practitioner).  Dosing will be stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC.  
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
GCP 
• 
No study activity (i.e., all subjects have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN  
GDC-9545 is not approved, and clinical development is ongoing.  The safety plan for 
volunteers in this study is based on clinical experience with GDC-9545 in completed and 
ongoing studies.  The anticipated important safety risks for this study are outlined below.  
Please refer to the GDC-9545 IB for a complete summary of safety information. 
Several measures will be taken to ensure the safety of subjects participating in this 
study.  Eligibility criteria have been designed to exclude subjects at higher risk for 
toxicities.  Subjects will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.   
5.1.1 
Risks Associated with GDC-9545  
As of the data cutoff of 31 Jan 2020, the safety of GDC-9545 has previously been 
evaluated in a comprehensive pre-clinical safety program and in clinical studies in more 
than 160 ER+ breast cancer patients.  Preclinical and clinical findings for GDC-9545 are 
summarized in Section 1.2. 


 
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Overall, GDC-9545 was well tolerated at all dose levels in patients with early breast 
cancer; all reported adverse events have been Grade 1 or 2 severity, except a Grade 3 
serious adverse event of breast abscess in one patient at 10 mg dose level, which was 
considered unrelated to GDC-9545 by the Investigator.  With the exception of one event 
of fatigue (which was also considered related to progressive disease), no serious 
adverse drug reactions have been reported in the single agent studies; additionally, no 
identified risks have been confirmed for GDC-9545.  
On the basis of nonclinical toxicology findings for GDC-9545 and known toxicities 
associated with other drugs in the ER antagonist class, the potential risks of GDC-9545 
are hepatotoxicity, GI toxicities, venous thromboembolic events, bradycardia, renal 
dysfunction, changes in female reproductive organs and menopausal symptoms, 
male/female infertility, QT prolongation and embryofetal toxicity.  These potential risks 
will be managed as outlined in Section 1.3.2. 
GDC-9545 has been assessed to have a low potential for clinically relevant Cytochrome 
P450 mediated drug-drug interactions.  Nonetheless, potential drug-drug interactions 
with other medications will be avoided by restrictions on concomitant medication use. 
In pre-clinical toxicity studies, GDC-9545 was found to be not mutagenic in the bacterial 
mutagenesis assay, did not induce an increase in micronucleus formation in human 
lymphocytes in in vitro studies and was not phototoxic in an in vitro mammalian 
cell-based assay. 
Overall, no significant safety concerns have been identified about the use of 30 mg 
GDC-9545 in healthy volunteers. 
5.1.2 
Risks Associated with Radiation 
Subjects will be exposed to ionizing radiation of NMT 4.6 MBq (124 µCi) [14C].  The 
effective dose that each subject will receive from one administration of 4.6 MBq 
(124 µCi) [14C] will not exceed 0.7 mSv.  This is approximately 3.1 months of the 
average radiation exposure received in the UK each year (2.7 mSv; data obtained from 
Public Health England Ionising Radiation Exposure of the UK Population: 2010 Review) 
and is equivalent to slightly less than the radiation dose that would result from 2 x-rays of 
the abdomen.  An increase in the amount of radiation that is received above natural 
radiation carries a risk of later developing serious and possibly fatal conditions.  
However, the risk associated with the maximum possible dose of radiation in this study 
is very small indeed and is considered to be acceptable. 
5.1.3 
COVID-19 Related Risks and Risk Mitigation Measures 
The following risks and risk mitigating measures apply to the time in which the study is 
conducted during the COVID-19 pandemic. 


 
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5.1.3.1 
IMP-Related Risk 
Against the background of the COVID-19 pandemic, the potential risk of a subject 
developing COVID-19 has been considered in terms of the risk-benefit evaluation.  The 
mode of action of the IMP – as ER antagonist – has been considered alongside 
available pre-clinical and clinical data (including class effects) and it is considered that a 
subject would not be at increased risk of either becoming infected with SARS-CoV-2 (the 
virus that causes COVID-19) or experiencing a more severe illness.  That is, the IMP 
has no known immunomodulatory effect that would confer an increased risk to healthy 
subjects enrolled in the study. 
5.1.3.2 
General COVID-19-Related Risk Mitigation Measures 
General risk mitigation against COVID-19 will be implemented in accordance with 
Quotient Sciences’ monitoring and prevention control measures. 
The risk mitigation measures, where applicable, will be amended based on emerging 
government guidance. 
5.1.4 
General Risks 
Collecting a blood sample from a vein may cause pain, swelling, bruising, light 
headedness, fainting, and very rarely, clot formation, nerve damage and/or infection at 
the site of the needle stick. 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a subject and it is possible that bruising and/or inflammation may be experienced 
at the site of cannulation.  
Electrocardiogram (ECG) stickers on the subjects' chests and limbs may cause some 
local irritation and may be uncomfortable to remove but subjects will be closely 
monitored to ensure any local irritation does not persist. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 


 
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5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 for more 
information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the Investigator, places the 
subject at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs subject hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the subject's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the Investigator's judgment (e.g., may jeopardize 
the subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 


 
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Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 
for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
• 
Cases of potential drug-induced kidney injury 
• 
Grade ≥3 nausea/vomiting/diarrhea 
• 
Grade ≥2 thromboembolic events (pulmonary embolism, deep vein thrombosis, and 
embolism) 
• 
Grade ≥3 renal failure (including acute kidney injury or other similar medical 
concepts) 
• 
Grade ≥3 hepatitis or elevation in ALT or AST 
• 
Grade ≥2 vaginal or uterine hemorrhage 
• 
Grade ≥2 bradycardia 
• 
Any grade of endometrial cancer. 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a subject exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
  


 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each subject contact.  All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all subject evaluation timepoints.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events  
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by subjects who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section  5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 6: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the subject or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the subject's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
For subjects receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction”) on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
subject experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
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report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
subject evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between subject evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 


 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the Investigator's judgment 
 
It is the Investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  upper limit of normal [ULN] associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the Investigator's judgment  
 
It is the Investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 


 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, Investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
• 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).   
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the Medical History. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 


 
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that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The subject has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of subject requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Cases of Accidental Overdose or Medication Error  
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
GDC-9545 and [14C]-GDC-9545, adverse events associated with special situations 
should be recorded as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 


 
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• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with GDC-9545 or [14C]-GDC-9545, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
• 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event.  The following is a 
list of events that the Investigator must report to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the Investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 


 
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than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information 
Genentech Medical Monitor contact information: 
Medical Monitors: 
MD, MPH (Primary) 
Telephone Nos.: 
(Mobile – USA) 
 
(Office – USA) 
ARSAC Practitioner Contact Information 
CRO ARSAC Practitioner contact information: 
ARSAC Practitioner: 
MB BChir, MRCGP, MFPM 
Telephone No.: 
(Mobile – UK) 
Email: 
  
5.4.2 
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to Investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to Investigators: 
– 
Fax: 
or 
 or
or
– 
Email: welwyn.pds-pc@roche.com 


 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to Investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to Investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur  28 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Subjects 
Subjects will be instructed to immediately inform the Investigator if they become 
pregnant during the study or within 30 days after the final dose of study drug.  A paper 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to Investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The Investigator should discontinue study drug and counsel the 
subject, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the subject should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the Investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.   
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 


 
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recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female subject exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the subject 
is lost to follow-up, or the subject withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the subject's medical record to facilitate source data 
verification.  
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the Investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the Investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 


 
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Interest Reporting Form using the fax number or email address provided to 
Investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to Investigators, ECs, and applicable health 
authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the following reference document: 
• 
GDC-9545 IB 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
It is the responsibility of the Sponsor to determine whether an event requires expedited 
reporting and to notify the Investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
Suspected unexpected serious adverse reactions (SUSARs) are adverse events that are 
believed to be related to an IMP and are both unexpected (i.e., the nature or severity is 
not expected from the information provided in the IB) and serious. SUSARs are subject 
to expedited reporting to the MHRA, EMA, and EC. 
It is the responsibility of the Sponsor to report fatal or life-threatening SUSARs to the 
MHRA as soon as possible, but no later than 7 calendar days after they first became 
aware of the reaction.  Any additional relevant information should be sent within 8 days 
of the report.   
The Sponsor is required to notify the EC of any SUSAR as soon as possible, but no later 
than 7 calendar days after they first became aware of the reaction.  Any additional 
relevant information should be sent within 8 days of the report.  The task of reporting 
fatal or life-threatening SUSARs may be delegated to the Investigator. 


 
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The ARSAC Practitioner will be notified of any fatal or life-threatening SUSAR that is 
considered related to the exposure to radioactivity. 
Other SUSARs 
It is the responsibility of the Sponsor to report other SUSARs to the MHRA as soon as 
possible, but no later than 15 calendar days after they first became aware of the 
reaction.   
The Sponsor is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction.  The task of 
reporting other SUSARs may be delegated to the Investigator. 
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary objectives of Part 1 of this study is to characterize the absorption, 
metabolism, excretion, PK of GDC-9545.  No formal statistical analysis will be performed 
for Part 1 of this study.  
The primary objectives of Part 2 of this study are to evaluate the absolute and relative 
bioavailability of GDC-9545.  A mixed-effect analysis of variance model for the 
two-period crossover design will be used for formulation comparison.  A separate mixed-
effect analysis of variance model will be used for the absolute bioavailability comparison. 
Descriptive statistics (e.g., mean, median, standard deviation, minimum, maximum and 
number of subjects with an observation [n]) will be calculated for PK, mass balance and 
safety data in both Parts 1 and 2 of the study.  Additional statistics will be provided for 
PK-related data, including coefficient of variation (CV%), geometric mean and geometric 
CV%. 
All safety, mass balance recovery, and PK data will be listed. 
A study specific Statistical Analysis Plan (SAP) will be produced which will detail the 
statistical and reporting requirement for the study in more detail. The SAP will be 
finalized prior to database lock.  
6.1 
DETERMINATION OF SAMPLE SIZE 
For Part 1, it is planned to enroll 6 subjects to ensure data in a minimum of 4 evaluable 
subjects.  For Part 2, it is planned to enroll 10 subjects to ensure data in a minimum of 
8 evaluable subjects.  No replacement subjects are to be used in Part 1 of this study.  
Up to 4 replacement subjects are permitted in Part 2 of this study to ensure there are 
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The study is exploratory and no formal sample size calculation has been made.  Based 
on experience from previous studies of a similar design, a sample size of 6 subjects for 
Part 1 and 10 subjects for Part 2 is considered appropriate to meet the objectives of the 
study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of subjects who enroll, are randomized (Part 2 only), are dosed, 
discontinue, or complete the study will be summarized.  Reasons for premature study 
discontinuation will be listed and summarized.  Enrollment and major protocol deviations 
will be listed and evaluated for their potential effects on the interpretation of study 
results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, height, 
weight, and BMI) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
For Part 1, summaries will be presented overall. For Part 2, summaries will be presented 
by treatment sequence; if all subjects receive all treatments, summaries will be 
presented overall only, unless a sequence effect is observed in the formal statistical 
analyses described below. Additionally, all data will be listed. 
Demographic and baseline characteristics will be recorded at screening. 
6.4 
MASS BALANCE ANALYSES (PART 1 ONLY) 
Urine and fecal samples will be collected for the analysis of TR in Part 1.  The following 
mass balance parameters will be calculated by Quotient Sciences from urine and feces 
separately and total (urine and feces combined):  
• 
Aeu: amount of TR excreted in urine 
• 
CumAeu: cumulative amount of TR excreted in urine 
• 
Feu: amount of TR excreted in urine expressed as a percentage of the radioactive 
dose administered 
• 
CumFeu: cumulative amount of TR excreted in urine expressed as a percentage of 
the radioactive dose administered 
• 
Aef: amount of TR eliminated in feces 
• 
CumAef: cumulative amount of TR eliminated in feces 
• 
Fef: amount of TR eliminated in feces expressed as a percentage of the radioactive 
dose administered 
• 
CumFef: cumulative amount of TR eliminated in feces expressed as a percentage of 
the radioactive dose administered 
• 
Aetotal: amount of TR excreted in urine and feces combined 


 
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• 
CumAetotal: cumulative amount of TR excreted in urine and feces combined 
• 
Fetotal: amount of TR excreted in urine and feces combined expressed as a 
percentage of the radioactive dose administered 
• 
CumFetotal: cumulative amount of TR excreted in urine and feces combined 
expressed as a percentage of the radioactive dose administered 
 
6.5 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of subjects with sufficient data to enable 
estimation of key parameters (e.g., AUC, time to maximum concentration [tmax], 
maximum concentration [Cmax], half-life [t1/2) with subjects grouped according to 
treatment received.  
Plasma GDC-9545, plasma TR and whole blood TR concentration data will be listed and 
summarized by treatment using descriptive statistics.  Individual and mean concentration 
versus time profiles will be plotted. 
The PK of GDC-9545 in plasma and TR in whole blood and plasma will be summarized 
by estimating the following parameters (as appropriate for data collected): 
• 
Cmax: maximum observed concentration 
• 
tmax: time of maximum observed concentration 
• 
AUC0-t: area under the curve from time 0 to the time of last measurable 
concentration 
• 
AUC0-inf: area under the curve from time 0 extrapolated to infinity 
• 
λZ: first order rate constant associated with the terminal (log-linear) portion of the 
curve 
• 
t1/2: terminal elimination half-life 
• 
CL: total body clearance calculated after a single IV administration (for GDC-9545 
only; Part 2 IV dose only) 
• 
CL/F: total body clearance calculated after a single extravascular administration 
where F (fraction of dose bioavailable) is unknown (for GDC-9545 only; oral doses 
only) 
• 
Vz: volume of distribution based on the terminal phase calculated using AUC0-inf after 
a single IV administration (for GDC-9545 only; Part 2 IV dose only) 
• 
Vz/F: apparent volume of distribution (for GDC-9545 only; oral doses only) 
• 
Ratio between whole blood and plasma concentrations for TR (Part 1 only) 
• 
Ratio between whole blood and plasma AUC0-inf values for TR (Part 1 only) 
• 
F: Absolute bioavailability calculated using AUC0-inf (for GDC-9545 only; oral doses 
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• 
Frel Cmax: Relative bioavailability based on Cmax (for GDC-9545 only; GDC-9545/F18 
capsule, 30 mg in Part 2 only) 
• 
Frel AUC0-t: Relative bioavailability based on AUC0-t (for GDC-9545 only; 
GDC-9545/F18 capsule, 30 mg in Part 2 only) 
• 
Frel AUC0-inf: Relative bioavailability based on AUC0-inf (for GDC-9545 only; 
GDC-9545/F18 capsule, 30 mg in Part 2 only) 
The absolute bioavailability of GDC-9545/F12 capsule and GDC-9545/F18 capsule will 
be calculated using the AUC0-inf values obtained after oral and IV administration of 
GDC-9545. The mixed-effect analysis of variance model will be used for absolute 
bioavailability determination. The model will include formulation and period as fixed 
effects and a random subject effect. 
To evaluate the relative bioavailability of GDC-9545 as GDC-9545/F18 capsule 
compared to GDC-9545/F12 capsule, the PK parameters Cmax and AUC0-inf for 
GDC-9545 will be analyzed.  The mixed-effect analysis of variance model for the 
two-period crossover design will be used for formulation comparison.  The model will 
include formulation and period as fixed effects and random subject effect (i.e., assuming 
a compound symmetry covariance structure).  
Log-transformed Cmax, AUC0-t, and AUC0-inf values will be evaluated to estimate ratios of 
geometric mean values and the corresponding 90% confidence intervals (CIs) (test: 
GDC-9545/F18 capsule, reference: GDC-9545/F12 capsule; or test: GDC-9545/F12 
capsule, reference: GDC-9545 Solution for Infusion; or test: GDC-9545/F18 capsule, 
reference: GDC-9545 Solution for Infusion). 
6.6 
METABOLITE PROFILING AND IDENTIFICATION ANALYSES 
Metabolite profiling of plasma, urine and feces will be performed using liquid 
chromatography-high resolution mass spectrometry where appropriate.  
These aspects will be reported separately from the Clinical Study Report as a 
standalone document. 
6.7 
SAFETY ANALYSES 
The safety analysis population will consist of all subjects who received at least one dose 
of study drug, with subjects grouped according to treatment received.  
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded from 1 
to 5 based on the adverse event severity grading scale for the NCI CTCAE (see 
Section 5.3.3). Adverse events of special interest will also be collected and reported (see 
Section 5.4.2). 


 
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Summary tables will be presented by treatment.  If a subject has more than one episode 
of a particular event, only one episode (the most severe or the strongest causal 
relationship to study drug) will be counted.  A subject with more than one different 
adverse event within a particular body system will only be counted once in the total 
number of subjects experiencing adverse events for the body system.  Similarly, a 
subject who experiences an adverse event in more than one body system will only be 
counted once in the total number of subjects experiencing adverse events in all body 
systems.  
Selected laboratory and vital sign anomalies will be presented by shift tables and will be 
listed. 
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Analysis 
Part 1 and Part 2 will be analyzed separately. 
No interim analyses are planned for Part 1.  
The following in-study decision will be made during Part 2 of this study: 
• 
Progression from sentinel group to main group where sentinel dosing is used for 
Treatment B 
For Treatment B, to assess tolerability of the IV administration, the first subject will be 
dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if 
there are no acute safety findings for the first subject. If the first two subjects tolerated 
the IV dose, in the opinion of the Principal Investigator and Medical Monitor, the 
remaining subjects will be dosed. The third subject will be dosed at least 20 hours after 
the second subject (i.e., at least 24 hours after the first subject). All subsequent dosing 
of the IV formulation will be staggered by at least 15 minutes. 
The decision to proceed with the main group will be made by the Investigator, based on 
safety data until up to 24 hours post-dose for the two sentinel subjects.  The Investigator 
will inform the sponsor of any safety concerns.  
The decision to proceed to the next dose level will be based on safety and tolerability 
data.  The following data are required: 
• 
Adverse events 
• 
ECGs 
• 
Vital signs  


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data.  The CRO will supply eCRF specifications 
for this study.  Data entered manually will be collected via EDC through use of eCRFs.  
The site will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the CRO’s Data Management department will request data clarification 
from the site, which Data Management will resolve electronically in the EDC system. 
The CRO will produce a Data Management Plan that describes the quality checking to 
be performed on the data.  Laboratory data will be sent directly to the CRO, using the 
CRO’s standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO's Data Management Plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor's 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO's standard procedures.  
AEs, medical histories and medications will be coded as detailed in the Data 
Management Plan.  An independent coding review will also be performed within the Data 
Sciences department. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  The site 
will receive training for appropriate eCRF completion.  eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from 
the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive subject data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 


 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which subject 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, 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, subject files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the Investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, , Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 


 
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relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the applicable laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to 
the individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the E.U.  Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before EC submission.  
The final EC−approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The Investigator or authorized designee will explain to each subject the 
objectives, methods, and potential risks associated with each optional procedure.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a subject's agreement to participate in optional procedures.  Subjects who 
decline to participate will not provide a separate signature. 


 
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The Consent Forms must be signed and dated by the subject or the subject's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
subject to participate.  The final revised EC-approved Consent Forms must be provided 
to the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
subject is participating in the study, the subject or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each subject shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the subject or the subject's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each subject's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the subject, 
and relevant supporting information must be submitted to the EC by the Principal 
Investigator and reviewed and approved by the EC before the study is initiated.  
In addition, any subject recruitment materials must be approved by the EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the EC.  Investigators are also responsible for 
promptly informing the EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and EC.  Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their EC and 
archived in the site's study file.  


 
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8.4 
ADMINISTRATION OF RADIATION 
Dr 
 will be the ARSAC Practitioner for this study, which includes the 
administration of radiation at Quotient Sciences.  Administration will be conducted in 
accordance with Dr 
’s current ARSAC Practitioner license and Quotient Sciences’ 
current ARSAC Employer license.  Additionally, a research application will be submitted 
to ARSAC to obtain approval for the conduct of the study before dosing. 
The protocol will be reviewed and the final version will be approved by the ARSAC 
Practitioner, Dr 
. 
8.5 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number.  This means that 
subject names are not included in data sets that are transmitted to any Sponsor location. 
Subject 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 
subject, unless permitted or required by law. 
Medical information may be given to a subject's personal physician or other appropriate 
medical personnel responsible for the subject'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 
subjects 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 national and local health authorities; Sponsor monitors, 
representatives, and collaborators; and the EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5). 
8.6 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 


 
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financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of EC and governmental 
approval.  In addition, at the end of the study, the Investigator will receive the subject 
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 subject safety and 
data integrity to the Sponsor and to the EC in accordance with established EC policies 
and procedures.  The Sponsor will review all protocol deviations and assess whether 
any represent a serious breach of GCP 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 the Sponsor or an authorized representative for 
inspection of study data, subjects' medical records, and eCRFs.  The Investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech, Inc. 
The study will be conducted at a single-center: Quotient Sciences, Mere Way, 
Ruddington Fields, Ruddington, Nottingham, NG11 6JS, UK. 
Central facilities will be used for certain study assessments throughout the study (e.g., 
clinical laboratory tests, PK analyses and metabolite profiling and identification) as 
specified in Section 4.5. 
Monitoring will be performed by
 Wirral Clinical Consultancy Ltd, 76 Pipers 
Lane, Lower Heswall Wirral, Cheshire, CH60 9HN, UK. 


 
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The ARSAC Practitioner will be 
MB BChir, MRCGP, MFPM, Tel: 
 email:
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.5 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in subjects involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in subjects involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the EC and regulatory authorities (as locally required) 
before implementation of any substantial changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
Any amendments relating to the administration of radioactive substances will be 
reviewed by the ARSAC Practitioner prior to submission to ARSAC as required by the 
current ARSAC Notes for Guidance.  The ARSAC Practitioner will also be notified of any 
substantial amendments to the PIS and ICF and/or protocol. 


 
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10. 
REFERENCES 
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 
Cancer J Clin 2018;68(6):394−424. 
FDA Guidance: Food effect bioavailability and fed bioequivalence studies. 2002. 
EMA – Guidance on the investigation of bioequivalence. 20 Jan 2010. 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. Statutory 
Instrument 2017 No. 1322. 
Ionising Radiation Exposure of the UK population: 2010 Review. Public Health England. 
Apr 2016. https://www.gov.uk/government/publications/ionising-radiation-
exposure-of-the-uk-population-2010-review 
Notes for guidance on the clinical administration of radiopharmaceuticals and use of 
sealed radioactive sources. Administration of Radioactive Substances Advisory 
Committee. Sep 2020. 
RO7197597 (GDC-9545) Investigator’s Brochure. F. Hoffmann-La Roche Ltd. Version 4, 
May 2020. 
 
 
 


 
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Appendix 1  
Part 1 Schedule of Activities 
Study Procedures 
Screening 
Residency in Clinical Unit 
Days 
–28 to –2 
–1a 
1 
2 
3 
4 
5 
6 
Time after study drug dosing 
(hours) b 
 
 
Pre-
dose 
0 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 24 48 72 96 120
Informed consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Vital signs g 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Laboratory safety tests h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screen k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol and FSH l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test m 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1: Part 1 Schedule of Activities 
  
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Study Procedures 
Screening 
Residency in Clinical Unit 
Days 
–28 to –2 
–1a 
1 
2 
3 
4 
5 
6 
Time after study drug dosing 
(hours) b 
 
 
Pre-
dose 
0 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 24 48 72 96 120
Adverse event monitoring n 
 
Prior and concomitant medications o 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples for GDC-9545 and 
total radioactivity PK p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Whole blood samples for total 
radioactivity PK p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Plasma samples for metabolite 
profiling and ID p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Urine samples for total radioactivity 
and metabolite profiling and 
identification q 
 
 
 
Feces samples for total radioactivity 
and metabolite profiling and 
identification r 
 
 
Confinement in the clinic 
 
 
 


Appendix 1: Part 1 Schedule of Activities 
  
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Study Procedures 
Residency in Clinical Unit 
Return Visits 
Days 7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21s 
28s 
35s 
42s 
Time after study drug dosing 
(hours) b 144 168 
192 
216 
240 
264 
288 
312 
336 
360 
384 
408 
432 
456 
480 648 816 984 
Limited physical examination f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
12-lead safety ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Laboratory safety tests h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse event monitoring n 
 
Prior and concomitant medications 
o 
 
Plasma samples for GDC-9545 
and total radioactivity PK p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood samples for total 
radioactivity PK p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma samples for metabolite 
profiling and ID p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine samples for total radioactivity 
and metabolite profiling and 
identification q 
 
X 
X 
X 
Feces samples for total 
radioactivity and metabolite 
profiling and identification r 
 
X 
X 
X 
Confinement in the clinic 
 
X 
X 
X 


Appendix 1: Part 1 Schedule of Activities 
  
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Study Procedures 
Residency in Clinical Unit 
Return Visit 
Days 7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21s 
28s 
35s 
42s 
Time after study drug dosing 
(hours) b 144 168 
192 
216 
240 
264 
288 
312 
336 
360 
384 
408 
432 
456 
480 648 816 984 
Return visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
a Admission to the clinical unit.  Eligibility will be reassessed at admission/pre-dose. 
b All assessments will be timed and performed relative to the start of dosing 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
d Update only 
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, GI, 
genitourinary, and neurologic systems. 
f Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated. 
g Includes pulse rate, and systolic and diastolic blood pressure while the subject is in a supine position, and oral temperature at all time points. 
h Hematology includes white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit (packed cell volume), mean cell 
hemoglobin, mean cell hemoglobin concentration, mean cell volume, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).  Chemistry panel (serum) includes magnesium, sodium, potassium, chloride, glucose, fasting glucose, urea, 
creatinine, creatine kinase, total protein, albumin, phosphate (inorganic), calcium, total bilirubin, direct bilirubin (only if total is elevated), alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and bicarbonate.  
Creatinine clearance will be estimated at screening from serum creatinine using the Cockcroft-Gault equation for eligibility purposes.  
Coagulation panel includes international normalized ratio (INR), activated partial thromboplastin time (APTT), thrombin time and prothrombin 
time (PT). 
i Includes pH, specific gravity, glucose, protein, ketones, blood, bilirubin, leukocytes, nitrites, urobilinogen. Microbiology and/or microscopic 
urinalysis examination, at the discretion of the Investigator based on urinalysis results (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria). 
j Amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, 
phencyclidine, and tricyclic anti-depressants. 
k HBsAg, HCV Antibody, HIV Antibody for all subjects. 
l Estradiol and FSH for post-menopausal female subjects only. 


Appendix 1: Part 1 Schedule of Activities 
  
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m All subjects must have a negative highly sensitive serum pregnancy test result at screening and a negative highly sensitive urine pregnancy test 
at admission. 
n After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All deaths that occur during the protocol-specified adverse event reporting period (see Section 5.3.1), regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  Deaths that occur after the 
adverse event reporting period should be reported as described in Section 5.6.  In addition, the Sponsor should be notified if the Investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
o Medication (e.g., prescription drugs, over-the-counter drugs, HRT, vaccines, topical medications, herbal or homeopathic remedies, nutritional 
supplements) used by a subject in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until discharge from the 
study. 
p See Appendix 3 for detailed schedule.  Blood sample collection will be at pre-dose, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, and at 
24-hour intervals thereafter until study completion (including after discharge, if needed)/early termination.  Permissible time windows for PK 
sampling are: pre-dose, ≤1 hour before dosing; 1 hour post-dose, ±5 minutes; 1.5 to 8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 
480 hours, ±4 hours; 648 to 984 hours, ±1 day 
q A single urine sample will be collected at pre-dose (the first void of the day) and then at the following collection periods: 0 to 12 hours, 12 to 24 
hours, and then daily (24 hour intervals) until the mass balance discharge criteria have been met or until Day 21, and then on a weekly basis 
starting on Day 28 (until criteria met or Day 42 reached). 
r The pre-dose feces sample will be taken in the 24 hours period before dosing (between admission and pre-dose).  Post-dose feces will be 
collected at 24 hour intervals until the mass balance discharge criteria have been met or until Day 21, and then on a weekly basis starting on 
Day 28 (until criteria met or Day 42 reached). 
s It is planned that subjects will remain resident in the clinical unit until 480 hours post-dose (Day 21) when they will be discharged from the 
clinical unit.  The same procedures are to be performed at early termination/withdrawal as at discharge.  Subjects may be discharged as a 
group earlier if the mass balance discharge criteria have been achieved.  If the criteria have not been met by Day 21, subjects will be 
discharged from the clinical unit and those who have not met the discharge criteria will return for outpatient visits every 7 days for a 24-hour 
sample collection interval until the mass balance discharge criteria are met (the maximum number of 24-hour return visits will not exceed 3).  
Discharged subjects may be asked to return for these visits if samples are needed post-discharge, prior to study completion.  If additional 
residency is not considered appropriate or necessary, then home collections of urine and/or feces may be requested at the discretion of the 
Investigator for individual subjects.  Safety discharge assessments will be performed at the time of actual discharge or early 
termination/withdrawal from the clinical unit.  PK, TR and metabolite profiling and identification blood samples to be collected at 480 hours 
post-dose or at time of actual discharge/early termination if earlier.  Any subject who discontinues or is withdrawn from the study after being 
discharged from the clinical unit will be asked to return to the clinical unit to undergo early termination/withdrawal procedures. 


 
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Appendix 2  
Part 2 Schedule of Activities 
Study Procedures 
Screening  
Study days in each period 
 
–28 to –2 
-1a 
1 
2 
Time after study drug dosing (hours) 
– (relative to start of IV infusion for 
Treatment B) b 
 
 
Pre-
dose 
0 0.25 0.5 0.58 0.67 1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 24 
Informed consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination g 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Vital signs i 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Laboratory safety tests j 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis k 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen l 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screen m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol and FSH n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test o 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2: Part 2 Schedule of Activities  
  
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93/Protocol GP42662 (QSC204283), Version 4 
Study Procedures 
Screening  
Study days in each period 
 
–28 to –2 
-1a 
1 
2 
Time after study drug dosing (hours) 
– (relative to start of IV infusion for 
Treatment B) b 
 
 
Pre-
dose 
0 0.25 0.5 0.58 0.67 1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 24 
Adverse event monitoring p 
 
Prior and concomitant medications q 
 
Study drug administration r 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples for GDC-9545 PK s 
 
 
X 
 
Xt 
Xt 
Xt 
Xt 
X 
X 
X 
Xu 
X 
X 
Xu 
X 
X 
X 
X 
Confinement in the clinic 
 
 
 
 
 
 
 
 
 
 


Appendix 2: Part 2 Schedule of Activities  
  
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Study Procedures 
Study days in each period 
Follow-Up 
Phone Call 
 
3 
4 
5 
6 
7 
8v 
14 to 16w 
Time after study drug dosing 
(hours) – (relative to start of IV 
infusion for Treatment B) b 
48 
72 
96 
120 
144 
168 
 
Limited physical examination g 
 
 
 
 
 
Xx 
 
12-lead safety ECG 
 
 
 
 
 
Xx 
 
Vital signs i 
 
 
 
 
 
Xx 
 
Laboratory safety tests j 
 
 
 
 
 
Xx 
 
Urinalysis k 
 
 
 
 
 
Xx 
 
Adverse event monitoring p 
 
Prior and concomitant medications 
q 
 
Plasma samples for GDC-9545 PK 
s 
X 
X 
X 
X 
X 
Xy 
 
Confinement in the clinic 
 
 
0.25 hours = 15 minutes, 0.5 hours = 30 minutes, 0.58 hours = 35 minutes; 0.67 hours = 40 minutes 
a Admission to the clinical unit (Period 1 only).  Subjects will be resident in the clinical unit for 28 to 29 consecutive nights that will cover all 
3 treatment periods. Eligibility will be reassessed at admission/pre-dose. 
b All assessments will be timed and performed relative to the start of dosing 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
d Period 1 only 
e Update only (Period 1 only). 


Appendix 2: Part 2 Schedule of Activities  
  
GDC-9545—Genentech, Inc. 
95/Protocol GP42662 (QSC204283), Version 4 
f Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, GI, 
genitourinary, and neurologic systems. 
g Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated. 
h Periods 1, 2 and 3 
i Includes pulse rate, and systolic and diastolic blood pressure while the subject is in a supine position, and oral temperature at all time points. 
j Hematology includes white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit (packed cell volume), mean cell 
hemoglobin, mean cell hemoglobin concentration, mean cell volume, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).  Chemistry panel (serum) includes magnesium, sodium, potassium, chloride, glucose, fasting glucose, urea, 
creatinine, creatine kinase, total protein, albumin, phosphate (inorganic), calcium, total bilirubin, direct bilirubin (only if total is elevated), alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and bicarbonate.  
Creatinine clearance will be estimated at screening from serum creatinine using the Cockcroft-Gault equation for eligibility purposes.  
Coagulation panel includes international normalized ratio (INR), activated partial thromboplastin time (APTT), thrombin time and prothrombin 
time (PT). 
k Includes pH, specific gravity, glucose, protein, ketones, blood, bilirubin, leukocytes, nitrites, urobilinogen. Microbiology and/or microscopic 
urinalysis examination, at the discretion of the Investigator based on urinalysis results (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria). 
l Amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, 
phencyclidine, and tricyclic anti-depressants. 
m HBsAg, HCV Antibody, HIV Antibody for all subjects. 
n Estradiol and FSH for post-menopausal female subjects only. 
o All subjects must have a negative highly sensitive serum pregnancy test result at screening and a negative highly sensitive urine pregnancy test 
at admission. 
p After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All deaths that occur during the protocol-specified adverse event reporting period (see Section 5.3.1), regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  Deaths that occur after the 
adverse event reporting period should be reported as described in Section 5.6.  In addition, the Sponsor should be notified if the Investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
q Medication (e.g., prescription drugs, over-the-counter drugs, HRT, vaccines, topical medications, herbal or homeopathic remedies, nutritional 
supplements) used by a subject in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until discharge from the 
study. 


Appendix 2: Part 2 Schedule of Activities  
  
GDC-9545—Genentech, Inc. 
96/Protocol GP42662 (QSC204283), Version 4 
r Treatment B will be administered intravenously over 30 minutes (as an infusion). For Treatment B only, to assess tolerability of the IV 
administration, the first subject will be dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if there are no 
acute safety findings for the first subject. If the first two subjects tolerated the IV dose, in the opinion of the Principal Investigator and Medical 
Monitor, the remaining subjects will be dosed. The third subject will be dosed at least 20 hours after the second subject (i.e., at least 24 hours 
after the first subject). All subsequent dosing of the IV formulation will be staggered by at least 15 minutes. For Treatments C and D, all subjects 
will be dosed as a single cohort. 
s See Appendix 4 for detailed schedule.  Permissible time windows for PK sampling and other assessments are: pre-dose, ≤1 hour before dosing; 
0.25 to 0.5 hours post-dose, ±2 minutes; 0.58 to 1 hour, ±5 minutes; 1.5 to 8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 168 hours, 
±4 hours. 
t Treatment B (IV dose only). 0.5 hours sample to be taken immediately after IV administration (i.e., 30 minutes after the start of the IV 
administration) 
u Treatments C and D (oral doses) only. 
v Discharge from clinical unit in Period 3 only.  The same procedures are to be performed at early termination/withdrawal as at discharge. 
w Follow-up telephone call at 13 to 15 days post-final dose. 
x Period 3 only; safety discharge assessments will be performed at the time of actual discharge/early termination from the clinical unit 
y Periods 1, 2 and 3. In Period 3, PK blood samples to be collected at 168 hours post-dose or at time of actual discharge/early termination if 
earlier. 
 
 


 
GDC-9545—Genentech, Inc. 
97/Protocol GP42662 (QSC204283), Version 4 
Appendix 3  
Part 1 Schedule of Pharmacokinetic Samples 
Visit a 
Time point a 
Sample Type 
Day 1 
Pre-dose 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
0 to 12.0 hours 
post-dose 
Urine (total radioactivity and metabolite profiling and 
identification)b 
0 to 24.0 hours  
Feces (total radioactivity and metabolite profiling and 
identification)c 
1.0 hour  
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
1.5 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
2.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
2.5 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
3.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
4.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
5.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
6.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
8.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 


Appendix 3  
Part 1 Schedule of Pharmacokinetic Assessments  
GDC-9545—Genentech, Inc. 
98/Protocol GP42662 (QSC204283), Version 4 
Visit a 
Time point a 
Sample Type 
Day 1 
12.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
12.0 to 24.0 hours  
Urine (total radioactivity and metabolite profiling and 
identification)b 
Day 2 
24.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
24.0 to 48.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 3 
48.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
48.0 to 72.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 4 
72.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
72.0 to 96.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 5 
96.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
96.0 to 120.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 6 
120.0 hours  
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
120.0 to 144.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 


Appendix 3  
Part 1 Schedule of Pharmacokinetic Assessments  
GDC-9545—Genentech, Inc. 
99/Protocol GP42662 (QSC204283), Version 4 
Visit a 
Time point a 
Sample Type 
Day 7 
144.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
144.0 to 168.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 8 
168.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
168.0 to 192.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 9 
192.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
192.0 to 216.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 10 
216.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
261.0 to 240.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 11 
240.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
240.0 to 264.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 12  
264.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
264.0 to 288.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 


Appendix 3  
Part 1 Schedule of Pharmacokinetic Assessments  
GDC-9545—Genentech, Inc. 
100/Protocol GP42662 (QSC204283), Version 4 
Visit a 
Time point a 
Sample Type 
Day 12 
264.0 to 288.0 hours 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 13 
288.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
288.0 to 312.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 14 
312.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
312.0 to 336.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 15 
336.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
336.0 to 360.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 16 
360.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
360.0 to 384.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 17 
384.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
384.0 to 408.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 18 
408.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 


Appendix 3  
Part 1 Schedule of Pharmacokinetic Assessments  
GDC-9545—Genentech, Inc. 
101/Protocol GP42662 (QSC204283), Version 4 
Visit a 
Time point a 
Sample Type 
Day 18 
408.0 to 432.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 19 
432.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
432.0 to 456.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 20 
456.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
456.0 to 480.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 21 
480.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
Day 28 
648.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
648.0 to 672.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 35 
816.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
816.0 to 840.0 hours 
Urine (total radioactivity and metabolite profiling and 
identification)b 
Feces (total radioactivity and metabolite profiling and 
identification)c 
Day 42 
984.0 hours 
GDC-9545 and TR PK, and metabolite profiling and 
identification (plasma) 
TR PK (whole blood) 
984.0 to 1008.0 hours Urine (total radioactivity and metabolite profiling and 
identification)b 


Appendix 3  
Part 1 Schedule of Pharmacokinetic Assessments  
GDC-9545—Genentech, Inc. 
102/Protocol GP42662 (QSC204283), Version 4 
Visit a 
Time point a 
Sample Type 
Day 42 
984.0 to 1008.0 hours Feces (total radioactivity and metabolite profiling and 
identification)c 
PK = pharmacokinetic, TR = total radioactivity. 
a It is planned that subjects will be released as a group when all subjects have achieved the 
mass balance discharge criteria.  This may result in the subjects being discharged as a group 
prior to completion of the planned residency period.  Once the mass balance discharge 
criteria have been achieved, collection of all samples (blood, urine, and feces) may be 
stopped and the subjects will undergo discharge assessments.  Discharged subjects may be 
asked to return for these visits if samples are needed post-discharge, prior to study 
completion, if needed. 
Blood sample collection will be at pre-dose, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, 
and at 24-hour intervals thereafter until study completion (including after discharge, if 
needed)/early termination 
Permissible time windows for PK sampling are: pre-dose, ≤1 hour before dosing; 1 hour post-
dose, ±5 minutes; 1.5 to 8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 480 hours, 
±4 hours; 648 to 984 hours, ±1 day 
b A single urine sample will be collected at pre-dose (the first void of the day) and then at the 
following collection periods: 0 to 12 hours, 12 to 24 hours, and then daily (24 hour intervals) 
until the mass balance discharge criteria have been met or until Day 21, and then on a weekly 
basis starting on Day 28 (until criteria met or Day 42 reached). 
c The pre-dose feces sample will be taken in the 24 hours period before dosing (between 
admission and pre-dose).  Post-dose feces will be collected at 24 hour intervals until the 
mass balance discharge criteria have been met or until Day 21, and then on a weekly basis 
starting on Day 28 (until criteria met or Day 42 reached). 
 
 


 
GDC-9545—Genentech, Inc. 
103/Protocol GP42662 (QSC204283), Version 4 
Appendix 4  
Part 2 Schedule of Pharmacokinetic Samples 
Visit a 
Time point a 
Sample Type 
Day 1 
Pre-dose 
GDC-9545 PK (plasma) 
0.25 hours post-dose b 
GDC-9545 PK (plasma) 
0.5 hours c 
GDC-9545 PK (plasma) 
0.58 hours d 
GDC-9545 PK (plasma) 
0.67 hours e 
GDC-9545 PK (plasma) 
1.0 hours 
GDC-9545 PK (plasma) 
1.5 hours 
GDC-9545 PK (plasma) 
2.0 hours 
GDC-9545 PK (plasma) 
2.5 hours f 
GDC-9545 PK (plasma) 
3.0 hours 
GDC-9545 PK (plasma) 
4.0 hours 
GDC-9545 PK (plasma) 
5.0 hours f 
GDC-9545 PK (plasma) 
6.0 hours 
GDC-9545 PK (plasma) 
8.0 hours 
GDC-9545 PK (plasma) 
12.0 hours 
GDC-9545 PK (plasma) 
Day 2 
24.0 hours 
GDC-9545 PK (plasma) 
Day 3 
48.0 hours 
GDC-9545 PK (plasma) 
Day 4 
72.0 hours 
GDC-9545 PK (plasma) 
Day 5 
96.0 hours 
GDC-9545 PK (plasma) 
Day 6 
120.0 hours 
GDC-9545 PK (plasma) 
Day 7 
144.0 hours 
GDC-9545 PK (plasma) 
Day 8 
168.0 hours 
GDC-9545 PK (plasma) 
PK = pharmacokinetic. 
a Visit and time points are applicable to all periods in Part 2, except where indicated.  For 
Treatment B (IV dose), time points are relative to the start of the IV administration. 
b 
 Treatment B (IV dose) only 
c Treatment B (IV dose only); sample to be taken immediately after IV administration (i.e., 
30 minutes after the start of the IV administration) 
d Treatment B (IV dose only); sample to be taken 5 minutes after the end of IV administration 
(i.e., 35 minutes after the start of the IV administration) 
e Treatment B (IV dose only); sample to be taken 10 minutes after the end of IV administration 
(i.e., 40 minutes after the start of the IV administration) 
f Treatments C and D (oral doses) only 
Permissible time windows for PK sampling and other assessments are: pre-dose, ≤1 hour 
before dosing; 0.25 to 0.5 hours post-dose, ±2 minutes; 0.58 to 1 hour, ±5 minutes; 1.5 to 
8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 168 hours, ±4 hours 
 

SAP_001.pdf: 
 
Official Title: 
A Phase I, Single Center, Open-Label, Partially Randomized, Two 
Part Study to Investigate the Absorption, Metabolism, and Excretion 
of [14C]-GDC-9545 Following a Single Oral Dose (Part 1) and to 
Evaluate the Absolute Bioavailability of Oral Capsule Formulations of 
GDC-9545 F12 and F18 and the Relative Bioavailability of F18 
Compared to F12 (Part 2) in Healthy Female Subjects of Non-
Childbearing Potential 
NCT Number: 
NCT04680273 
Document Date(s): 
Reporting and Analysis Plan (RAP) Version 1.0: 22-January-2021 
 




    
 
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Author 
 
Signed as per file note AH-348 
 
 
22 Jan 2021 
 
 (Quotient) 
 
Date 
 
Approvers 
 
Signed as per file note AH-348 
 
 
22 Jan 2021 
 
 (Quotient) 
 
Date 
 
Signed as per file note AH-348 
 
 
22 Jan 2021 
 
 (Quotient) 
 
Date 
 
Signed as per file note AH-348 
 
 
22 Jan 2021 
 
 (Quotient) 
 
Date 
 
Signed as per file note AH-348 
 
 
22 Jan 2021 
Nand Singh 
Principal Investigator (Quotient) 
 
Date 
 
 
 
 
 
 (Pharmaron) 
 
Date 
 
 
 
 
 
Study Biostatistician (Genentech, Inc.) 
 
Date 
 




    
 
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1 
Table of Contents 
1 
Table of Contents ............................................................................................ 3 
2 
List of Abbreviations ........................................................................................ 6 
3 
Introduction ..................................................................................................... 9 
3.1 
Responsibilities ................................................................................. 9 
3.2 
Definitions.......................................................................................... 9 
3.2.1 
Subject Definitions ............................................................................. 9 
3.2.2 
Definition of Treatments ................................................................... 10 
3.2.3 
Definition of Visits ............................................................................ 10 
4 
Objectives ..................................................................................................... 10 
4.1 
Primary Objectives .......................................................................... 10 
4.2 
Secondary Objectives ...................................................................... 11 
4.3 
Study Endpoints .............................................................................. 11 
4.3.1 
Primary Endpoints ........................................................................... 11 
4.3.2 
Secondary Endpoints ...................................................................... 11 
5 
Study Design ................................................................................................. 12 
5.1 
Brief Description .............................................................................. 12 
5.1.1 
Part 1 ............................................................................................... 12 
5.1.2 
Part 2 ............................................................................................... 13 
5.2 
Criteria for In-Study Decisions ......................................................... 14 
5.3 
Study Sample Size .......................................................................... 15 
5.4 
Randomization (including Replacement Subjects) ........................... 15 
5.4.1 
Part 1 ............................................................................................... 15 
5.4.2 
Part 2 ............................................................................................... 15 
5.5 
Blinding Issues ................................................................................ 15 
6 
Populations and Analysis Sets ...................................................................... 16 
6.1 
Safety Population and Safety Analysis Set ...................................... 16 
6.2 
Mass Balance Population and Mass Balance Analysis Set .............. 16 
6.3 
Pharmacokinetic Population and Pharmacokinetic Analysis 
Sets ................................................................................................. 17 
7 
Subject Disposition, Demographics and Baseline Characteristics ................. 18 
7.1 
Screening Failures ........................................................................... 18 
7.2 
Subject Disposition and Withdrawals ............................................... 18 
7.3 
Analysis Populations ....................................................................... 18 
7.4 
Analysis Sets and Subsets .............................................................. 18 
7.5 
Demographic Characteristics and Lifestyle Details .......................... 19 
7.6 
Medical/Surgical History .................................................................. 19 
7.7 
Prior and Concomitant Medication ................................................... 20 
7.8 
Other Baseline Characteristics ........................................................ 20 
8 
Efficacy ......................................................................................................... 20 


    
 
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9 
Mass Balance and Pharmacokinetics ............................................................ 20 
9.1 
Mass Balance Parameter Estimation and Reporting ........................ 20 
9.1.1 
Definition of Mass Balance Parameters ........................................... 21 
9.1.2 
Rules for Mass Balance Parameter Estimation ................................ 22 
9.1.3 
Mass Balance Summary Tables ...................................................... 24 
9.1.4 
Mass Balance Figures ..................................................................... 24 
9.1.5 
Mass Balance Listings ..................................................................... 25 
9.1.6 
Statistical Analysis of Mass Balance Parameters............................. 25 
9.2 
Pharmacokinetic Parameter Estimation and Reporting .................... 25 
9.2.1 
Definition of Pharmacokinetic Parameters ....................................... 25 
9.2.2 
Rules for Pharmacokinetic Parameter Estimation using 
WinNonlin ........................................................................................ 28 
9.2.3 
Pharmacokinetic Parameter Reporting Specifications ..................... 29 
9.2.4 
Bioanalytical and Pharmacokinetic Summary Tables ....................... 31 
9.2.5 
Bioanalytical and Pharmacokinetic Figures...................................... 31 
9.2.6 
Bioanalytical and Pharmacokinetic Listings ..................................... 32 
9.2.7 
Statistical Analysis of Pharmacokinetic Parameters ......................... 32 
10 
Safety Assessments ...................................................................................... 34 
10.1 
Extent of Exposure and Treatment Compliance ............................... 35 
10.2 
Meal Details ..................................................................................... 35 
10.3 
Adverse Events ............................................................................... 35 
10.3.1 
Summary Tables for Adverse Events ............................................... 36 
10.3.2 
Listings for Adverse Events ............................................................. 39 
10.4 
Laboratory Evaluations .................................................................... 39 
10.4.1 
Summary Tables for Laboratory Evaluations ................................... 39 
10.4.2 
Listings for Laboratory Evaluations .................................................. 40 
10.5 
Vital Signs ....................................................................................... 40 
10.5.1 
Summary Tables for Vital Signs ....................................................... 40 
10.5.2 
Listings for Vital Signs ..................................................................... 40 
10.6 
ECGs ............................................................................................... 41 
10.6.1 
Summary Tables for ECGs .............................................................. 41 
10.6.2 
Listings for ECGs ............................................................................. 41 
10.7 
Physical Examination ...................................................................... 42 
11 
Interim Statistical Analyses ........................................................................... 42 
12 
Changes in the Conduct of the Study or Planned Analysis ............................ 42 
12.1 
Changes in the Conduct of the Study .............................................. 42 
12.2 
Changes to the Planned Analyses ................................................... 42 
12.3 
Any Other Relevant Changes .......................................................... 43 
13 
Overall Considerations .................................................................................. 43 
13.1 
Statistical Programming and Analysis .............................................. 43 
13.2 
Quality Control of Summary Tables, Figures and Listings and 
Statistical Analysis ........................................................................... 45 
13.2.1 
Quality Control - Summary Tables ................................................... 45 
13.2.2 
Quality Control - Figures .................................................................. 45 
13.2.3 
Quality Control - Data Listings ......................................................... 46 


    
 
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13.2.4 
Quality Control - Statistical Analysis ................................................ 46 
14 
SAS Data Transfer ........................................................................................ 46 
15 
Programming Conventions ............................................................................ 47 
16 
Reference List ............................................................................................... 47 
17 
Index of Tables ............................................................................................. 48 
18 
Index of Figures ............................................................................................ 55 
19 
Index of Listings ............................................................................................ 60 
20 
Mock Tables .................................................................................................. 67 
Appendix 1: Part 1 Schedule of Activities .................................................................. 107 
Appendix 2: Part 2 Schedule of Activities .................................................................. 112 
 


    
 
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2 
List of Abbreviations 
14C 
carbon-14 
ADaM 
analysis data model  
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve  
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
COVID-19 
Coronavirus disease 2019 
CSR 
clinical study report 
CV% 
Coefficient of variation 
CVw% 
Intra-subject variability 
D 
‘substantial’ decrease from baseline for vital signs parameters 
DP 
decimal place 
ECG 
electrocardiogram 
F 
absolute bioavailability 
Frel 
relative bioavailability 
GMR 
geometric mean ratio 
h 
hour 
H 
flag used for value that is above normal reference range 
HR 
heart rate 


    
 
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I 
‘substantial’ increase from baseline for vital signs parameters 
increase in QTcF interval from baseline 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IV 
intravenous 
L 
flag used for value that is below normal reference range 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
LOD 
limit of detection 
Max 
maximum 
MBq 
megabecquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
µCi 
microcurie 
Min 
minimum 
n 
number of subjects with an observation 
N 
number of subjects in the dataset 
NA 
not applicable 
NC 
not calculated 
ND 
not detected 
NMT 
no more than 
NR 
not reportable 
NS 
no sample 
PI 
principal investigator 
PK 
pharmacokinetic 
PT 
preferred term 


    
 
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QC 
quality control 
RAP 
reporting analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
SF 
significant figure 
SI 
substantial increase in QTcF interval from baseline 
SOC 
system organ class 
SOP 
standard operating procedure 
TFL 
tables, figures and listings 
TR 
total radioactivity 
WB 
whole blood 
WHO  
World Health Organisation  
 


    
 
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3 
Introduction 
This document details the following for Quotient Sciences (Quotient) Study QSC204283 
(GP42662): 
• 
criteria to be used for the definition of the populations and analysis sets relating to 
safety, pharmacokinetic (PK) and mass balance data 
• 
handling of missing data 
• 
proposed tables, figures and listings for demographic, dosing, PK, mass balance and 
safety data  
• 
methods for PK parameter estimation and the formal statistical analysis  
 
This document has been compiled according to the Quotient standard operating 
procedure (SOP) “Production of Reporting and Analysis Plans” and has been written 
based on information contained in the final study protocol version 3.0 dated 19 Jan 2021. 
3.1 
Responsibilities 
The Data Sciences Department at Quotient will be responsible for the production of the 
following items using Quotient SOPs: Clinical Data Interchange Standards Consortium 
(CDISC) study data tabulation model (SDTM) and analysis data model (ADaM) datasets, 
PK parameter estimation and output, mass balance parameter estimation and output; 
including all summary tables, figures and data listings (TFLs), and formal statistical 
analysis; and the clinical study report (CSR). 
Quotient will provide three sets of TFLs during the study: 
• 
after database close but prior to database lock for Genentech, Inc.  
• 
post database lock TFLs (draft) for Genentech, Inc review and  
• 
post-review TFLs (final) for inclusion into the CSR 
Quotient will be responsible for the quality control (QC) of all deliverables prior to the 
client review (Section 13.2).   
Metabolite profiling will be the responsibility of Genentech, Inc., and will be the subject 
of a separate Analytical Work Plan. These aspects will be reported separately from the 
Clinical Study Report as a standalone document. 
3.2 
Definitions 
3.2.1 
Subject Definitions 
During the clinical phase of the study, an evaluable subject is defined as a subject; 
• 
Part 1: who has provided mass balance and PK samples for up to 480 hours (up to 
Day 21) or until they have met the mass balance discharge criteria (i.e., cumulative 
recovery of radioactivity exceeds 90% of the administered dose; OR radioactivity in 
urine and feces is less than 1% of the administered dose over a 24 hour period on 2 
consecutive PK sample collection days, as determined by quick counts). 
• 
Part 2: who has received an investigational medicinal product (IMP) and has 
sufficient drug concentration measurements up to 168 hours after dosing for 


    
 
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evaluation of defined PK parameters for each treatment, and have completed all 
planned safety assessments up to 168 hours after dosing for each treatment. 
These will be monitored during the clinical phase to identify any requirement for 
replacement subjects (i.e. Part 2). This definition will not be used during the reporting 
phase including the identification of analysis populations and datasets. 
An enrolled subject is defined as a subject who signed the informed consent, qualified 
per the inclusion/exclusion criteria and were allocated a unique identification number 
(Part 1) or were randomized (Part 2). 
3.2.2 
Definition of Treatments 
Throughout the reporting of the study, IMP will be referred to as treatments will be 
reported as detailed in Table 1 below: 
Table 1 Study Treatments 
Part 
Treatment 
Description 
Label 
for 
Reporting 
Purposes 
1 
A 
[14C]-GDC-9545 capsule, 30 mg ([NMT 4.6 
MBq[124 µCi]) in fasted state 
[14C]-GDC-9545 Cap 
2 
B 
GDC-9545 IV administration of 30 mg as a 
solution for infusion, 3 mg/mL (10 mL), over 
30 min in fasted state 
GDC-9545 IV  
C 
GDC-9545/F12 capsule, 30 mg in fasted state 
GDC-9545/F12 Cap 
D 
GDC-9545/F18 capsule, 30 mg in fasted state 
GDC-9545/F18 Cap 
3.2.3 
Definition of Visits 
For clinical data, visits will be referred to as Day throughout this document and will be 
referred to Screening, Day -1 (Admission) and Day 1 through to Day 42 (Part 1) and 
Day 1 through to Day 8 of the respective treatment period and follow up (14 to 16 days 
after final dose) [Part 2]. Time points within these days are detailed in the schedule of 
activities in Appendix 1 and 2, for Part 1 and Part 2 respectively. 
Baseline is defined as nominally the last measurement recorded prior to the first dose of 
IMP for Part 1 and last measurement recorded prior to receiving IMP for each dosing 
period in Part 2. 
4 
Objectives 
4.1 
Primary Objectives 
The primary objectives of this study are: 
• 
To determine the mass balance and routes of elimination of [14C]-GDC-9545 
following a single oral dose of [14C]-GDC-9545 capsule, 30 mg containing not more 
than (NMT) 4.6 megabecquerel (MBq; 124 microcurie [µCi]) (Part 1) 
• 
To assess the PK of GDC-9545 and total drug-derived material in plasma following 
a single oral dose of [14C]-GDC-9545 capsule, 30 mg (NMT 4.6 MBq [124 µCi]) 
(Part 1) 


    
 
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• 
To determine the absolute bioavailability of an oral GDC-9545/F12 capsule, 30 mg 
and an oral GDC-9545/F18 capsule, 30 mg (Part 2) 
• 
To determine the relative bioavailability of GDC-9545/F18 capsule, 30 mg compared 
to the GDC-9545/F12 capsule, 30 mg (Part 2) 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
• 
To characterize and identify metabolites of [14C]-GDC-9545 in plasma, urine, and 
feces (Part 1)a 
• 
To characterize the PK of GDC-9545 following oral and IV administration (Part 2) 
• 
To evaluate the safety and tolerability of single doses of GDC-9545 (Parts 1 and 2) 
4.3 
Study Endpoints 
4.3.1 
Primary Endpoints 
The primary endpoints of this study are: 
• 
Mass balance recovery of total radioactivity (TR) in all excreta (urine and feces): 
CumAe and CumFe (Part 1) 
• 
Determination of routes and rates of elimination of [14C]-GDC-9545 by Ae, CumAe, Fe 
and CumFe by interval for all excreta (urine and feces) (Part 1) 
• 
Calculation of PK parameters as appropriate for GDC-9545 (plasma only) and TR 
(plasma and whole blood) (Part 1) 
• 
Assessment of the concentrations of TR in whole blood and plasma (Part 1) 
• 
Evaluation of whole blood:plasma concentration ratios for TR (Part 1) 
• 
Absolute bioavailability assessment based on the PK parameter AUC0-inf for 
GDC-9545 (Part 2) 
• 
Relative bioavailability assessment based on the PK parameters Cmax and AUC0-inf 
for GDC-9545 (Part 2) 
4.3.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
• 
Characterization of abundant metabolites by liquid chromatography-high resolution 
mass spectrometry (Part 1)a 
• 
Calculation of PK parameters as appropriate for GDC-9545 in plasma only (Part 2) 
• 
Incidence and severity of adverse events (AEs) [Parts 1 and 2] 
• 
Incidence of abnormalities in laboratory safety tests, 12-lead ECGs and vital sign 
measurements (Parts 1 and 2) 
Note the objective and endpoint with a are related to metabolite profiling and identification 
hence will be reported separately from the CSR.  


    
 
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5 
Study Design 
5.1 
Brief Description 
5.1.1 
Part 1 
Part 1 is an open-label, single-treatment design to evaluate the mass balance and routes 
of elimination of [14C]-GDC-9545. It is planned to enroll 6 subjects to ensure data in a 
minimum of 4 evaluable subjects 
Each subject will receive a single oral dose of [14C]-GDC-9545 capsule, 30 mg (NMT 
4.6 MBq [124 µCi]) with approximately 240 mL water in the fasted state (Treatment A). 
Subjects will undergo preliminary screening procedures for the study up to 28 days 
(Day -28 to Day -2) before [14C]-GDC-9545 administration on Day 1. Subjects will be 
admitted in the morning on the day prior to [14C]-GDC-9545 administration (Day -1) and 
will be dosed in the morning of Day 1 following an overnight fast of a minimum of 
10 hours.  
It is planned that subjects will remain resident in the clinical unit until 480 hours post-dose 
(Day 21) when they will be discharged from the clinical unit. 
It is planned that subjects will be released as a group when all subjects have achieved 
the following mass balance discharge criteria: 
• 
Cumulative recovery of radioactivity exceeds 90% of the administered dose; OR 
• 
Radioactivity in urine and feces is less than 1% of the administered dose over a 
24 hour period on 2 consecutive PK sample collection days, as determined by quick 
counts 
This may result in the subjects being discharged as a group prior to completion of the 
planned residency period. Once the mass balance discharge criteria have been 
achieved, collection of all samples (blood, urine, and feces) will be stopped and the 
subjects will undergo discharge assessments. If the mass balance discharge criteria 
have not been met by all subjects by Day 21, subjects will be discharged from the clinical 
unit and those who have not met discharge criteria will return for outpatient visits every 
7 days for a 24-hour sample collection interval (i.e., subjects will be resident in the clinical 
unit for 24 hours during each return visit) until the mass balance discharge criteria are 
met (the maximum number of 24-hour return visits will not exceed 3). During the period 
of weekly collection, mass balance cumulative recovery will be estimated by means of 
interpolation. 
If additional residency is not considered appropriate or necessary, then home collections 
of urine and/or feces may be requested at the discretion of the Investigator for individual 
subjects. 
Figure 1 presents an overview of the study design for Part 1.   


    
 
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Figure 1 
Overview of Part 1 Design 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 21a  
a Subjects may be discharged as a group earlier if the mass balance discharge criteria have been 
achieved. If the criteria have not been met by Day 21, subjects will be discharged from the clinical unit and 
those who have not met the discharge criteria will return for outpatient visits every 7 days for a 24-hour 
sample collection interval until the mass balance discharge criteria are met (the maximum number of 24-
hour return visits will not exceed 3). If additional residency is not considered appropriate or necessary, 
then home collections of urine and/or feces may be requested at the discretion of the Investigator for 
individual subjects. 
5.1.2 
Part 2 
Part 2 is a randomized, open-label, three-treatment, two-sequence crossover design 
conducted over three periods. It is planned to enroll 10 subjects to ensure data in a 
minimum of 8 evaluable subjects. 
Subjects will undergo preliminary screening procedures for the study up to 28 days 
(Day -28 to Day -2) before GDC-9545 administration on Day 1 of Period 1. Subjects will 
be admitted in the morning on the day prior to the first GDC-9545 administration (Day -1 
of Period 1). Subjects will be resident in the clinical unit from the morning of Day -1 in 
Period 1 until Day 8 in Period 3 (i.e., for 28 to 29 consecutive nights that will cover all 
3 treatment periods). 
Subjects will be randomly allocated to one of two treatment sequences (BCD and BDC; 
see Section 5.4.2) on the morning of Period 1. For each treatment period, subjects will 
be dosed in the morning of Day 1 following an overnight fast of a minimum of 10 hours. 
The treatment descriptions are given in Table 1. 
For Treatment B (see Table 1), to assess tolerability of the IV administration, the first 
subject will be dosed as a sentinel; then, at least 4 hours later, the second subject will 
be dosed only if there are no acute safety findings for the first subject. If the first two 
subjects tolerated the IV dose, in the opinion of the Principal Investigator (PI) and Medical 
Monitor per the criteria in protocol Section 6.8.1Error! Reference source not found., 
the remaining subjects will be dosed. The third subject will be dosed at least 20 hours 
after the second subject (i.e., at least 24 hours after the first subject). All subsequent 
dosing of the IV formulation will be staggered by at least 15 minutes. 
Figure 2 presents an overview of the study design for Part 2. 


    
 
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Figure 2 
Overview of Part 2 Design 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 (Period 1 only) 
 
Dose 
Day 1 (Periods 1, 2 and 3)a 
 
Discharge 
Day 8 (Period 3 only) 
 
Follow-Up Call 
14 to 16 days post-final dose 
a Subjects will receive Treatments B in Period 1, and C and D in Periods 2 and 3 in a randomized manner. 
There will be a minimum washout of 10 days between each IMP administration. 
5.2 
Criteria for In-Study Decisions 
No interim analyses are planned for Part 1.  
The following in-study decision will be made during Part 2 of this study: 
• 
Progression from sentinel group to main group where sentinel dosing is used for 
Treatment B 
For Treatment B, to assess tolerability of the IV administration, the first subject will be 
dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if 
there are no acute safety findings for the first subject. If the first two subjects tolerated 
the IV dose, in the opinion of the Principal Investigator and Medical Monitor, the 
remaining subjects will be dosed. The third subject will be dosed at least 20 hours after 
the second subject (i.e., at least 24 hours after the first subject). All subsequent dosing 
of the IV formulation will be staggered by at least 15 minutes. 
The decision to proceed with the main group will be made by the Investigator, based on 
safety data until up to 24 hours post-dose for the two sentinel subjects. The Investigator 
will inform the Sponsor of any safety concerns.  
The decision to proceed to the next dose level will be based on safety and tolerability 
data. The following data are required: 
• 
Adverse events 
• 
ECGs 
• 
Vital signs  


    
 
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5.3 
Study Sample Size 
For Part 1, it is planned to enroll 6 subjects to ensure data in a minimum of 4 evaluable 
subjects. For Part 2, it is planned to enroll 10 subjects to ensure data in a minimum of 
8 evaluable subjects. No replacement subjects are to be used in Part 1 of this study. Up 
to 4 replacement subjects are permitted in Part 2 of this study to ensure there are 
8 evaluable subjects. 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a sample size of 6 subjects for 
Part 1 and 10 subjects for Part 2 is considered appropriate to meet the objectives of the 
study. 
5.4 
Randomization (including Replacement Subjects) 
5.4.1 
Part 1 
Part 1 is non-randomized; therefore a randomization schedule will not be produced. 
Eligible subjects will be assigned a unique identification number on the morning of dosing 
(Period 1, Day 1) according to the code 
 to 
 for Part 1, using the lowest number 
available. 
All subjects in Part 1 will receive Treatment A in Period 1 (see Table 1). 
5.4.2 
Part 2 
Using a computer-generated randomization schedule, subject numbers will be allocated 
to one of two treatment sequences (Table 2) in Part 2. The allocation will be balanced 
with 5 subjects assigned to each of the treatment sequences. The treatment descriptions 
are given in Table 1. 
Table 2  
Part 2 Treatment Sequences 
Treatment Sequence 
Period 1 
Period 2 
Period 3 
BCD 
B 
C 
D 
BDC 
B 
D 
C 
Eligible subjects will be assigned a unique identification number on the morning of dosing 
in Period 1 according to the code 
 to 
for Part 2, using the lowest number 
available. Replacement subjects will be allocated subject numbers
to
 where the 
last 2 digits are the same as those of the original subject (e.g., if Subject 
withdraws 
the replacement will have Subject Number
). Replacement subjects will be assigned 
to the same treatment sequence as the subject they replaced and will receive any 
treatments that the replaced subject did not receive in addition to any treatments that are 
required to make the required comparison of interest. 
5.5 
Blinding Issues 
This is an open-label study and therefore blinding is not required. 


    
 
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6 
Populations and Analysis Sets 
6.1 
Safety Population and Safety Analysis Set 
The safety population will be defined separately for each study part including all subjects 
who have received at least one dose of IMP of the respective part. 
The safety analysis set will be defined separately for each study part and will be defined 
on a treatment basis and will include all relevant data from the subjects included in the 
safety population who have received that treatment. 
The safety population will be confirmed by Quotient with approval from Genentech after 
database lock and will be summarized for the populations table and to determine the 
subjects to be included in the safety analysis set. 
The safety analysis set will be confirmed by Quotient with approval from Genentech at 
the same time as the safety population and will be summarized for the analysis of 
demographic and baseline characteristics, and all safety data. 
All enrolled subjects will be used for the safety data listings. 
6.2 
Mass Balance Population and Mass Balance Analysis Set 
In Part 1, the mass balance population will include all subjects who have received a dose 
of IMP and who have evaluable total radioactivity concentration (urinary and fecal) data 
and who have no protocol deviations that affect the mass balance analysis. Such 
protocol deviations would include anything that affects the accurate measurement of the 
amount of urine or feces collected or any adverse events that may affect the mass 
balance analysis, for example: 
• 
Spillage of urine and/or feces 
• 
Missing collections 
• 
Adverse events that may affect the mass balance analysis*  
*for example, if vomiting is observed, this will be assessed on a case by case basis to 
determine the potential impact on the mass balance recovery 
The mass balance population will be confirmed by Quotient with approval from 
Genentech once all urinary and fecal data have been received and will be summarized 
for the populations table and to determine the subjects to be included in the mass 
balance analysis set  
The mass balance analysis set will include all relevant data from the subjects included 
in the mass balance population who have received Treatment A. 
If required, a mass balance analysis subset or subsets will also be documented by 
Quotient, with approval from Genentech, at the same time as the mass balance 
population and analysis set, if additional subjects are required to be excluded from the 
summary tables and figures (for example to exclude subjects who have incomplete 
collections for one matrix).  


    
 
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All enrolled subjects will be used for the mass balance data listings and individual figures. 
The mass balance population will be used for the populations table. The mass balance 
analysis set and/or the mass balance analysis subset(s), if defined, will be used for the 
provision of mass balance summary tables and figures and will be documented as the 
same time as the mass balance population. 
The mass balance population is applicable to Part 1 only. 
6.3 
Pharmacokinetic Population and Pharmacokinetic Analysis Sets 
The PK population will be defined separately for study parts 1 and 2 and will include all 
subjects who have received at least one dose of IMP in each study part and who satisfy 
the following criteria for at least 1 profile: 
• 
No missing samples or invalid post-dose analytical results at critical time points e.g. 
around Cmax 
• 
No relevant protocol deviations which may impact the study objectives with respect 
to the PK endpoints 
• 
For Part 1 & 2 oral doses: no relevant AEs, such as vomiting, which suggest that the 
whole dose was not available for absorption for a particular subject 
• 
For Part 2 intravenous dose: no relevant AEs, which suggest that the whole dose 
was not fully delivered for a particular subject 
The PK analysis set will be defined on a per-treatment basis and will include all relevant 
data from the subjects included in the PK population who have received that treatment. 
Individual subjects (i.e. on a per treatment basis) will be excluded from the PK analysis 
set where deemed appropriate such as if the subject’s data for the treatment affected did 
not meet the bullet point criteria above for at least one individual profile (i.e. analyte), or 
other study emergent point related to PK analysis or interpretation. 
Individual subject profiles (i.e. on a per analyte basis) will be flagged and excluded from 
the PK summary statistics, where deemed appropriate such as if the profile in the 
treatment affected did not meet the bullet point criteria above, or other study emergent 
point related to PK analysis or interpretation. 
The PK population and analysis set will be confirmed by Quotient with approval from 
Genentech following derivation of all PK parameter estimates. 
If required, a PK analysis subset(s) will also be documented by Quotient, with approval 
from Genentech, at the same time as the PK population and analysis set, if additional 
subjects are required to be excluded from the summary tables and figures or statistical 
analysis.  
All enrolled subjects will be used for the PK data listings. The PK population will be used 
for the populations table. The PK analysis set and/or the PK analysis subset(s), if 
defined, will be used for the provision of PK summary tables, figures and formal statistical 
analysis and will be documented as the same time as the PK population. 


    
 
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7 
Subject 
Disposition, 
Demographics 
and 
Baseline 
Characteristics 
No formal statistical testing will be performed on subject disposition, or on demographic 
or baseline data. Summaries of subject disposition and analyses populations will be 
based on all enrolled subjects of the respectively study part and summaries of all other 
data described in this section will be based on the safety analysis set of the respectively 
study part unless otherwise stated. Separate tables and listings will be produced for each 
study part. 
7.1 
Screening Failures 
Data for subjects who have failed screening will be databased but will not be cleaned 
and therefore will not be included in the SDTM or ADaM datasets or any of the tables, 
figures or data listings or the CSR. 
7.2 
Subject Disposition and Withdrawals 
The number and percentage of subjects enrolled, dosed, completed and discontinued 
will be presented by; overall in Part 1 and sequence and overall in Part 2. If all subjects 
in Part 2 receive all treatments then this will be presented by overall only. If any subjects 
discontinued from the study early then the number of subjects for each reason for 
discontinuation will be presented by; overall (Part 1) and sequence and overall (Part 2). 
However, if none of the subjects discontinued from the study early, then the reasons for 
discontinuation will not be populated in the summary table. A subject may be 
discontinued from the study early for 1 reason only. 
Subject disposition and withdrawal data will be listed including details of informed 
consent. 
Protocol deviations and any violations of the inclusion/exclusion criteria will also be listed. 
7.3 
Analysis Populations 
A summary table will be produced detailing the number and percentage of subjects in 
each safety, mass balance (Part 1 only) and PK population by; overall in Part 1 and 
sequence and overall in Part 2. If all subjects in Part 2 receive all treatments then this 
will be presented by overall only. The reasons for exclusion from each population will 
also be included in the summary table. However, if none of the subjects were excluded 
from a population, then the reasons for exclusion will not be populated in the summary 
table. A subject may be excluded from a population for more than 1 reason. The 
denominator for the percentage the number of subjects enrolled (Part 1) and the number 
of subjects enrolled in the respective sequence (Part 2). 
Details of subjects included and excluded in the different analysis populations will be 
listed. 
7.4 
Analysis Sets and Subsets 
A summary tables for each study part will be produced detailing the number and 
percentage of subjects in each of the safety/mass balance (Part 1 only)/PK analysis sets 
and safety/mass balance (Part 1)/PK analysis subsets (if applicable) for each treatment 


    
 
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(Part 2 only) and overall. The table will be based on the relevant population the analysis 
set/subset is derived from (i.e., the safety/mas balance/PK population). Separate tables 
will be presented for the safety (analysis set only), mass balance and PK (analysis set 
and analysis subsets to be included in the same table, if applicable). The reasons for 
exclusion from each analysis set/subset will also be included in the summary. However, 
if none of the subjects were excluded from a population, then the reasons for exclusion 
will not be populated in the summary table. A subject may be excluded from a population 
for more than 1 reason. The denominator for the percentage is the number of subjects 
in each population. 
Details of subjects included and excluded in the different analysis sets/subsets (where 
appropriate) will be listed. 
7.5 
Demographic Characteristics and Lifestyle Details 
Demographic data (date of birth, ethnicity, race, sex, height [cm], weight [kg] and body 
mass index [BMI; kg/m2]) will be recorded at screening. Age will be calculated using the 
following formula: 
Age (years) = 
Date of Informed Consent – Date of Birth 
365.25 
and will be rounded down to the nearest year (using the SAS Software floor function).  
Summary statistics (n, mean, SD, median, minimum and maximum) will be presented for 
age, height, weight and BMI at screening by; overall in Part 1 and sequence and overall 
in Part 2. The number and percentage of subjects will be presented by; overall in Part 1 
and sequence and overall in Part 2 for ethnicity, race and sex. If all subjects in Part 2 
receive all treatments then this will be presented by overall only, unless a sequence 
effect is observed in the formal statistical analyses described below. The denominator 
for the percentage is all subjects in the safety analysis set for the respective study part. 
If any values are missing, a “missing” row will be presented on the table. 
Lifestyle details (i.e., smoking history [does the subject smoke, use e-cigarettes or use 
nicotine replacement products?] and alcohol consumption) will be summarized by; 
overall in Part 1 and sequence and overall in Part 2 as a categorical variable. If all 
subjects in Part 2 receive all treatments then this will be presented by overall only. 
Demographic and lifestyle data for all enrolled subjects will be listed. 
7.6 
Medical/Surgical History 
Medical/surgical history will be recorded for each subject at the screening visit and 
updated on admission will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA v23.1). All medical/surgical history data will be listed by subject, MedDRA 
system organ class (SOC) and preferred term (PT). 


    
 
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7.7 
Prior and Concomitant Medication 
Medications (product name) will be coded using the World Health Organization (WHO) 
Drug Dictionary Global Drug Reference: 2020 September B3 version using the following 
Anatomical Therapeutic Chemical (ATC) classification codes 
• 
product name 
• 
preferred name  
• 
drug code 
• 
therapeutic subgroup (ATC 2nd level code) 
• 
chemical subgroup (ATC 4th level code) 
Prior medications are defined as medications that start and stop prior to the first dose of 
IMP. All other medications will be defined as concomitant medications including those 
that start prior to the first dose of IMP and continue thereafter. Any medications with an 
unknown start or stop date will be assumed to be concomitant medications unless a 
partial start or stop date indicates otherwise.  
All medications, including coded terms, and the underlying indication for which the 
medication was given, will be listed. All medications, including coded terms, will be listed 
One combined data listing of prior and concomitant medications will be provided. All prior 
medications as defined above will be flagged with a “#” symbol. Within this flagged group 
medications that started after screening and stopped before dosing of IMP will also be 
flagged using a “*” symbol. 
7.8 
Other Baseline Characteristics 
All other baseline characteristics, as listed below, at screening and on admission (unless 
otherwise stated) will be listed by subject for all enrolled subjects of the respectively study 
part: 
• 
urine drug screen 
• 
alcohol breath test  
• 
carbon monoxide breath test  
• 
virology (screening only) 
• 
urine/serum pregnancy test (serum pregnancy test at screening and urine pregnancy 
test at admission) 
• 
follicle stimulating hormone (post-menopausal subjects at screening only) 
• 
estradiol (post-menopausal subjects at screening only) 
• 
creatinine clearance (screening only) 
8 
Efficacy 
Not applicable. 
9 
Mass Balance and Pharmacokinetics 
9.1 
Mass Balance Parameter Estimation and Reporting 
Pharmaron will provide the following concentration and weight data on a per subject 
basis for each collection interval as specified in the clinical protocol in Part 1: 


    
 
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• 
Total radioactivity concentration for urine and feces (mass unit equivalents/g)  
• 
Weight of urine (g)  
• 
Feces weight (g) i.e. not fecal homogenate weight 
Quotient Data Sciences will be responsible for the calculation of excretion and recovery 
of total radioactivity in urine and feces and combined urine and feces inclusion into the 
clinical study report. 
9.1.1 
Definition of Mass Balance Parameters 
A list of mass balance parameter definitions is provided in Table 3. 
Table 3 
Mass Balance Parameters and Reporting Specifications 
Parameter 
Definition 
Units 
DP or 
SF 
No. of 
DP/SF 
Ae(urine) 
amount of total radioactivity excreted in urine 
Mass unit 
equiv 
SF 
3 
Fe(urine) 
amount of total radioactivity excreted in urine 
expressed as a percentage of the radioactive 
dose administered 
% 
DP 
2 
CumAe(urine) 
cumulative amount of total radioactivity 
excreted in urine 
Mass unit 
equiv 
SF 
3 
CumFe (urine) 
cumulative amount of total radioactivity 
excreted in urine expressed as a percentage 
of the radioactive dose administered 
% 
DP 
2 
Ae(feces) 
amount of total radioactivity eliminated in 
feces 
Mass unit 
equiv 
SF 
3 
Fe(feces) 
amount of total radioactivity eliminated in 
feces expressed as a percentage of the 
radioactive dose administered 
% 
DP 
2 
CumAe(feces) 
cumulative amount of total radioactivity 
eliminated in feces 
Mass unit 
equiv 
SF 
3 
CumFe(feces) 
cumulative amount of total radioactivity 
eliminated in feces expressed as a 
percentage of the radioactive dose 
administered 
% 
DP 
2 
Ae(total) 
amount of total radioactivity excreted in urine 
and feces combined 
Mass unit 
equiv 
SF 
3 
Fe (total) 
amount of total radioactivity excreted in urine 
and feces combined expressed as a 
percentage of the radioactive dose 
administered 
% 
DP 
2 
CumAe(total) 
cumulative amount of total radioactivity 
excreted in urine and feces combined 
Mass unit 
equiv 
SF 
3 
CumFe (total) 
cumulative amount of total radioactivity 
excreted in urine and feces combined 
expressed as a percentage of the radioactive 
dose administered 
% 
DP 
2 
Dose will be used in the calculation of mass balance parameters as per Table 4. 


    
 
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Table 4 
Mass Balance Dose Specifications 
Radioactive dose level for mass balance 
analysis  
Actual 
Rounded dose level   
As provided by Pharmaron 
9.1.2 
Rules for Mass Balance Parameter Estimation  
The following will be calculated for total radioactivity in urine, feces and urine and feces 
combined by Quotient Data Sciences (note that the amount excreted in pre-dose 
samples will not be included in the calculation of the cumulative amount excreted or in 
the calculation of the cumulative percentage of the radioactive dose excreted): 
• 
The amount excreted in urine i.e. Ae(urine) and the amount excreted in feces i.e. 
Ae(feces) will be calculated for each collection interval using the following formula 
(where matrix is either urine or feces): 
Ae(<matrix>) = concentration * weight 
• 
The total amount excreted in urine and feces combined, i.e. Ae(total), will be 
calculated for each collection interval using the following formula: 
Ae(total) = Ae(urine) + Ae(feces) 
• 
The cumulative amount excreted in urine i.e. CumAe(urine) and the cumulative 
amount excreted in feces i.e. CumAe(feces) will be calculated by the incremental 
summation of the Ae(<matrix>) across all collection intervals (where matrix is either 
urine or feces). The amount excreted in the pre-dose sample should not be included 
in the calculation of the cumulative amount excreted. 
• 
The cumulative amount excreted in urine and feces combined i.e. CumAe(total) will 
be calculated across all collection intervals using the following formula: 
CumAe(total) = CumAe(urine) + CumAe(feces) 
• 
The % amount of the total radioactive excreted in urine i.e. Fe(urine) and the 
% amount of the total radioactive dose excreted in feces i.e. Fe(feces) will be 
calculated for each collection interval using the following formula (where matrix is 
either urine or feces): 
Fe(<matrix>) = 100 * Ae(<matrix>) / Total Radioactive Dose Administered 
• 
The % amount of the total radioactive dose excreted in urine and feces combined will 
be calculated for each collection interval using the following formula: 
Fe(total) = Fe(urine) + Fe(feces) 
• 
The cumulative % amount of the total radioactive dose excreted in urine i.e. 
CumFe(urine) and the cumulative % amount of the total radioactive dose excreted 
in feces i.e. CumFe(feces) will be calculated by the incremental summation of the 
Fe(<matrix>) across all collection intervals (where matrix is either urine or feces). 


    
 
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The % amount of the total radioactive dose excreted in the pre-dose sample should 
not be included in the calculation of the cumulative % of dose excreted. 
• 
The cumulative % amount of the total radioactive dose excreted in urine and feces 
combined will be calculated for each collection interval using the following formula: 
CumFe(total) = CumFe(urine) + CumFe(feces) 
• 
Following Day 21, where urine/fecal collections are no longer continuous and spot 
sampling days (i.e. 24 h) commence, additional interpolation of Ae will be calculated 
to estimate amount excreted on non-collection days (i.e. over the entire interpolation 
interval), as follows: 
𝐴𝑒 (𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙) = (𝐴𝑒 24ℎ [𝐷𝑎𝑦 𝑥 +  𝐷𝑎𝑦 𝑦]
2
) ∗ 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 (𝑑𝑎𝑦𝑠) 
where Day x and Day y are the actual amounts excreted for the preceding and 
proceeding days of the interpolation interval and the interval is considered to be from 
Day X+1 to Day Y-1. 
Home collections of urine and/or feces may be requested at the discretion of the 
investigator for individual subjects. For amount excreted and cumulative excretion this 
will be calculated for all time points including home collection, if applicable 
For urine and feces, where a subject has failed to void over a particular collection interval 
the Amount Eliminated (Ae) will be set to zero. 
If part of a void over a particular collection interval is missing due to spillage or accidental 
discarding, the Ae will still be calculated providing other samples have be collected within 
the interval. Where no other samples are collected within the interval the data will be set 
to missing for the purposes of the calculation of Ae, CumAe and CumFe. In both 
scenarios the data will be flagged to highlight a missing void. 
Imputation of non-numerical values reported in the urine and fecal data (i.e. 
concentrations that are not detected [ND]) will be entered as zero for calculation of 
parameters such as mean and SD. 
When converting urine collection weights to urine volume (if required), the following 
conversion factor will be used: 
1.02 g of urine = 1 mL of urine 
This will be calculated in SAS as follows: 
Urine weight (g) / 1.02 = Urine volume (mL) 
If total radioactivity concentrations in urine have been provided in mass unit/g units the 
following conversion (if required) will be performed using SAS: 
Concentration (mass units/g) * 1.02 = Concentration (mass units/mL) 


    
 
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The radioactivity associated with toilet paper may be determined with the approval of 
Genentech. The results will be reported for each subject as a single value for the whole 
collection period and included in the calculation of total amount excreted and % of dose 
recovered. Accidental sources of elimination, e.g., emesis, will be collected and sent 
for total radioactivity analysis. This will be reported on a case by case basis and details 
will be included in the documentation of the mass balance population. 
9.1.3 
Mass Balance Summary Tables 
Summary statistics (i.e. n, mean, SD, CV%, minimum, median and maximum) will be 
presented for amount excreted (Ae) and recovery (Fe) by collection period (including 
interpolated periods which will be marked with a #) for the following: 
• 
Urine [i.e. Ae(urine) and Fe(urine)] for total radioactivity 
• 
Feces [i.e. Ae(feces) and Fe(feces)] for total radioactivity 
• 
Urine and feces combined [i.e. Ae(total) and Fe(total)] for total radioactivity 
In addition, summary statistics (i.e. n, mean, SD, CV%, minimum, median and maximum) 
will be presented for the cumulative excretion and cumulative recovery by collection 
period (including interpolated periods which will be marked with a #) for each of the 
following:  
• 
Urine [i.e. CumAe(urine) and CumFe(urine)] for total radioactivity 
• 
Feces [i.e. CumAe(feces) and CumFe(feces)] for total radioactivity 
• 
Urine and feces combined [i.e. CumAe(total) and CumFe(total)] for total radioactivity 
Imputation of non-numerical values reported in the urine and fecal data set (i.e. 
concentrations that are ND) will be entered as zero for calculation of statistics such as 
mean and SD.  
Finally, summary statistics (i.e. n, mean, SD, CV%, minimum, median and maximum) 
will be presented for the cumulative excretion and cumulative recovery for the study as 
a whole for each of the following: 
• 
Urine [i.e. CumAe(urine) and CumFe(urine)] for total radioactivity 
• 
Feces [i.e. CumAe(feces) and CumFe(feces)] for total radioactivity 
• 
Urine and feces combined [i.e. CumAe(total) and CumFe(total)] for total radioactivity 
If any subject withdraws prior to the end of a study visit or if subjects have differing 
collection intervals [(e.g. Day 10 for some subjects and Day 14 for others)] then a last 
observation carried forward (LOCF) approach will be used whilst calculating cumulative 
Ae and Fe (i.e. CumAe and CumFe), where the last observed value will be carried 
forward to the subsequent time point. The number of subjects included at each collection 
interval will therefore remain the same regardless of subject withdrawals. The LOCF 
approach will be used for all summary tables detailed above. 
9.1.4 
Mass Balance Figures 
Mean mass balance figures will be presented for the mass balance analysis set. 


    
 
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Mean cumulative excretion (i.e. CumAe) and cumulative recovery (i.e. CumFe) vs time 
curves will be produced on a linear/linear scale and will include ± SD bars. These plots 
will be produced for CumAe and CumFe, respectively, with urine, feces and total 
overlaid: 
• 
Urine [i.e. CumAe(urine) and CumFe(urine)] for total radioactivity 
• 
Feces [i.e. CumAe(feces) and CumFe (feces)] for total radioactivity 
• 
Urine and feces combined [i.e. CumAe(total) and CumFe(total)] for total radioactivity 
A legend identifying each profile (i.e. urine, feces and total) will be displayed on the mean 
plots. Figures will be produced using the LOCF imputation strategy (see Section 
9.1.3Error! Reference source not found. figures as required). figures as required). 
Spaghetti plots of individual cumulative excretion for CumAe(urine), CumAe(feces) 
and CumAe(total) against actual collection period after dosing will be produced on a 
linear/linear scale for total radioactivity. In addition, spaghetti plots of individual 
cumulative recovery for CumFe(urine), CumFe(feces) and CumFe(total) against actual 
collection period after dosing will be produced on a linear/linear scale for total 
radioactivity. Each subject’s profile will be represented on these plots with a different 
letter or symbol and a legend will be included on the plots to define the letters/symbols 
used. All enrolled subjects will be used for the provision of spaghetti plots. 
9.1.5 
Mass Balance Listings 
The sample collection data (e.g. collection intervals) for all urine and fecal samples will 
be listed. In addition, all total radioactivity concentrations, urine and fecal weights and all 
mass balance parameters will be listed on a per subject basis. The LOCF approach will 
be used for all cumulative mass balance parameters. Where LOCF values appear in the 
listings they will be flagged. In addition, where values were calculated for interpolated 
days these will be flagged. 
9.1.6 
Statistical Analysis of Mass Balance Parameters 
No formal statistical analysis is required for the mass balance data in this study. 
Descriptive statistics are considered adequate for a study of this type. 
9.2 
Pharmacokinetic Parameter Estimation and Reporting 
The PK parameters will be estimated where possible and appropriate for each subject 
profile by non-compartmental analysis methods using Phoenix WinNonlin software (v8.0 
or a more recent version, Certara USA, Inc., USA) for: 
• 
GDC-9545 in plasma and total radioactivity in plasma and whole blood in Part 1 
• 
GDC-9545 in plasma in Part 2 
Additional parameters may be calculated if required, depending on the data. 
9.2.1 
Definition of Pharmacokinetic Parameters 
Plasma and whole blood PK parameter definitions are provided in Table 5. 


    
 
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Table 5 
Plasma and Whole Blood Pharmacokinetic Parameter Definitions and 
Rounding Specifications 
Parameter 
Definition 
Unit 
DP or 
SF 
No. of 
DP/SF 
Cmax 
Maximum observed concentration 
ng/mL 
SF 
3 
tmax 
Time of maximum observed 
concentration 
h 
DP 
2 
AUC(0-t) 
Area under the curve from time 0 to 
the time of last measurable 
concentration 
ng.h/mL 
SF 
3 
AUC(0-inf) 
Area under the curve from time 0 
extrapolated to infinity  
ng.h/mL 
SF 
3 
%AUCextrap 
Area under the curve (AUC) from time 
of the last measurable concentration 
to infinity as a percentage of the area 
under the curve extrapolated to infinity 
% 
DP 
2 
t1/2  
Terminal elimination half-life 
h 
DP 
2 
lambda-z 
First order rate constant associated 
with the terminal (log-linear) portion of 
the curve 
1/h 
DP 
4 
CL 
Total body clearance calculated after 
a single intravenous administration  
L/h 
SF 
3 
CL/F 
Total body clearance calculated after 
a single extravascular administration 
where F (fraction of dose bioavailable) 
is unknown  
L/h 
SF 
3 
Vz 
Volume of distribution based on the 
terminal phase calculated using 
AUC(0inf) after a single intravenous 
administration  
L 
SF 
3 
Vz/F 
Apparent volume of distribution based 
on the terminal phase calculated using 
AUC(0-inf) after a single extravascular 
administration where F (fraction of 
dose bioavailable) is unknown  
L 
SF 
3 
F 
Absolute bioavailability calculated 
using AUC(0-inf)  
% 
DP 
2 
Frel Cmax 
Relative bioavailability based on Cmax  
% 
DP 
2 
Frel AUC(0-t)  
Relative bioavailability based on 
AUC(0-t)  
% 
DP 
2 
Frel AUC(0-inf)  
Relative bioavailability based on 
AUC(0inf)  
% 
DP 
2 
WB:P AUC(0-inf)  
Total radioactivity blood to plasma 
concentration ratio based on AUC(0-
inf)  
N/A 
DP 
2 
lambda-z lower* 
Lower limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
lambda-z upper* 
Upper limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
DP=decimal places 
SF=significant figures 
*=these values should be listed but omitted from the descriptive statistics 
NA=not applicable 
Total radioactivity blood to plasma concentration ratios will also be determined (Part 1 
only). 
Dose will be used in the calculation of relevant PK parameters as per Table 6. 


    
 
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Table 6 
Pharmacokinetic Parameter Dose Specifications 
Dose Route 
Nominal/Actual 
Precision 
IV (Part 2, Treatment B only)  
Actual 
As received from Pharmaron 
Oral 
Nominal 
As per protocol  
 
Absolute bioavailability (F) will be calculated in Part 2 for individual subjects as follows: 
F = {AUC [GDC −9545](oral)
AUC [GDC −9545](IV) × Dose(IV)
Dose(oral)} × 100 
F will be calculated using AUC(0-inf). If for any reason the AUC(0-inf) is not calculable 
then an alternative or additional AUC over a partial area may be used to calculate F for 
all subjects. 
The following comparisons will be made:  
• 
GDC-9545/F12 capsule, 30 mg versus GDC-9545 intravenous infusion (absolute 
bioavailability) 
• 
GDC-9545/F18 capsule, 30 mg versus GDC-9545 intravenous infusion (absolute 
bioavailability) 
Relative bioavailability (Frel) will be calculated in Part 2 for individual subjects as follows: 
(Frel) will be calculated in Part 2 for individual subjects as follows: 
Frel = {
AUC or Cmax (test)
AUC or Cmax (reference)} × 100 
Frel will be calculated using Cmax, AUC(0-t) and AUC(0-inf). If for any reason the AUC(0-
inf) is not calculable then an alternative or additional AUC over a partial area may be 
used to calculate Frel for all subjects. 
The following comparison will be made:  
• 
GDC-9545/F18 capsule, 30 mg (test) versus GDC-9545/F12 capsule, 30 mg 
(reference) [relative bioavailability] 
Ratio of GDC-9545 AUC(0-inf) over total radioactivity AUC(0-inf) will be calculated in 
Part 1 for individual subjects as follows: 
AUC(0 −inf)[GDC −9545]
AUC(0 −inf)[Total radioactivity] 
 
Total radioactivity blood to plasma ratios based on AUC(0-inf) will be calculated in Part 
1 for individual subjects as follows: 
AUC(0 −inf)[whole blood total radioactivity]
AUC(0 −inf)[plasma total radioactivity]
 


    
 
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If for any reason the AUC(0-inf) is not calculable then an alternative or additional AUC 
over a partial area may be used to calculate ratio of plasma total radioactivity over whole 
blood total radioactivity. 
Total radioactivity blood to plasma ratios will be determined using SAS by the Lead 
Statistical Programmer (or designee) at the time points defined in the protocol. If either 
the blood or plasma concentration values are BLQ at any given timepoint the ratio will 
not be calculated. 
When converting blood collection weights to blood volume (if required) for the calculation 
of the whole blood:plasma ratio, the following conversion factor will be used: 
1.06 g of blood = 1 mL of blood 
This will be calculated in SAS as follows: 
Blood weight (g) / 1.06 = Blood volume (mL) 
Alternatively, where total radioactivity concentrations in blood have been provided in 
mass unit/g units the following conversion will be performed using SAS: 
Concentration (mass units/g) * 1.06 = Concentration (mass units/mL) 
9.2.2 
Rules for Pharmacokinetic Parameter Estimation using WinNonlin 
The imputation of non-numerical (e.g. below the limit of quantification [BLQ] or below the 
level of detection [LOD]) or negative values (e.g. pre-dose sampling times) reported in 
the input data set will be performed as follows for calculation of PK parameters: 
• 
Pre-dose sample times will be entered as zero 
• 
Values that are BLQ* obtained prior to Cmax will be entered as zero 
• 
Values that are BLQ* after Cmax will be treated as missing but where BLQ 
concentrations are defined as parameters these will be reported as BLQ 
• 
Values that are BLQ* after Cmax may be imputed as zero for the calculation of partial 
AUCs, in cases where lambda-z cannot be determined 
• 
Values that are measurable after at least 2 consecutive BLQ* values after Cmax will 
be treated as missing for the calculation of PK parameters 
• 
Values that are reported as “No Result” or “Not Reportable” (NR), “Not Calculated” 
(NC) or “No Sample” (NS) etc. will be generally be considered missing 
* values that are reported as below the LOD will be treated in the same way as samples 
reported as BLQ. 
Missing or unusual concentration values in the input data may be queried to ascertain 
any underlying cause. Exclusion of missing or unusual concentration values, or repeat 
bioanalysis of samples, will only be performed if a definitive root cause can be 
established and approval from Genentech has been obtained. Any exclusions of 
concentration values or repeat analysis of samples will be documented appropriately.  


    
 
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Plasma and whole blood PK parameters will be estimated using standard Phoenix 
WinNonlin methods, details of which may be found in the documentation accompanying 
the WinNonlin software package. The rules specified in Table 7 will be applied: 
Table 7 
Pharmacokinetic Parameter Estimation Details 
Sampling times 
Actual for oral doses  
Actual (relative to start of infusion) for IV doses 
 
Calculation method 
Linear up log down 
Number of points used for lambda-z 
At least 3, not including Cmax 
Minimum requirements for AUC  
At least 3 consecutive measurable concentrations 
 
Prior to PK parameter estimation the bioanalytical data of GDC-9545 for Part 1 may be 
corrected to account for the proportion of administered 14C material not measured due 
to the use of a 12C LC-MS/MS analysis method. Data correction will only be performed if 
the 14C contribution exceeds 1% of the dose administered. GDC-9545 bioanalytical data 
will be multiplied by the determined data correction factor in SAS. 
Where possible, the terminal elimination rate constant (lambda-z) will be calculated for 
all subject profiles. The value of lambda-z will be determined by the slope of the 
regression line of the natural log transformed concentrations vs time.  
The WinNonlin determined choice of data points for determination of lambda-z will be 
reviewed by the pharmacokineticist who may adjust the selection in order to provide a 
more appropriate fit. The choice of data points for determination of lambda-z for each 
profile will be confirmed following a documented peer review.  
9.2.3 
Pharmacokinetic Parameter Reporting Specifications 
The following parameters will be reported for each study part, treatment, analyte and 
matrix as applicable, according to the rounding specifications provided in Table 5: 
Part 1 - following oral administration of 14C-GDC-9545 (plasma GDC-9545): 
• 
Cmax, Tmax, AUC(0-t), AUC(0-inf), AUCextrap, T1/2, lambda-z, CL/F, Vz/F, 
lambda-z lower, lambda-z upper 
Part 1 - following oral administration of 14C-GDC-9545 (total radioactivity in plasma and 
whole blood): 
• 
Cmax, Tmax, AUC(0-t), AUC(0-inf), AUCextrap, T1/2, lambdaz, WB:P AUC(0inf) 
[whole blood only], lambdaz lower, lambdaz upper 
Part 2 - following IV administration (plasma GDC-9545): 
• 
Cmax, Tmax, AUC(0-t), AUC(0-inf), AUCextrap, T1/2, lambda-z, CL, Vz, lambdaz 
lower, lambdaz upper 


    
 
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Part 2 - following oral administrations (plasma GDC-9545): 
• 
Cmax, Tmax, AUC(0-t), AUC(0-inf), AUCextrap, T1/2, lambda-z, CL/F, Vz/F, F, Frel 
Cmax, Frel AUC(0-t), Frel AUC(0-inf) , lambdaz lower, lambdaz upper 
The flags/footnotes given in Table 8 will be applied to the PK parameters where relevant 
and will be shown in PK parameter listings. Additional flags may be applied based on 
emerging data. 
Table 8 
Pharmacokinetic parameter Flags and Footnotes 
Flag 
Footnote 
a 
Adjusted rsq of regression (the goodness of fit statistic for the elimination phase) was <0.9  
b 
Period used for regression analysis was less than 2-fold the calculated half-life 
c 
Extrapolated portion of AUC(0-inf) >20% 
d 
Insufficient post-Cmax data points for estimation of lambda-z 
e 
Entire profile BLQ, no PK parameters could be calculated 
f 
Fewer than 3 consecutive measurable concentrations, AUCs not calculated 
g 
Measurable pre-dose values were observed, however were considered less than 5 % of 
Cmax  
In the event that the adjusted rsq of regression was <0.9 (“a” flag) then lambda-z and 
parameter estimates derived using lambda-z and AUC(0inf) will be deemed unreliable 
and will be flagged and listed but excluded from the summary statistics and statistical 
analysis (Part 2 only). 
In the event that the time period used for regression analysis was less than 2-fold the 
calculated half-life (“b” flag) T1/2 will be flagged, listed, and included in summary 
statistics. 
In the event that the extrapolated portion of AUC(0-inf) >20% (“c” flag), then AUC(0-inf) 
and parameter estimates derived using AUC(0inf) will be deemed unreliable and will be 
flagged and listed but excluded from the summary statistics and statistical analysis (Part 
2 only). 
In the event that there are insufficient post-Cmax data points for estimation of lambda-z 
(“d” flag) then lambda-z and parameter estimates derived using lambda-z and AUC(0inf) 
will be reported as ‘NC’. 
In the event that there are fewer than 3 consecutive measurable concentrations (“f” flag) 
then all AUC parameter estimates will be reported as NC. 
In the event that measurable pre-dose values less than 5% of Cmax were observed 
(“g” flag), all parameter estimates for the profiles affected will be listed, flagged and 
included in summary statistics and formal statistical analysis (Part 2 only).  
Note: in the event that measurable pre-dose concentrations greater than 5% of Cmax 
are observed, requirements for additional flags and further action will be agreed with 
Genentech and documented at the same time as the PK population. 


    
 
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9.2.4 
Bioanalytical and Pharmacokinetic Summary Tables 
Summary statistics (i.e. n, mean, SD, CV%, median, minimum, maximum, geometric 
mean, geometric SD and geometric CV%) of concentration data will be calculated for the 
following analytes/matrices by treatment. The number of BLQ values (n#) per time point 
will also be presented. Geometric statistics will not be calculated for Day 1, pre-dose 
concentrations.  
• 
Plasma concentrations of GDC-9545 by time point  
• 
Plasma concentrations of total radioactivity by time point (Part 1 only) 
• 
Whole blood concentrations of total radioactivity by time point (Part 1 only) 
• 
Whole blood:plasma concentration ratio of total radioactivity by time point (Part 1 
only) 
Summary statistics (i.e. n, mean, SD, CV%, median, minimum and maximum) of plasma 
and whole blood PK parameters will be calculated for GDC-9545 (plasma only) and total 
radioactivity (where applicable) by treatment. Geometric mean, geometric SD and 
geometric CV% will be presented for all plasma and whole blood PK parameters except 
Tmax.  
Non-measurable values reported in the plasma and whole blood concentration data (i.e. 
values that are BLQ), will be entered as zero for the determination of summary statistics 
with the exception of geometric means, geometric SD and geometric CV%, where BLQ 
values will be imputed as half the lower limit of quantification (LLOQ) value. This also 
applies to any concentrations that are defined as PK parameters. Data recorded as NR, 
NS or NC will be handled as missing (i.e. no assumption will be made about the actual 
concentration). 
9.2.5 
Bioanalytical and Pharmacokinetic Figures 
Mean, spaghetti and individual plasma and whole blood concentration vs time plots will 
be produced on both the linear/linear scale and on log10/linear scale.  
For all plots on a linear/linear scale, post-dose concentration values reported as BLQ will 
be set to zero, up to the point at which all concentrations fall below BLQ, after which they 
will be presented as missing.  
For all plots on a log 10/linear scale, post-dose concentration values reported as BLQ 
will be set to half the BLQ value, up to the point at which all concentrations fall below 
BLQ, after which they will be presented as missing.  
Where curves from multiple treatment regimens or subjects are overlaid on the same 
plot, symbols will be used to identify different subjects/ treatment regimens and a legend 
will be included on the plots to define the symbols used. 
Mean plasma and whole blood concentration vs time plots (using nominal times) will be 
produced for: 
• 
Whole blood and plasma concentrations of total radioactivity on same plot (Part 1) 
• 
Plasma concentrations of GDC-9545 and total radioactivity on the same plot (Part 1) 


    
 
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• 
Plasma concentrations of GDC-9545 for the oral dose(s) and IV dose on the same 
plot (Part 2) 
These will be produced as follows: 
• 
Linear/linear scale using arithmetic mean concentrations (error bars ± arithmetic SD) 
• 
Log10/linear scale using geometric mean concentrations (error bars x/÷ geometric 
SD) 
Separate concentration vs time spaghetti plots (using actual sampling time after dosing) 
will be produced for each treatment and analyte (where applicable) with each plot 
displaying 1 line per subject. 
Individual concentration vs time plots (using actual sampling times after dosing) will be 
produced separately for each individual subject with all treatments and analytes/matrices 
(where applicable) on the same plot. 
9.2.6 
Bioanalytical and Pharmacokinetic Listings 
The sample collection data (e.g. collection times) for PK samples will be listed. In 
addition, all concentration data and PK parameters will be listed on a per subject basis. 
Any flags used will be included as a footnote with the appropriate definition. 
9.2.7 
Statistical Analysis of Pharmacokinetic Parameters 
No formal statistical analysis will be carried out on Part 1 data. 
Part 2 
Absolute Bioavailability 
Formal statistical analysis will be performed on the PK parameter AUC(0-inf). AUC(0inf) 
will undergo a natural logarithmic transformation and will be analyzed using mixed effect 
modelling techniques. The model will include terms for treatment and sequence fitted as 
fixed effects and subject nested within sequence as a random effect (i.e., assuming a 
compound symmetry covariance structure). The following treatment comparisons (test 
versus reference) are of interest: 
• 
GDC-9545/F12 Capsule (test) compared to GDC-9545 IV dose (reference) 
• 
GDC-9545/F18 Capsule (test) compared to GDC-9545 IV dose (reference) 
Only subjects who received and have reliable estimates of AUC(0-inf) for at least the 
reference IV dose and one of the test capsules will be included in the statistical analysis.  
If the number of subjects with reliable estimates of AUC(0-inf) for any comparison falls 
below the planned number of evaluable subjects, then consideration will be given as to 
whether formal statistical analysis will be performed or if an alternative AUC parameter 
will be used. 
The adjusted means including differences from the comparisons and their associated 
90% CIs obtained from the model will be back transformed on the log scale to obtain 


    
 
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adjusted geometric means, adjusted geometric mean ratios (GMRs) and 90% CIs of the 
ratios. GMRs and 90% CIs for each comparison will be presented. 
In addition, intra-subject variability values (denoted as CVw in the results table) will also 
be presented. 
The intra-subject variability values will be calculated for all treatments combined and are 
obtained from the residual term from the SAS Software output. These values are 
calculated as follows: 
CVw = 100 x (exp(Mean Square Error) -1)1/2 
The statistical analysis will be performed using actual treatment received. The model will 
be fitted using the SAS Software procedure PROC MIXED, the method will specified as 
Restricted Maximum Likelihood and the denominator degrees of freedom for the fixed 
effects will be calculated using Kenward and Roger’s method [1]. The following is an 
example of the SAS Software code that will be used: 
PROC MIXED DATA=<input dataset name> METHOD=REML ORDER=INTERNAL; 
 
CLASS SUBJIDN TRTAN TRTSEQPN; 
 
MODEL LVAR = TRTAN TRTSEQPN / OUTP=PRED DDFM=KR; 
 
RANDOM SUBJIDN(TRTSEQPN); 
 
ESTIMATE <relevant pairwise treatment comparisons> / CL ALPHA=0.10; 
 
LSMEANS TRTAN / ALPHA=0.10; 
 
ODS OUTPUT LSMEANS=MEANS ESTIMATES=EST COVPARMS=CVW; 
RUN; 
where 
• 
LVAR is the natural log transformed PK parameter of interest 
• 
SUBJIDN is the numeric subject identifier variable 
• 
TRTSEQPN is the numeric sequence variable for the planned sequence received  
• 
TRTAN is the numeric treatment variable for the actual treatment received   
Relative Bioavailability 
Formal statistical analysis will be performed on the PK parameters Cmax, AUC(0-t) and 
AUC(0-inf). The PK parameters will undergo a natural logarithmic transformation and will 
be analyzed using mixed effect modelling techniques. The model will include terms for 
treatment, sequence and period fitted as fixed effects and subject nested within 
sequence as a random effect (i.e., assuming a compound symmetry covariance 
structure). The null hypothesis is that there is no difference between GDC-9545/F18 
(test) and GDC-9545/F12 (reference). 
Only subjects with parameters for both treatments will be included in the statistical 
analysis. 
The adjusted means including differences from the comparisons and their associated 
90% CIs obtained from the model will be back transformed on the log scale to obtain 
adjusted geometric mean ratios (GMRs) and 90% CIs of the ratios. GMRs and 90% CIs 
for each comparison will be presented. 


    
 
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In addition, p-values associated with the treatment comparison and CVw values will also 
be presented. The intra-subject variability values will be calculated for both treatments 
combined using the formula shown above (i.e. absolute bioavailability). 
The fixed effects table from the model with F-statistic and p-value for the relevant effects 
will be presented in a separate table. 
The statistical analysis will be performed using actual treatment received and planned 
sequence. The model will be fitted using the SAS Software procedure PROC MIXED, 
the method will specified as Restricted Maximum Likelihood and the denominator 
degrees of freedom for the fixed effects will be calculated using Kenward and Roger’s 
method [1]. The following is an example of the SAS Software code that will be used: 
PROC MIXED DATA=<input dataset name> METHOD=REML ORDER=INTERNAL; 
 
CLASS SUBJIDN TRTAN APERIODN TRTSEQPN; 
 
MODEL LVAR = TRTAN APERIODN TRTSEQPN/ OUTP=PRED DDFM=KR; 
 
RANDOM SUBJIDN(TRTSEQPN); 
 
ESTIMATE <relevant pairwise treatment comparisons> / CL ALPHA=0.10; 
 
LSMEANS TRTAN / ALPHA=0.10; 
 
ODS OUTPUT LSMEANS=MEANS ESTIMATES=EST COVPARMS=CVW; 
RUN; 
where 
• 
LVAR is the natural log transformed PK parameter of interest 
• 
SUBJIDN is the numeric subject identifier variable 
• 
APERIODN is the numeric period variable 
• 
TRTAN is the numeric treatment variable for the actual treatment received  
• 
TRTSEQPN is the numeric sequence variable for the planned sequence received  
If there are any deviations from the planned treatment or sequence, then the analysis 
models specified above or methods of analysis may be re-evaluated, as appropriate. 
Details of any deviations from the planned analysis will be documented in the CSR. 
For each analysis, distributional assumptions underlying the statistical analyses will be 
assessed by visual inspection of residual plots. Normality will be examined by normal 
probability plots, while homogeneity of variance will be assessed by plotting the residuals 
against the predicted values for the model. If the distributional assumptions for the 
parametric approach are not satisfied, then additional sensitivity analyses may be 
performed including the removal of potential outliers or the use of non-parametric 
methods to assess the robustness of the original analysis. This will be documented in 
the CSR together with the reasoning supporting the most appropriate action taken, if 
applicable. In general terms the results of the original analysis will always be presented 
in the CSR. 
10 Safety Assessments 
Safety data summaries will be presented by actual treatment and the respectively safety 
analysis set will be used throughout.  
Separate summary tables and listings will be produced for each study part. 


    
 
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10.1 
Extent of Exposure and Treatment Compliance 
The total dose given (as measured in mg) and the TR dose (as measured in MBq and 
microcurie [µCi]) will be summarized (i.e., n, mean, SD, median, minimum and maximum) 
in Part 1. 
The number and percentage of subjects dosed with IMP will be summarized for each 
treatment and overall in Part 2. 
Dosing details (including the date and time of all IMP administrations and any comments) 
will be listed for all enrolled subjects. Any recorded deviations from the planned dosing 
treatment will be listed as protocol deviations. 
10.2 
Meal Details 
Meal details as recorded on the eCRF will be listed for all enrolled subjects of the 
respectively study part. Any recorded deviations from the planned meal times will be 
listed as protocol deviations. 
10.3 
Adverse Events 
Throughout the study, all adverse events (AE) will be evaluated by the PI and noted in 
the AE section of the eCRF. An AE is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product, regardless of causal 
attribution. Adverse events that occur before dosing which is not considered serious will 
not be included in the database and hence, will not be reported. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v23.1 
or more recent version), and reported by SOC and PT. 
For Part 2, AEs will be assigned to the treatment of the period in which the AE first 
occurred. Where the severity of an AE intensifies or symptoms change in a subsequent 
period, this will be defined as a new AE and included under the treatment associated 
with the subsequent period. Adverse events that occur during the washout period will 
be assigned to the treatment the subject received during the period immediately before 
the washout period. 
An IMP-related AE is any AE where a causal relationship with the IMP is at least a 
reasonable possibility. When considering their relationship to IMP, AEs will be 
classified as follows 
• 
“YES” (i.e., there is a plausible temporal relationship between the onset of the 
adverse event and administration of the study drug, and the adverse event cannot 
be readily explained by the subject's clinical state, intercurrent illness, or concomitant 
therapies; and/or the adverse event follows a known pattern of response to the study 
drug; and/or the adverse event abates or resolves upon discontinuation of the study 
drug or dose reduction and, if applicable, reappears upon re-challenge.) 
• 
“NO” (i.e., evidence exists that the adverse event has an etiology other than the study 
drug [e.g., pre-existing medical condition, underlying disease, intercurrent illness, or 
concomitant medication]; and/or the adverse event has no plausible temporal 
relationship to administration of the study drug [e.g., cancer diagnosed 2 days after 
first dose of study drug]). 


    
 
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The severity of AEs will be assessed according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE, v5.0) grading scale when 
considering their initial and maximum severity separately. All summary tables will be 
based on maximum severity but relevant listings will include both initial and maximum 
severity: The same grading scale for events listed in NCI CTAE and those not specifically 
listed in NCI CTCAE will be used, see below: 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age 
appropriate instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
livingb, c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to AEd 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, 
using the toilet, and taking medications, as performed by subjects who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious AE. 
d Grade 4 and 5 events must be reported as serious AEs. 
If the severity or relationship to IMP of a AE is missing, the severity/relationship will be 
tabulated as “missing” in the summary tables. 
Where the start date of an AE is missing and the stop date is on or after the day of first 
dose of IMP or both the start and stop dates are missing then a “worst-case” scenario 
will be assumed, i.e., the AE is assumed to have occurred post-dose. If a partial start 
date/time is available, then the event will be considered to have occurred post-dose 
unless the partial information suggests otherwise. 
10.3.1 
Summary Tables for Adverse Events 
Any AEs which occurred pre-dose will be excluded from the summary tables but will be 
listed.   
Descriptive statistical methods will be used to summarize the AE data.  
AEs with the following preferred terms will be combined and presented together: 
• 
“sinus bradycardia” and “bradycardia” 
• 
“neutropenia” and “neutrophil count decreased” 
• 
“thrombocytopenia” and “platelet count decreased” 
• 
“thrombocytosis” and “platelet count increased” 
• 
“leukopenia” and “leukocyte count decreased” 
• 
“leukocytosis” and “leukocyte count increase”  


    
 
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The number and percentage of subjects reporting each AE will be summarized for both 
SOC and PT. For summaries by SOC and PT, with the exception of AEs by severity and 
relationship to IMP, the number of subjects and the number of events will be summarized. 
For summaries by severity and relationship only the number of subjects will be 
summarized. 
For counts of subjects experiencing events the following will apply: 
• 
a subject experiencing AEs in more than one body system, within a study part/period, 
will be counted once in the total number of subjects with AEs in that study part/period;  
• 
a subject with more than 1 AE in the same SOC, within a study part/period, counts 
only once at the SOC level; 
• 
a subject with more than 1 AE in the same PT, within a study part/period, counts only 
once at the PT level; 
• 
a subject with either or both PT for the combined preferred terms, within a study 
part/period, counts only once at the combined PT level. 
For event counts, all events are included. 
When it is necessary to calculate percentages, the denominator will be the total number 
of subjects in the safety analysis set for that treatment or study part/period and the 
numerator will be the total number of subjects reporting a AE within the relevant category. 
Summaries presented for SOC and PT will be presented in descending order of 
frequency overall i.e., most frequently reported SOC in the study part and then by most 
frequently reported PT in the study part within each SOC. 
10.3.1.1 
Overall Summary of Adverse Events 
The following will be summarized by treatment and overall (Part 2 only) for the safety 
analysis set: 
• 
number and percentage of subjects reporting at least 1 AE 
• 
number and percentage of subjects reporting at least 1 Grade 3 AE 
• 
number and percentage of subjects reporting at least 1 Grade 4 AE 
• 
number and percentage of subjects reporting at least 1 IMP-related AE  
• 
number and percentage of subjects reporting at least 1 AE of special interest 
• 
number and percentage of subjects reporting at least 1 serious AE 
• 
number and percentage of subjects reporting at least 1 AE leading to IMP withdrawal 
• 
number and percentage of subjects reporting at least 1 Grade 5 AE  
• 
total number of AEs 
• 
total number of Grade 3 AEs 
• 
total number of Grade 4 AEs 
• 
total number of IMP-related AEs 
• 
total number of AEs of special interest 
• 
total number of serious AEs 
• 
total number of AEs leading to IMP withdrawal 
• 
total number of Grade 5 AEs  


    
 
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10.3.1.2 
Summary of Adverse Events  
All subjects reporting AEs will be summarized by treatment. Counts will be given for 
number of subjects and number of events. Subjects experiencing more than 1 AE within 
a treatment will be counted only once for number of subjects but will be counted more 
than once for number of events.  
Additionally, subjects reporting AEs will be summarized for SOC and PT treatment. 
Counts will be given for number of subjects and number of events. For programming 
purposes counts of number of subjects will be by maximum severity i.e., subjects 
experiencing more than 1 episode of a AE within a treatment will be counted only once 
within each SOC and PT using the most severe episode.  
10.3.1.3 
Summary of Adverse Events by Severity 
All subjects reporting AEs will be summarized by severity and treatment. Counts will be 
given for number of subjects, not number of events. Counts will be given by maximum 
severity (i.e., subjects experiencing more than 1 AE within a treatment will be counted 
only once using the most severe episode). 
Additionally, subjects reporting AEs will be summarized for SOC and PT by maximum 
severity and treatment. Counts will be given for total number of subjects, not for events. 
Counts by maximum severity will be given (i.e., subjects experiencing more than 1 AE 
within a treatment will be counted only once within each SOC and PT using the most 
severe episode). 
10.3.1.4 
Summary of Adverse Events by Relationship to IMP 
All subjects reporting AEs will be summarized by relationship to IMP and treatment. 
Counts will be given for number of subjects, not number of events. Counts will be given 
by the closest relationship to IMP (i.e., subjects experiencing more than 1 AE within a 
treatment will be counted only once using the most closely related event). 
Additionally, subjects reporting AEs will be summarized for SOC and PT by closest 
relationship to IMP and treatment. Counts will be given for total number of subjects, not 
for events. Counts by closest relationship will be given (i.e., subjects experiencing more 
than 1 AE within a treatment will be counted only once within each SOC and PT using 
the most closely related event). 
10.3.1.5 
Summary of Adverse Events of Special Interest 
All subjects reporting AEs of special interest will be summarized by treatment. Counts 
will be given for number of subjects and number of events. Subjects experiencing more 
than one AE of special interest within a treatment will be counted only once for number 
of subjects but will be counted more than once for number of events. 
Additionally, subjects reporting AEs of special interest will be summarized for SOC and 
PT by treatment. Counts will be given for number of subjects and number of events. For 
programming purposes counts of number of subjects will be by maximum severity i.e., 
subjects experiencing more than one episode of an AE of special interest within a 
treatment will be counted only once within each SOC and PT using the most severe 
episode. 


    
 
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10.3.1.6 
Summary of Serious Adverse Events 
All subjects reporting serious adverse events (SAEs) will be summarized by treatment. 
Counts will be given for number of subjects and number of events. Subjects experiencing 
more than one SAE within a treatment will be counted only once for number of subjects 
but will be counted more than once for number of events.  
Additionally, subjects reporting SAEs will be summarized for SOC and PT by treatment. 
Counts will be given for number of subjects and number of events. For programming 
purposes counts of number of subjects will be by maximum severity i.e., subjects 
experiencing more than one episode of a SAE within a treatment will be counted only 
once within each SOC and PT using the most severe episode.  
10.3.2 
Listings for Adverse Events 
A separate data listing of all post-dose AEs will be provided including the SOC and PT. 
In addition, listings of all AEs of special interest and SAEs (including pre-dose SAE if 
applicable) will be provided. 
In addition to the data recorded in the database, the listing will include derived onset and 
duration in days for TEAEs only. The onset will be calculated respective of last dose prior 
to TEAE and as follows: 
𝑂𝑛𝑠𝑒𝑡 (𝑑𝑎𝑦𝑠) = 𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑇𝐸𝐴𝐸−(𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑟 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒) + 1 
The duration will be calculated as follows: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝐸𝑛𝑑 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑇𝐸𝐴𝐸−𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑇𝐸𝐴𝐸+ 1 
Should the TEAE be ongoing or the end date of TEAE be missing, the end date of 
TEAE will be taken to be the date of last study contact for the subject concerned and 
the value will be presented as “ > X days”. For the calculation of onset and duration will 
be set to NC where the start date of TEAE is missing.   
10.4 
Laboratory Evaluations 
The details of sample collection for laboratory safety analysis are described in the study 
protocol. 
Where a value is provided by the safety laboratory as either above or below the limit of 
detection (LOD) this will be set to the respective LOD itself for descriptive summaries. 
The individual listings will show these as <X or >X, where X represents the lower or upper 
LOD. 
10.4.1 
Summary Tables for Laboratory Evaluations 
Hematology and coagulation, and clinical chemistry data will be summarized (n, mean, 
SD, median, minimum and maximum) for each laboratory parameter at each time point, 
including changes from baseline (Day -1, Period 1) at each postbaseline time point by 
treatment. 


    
 
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Shift tables from baseline to each scheduled postbaseline time point (with respect to the 
number and percentage of subjects with values below, within or above the reference 
range) will be presented by treatment. Percentages will be based on the number of 
subjects with measurements at baseline and the relevant postbaseline time point. 
Reference ranges for each laboratory parameter will be presented for the relevant 
parameter in each summary table. 
10.4.2 
Listings for Laboratory Evaluations 
The sample collection data (e.g., collection times) for laboratory analysis and urinalysis 
data will be listed. 
All individual subject data, for planned hematology and coagulation, clinical chemistry 
and urinalysis data including derivations, such as change from baseline, will be listed. If 
applicable, data from unscheduled laboratory tests will also be listed and flagged with a 
“#” to indicate it will not be used in the summary statistics. In these listings, individual 
data will be flagged with an “H” or an “L” for values that are higher or lower than their 
reference ranges, respectively. 
Separate listings of all hematology and coagulation, clinical chemistry and urinalysis 
values outside their reference ranges by subject will also be provided. References 
ranges will be supplied by the safety laboratory for hematology and clinical chemistry 
and per the eCRF for urinalysis (i.e., a positive or negative result) with the exception of 
the following reference ranges for urinalysis: 
• 
pH: 5.0 to 8.0 
• 
Specific gravity: 1.005 to 1.035 
10.5 
Vital Signs  
The details of measurement of supine vital signs are described in the study protocol. 
10.5.1 
Summary Tables for Vital Signs 
Vital signs data (i.e., systolic and diastolic blood pressure [BP], pulse rate and oral 
temperature), including change from baseline (Day 1, Pre-dose of each treatment period) 
will be summarized (i.e., n, mean, SD, median, minimum and maximum) at each 
postbaseline time point by treatment. 
In addition, the number of subjects with ‘substantial’ increases (“INC”) or decreases 
(“DEC”) or no substantial change (“NONE”) from baseline in systolic BP (>±20 mmHg), 
diastolic BP (>±10 mmHg) and pulse rate (>±15 bpm) will be summarized. 
10.5.2 
Listings for Vital Signs 
All individual vital signs data (i.e., systolic and diastolic BP, pulse rate and oral 
temperature) data will be listed, including change from baseline. Individual data will be 
flagged with an “H” or an “L” for values that are higher or lower than their reference 
ranges, respectively, and subjects with ‘substantial’ increases or decreases from 
baseline (as defined in Section 10.5.1) in systolic BP, diastolic BP and pulse rate will be 
flagged with an “I” (increase) or “D” (decrease), respectively. If applicable, data from 


    
 
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unscheduled vital signs assessments will also be listed and flagged with a “#” to indicate 
it will not be used in the summary statistics. 
In addition, a separate listing of all vital signs data outside their reference ranges by 
subject will also be provided. 
The reference ranges (from Quotient SOP “The Interpretation of the Electrocardiogram, 
Vital Signs and Clinical Laboratory Data During Phase I / II Clinical Trials” defined in 
Table 9 will be used.  
Table 9 
Vital Signs Reference Ranges 
Parameter 
Split 
Lower limit 
Upper limit 
Systolic BP 
18-45 years 
90 mmHg 
140 mmHg 
Systolic BP 
>45 years 
90 mmHg 
160 mmHg 
Diastolic BP 
NA 
50 mmHg 
90 mmHg 
Pulse rate 
NA 
51 bpm 
100 bpm 
Oral Body Temperature 
NA 
35.5ºC 
37.5ºC 
NA=Not applicable 
10.6 
ECGs 
The details of measurement of supine ECG parameters (i.e., ventricular rate, RR interval, 
uncorrected QT interval, QTcF interval, PR interval, QRS interval, QRS axis, rhythm and 
interpretation) are described in the study protocol. ECG parameters will be reported in 
the order given above i.e., both summary tables and data listings. 
10.6.1 
Summary Tables for ECGs 
ECG data, including change from baseline (Day 1, Pre-dose of each treatment period), 
will be summarized (i.e., mean, SD, median, minimum, maximum and n) at each 
postbaseline time point by treatment. 
The number and percentage of subjects with normal and prolonged QT intervals 
corrected for heart rate using Fridericia’s correction (i.e., QTcF) and increases in QTcF 
intervals from baseline within the categories defined in Table 10 (based on the 
International Council on Harmonization [ICH] E14 guideline [2]) will be summarized by 
time point. Percentages will be based on the number of subjects with measurements at 
the relevant time point.   
Table 10 
ICH E14 Ranges for QTcF Intervals 
Parameter 
ICH E14 Range 
QTcF interval 
≤450 msec (normal) 
451-480 msec 
481-500 msec 
>500 msec 
Increase in QTcF interval from 
baseline 
<30 msec 
30-60 msec 
>60 msec 
10.6.2 
Listings for ECGs 
All ECG measurements, including derivations such as change from baseline will be 
listed.  


    
 
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All ECG measurements will be flagged with an “H” or an “L” for values that are higher or 
lower than their reference ranges, respectively. If applicable, data from unscheduled 
ECG assessments will also be listed and flagged with a “#” to indicate it will not be used 
in the summary statistics. 
In addition, subjects with increase in QTcF interval from baseline (30-60 msec) and with 
‘substantial increases’ (>60 msec) will be flagged with ‘I’ and ‘SI’, respectively. 
A separate listing of all ECG parameters outside their reference range by subject will 
also be provided. 
The reference ranges taken from the exclusion criteria of the protocol for ventricular rate 
and from Quotient SOP “The Interpretation of the Electrocardiogram, Vital Signs and 
Clinical Laboratory Data During Phase I / II Clinical Trials” for all other ECG parameters, 
as defined in Table 11, will be used, apart from the reference range for RR interval (msec) 
which is calculated by the following formula: 
RR interval =
60000
heart rate 
Table 11 
ECG Reference Ranges 
Parameter 
Split 
Lower limit 
Upper limit 
Ventricular Rate (HR) 
NA 
51 bpm 
100 bpm 
RR Interval 
NA 
600 msec 
1176 msec 
QT Interval 
NA 
200 msec 
500 msec 
QTcF Interval  
Females 
NA 
470 msec 
PR Interval 
NA 
120 msec 
220 msec 
QRS Duration 
NA 
NA 
120 msec 
QRS Axis 
NA 
-30º 
100º 
Rhythm 
NA 
Sinus rhythm, 
Sinus bradycardia (rate dependent), 
Sinus arrhythmia 
HR=heart rate 
NA=Not applicable 
10.7 
Physical Examination  
All physical examination details and comments on any physical examination findings will 
be listed.  
11 Interim Statistical Analyses 
No interim statistical analysis is planned for this study. 
12 Changes in the Conduct of the Study or Planned Analysis 
12.1 
Changes in the Conduct of the Study 
No changes in the conduct of the study had been reported at the time this document was 
written. 
12.2 
Changes to the Planned Analyses 
For the formal statistical analysis of: 


    
 
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• 
Absolute bioavailability the fixed effect period has been replaced with sequence as a 
fixed effect in the mixed effects model since period and treatment are confounded as 
Treatment B is always given in period 1. 
• 
Relative bioavailability an additional fixed effect (i.e. sequence) has been included in 
the mixed effects model as the two treatments are given in a randomized manner. 
12.3 
Any Other Relevant Changes 
Not applicable. 
13 Overall Considerations 
13.1 
Statistical Programming and Analysis 
The Data Sciences Department at Quotient will perform the statistical programming and 
analysis to produce all analysis datasets, summary tables, figures and data listings using 
the statistical SAS Software v9.4. 
In general terms, categorical data will be presented using counts and percentages, while 
continuous variables will be presented using the n, mean, median, SD, minimum and 
maximum. For PK data additional statistics including CV%, geometric mean, geometric 
SD and geometric CV% will be presented, as appropriate.  
The geometric mean is obtained by applying a natural log transformation to the raw data, 
calculating the arithmetic mean of the transformed values and then back transforming 
the arithmetic mean. 
The following formula will be used to calculate the geometric SD: 
geometric SD = exp{SD[log(raw data)]} 
i.e., a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated, and then the arithmetic SD of the transformed values 
is back transformed. 
The following formula will be used to calculate the geometric CV%: 
geometric CV% = 100 × (exp{SD[(log(raw data)]}2 -1)1/2 
i.e., a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated. This value is then squared. The square value is back 
transformed and a value of 1 is subtracted from the back transformed value. A square 
root is then applied and the resulting value is multiplied by 100. 
In general summary statistics and statistical analysis results will be presented as detailed 
in Table 12, unless otherwise stated: 


    
 
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Table 12 Reporting Conventions for Summary Statistics and Statistical Analysis 
Data Type 
Statistic 
Number of decimal places for reporting (i) 
Frequency 
Counts (n) 
None 
Percentages (%) 
1 decimal place 
Summary statistic 
n 
None 
Mean 
i + 1 decimal places 
Median 
i + 1 decimal places 
SD 
i + 1 decimal places 
Min 
i decimal places 
Max 
i decimal places 
CV% 
1 decimal place 
Geometric n 
None 
Geometric Mean 
i + 1 decimal place 
Geometric SD 
i + 1 decimal places 
Geometric CV% 
1 decimal place 
Statistical analysis 
Ratios (%) 
2 decimal places 
Confidence intervals (%) 
2 decimal places 
p-values 
if <0.001: presented as <0.001 
if ≥0.001 and <0.099: presented to 3 decimal places 
all other p-values will be presented to 2 decimal places 
i refers to the number of decimal places reported in the eCRF or other appropriate source data for the original 
data. Where bioanalytical or PK data are received rounded in significant figures rather than decimal places, 
summary statistics will be supplied to the same precision. 
Details of how the individual PK parameters will be presented are detailed in Section 9.2 
Where data requires rounding, values ending with 1 to 4 will be rounded down and values 
ending with 5 to 9 will be rounded up. 
All data listings will be based on all enrolled subjects i.e., subjects who signed informed 
consent and have met the inclusion/exclusion criteria and were assigned a unique 
identification number (Part 1) or randomized (Part 2). Details of age and sex will be 
included on all data listings. 
All statistical tests relating to PK parameters will be 2-sided and will be performed using 
a 10% significance level, leading to 90% (2-sided) confidence intervals (CIs). 
If any baseline measurements are found to be missing then consideration will be given 
to imputation using the preceding time point (e.g., Screening, Admission, if applicable). 
Unscheduled assessment may be used if appropriate. Details of any such imputations 
will be documented as part of the safety analysis set. 
There will be no other imputations for the safety data with regard to missing values or 
study discontinuation (i.e., subjects who do not complete the study). Imputation for mass 
balance parameter estimation using SAS Software is described in Section 9.1.2, for PK 
parameter estimation using WinNonlin is described in Section 9.2.2. 
If partial dates are available for smoking history, prior medications or medical/surgical 
history, there will be no date imputations. The data listings will only show the date 
information for the date part that is available, e.g., if only the year part of the date is 
available then YYYY will be presented in the listing. If the full date information is missing, 
then this will be presented as missing on the data listing. 


    
 
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Separate summary tables, figures and data listings will be produced for Part 1 and Part 2 
of the study, respectively. The different parts will be identified by a subtitle indicating the 
relevant part. The text in the remainder of this document refers to both parts, unless 
specified otherwise. 
If all or part of this study is conducted during the Coronavirus disease 2019 [COVID-19] 
pandemic and there is evidence that data relating to primary and/or key secondary 
endpoints may have been affected in a way that may bias results, then sensitivity 
analyses may be conducted. Requirements for any sensitivity analyses will be 
documented at the same time as the related population (i.e. safety, mass balance or PK 
Concentration) and details of any sensitivity analyses which were carried out would be 
fully documented in the CSR. 
13.2 
Quality Control of Summary Tables, Figures and Listings and Statistical 
Analysis 
Isolated data errors detected as a result of the QC checks that are deemed significant 
(i.e., errors that would impact the interpretation of the results in relation to the study 
objectives) will be corrected as per the data management plan. Systematic data errors 
will be investigated further. The data will be corrected if necessary, and the appropriate 
table, figure, and/or listing re-generated and then rechecked. 
In addition to QC checks, a documented peer review will be performed of all SAS 
Software generated report standard summary tables, figures and data listings, including 
a review of SAS Software code and program log files. 
13.2.1 
Quality Control - Summary Tables 
Manual QC methods (i.e., comparison of results in the table to results calculated by a 
calculator or spreadsheet) will be used for all analyses and summary tables. All summary 
tables will be QC’d as follows: 
• 
where tables are presented by treatment/sequence (i.e., no time points), QC will 
alternate between treatment/sequence to avoid the same treatment/sequence being 
QC’d every time however, all summary statistics for that treatment/sequence will be 
checked 
• 
where tables are presented by treatment and time point, QC will alternate between 
treatment and time point to avoid the same treatment and time point being QC’d 
every time, however a single treatment at 1 time point in each table will be checked 
• 
where tables are produced using a macro for multiple parameters, a minimum of 
3 tables, using different treatments or combinations of treatments and time point as 
appropriate, will be QC’d 
• 
for AEs, the treatment details will be 100% QC’d against the treatment allocation 
list/randomization schedule for all subjects  
• 
AE summary tables will be 100% checked using the relevant data listing 
13.2.2 
Quality Control - Figures 
All figures will be QC’d manually using the corresponding/appropriate summary table or 
data listing, as follows: 


    
 
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• 
across all figures, QC will alternate between treatments to avoid the same treatment 
being QC’d every time 
• 
where a figure presents data from more than 1 treatment, only 1 treatment will be 
QC’d; however, all data points for that treatment will be checked  
• 
where figures are produced using a macro for individual subjects and/or multiple 
parameters, a minimum of 3 figures will be QC’d 
• 
mean figures will be QC’d using the corresponding summary table 
• 
figures showing individual data will be QC’d using the corresponding data listing 
13.2.3 
Quality Control - Data Listings 
All data listings will be subjected to a 100% manual check against the eCRF or other 
appropriate source data for a minimum of 2 subjects (1 from each study part). If 
appropriate, the subjects checked will include at least 1 subject who withdrew early from 
the study. 
The study treatment allocation details on the dosing data listing will be 100% QC checked 
against the study randomization schedule. 
13.2.4 
Quality Control - Statistical Analysis 
QC of statistical analyses will be performed by peer review of program code, log and 
output. This will be performed by a statistician at Quotient who is not responsible for 
performing the statistical analysis. 
14 SAS Data Transfer 
Study data in ADaM dataset format will be transferred to Genentech at the following 
milestones: 
• 
Pre database close 
• 
Pre database lock 
• 
Post database lock 
Data will be provided in SAS dataset format, each dataset will be contained in a 
respective SAS transport (XPT) file and conform to CDISC ADaM format (SDTM IG 1.1)   
The following standards and versions for creation and validation of the Clinical Data 
Interchange Standards Consortium (CDISC) Standardized Datasets will be used: 
• 
Study Data Tabulation Model (SDTM) Version: 1.4 
• 
SDTM Implementation Guide Version: 3.2 
• 
ADaM: Model 2.1  
• 
Implementation Guide 1.1 
• 
OpenCDISC Version: 2.2.0 
• 
CDISC SDTM Controlled Terminology Version: "2020-03-27 or latest available" 
• 
SDRG (Standard Data Review Guide): 1.2 or latest available (end of study transfer 
only) 
• 
ADRG (Standard Data Review Guide): 1.1 or latest available (end of study transfer 
only) 


    
 
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• 
Define.xml: 2.0> (end of study transfer only) 
• 
SAS v9.4 
• 
Pinnacle 21 
A define.xml will be provided to Genentech for ADaM datasets. This will be accompanied 
by a Data Reviewers Guide (in pdf format) and linked to the ADaM define.xml. Datasets 
will be provided in SAS transport file format (XPT), each dataset will be in an individual 
transport file. The define.xml will be issued on finalization of the CSR. 
15 Programming Conventions 
Quotient standards for layout of tables, figures and data listings and programming 
conventions will be used as follows: 
• 
courier new, font size 8 
• 
landscape 
• 
US letter size paper 
Tables and listings will be produced as MS Word 2016 documents and figures will be 
produced as PDF files. Listings will be sorted by subject ID number and period. 
The mock tables (Section 20) presented are a representation of Quotient reporting 
standards. However, these are provided for illustrative purposes only. The numbering 
and titles of all tables, figures and listings and the formatting, labelling, footnotes and 
cosmetic appearance of output may be modified or additional labelling/footnotes may 
need to be added during analysis and reporting, for clarification purposes. Any such 
changes will not be regarded as changes to planned analyses. 
16 Reference List 
[1] Brown, Prescott, Repeated Measures data. In Brown H and Prescott R, 3rd edition. 
Applied Mixed Models in Medicine. Chichester, UK: John Wiley &Sons Ltd., 2015: 
242-243  
[2] International Council for Harmonisation (ICH) Topic E14, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic 
Drugs Guidelines approved by the Committee for Medicinal Products for Human Use 
(CHMP) in May 2005 which came into force November 2005. 
 
 
















    
 
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18 Index of Figures 
























    
 
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20 Mock Tables


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
Part 1 
 
                                           [14C]-GDC-9545 Cap    
                                                 (N=XX)        
                                                 n (%)         
 _____________________________________________________________ 
                                                               
 Subjects enrolled (1)                         xx (xx.x)       
 Subjects dosed                                xx (xx.x)       
 Subjects completed                            xx (xx.x)       
 Subjects discontinued                         xx (xx.x)       
                                                               
 Reason for discontinuation                                    
   REASON 1                                    xx (xx.x)       
   REASON 2                                    xx (xx.x)       
   REASON 3                                    xx (xx.x)       
   …                                               …           
   <All categories on source>                  xx (xx.x)       
                                                               
                                                               
                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      (1) An enrolled subject is defined as a subject who signed the informed consent, qualified per the inclusion/exclusion criteria                         
      and was allocated a unique identification number                                                                                                        
      A subject may be discontinued for one reason only                                                                                                       
      Percentages are based on the number of subjects enrolled                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for discontinuation as recorded on the eCRF. If none of the subjects                          
                   discontinued from the study early then reasons for discontinuation will not be populated in the summary table)                             


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
Part 1 
 
                                                                [14C]-GDC-9545 Cap    
                                                                     (N=XX)        
                                                                     n (%)         
 _________________________________________________________________________________ 
                                                                                   
 Subjects in Safety Population                                     xx (xx.x)       
   Reasons for exclusion from Safety Population                                    
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Subjects in Mass Balance Population                               xx (xx.x)       
   Reasons for exclusion from Mass Balance Population                              
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Subjects in PK Population                                         xx (xx.x)       
   Reasons for exclusion from PK Population                                        
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      A subject may be excluded for more than 1 reason                                                                                                        
      Percentages are based on the number of subjects enrolled                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from a 
population, then reasons for exclusion will not be populated in the summary table)                                                                        
 
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.2.2 
Safety Analysis Set 
Summary Statistics: Safety Population 
Part 1 
 
                                                                [14C]-GDC-9545 Cap 
                                                                     (N=XX)        
                                                                     n (%)         
 _________________________________________________________________________________ 
                                                                                   
 Subjects in Safety Analysis Set                                   xx (xx.x)       
   Reasons for exclusion from Safety Analysis Set                                  
   <All categories from source>                                    xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      A subject may be excluded for more than 1 reason                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from the safety                          
                   analysis set, then reasons for exclusion will not be populated in the summary table. Similar tables will  
                   be produced for                      
                   • Mass Balance Analysis Set, i.e. Table [14.1.1.2.3] and                                                                                   
                   • PK Analysis Set, i.e. Table [14.1.1.2.4]                                                                                                 
                   Each analysis set will be a subset of their respective populations and percentages will be based on number  
                   of subjects in each population)                                                                                                            
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
Part 2 
 
                                   Treatment Sequence                  
                                _________________________              
                                    BCD          BDC        Overall    
                                   (N=X)        (N=X)        (N=X)     
                                   n (%)        n (%)        n (%)     
 _____________________________________________________________________ 
                                                                       
 Subjects enrolled (1)           xx (xx.x)    xx (xx.x)    xx (xx.x)   
 Subjects dosed                  xx (xx.x)    xx (xx.x)    xx (xx.x)   
 Subjects completed              xx (xx.x)    xx (xx.x)    xx (xx.x)   
 Subjects discontinued           xx (xx.x)    xx (xx.x)    xx (xx.x)   
                                                                       
 Reason for discontinuation                                            
   REASON 1                      xx (xx.x)    xx (xx.x)    xx (xx.x)   
   REASON 2                      xx (xx.x)    xx (xx.x)    xx (xx.x)   
   REASON 3                      xx (xx.x)    xx (xx.x)    xx (xx.x)   
   …                                 …            …            …       
   <All categories on source>    xx (xx.x)    xx (xx.x)    xx (xx.x)   
                                                                       
                                                                       
                                                                       
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      (1) An enrolled subject signed the informed consent, qualified per the inclusion/exclusion criteria and was randomized                                  
      A subject may be discontinued for 1 reason only                                                                                                         
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for discontinuation as recorded                                                               
                  on the source. If none of the subjects discontinued from the study early                                                                    
                  then reasons for discontinuation will not be populated in the summary table)                                                                
(Programming note: Percentages are based on the number of subjects enrolled in the respective sequence)                                                       
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
Part 2 
  
 
                                                       Treatment Sequence                  
                                                    _________________________              
                                                        BCD          BDC        Overall    
                                                       (N=X)        (N=X)        (N=X)     
                                                       n (%)        n (%)        n (%)     
 _________________________________________________________________________________________ 
                                                                                           
 Subjects in safety population                       xx (xx.x)    xx (xx.x)    xx (xx.x)   
   Reason for exclusion from safety population                                             
   <All categories on source listing>                xx (xx.x)    xx (xx.x)    xx (xx.x)   
                                                         …            …            …       
                                                                                           
 Subjects in PK population                           xx (xx.x)    xx (xx.x)    xx (xx.x)   
   Reason for exclusion from PK population                                                 
   <All categories on source listing>                xx (xx.x)    xx (xx.x)    xx (xx.x)   
                                                         …            …            …       
                                                                                           
                                                                                           
                                                                                           
                                                                                           
                                                                                           
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      A subject may be excluded for more than 1 reason                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: Percentages are based on the number of subjects enrolled in the respective sequence)    
(Programming note: If all subjects in Part 2 receive all treatments then this will be presented by overall only)                                              
 
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.2.2 
Safety Analysis Set 
Summary Statistics: Safety Population 
Part 2 
 
                                                         GDC-9545 IV GDC-9545/F12 Cap  GDC-9545/F18 Cap   
                                                            (N=X)          (N=X)            (N=X)    
                                                            n (%)          n (%)            n (%)    
 __________________________________________________________________________________________________________ 
                                                                                   
 Subjects in safety analysis set                          xx (xx.x)     xx (xx.x)          xx (xx.x)     
   Reasons for exclusion from safety analysis set                                  
   <All categories from source>                           xx (xx.x)     xx (xx.x)          xx (xx.x)     
                                                              …             …                 … 
                                                                                   
                                                                                   
                                                                                   
                                                                                   
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      A subject may be excluded for more than 1 reason                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: A similar table will be produced for the PK Analysis Set (and Subset[s], if required), i.e. Table [14.1.2.2.3]                             
                  Each analysis set/subset will be a subset of their respective population and percentages                                                    
                  will be based on number of subjects in each population)                                                                                     
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
Part 1 
 
                                                                    [14C]-GDC-9545 Cap 
                                                                         (N=XX)        
______________________________________________________________________________________ 
                                                                                       
Age (years)              n                                                 xx          
                         Mean                                            xx.xx         
                         SD                                              xx.xx         
                         Median                                          xx.xx         
                         Min                                              xx.x         
                         Max                                              xx.x         
                                                                                       
Ethnicity n(%)           <All categories on source>                    xx (xx.x)       
                                                                                       
Race n(%)                <All categories on source>                    xx (xx.x)       
                                                                                       
Sex n(%)                 Females                                       xx (xx.x)       
                                                                                       
Height (cm)              …                                                 …           
                                                                                       
Weight (kg)              …                                                 …           
                                                                                       
BMI (kg/m^2)             …                                                 …           
                                                                                       
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will continue for all categories of ethnicity and race. Height, Weight and BMI will be summarized using 
the same descriptive statistics as Age. If any values are missing, then a ‘missing’ row will be presented in the table)                           
 
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.4 
Lifestyle Details: Smoking History and Alcohol Consumption 
Summary Statistics: Safety Analysis Set 
 
                                                            [14C]-GDC-9545 Cap 
                                                                 (N=XX)        
                                                                 n (%)         
______________________________________________________________________________ 
                                                                               
Does the subject smoke (1)      NO                             xx (xx.x)       
                                PREVIOUSLY                     xx (xx.x)       
                                                                               
                                                                               
Alcohol Consumption (2)         NONE                           xx (xx.x)       
                                YES: NOT EXCESSIVE             xx (xx.x)       
                                                                               
                                                                               
                                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      (1) Anyone who smoked or used e-cigarettes or nicotine replacement products in the last 12 months is excluded from the study                            
      (2) Anyone who excessively consumes alcohol (>14 units/week) is excluded from the study                                                           
      1 unit = 1/2 pint beer, 25 mL of 40% spirit, 1.5 to 2 units = 125 mL glass of wine depending on type                                                    
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX      
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                                         Treatment Sequence                        
                                                   _______________________________                 
                                                         BCD             BDC           Overall     
                                                        (N=X)           (N=X)           (N=X)      
__________________________________________________________________________________________________ 
                                                                                                   
Age (years)         n                                    xx              xx              xx        
                    Mean                                xx.xx           xx.xx           xx.xx      
                    SD                                  xx.xx           xx.xx           xx.xx      
                    Median                              xx.xx           xx.xx           xx.xx      
                    Min                                 xx.x            xx.x            xx.x       
                    Max                                 xx.x            xx.x            xx.x       
                                                                                                   
Ethnicity n(%)      <All categories on source>        xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                                                   
Race n(%)           <All categories on source>        xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                                                   
Sex n(%)             
                    Female                            xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                                                   
Height (cm)         …                                     …               …               …        
                                                                                                   
Weight (kg)         …                                     …               …               …        
                                                                                                   
BMI (kg/m^2)        …                                     …               …               …        
                                                                                                   
                                                                                                   
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
 (Programming note: This table will continue for all categories of ethnicity and race                                                                         
                  Height, Weight and BMI will be assessed using the same descriptive statistics as Age                                                        
                  If any values are missing, then a “missing” row will be included in the table, as applicable)                                               


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.4 
Lifestyle Details: Smoking History and Alcohol Consumption 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                                              Treatment Sequence                        
                                                        _______________________________                 
                                                              BCD             BDC           Overall     
                                                             (N=X)           (N=X)           (N=X)      
                                                             n (%)           n (%)           n (%)      
_______________________________________________________________________________________________________ 
                                                                                                        
Does the subject smoke? (1)   NO                           xx (xx.x)       xx (xx.x)       xx (xx.x)    
                              PREVIOUSLY                   xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                                                        
Alcohol Consumption (2)       NONE                         xx (xx.x)       xx (xx.x)       xx (xx.x)    
                              YES: NOT EXCESSIVE           xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                                                        
                                                                                                        
                                                                                                        
                                                                                                        
                                                                                                        
                                                                                                        
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      (1) Anyone who smoked or used e-cigarettes or nicotine replacement products in the last 12 months is excluded from the study                            
      (2) Anyone who excessively consumes alcohol (>14 units/week) is excluded from the study                                                           
      1 unit = 1/2 pint beer, 25 mL of 40% spirit, 1.5 to 2 units = 125 mL glass of wine depending on type                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                           
 
 


    
 
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Page 78 of 116 
 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.1.5 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
Part 1 
 
                                     [14C]-GDC-9545 Cap 
                                         (N=XX)                      
                     _______________________________________________ 
                           mg              MBq             µCi       
____________________________________________________________________ 
                                                                     
n                          xx              xx              xx        
Mean                      xx.xx           xx.xx           xx.xx      
SD                        xx.xx           xx.xx           xx.xx      
Median                    xx.xx           xx.xx           xx.xx      
Min                       xx.x            xx.x            xx.x       
Max                       xx.x            xx.x            xx.x       
                                                                     
                                                                     
                                                                     
                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                  
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.1.2.5 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                    Subjects Dosed       
                                         (N=X)           
Treatment                                n (%)           
________________________________________________________ 
                                                         
GDC-9545 IV                            xx (xx.x)         
GDC-9545/F12 Cap                       xx (xx.x)  
GDC-9545/F18 Cap                       xx (xx.x)        
                                                         
Overall                                xx (xx.x)         
                                                         
                                                         
                                                         
                                                         
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
           
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
21 Jan 2021 
     
 
Page 80 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.1.1.1 
Excretion: Total Radioactivity 
Ae(Urine) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
ADMISSION - 0 H                 xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME1 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME2 - TIME3#                  xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      Where a subject has failed to void or has a ND concentration over a particular collection interval, the amount excreted (Ae)                            
      has been set to zero  
      # represents an interpolated period                                                                                                                     
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming Note: This table will be continued for all collection periods. Similar tables will be produced for                                               
                   • Fe(Urine) (Recovery), i.e. Table [14.2.1.1.3]                                                                                            
                   • Ae(Feces), i.e. Table [14.2.1.2.1]                                                                                                       
                   • Fe(Feces) (Recovery), i.e. Table [14.2.1.2.3]                                                                                            
                   • Combined (Ae[total]), i.e. Table [14.2.1.3.1] and                                                                                        
                   • Combined (Fe[total]) (Recovery), i.e. Table [14.2.1.3.3])                                                                                


    
 
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Page 81 of 116 
 
 
 
 
 
 
 Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.1.1.2 
Excretion: Total Radioactivity 
Cumulative Ae(Urine) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
Part 1 
 
[14C]-GDC-9545 Cap (N=XX) 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
ADMISSION - 0 H                 xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME3                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all collection periods. Similar tables will be produced for                                               
                   • Cumulative Fe(Urine) (Recovery), i.e. Table [14.2.1.1.4]                                                                                 
                   • Cumulative Ae(Feces), i.e. Table [14.2.1.2.2]                                                                                            
                   • Cumulative Fe(Feces) (Recovery), i.e. Table [14.2.1.2.4]                                                                                 
                   • Combined Cumulative (Ae[total]), i.e. Table [14.2.1.3.2] and                                                                             
                   • Combined Cumulative (Fe[total]) (Recovery), i.e. Table [14.2.1.3.4])                                                                     
                        
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 82 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.1.4 
Excretion and Recovery: Total Radioactivity 
Cumulative Excretion and Recovery Parameters 
Summary Statistics: Mass Balance Analysis Set 
Part 1 
 
[14C]-GDC-9545 Cap (N=XX) 
 
                        Urine                 Feces                 Total         
                _____________________ _____________________ _____________________ 
                  CumAe      CumFe      CumAe      CumFe      CumAe      CumFe   
                 (units)      (%)      (units)      (%)      (units)      (%)     
_________________________________________________________________________________ 
                                                                                  
n                   xx         xx         xx         xx         xx         xx     
Mean              xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
SD                xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
CV%                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Median            xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
Min                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Max                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
                                                                                  
                                                                                  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      CumAe represents the cumulative excretion. CumFe represents the cumulative recovery as a percentage of the radioactive dose                             
      administered                                                                                                                                            
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
 
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 83 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.1.5.1 
Plasma Pharmacokinetic Concentrations: GDC-9545 <(units)> 
Summary Statistics: PK Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
 
                                              Arithmetic (1)                            Geometric (2)         
                          ______________________________________________________ ___________________________ 
Time Point                 n    n#   Mean     SD      CV%   Median  Min    Max      Mean     SD      CV%   
_____________________________________________________________________________________________________________ 
                                                                                                              
PRE-DOSE                   xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x      NC      NC      NC 
TIME POINT 1               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x     xx.xx   xx.x    xx.x 
TIME POINT 2               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x     xx.xx   xx.x    xx.x      
TIME POINT 3               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x     xx.xx   xx.x    xx.x     
…                          …    …      …       …       …      …      …      …         …       …       …    
<All other time points>    xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x     xx.xx   xx.x    xx.x      
                                                                                                             
                                                                                                             
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      n# indicates the number of subjects with a BLQ value recorded at the time point indicated                                                               
      (1) For arithmetic summary statistics, concentration values reported as < BLQ> have been set to zero                                                    
      (2) For calculation of geometric summary statistics, values reported as < BLQ> have been set to ½ × <LLOQ>, except for                               
      pre-dose values which will not be summarized. The < LLOQ> value was <value, units>                                                                      
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all time points. Similar tables will be produced for                                                      
                   • Plasma Pharmacokinetic Concentrations: Total Radioactivity, i.e. Table [14.2.1.5.2]  
                   • Whole Blood Pharmacokinetic Concentration, i.e. Table [14.2.1.5.3]) and   
    • Whole Blood: Plasma Concentration Ratio, i.e. Table [14.2.1.5.4]) 
                                                                   
                    
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 84 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.2.5.1 
Plasma Pharmacokinetic Concentrations: GDC-9545 <(units)> 
Summary Statistics: <PK Analysis Set/PK Analysis Subset> 
Part 2 
 
                                                              Arithmetic (1)                              Geometric (2)       
                                      ______________________________________________________________ ________________________ 
Treatment   Time Point                  n    n#     Mean     SD      CV%    Median     Min     Max     Mean     SD      CV%   
_____________________________________________________________________________________________________________________________ 
                                                                                                                              
GDC-9545 IV PRE-DOSE                   xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x      NC      NC      NC    
(N=X)       TIME POINT 1               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
            TIME POINT 2               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
            TIME POINT 3               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
            …                           …     …      …        …       …        …        …       …       …        …       …    
            <All other time points>    xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
                                                                                                                              
GDC-9545/   PRE-DOSE                   xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x      NC      NC      NC    
F12 Cap     TIME POINT 1               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
(N=X)       TIME POINT 2               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
            TIME POINT 3               xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x   
            …                           …     …      …        …       …        …        …       …       …        …       …    
            <All other time points>    xx    xx    xx.xx    xx.xx   xx.x     xx.xx    xx.x    xx.x    xx.xx    xx.xx   xx.x  
 
…           …                           …     …      …        …       …        …        …       …       …        …       …    
  
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      n# indicates the number of subjects with a BLQ value recorded at the time point indicated                                                               
      (1) For arithmetic summary statistics, concentration values reported as BLQ have been set to zero                                                       
      (2) For calculation of geometric summary statistics, values reported as BLQ have been set to ½ × LLOQ, except for                                       
      pre-dose values which will not be summarized. The LLOQ value was <value, units>                                                                         
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for each treatment and all time points)                
                                                         
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.1.6.1 
Plasma Pharmacokinetic Parameters: GDC-9545 
Summary Statistics: PK Analysis Set 
Part 1 
 
[14C]-GDC-9545 Cap (N=XX) 
 
                   Parameter 1  Parameter 2  Parameter 3          All Other PK Parameters  
Statistic            (units)      (units)      (units)    ......          (units)          
__________________________________________________________________________________________ 
                                                                                           
n                       xx           xx           xx        …               xx             
Mean                  xx.xx        xx.xx        xx.xx       …              xx.xx           
SD                    xx.xx        xx.xx        xx.xx       …              xx.xx           
CV%                    xx.x         xx.x         xx.x       …              xx.x            
Median                xx.xx        xx.xx        xx.xx       …              xx.xx           
Min                    xx.x         xx.x         xx.x       …              xx.x            
Max                    xx.x         xx.x         xx.x       …              xx.x            
Geometric Mean        xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric SD          xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric CV%          xx.x         xx.x         xx.x       …              xx.x            
                                                                                           
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      <For concentration parameters, BLQ values will be set to 0 for arithmetic statistics and to ½ × LLOQ for geometric statistics>                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: A similar table will be produced for                                                                                                       
                   • Plasma Pharmacokinetic Parameters: Total Radioactivity, i.e. Table [14.2.1.6.2]) and 
                   • Whole Blood Pharmacokinetic Parameters: Total Radioactivity, i.e. Table [14.2.1.6.3])                                                    
 
 
 


    
 
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Page 86 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.2.2.6.1 
Plasma Pharmacokinetic Parameters: GDC-9545 
Summary Statistics: <PK Analysis Set/PK Analysis Subset> 
Part 2 
 
                                  Parameter 1  Parameter 2  Parameter 3          All Other PK Parameters  
Treatment      Statistic            (units)      (units)      (units)    ......          (units)          
_________________________________________________________________________________________________________ 
                                                                                                          
GDC-9545 IV    n                       xx           xx           xx        …               xx             
(N=X)          Mean                  xx.xx        xx.xx        xx.xx       …              xx.xx           
               SD                    xx.xx        xx.xx        xx.xx       …              xx.xx           
               CV%                    xx.x         xx.x         xx.x       …              xx.x            
               Median                xx.xx        xx.xx        xx.xx       …              xx.xx           
               Min                    xx.x         xx.x         xx.x       …              xx.x            
               Max                    xx.x         xx.x         xx.x       …              xx.x            
               Geometric Mean        xx.xx        xx.xx        xx.xx       …              xx.xx           
               Geometric SD          xx.xx        xx.xx        xx.xx       …              xx.xx           
               Geometric CV%          xx.x         xx.x         xx.x       …              xx.x            
                                                                                                          
GDC-9545/F12   …                       …            …            …         …                …             
Cap (N=X)                                                                                      
 
…              …                       …            …            …         …                …                           
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      For concentration parameters, BLQ values will be set to 0 for arithmetic statistics and to ½ × LLOQ for geometric statistics                            
      The LLOQ value was <value, units>                                                                                                                       
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for each treatment and parameter) 
 
 
 


    
 
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Protocol: GP42662 
 
TABLE 14.2.2.7.1 
Plasma Pharmacokinetic Parameters: GDC-9545 
Statistical Analysis Results - Assessment of Absolute Bioavailability: <PK Analysis Set/PK Analysis Subset> 
Part 2 
                                          Test          Reference                                                      
                                     ________________ ________________                                                  
                                           Adj Geo          Adj Geo                                                    
                                             Mean             Mean    Ratio (%)      90% CI           CVw (%)   
Comparison            Parameter       n      (1)       n      (1)        (2)           (3)              (4)     
_____________________________________________________________________________________________________________________ 
                                                                                                        
GDC-9545/F12 Cap vs   AUC(0-inf)      xx     xx.xx     xx     xx.xx      xx.xx    (xx.xx, xx.xx)       xx.xxx   
GDC-9545 IV           (units)                                                                                           
      
                                                                                                   
GDC-9545/F18 Cap vs   AUC(0-inf)      xx     xx.xx     xx     xx.xx      xx.xx    (xx.xx, xx.xx)       xx.xxx   
GDC-9545 IV           (units)                                                                                           
                                                                                                                                                              
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      Results obtained from mixed effects model of natural log transformed PK parameters including terms for treatment and                                    
      sequence fitted as fixed effects and subject within sequence fitted as a random effect                                                   
      (1) Adj geo mean = adjusted geometric mean from model (2) Ratio of adj geo means with comparison presented                                              
      as test/reference (3) CI = confidence interval for ratio of adj geo means (4) CVw = Intra-subject variability                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: A similar table will be produced for Relative Bioavailability, Table [14.2.2.7.2], with the inclusion of a column 
for p-value)                                                                               


    
 
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Protocol: GP42662 
 
TABLE 14.2.2.7.3 
Plasma Pharmacokinetic Parameters: GDC-9545 
Statistical Analysis Results - Fixed Effects Table for Assessment of Relative Bioavailability: <PK Analysis Set/PK Analysis Subset> 
Part 2 
 
Parameter                 Effect (1)             df (2)          F-Statistic (3)        p-value (4)      
________________________________________________________________________________________________________ 
                                                                                                                                                              
AUC(0-inf) (units)        TREATMENT              xx,xx                 x.xx                0.xxx         
                            PERIOD               xx,xx                 x.xx                0.xxx         
                           SEQUENCE              xx,xx                 x.xx                0.xxx 
                                                                                                         
                                                                                                         
__________________________________________________________________________________________________________________________________                            
Note: The table accompanies the statistical analysis results given in Tablet 14.2.2.7.1 
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      Results obtained from mixed effects model of natural log transformed PK parameters including terms for treatment,                                       
      period and sequence fitted as fixed effects and subject nested within sequence fitted as a random effect                                                
      (1) Fixed effects from the model (2) degrees of freedom for the fixed effects (3) F-statistic from the model for the                                    
      relevant fixed effect (4) p-value (2-sided test with null hypothesis of no difference)                                              
      for the relevant fixed effect                                                                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: A similar table will be produced to accompany the relative bioavailability: Table [14.2.2.7.4])                                            


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.1.1 
Overall Summary of Adverse Events 
Summary Statistics: Safety Analysis Set 
Part 1 
 
                                                       [14C]-GDC-9545 Cap 
                                                            (N=XX)                 
                                             _____________________________________ 
                                                                   Total Number    
Event                                               n(%)            of Events      
__________________________________________________________________________________ 
                                                                                   
AEs                                              xx (xx.x)              xx         
                                                                                   
Grade 3 AEs (1)                                  xx (xx.x)              xx          
                                                                                   
Grade 4 AEs (2)                                  xx (xx.x)              xx               
                                                                                   
IMP related AEs                                  xx (xx.x)              xx         
                                                                                   
AEs of Special Interest                          xx (xx.x)              xx         
                                                                                   
Serious AEs                                      xx (xx.x)              xx    
 
AEs leading to IMP withdrawal                    xx (xx.x)              xx              
                                                                                   
Grade 5 (3)                                      xx (xx.x)              xx         
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      AEs are coded using MedDRA vXX.X    
(1) NCI CTCAE Grade 3: Severe or medically significant but not immediately life threatening, (2) NCI CTCAE Grade 4: Life-  
      Threatening consequences or urgent intervention indicated, (3) NCCI CTCAE Grade 5: Death related to AE    
      Serious AEs are those AEs which are graded as NCI CTCAE Grade 4 or 5                                                                                    
       
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.1.2 
Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
Part 1 
                                               [14C]-GDC-9545 Cap 
                                                   (N=XX)                 
                                    _____________________________________ 
System Organ Class                                        Total Number    
   Preferred Term                          n(%)            of Events      
_________________________________________________________________________ 
                                                                          
AEs                                     xx (xx.x)              xx         
                                                                          
SYSTEM ORGAN CLASS 1                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
SYSTEM ORGAN CLASS 2                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
…                                           …                  …          
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                     
      Subjects experiencing more than 1 episode of a AE are counted only once within each SOC and PT                                                          
      Counts of number of subjects are by maximum severity, i.e. subjects experiencing more than 1 episode of a AE are counted only                           
      once within each SOC and PT using the most severe episode                                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT)    
(Programming note: Similar tables will be produced for AEs of Special Interest, i.e. Table 14.3.1.5 and SAEs, i.e. Table 14.3.1.6.)                           


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.1.3 
Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
Part 1 
 
                                                           [14C]-GDC-9545 Cap 
                                                                  (N=XX)                      
                               ____________________________________________________________________________ 
System Organ Class                  Mild          Moderate         Severe     Life-threatening     Death 
   Preferred Term                   n(%)            n(%)            n(%)            n(%)            n(%)       
 
___________________________________________________________________________________________________________ 
                                                                               
AEs                               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
                                                                               
SYSTEM ORGAN CLASS 1              xx (xx.x)       xx (xx.x)       xx (xx.x        xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   etc                                …               …               …        
                                                                               
SYSTEM ORGAN CLASS 2              xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   etc                                …               …               …        
                                                                               
…                                     …               …               …        
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                     
      Counts are given for total number of subjects, not for events                                                                                           
      Counts of number of subjects are by maximum severity, i.e. subjects experiencing more than 1 episode of a AE are counted only                           
      once within each SOC and PT using the most severe episode                                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT)                                                                                           


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.1.4 
Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IMP 
Summary Statistics: Safety Analysis Set 
Part 1 
 
                                           [14C]-GDC-9545 Cap 
                                                 (N=XX)                             
                               __________________________________________ 
System Organ Class                    Yes                   No                 
   Preferred Term                     n(%)                 n(%)                          
_________________________________________________________________________ 
                                                                                               
AEs                                 xx (xx.x)            xx (xx.x)             
                                                                                                
SYSTEM ORGAN CLASS 1                xx (xx.x)            xx (xx.x)             
   PREFERRED TERM 1                 xx (xx.x)            xx (xx.x)                   
   PREFERRED TERM 2                 xx (xx.x)            xx (xx.x)             
   etc                                  …                    …                    
                                                                                              
SYSTEM ORGAN CLASS 2                xx (xx.x)            xx (xx.x)             
   PREFERRED TERM 1                 xx (xx.x)            xx (xx.x)             
   PREFERRED TERM 2                 xx (xx.x)            xx (xx.x)             
   etc                                  …                    …                    
                                                                                              
…                                       …                    …                         
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency   
      “Yes”= there is a plausible temporal relationship between the onset of the AE ad the administration of the study drug 
      “No”= the AE has no plausible temporal relationship to the administration of the study drug                                                             
      Counts are given for total number of subjects, not for events                                                                                           
      Counts are given by closest relationship, i.e. subjects experiencing more than 1 AE are counted only once within each SOC and                           
      PT using the most closely related event                                                                                                                 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT)                                                                                           
 
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.2.1 
Overall Summary of Adverse Events 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                  GDC-9545 IV             GDC-9545/F12 Cap           GDC-9545/F18 Cap              Overall           
                                      (N=X)                    (N=X)                       (N=X)                    (N=X)            
                          __________________________ __________________________ __________________________ ________________________ 
                                       Total Number               Total Number               Total Number             Total Number   
Event                        n(%)       of Events       n(%)       of Events       n(%)       of Events       n(%)      of Events    
_________________________________________________________________________________________________________________________________ 
                                                                                                                             
AEs                         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx               
                                                                                                                             
Grade 3 AEs (1)             xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx               
                                                                                                                             
Grade 4 AEs (2)             xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx               
                                                                                                                             
IMP related AEs             xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx              
                                                                                                                             
AE of Special Interest      xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx               
                                                                                                                             
Serious AEs                 xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx  
 
AEs leading to IMP          xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx     
withdrawal          
                                                                                                                             
Grade 5 AEs (3)             xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx         xx (xx.x)       xx                               
                                                                                                                            
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      AEs are coded using MedDRA vXX.X   
      (1) NCI CTCAE Grade 3: Severe or medically significant but not immediately life threatening, (2) NCI CTCAE Grade 4: Life-  
      Threatening consequences or urgent intervention indicated, (3) NCCI CTCAE Grade 5: Death related to AE                                                  
      Serious AEs are those AEs which are graded as NCI CTCAE Grade 4 or 5                                                                                    
          
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.2.2 
Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                           GDC-9545 IV             GDC-9545/F12 Cap           GDC-9545/F18 Cap               
                                              (N=X)                      (N=X)                      (N=X)            
                                    __________________________ __________________________ __________________________ 
                                                Total Number               Total Number               Total Number   
                                       n(%)       of Events       n(%)       of Events       n(%)       of Events    
____________________________________________________________________________________________________________________ 
                                                                                                                     
AEs                                 xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
                                                                                                                     
SYSTEM ORGAN CLASS 1                xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   PREFERRED TERM 1                 xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   PREFERRED TERM 2                 xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   etc                                  …             …            …             …            …             …        
                                                                                                                     
SYSTEM ORGAN CLASS 2                xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   PREFERRED TERM 1                 xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   PREFERRED TERM 2                 xx (xx.x)        xx        xx (xx.x)        xx        xx (xx.x)        xx        
   etc                                  …             …            …             …            …             …        
                                                                                                                     
                                                                                                                     
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                     
      Subjects experiencing more than 1 episode of a AE within a treatment are counted only once within each SOC and PT                                       
      Counts of number of subjects are by maximum severity, i.e. subjects experiencing more than 1 episode of a AE are                                        
      counted only once within each SOC and PT using the most severe episode                                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT)                                                                                           
(Programming note: Similar tables will be produced for AEs of Special Interest, i.e. Table 14.3.2.5 and SAEs, i.e. Table 14.3.2.6.)                           
 


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.2.3 
Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
Part 2 
 
GDC-9545 IV (N=X) 
                                
System Organ Class                  Mild          Moderate         Severe     Life-threatening     Death 
   Preferred Term                   n(%)            n(%)            n(%)            n(%)            n(%)       
 
___________________________________________________________________________________________________________ 
                                                                               
AEs                               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
                                                                               
SYSTEM ORGAN CLASS 1              xx (xx.x)       xx (xx.x)       xx (xx.x        xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   etc                                …               …               …        
                                                                               
SYSTEM ORGAN CLASS 2              xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       xx (xx.x)       
   etc                                …               …               …        
                                                                               
…                                     …               …               …        
                                                                                                                             
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                     
      Counts are given for total number of subjects, not for events                                                                                           
      Counts of number of subjects are by maximum severity, i.e. subjects experiencing more than 1 episode of a AE within a treatment 
are                                           
      counted only once within each SOC and PT using the most severe episode                                                                                  
                                                                                                                                                              
                                                                                                                                                             
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT)                                                                                           
(Programming note: This table will be continued for each treatment with a separate page for each) 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 96 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.3.2.4 
Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IMP 
Summary Statistics: Safety Analysis Set 
Part 2 
 
                                GDC-9545 IV           GDC-9545/F12 Cap          GDC-9545/F18 Cap 
                                    (N=X)                   (N=X)                     (N=X)     
                          _______________________   _______________________  __________________________  
                              Yes          No          Yes          No            Yes          No 
                              n(%)         n(%)        n(%)         n(%)          n(%)        n(%)                                               
________________________________________________________________________________________________________ 
                                                                                                                     
AEs                        xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)               
                                                                                                                     
SYSTEM ORGAN CLASS 1       xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)              
   PREFERRED TERM 1        xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)              
   PREFERRED TERM 2        xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)               
   etc                         …            …            …            …            …            …                   
                                                                                                                     
SYSTEM ORGAN CLASS 2       xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)               
   PREFERRED TERM 1        xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)               
   PREFERRED TERM 2        xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)    xx (xx.x)              
   etc                         …            …            …            …            …            …                   
                                                                                                                     
                                                                                                                     
                                                                                                                     
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      AEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                     
      “Yes”= there is a plausible temporal relationship between the onset of the AE and the administration of the study drug 
      “No”= the AE has no plausible temporal relationship to the administration of the study drug                                                             
      Counts are given for total number of subjects, not for events                                                                                           
      Counts are given by closest relationship, i.e. subjects experiencing more than 1 AE within a treatment are counted only once     
      within each SOC and PT using the most closely related event                                   
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT) 
 
 


    
 
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Protocol: GP42662 
 
TABLE 14.4.1.1 
Hematology and Coagulation 
Summary Statistics: Safety Analysis Set 
Part 1 
 
[14C]-GDC-9545 Cap (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
480 H                     xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      BASELINE is defined as Day -1, Admission                                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all hematology and coagulation parameters and all time points                                             
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, i.e. Table [14.4.1.3]                                                                                                
                   Parameter may be added as the first column in this table)                                                                                  


    
 
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Page 98 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.4.1.2 
Hematology and Coagulation 
Shift Analysis: Safety Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx] 
 
                                                Baseline                   
                              ____________________________________________ 
Time Point                        Below          Within         Above      
   Assessment            N#        n(%)           n(%)           n(%)      
__________________________________________________________________________ 
                                                                           
480 H                    xx                                                
   Below                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Within                       xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Above                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
                                                                           
 
 
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      BASELINE is defined as Day -1, Admission                                                                                                                
      N# is the total number of subjects that have a value at baseline and each given time-point and is used in the denominator for                           
      calculating the percentages of subjects, n indicates the number of subjects with a baseline and a post baseline assessment at                           
      the time point indicated. Below/within/above indicate the number (%) of subjects with assessments below/within/above the normal                         
      reference range                                                                                                                                         
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all hematology and coagulation parameters and all time points                                             
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, i.e. Table [14.4.1.4]                                                                                                
                   Parameter may be added as the first column in this table)                                                                                  
 
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 99 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.4.2.1 
Hematology and Coagulation 
Summary Statistics: Safety Analysis Set 
Part 2 
  
<Parameter> (<units>) [ref range xxx-xxx] 
 
                                                         Result                                Change from Baseline             
                                      ____________________________________________ ____________________________________________ 
Treatment      Time Point              n    Mean     SD    Median    Min     Max    n    Mean     SD    Median    Min     Max   
_______________________________________________________________________________________________________________________________ 
                                                                                                                                
               BASELINE                xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                
 
GDC-9545 IV    TIME POINT X            xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x 
(N=X)           
                                                                                                                                
GDC-9545/F12   TIME POINT X            xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x   
Cap (N=X)         
 
GDC-9545/F18   TIME POINT X            xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx   xx.xx   xx.xx   xx.xx   xx.x    xx.x  
Cap (N=XX)                                                                                                                                
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      BASELINE is defined as Day -1, Period 1 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for all hematology and coagulation parameters and all time points                                             
                   A similar table will be produced for Clinical Chemistry i.e. Table [14.4.2.3])                                                             
(Programming note: Parameter may be added as the first column in this table)   
(Programming note: The post-baseline timepoint for Period 1 is the Day -1 of Period 2 etc. and for Period 3 is 168h post-dose )                               


    
 
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Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.4.2.2 
Hematology and Coagulation 
Shift Analysis: Safety Analysis Set 
Part 2 
  
<Parameter> (<units>) [ref range, xxx-xxx (female)] 
 
                                 GDC-9545 IV                         GDC-9545/F12 Cap                      GDC-9545/F18 Cap           
                                     (N=X)                                 (N=X)                               (N=X)            
                                    Baseline                              Baseline                            Baseline           
                       __________________________________     _______________________________      _______________________________ 
Time Point               Below       Within      Above          Below      Within     Above     
   Assessment      N#     n(%)        n(%)        n(%)     N#    n(%)       n(%)       n(%)     N#    n(%)       n(%)       n(%)      
___________________________________________________________________________________________________________________________________ 
                                                                                                                  
TIMEPOINT X        xx                                      xx                                   xx      
   Below                xx (xx.x)   xx (xx.x)   xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)   
   Within               xx (xx.x)   xx (xx.x)   xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)   
   Above                xx (xx.x)   xx (xx.x)   xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)      xx (xx.x)  xx (xx.x)  xx (xx.x)   
                                                                                                                  
                                         
  
                                                                                                                  
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      BASELINE is defined as Day -1, Period 1 
      N# indicates the number of subjects with a baseline and a post baseline assessment at the time point indicated                                          
      Below/within/above indicate the n(%)=number(%) of subjects with assessments below/within/above the                                                      
      normal reference range at baseline                                                                                                                      
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
                                                                                                                                                              
(Programming note: This table will be continued for all hematology and coagulation parameters and all time points                                             
                  A similar table will be produced for Clinical Chemistry i.e. Table [14.4.2.4])                                                              
(Programming note: Parameter may be added as the first column in this table)                                                                                  
 
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
21 Jan 2021 
     
 
Page 101 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.1.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)] 
 
                                                                            Change from                Substantial   
                                        Result                               Baseline                    Change      
                         _____________________________________ _____________________________________ _______________ 
Time Point                n   Mean    SD   Median   Min   Max   n   Mean    SD   Median   Min   Max  DEC  NONE  INC  
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                 xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x                                                        
TIME POINT 1             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
TIME POINT 2             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
TIME POINT 3             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
…                         …    …      …       …      …     …    …    …      …       …      …     …    …     …    …   
<All other time points>  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
      Substantial change is defined as: > ± 20 mmHg Systolic BP, > ± 10 mmHg Diastolic BP and > ± 15 bpm pulse rate                                           
      DEC: number of subjects with substantial decrease from baseline, NONE: number of subjects with no substantial change from 
baseline,                        
      INC: number of subjects with substantial increase from baseline                                                                                         
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all vital signs parameters                                                                                
                   Parameter may be added as the first column in this table)                                                                                  


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 102 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.1.2.1 
ECGs 
Summary Statistics: Safety Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
<Parameter> (<units>) [<ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)> / <ref range xxx - xxx >] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
TIME POINT 1              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
TIME POINT 2              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
TIME POINT 3              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
…                          …      …       …       …       …       …      …      …       …       …       …       …    
<All other time points>   xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all ECG parameters, which will follow the order given in the RAP text                                     
                   Parameter may be added as the first column in this table)                                                                                  


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 103 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.1.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 
Part 1 
  
[14C]-GDC-9545 Cap (N=XX) 
 
                                                     QTcF                                    QTcF Interval             
                                                Interval (msec)                             Increase (msec)            
                              ___________________________________________________ ____________________________________ 
                                <=450       451-480        481-500        >500       <30         30-60         >60     
Time Point                N#     n(%)         n(%)           n(%)         n(%)       n(%)         n(%)         n(%)    
______________________________________________________________________________________________________________________ 
                                                                                                                       
BASELINE                  xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)                                       
TIME POINT 1              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
TIME POINT 2              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
TIME POINT 3              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
…                         …       …            …              …            …          …            …            …      
<All other time points>   xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of [14C]-GDC-9545 capsule, 30mg (NMT 4.6 MBq [124 µCi]) in Part 1 
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
      Categories for QTcF interval and QTcF interval increases are based on ICH E14 guidelines                                                                
      N# is the total number of subjects at the relevant time point and is used in the denominator for calculating the percentages of                         
      subjects, n indicates the number of subjects with observations at the given time point                                                                  
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                
 
 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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Page 104 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.2.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
Part 2 
  
<Parameter> (<units>) [ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)] 
 
                                                                                            Change from               Substantial  
                                                        Result                                Baseline                 Change (1)  
                                        ______________________________________ ______________________________________ ____________ 
Treatment      Time Point                n   Mean    SD    Median   Min   Max   n   Mean    SD    Median   Min   Max  DEC NONE INC 
__________________________________________________________________________________________________________________________________ 
                                                                                                                                   
GDC-9545 IV    BASELINE                 xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x                                                      
(N=X)          TIME POINT 1             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               TIME POINT 2             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               TIME POINT 3             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               …                         …    …      …       …       …     …    …    …      …       …       …     …    …   …    …  
               <All other time points>  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
                                                                                                                                   
GDC-9545/F12   BASELINE                 xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x                                                      
Cap (N=X)      TIME POINT 1             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               TIME POINT 2             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               TIME POINT 3             xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
               …                         …    …      …       …       …     …    …    …      …       …       …     …    …   …    …  
               <All other time points>  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx   xx.x  xx.x  xx   xx  xx  
                                                                                                                                   
…              …                         …    …      …       …       …     …    …    …      …       …       …     …    …   …    … 
                                                                                                                                   
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      BASELINE is defined as Day 1, Pre-dose of the corresponding study period                                                                                
      Substantial change is defined as: > ± 20 mmHg Systolic BP, > ± 10 mmHg Diastolic BP and > ± 15 bpm pulse rate  
      DEC: number of subjects with substantial decrease from baseline NONE: number of subjects with no substantial                                            
      change from baseline, INC: number of subjects with substantial increase from baseline                                                                   
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all vital signs parameters)                                                                               
(Programming note: Parameter may be added as the first column in this table)                                                                                  


    
 
SPS952 T1 V3.0  
 
 
Sponsor/Quotient Confidential 
 
Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
21 Jan 2021 
     
 
Page 105 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.2.2.1 
ECGs 
Summary Statistics: Safety Analysis Set 
Part 2 
  
<Parameter> (<units>) [<ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)> / <ref range xxx-xxx >] 
 
                                                         Result                                  Change from Baseline              
                                     ______________________________________________ ______________________________________________ 
Treatment   Time Point                 n    Mean     SD     Median    Min     Max     n    Mean     SD     Median    Min     Max   
__________________________________________________________________________________________________________________________________ 
                                                                                                                                   
GDC-9545 IV BASELINE                  xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x                                                  
(N=X)       TIME POINT 1              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
            TIME POINT 2              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
            TIME POINT 3              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
            …                          …      …       …       …        …       …      …      …       …       …        …       …    
            <All other time points>   xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
                                                                                                                                   
GDC-9545/   BASELINE                  xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x                                                  
F12 Cap     TIME POINT 1              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
(N=X)       TIME POINT 2              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
            TIME POINT 3              xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
            …                          …      …       …       …        …       …      …      …       …       …        …       …    
            <All other time points>   xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx    xx.x    xx.x   
                                                                                                                                   
…           …                          …      …       …       …        …       …      …      …       …       …        …       …                               
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      BASELINE is defined as Day 1, Pre-dose of the corresponding study period                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
                                                                                                                                                              
(Programming note: This table will be continued for all ECG parameters)                                                                                       
(Programming note: Parameter may be added as the first column in this table)                                                                                  


    
 
SPS952 T1 V3.0  
 
 
Sponsor/Quotient Confidential 
 
Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
21 Jan 2021 
     
 
Page 106 of 116 
 
 
 
 
 
 
Genentech, Inc.                                                                                                      Page x of y 
Protocol: GP42662 
 
TABLE 14.5.2.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 
Part 2 
                                                                 QTcF                                    QTcF Interval             
                                                            Interval (msec)                             Increase (msec)            
                                          ___________________________________________________ ____________________________________ 
                                            <=450       451-480        481-500        >500       <30         30-60         >60     
Treatment   Time Point                N#     n(%)         n(%)           n(%)         n(%)       n(%)         n(%)         n(%)    
__________________________________________________________________________________________________________________________________ 
                                                                                                                                   
GDC-9545 IV BASELINE                      xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)                                       
(N=X)       TIME POINT 1              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
            TIME POINT 2              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
            TIME POINT 3              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
            …                         …       …            …              …            …          …            …            …      
            <All other time points>   xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
                                                                                                                                   
GDC-9545/   BASELINE                      xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)                                       
F12 Cap     TIME POINT 1              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
(N=X)       TIME POINT 2              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
            TIME POINT 3              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
            …                         …       …            …              …            …          …            …            …      
            <All other time points>   xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
                                                                                                                                   
…           …                         …       …            …              …            …          …            …            …                                 
                                                                                                                                   
__________________________________________________________________________________________________________________________________                            
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were to receive GDC-9545 IV administration 30 mg as a solution for infusion, 3 mg/mL (10 mL)[B] in Period 1 and 
      GDC-9545/F12 capsule 30 mg [C] and GDC-9545/F18 capsule 30 mg [D] in a randomized manner in Period 2 and 3 in Part 2 
      BASELINE is defined as Day 1, Pre-dose of the corresponding study period                                                                                
      Categories for QTcF interval and QTcF interval increases are based on ICH E14 guidelines                                                                
      N# is the number of subjects with a value at baseline and the relevant post-dose time point. It is the denominator for                                  
      calculating the percentages of subjects, n indicates the number of subjects with observations at the given time point                                   
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                                                 DDMMMYYYY HH:MM                         
 
 
                                                   


    
 
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Appendix 1: Part 1 Schedule of Activities 
Study Procedures 
Screening 
Residency in Clinical Unit 
Days
–28 to –2 
–1a 
1 
2 
3 
4 
5 
6 
Time after study drug dosing (hours) b
 
 
Pre-
dose 
0 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 48 72 96 120 
Informed consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Vital signs g 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Laboratory safety tests h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screen k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol and FSH l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test m 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


    
 
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Study Procedures 
Screening 
Residency in Clinical Unit 
Days
–28 to –2 
–1a 
1 
2 
3 
4 
5 
6 
Time after study drug dosing (hours) b
 
 
Pre-
dose 
0 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 48 72 96 120 
Adverse event monitoring n 
 
Prior and concomitant medications o 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples for GDC-9545 and 
total radioactivity PK p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood samples for total 
radioactivity PK p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma samples for metabolite profiling 
and ID p 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine samples for total radioactivity and 
metabolite profiling and identification q 
 
 
 
Feces samples for total radioactivity 
and metabolite profiling and 
identification r 
 
 
Confinement in the clinic 
 
 
 
 


    
 
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Study Procedures 
Residency in Clinical Unit 
Return Visits 
Days
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21s 
28s 
35s 
42s 
Time after study drug dosing (hours) b 144 168 
192 
216 
240 
264 
288 
312 
336 
360 
384 
408 
432 
456 
480 
648 
816 984 
Limited physical examination f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
12-lead safety ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Laboratory safety tests h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse event monitoring n 
 
Prior and concomitant medications o 
 
Plasma samples for GDC-9545 and 
total radioactivity PK p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood samples for total 
radioactivity PK p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma samples for metabolite profiling 
and ID p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine samples for total radioactivity and 
metabolite profiling and identification q 
 
X 
X 
X 
Feces samples for total radioactivity 
and metabolite profiling and 
identification r 
 
X 
X 
X 
Confinement in the clinic 
 
X 
X 
X 
 
 


    
 
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a Admission to the clinical unit.  Eligibility will be reassessed at admission/pre-dose. 
b All assessments will be timed and performed relative to the start of dosing 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days before initiation 
of study treatment. 
d Update only 
e Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems. 
f 
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated. 
g Includes pulse rate, and systolic and diastolic blood pressure while the subject is in a supine position, and oral temperature at all time points. 
h Hematology includes white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit (packed cell volume), mean cell hemoglobin, mean 
cell hemoglobin concentration, mean cell volume, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes).  
Chemistry panel (serum) includes magnesium, sodium, potassium, chloride, glucose, fasting glucose, urea, creatinine, creatine kinase, total protein, albumin, 
phosphate (inorganic), calcium, total bilirubin, direct bilirubin (only if total is elevated), alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma glutamyl transferase (GGT), and bicarbonate.  Creatinine clearance will be estimated at screening from serum creatinine 
using the Cockcroft-Gault equation for eligibility purposes.  Coagulation panel includes international normalized ratio (INR), activated partial thromboplastin 
time (APTT), thrombin time and prothrombin time (PT). 
i 
Includes pH, specific gravity, glucose, protein, ketones, blood, bilirubin, leukocytes, nitrites, urobilinogen. Microbiology and/or microscopic urinalysis 
examination, at the discretion of the Investigator based on urinalysis results (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
j 
Amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, phencyclidine, and 
tricyclic anti-depressants. 
k HBsAg, HCV Antibody, HIV Antibody for all subjects. 
l 
Estradiol and FSH for post-menopausal female subjects only. 
m All subjects must have a negative highly sensitive serum pregnancy test result at screening and a negative highly sensitive urine pregnancy test at 
admission. 
n After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should 
be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  All deaths that occur during the 
protocol-specified adverse event reporting period (see protocol Section 5.3.1), regardless of relationship to study drug, must be recorded on the Adverse 
Event eCRF and immediately reported to the Sponsor (see protocol Section 5.4.2).  Deaths that occur after the adverse event reporting period should be 
reported as described in protocol Section 5.6.  In addition, the Sponsor should be notified if the Investigator becomes aware of any serious adverse event that 
is believed to be related to prior study drug treatment (see protocol Section 5.6). 
o Medication (e.g., prescription drugs, over-the-counter drugs, HRT, vaccines, topical medications, herbal or homeopathic remedies, nutritional supplements) 
used by a subject in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until discharge from the study. 


    
 
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p See Appendix 3 for detailed schedule.  Blood sample collection will be at pre-dose, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, and at 24-hour 
intervals thereafter until study completion/early termination.  Permissible time windows for PK sampling are: pre-dose, ≤1 hour before dosing; 1 hour post-
dose, ±5 minutes; 1.5 to 8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 480 hours, ±4 hours; 648 to 984 hours, ±1 day 
q A single urine sample will be collected at pre-dose (the first void of the day) and then at the following collection periods: 0 to 12 hours, 12 to 24 hours, and 
then daily (24 hour intervals) until the mass balance discharge criteria have been met or until Day 21, and then on a weekly basis starting on Day 28 (until 
criteria met or Day 42 reached). 
r The pre-dose feces sample will be taken in the 24 hours period before dosing (between admission and pre-dose).  Post-dose feces will be collected at 24 
hour intervals until the mass balance discharge criteria have been met or until Day 21, and then on a weekly basis starting on Day 28 (until criteria met or 
Day 42 reached). 
s It is planned that subjects will remain resident in the clinical unit until 480 hours post-dose (Day 21) when they will be discharged from the clinical unit. The 
same procedures are to be performed at early termination/withdrawal as at discharge.  Subjects may be discharged as a group earlier if the mass balance 
discharge criteria have been achieved.  If the criteria have not been met by Day 21, subjects will be discharged from the clinical unit and those who have not 
met the discharge criteria will return for outpatient visits every 7 days for a 24-hour sample collection interval until the mass balance discharge criteria are met 
(the maximum number of 24hour return visits will not exceed 3).  If additional residency is not considered appropriate or necessary, then home collections of 
urine and/or feces- may be requested at the discretion of the Investigator for individual subjects.  Safety discharge assessments will be performed at the time 
of actual discharge or early termination/withdrawal from the clinical unit.  PK, TR and metabolite profiling and identification blood samples to be collected at 
480 hours post-dose or at time of actual discharge/early termination, if earlier. Any subject who discontinues or is withdrawal from the study after being 
discharge from the clinical unit will be asked to return to clinical unit to undergo early termination/withdrawal procedures. 
 
 
 


    
 
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Appendix 2: Part 2 Schedule of Activities 
Study Procedures 
Screening  
Study days in each period 
 
–28 to –2 
-1a 
1 
2 
Time after study drug dosing (hours) – 
(relative to start of IV infusion for 
Treatment B) b 
 
 
Pre-
dose 
0 0.25 0.5 0.58 0.67 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 
Informed consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination g 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Vital signs i 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Laboratory safety tests j 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis k 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen l 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide breath test 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screen m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol and FSH n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test o 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


    
 
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Study Procedures 
Screening  
Study days in each period 
 
–28 to –2 
-1a 
1 
2 
Time after study drug dosing (hours) – 
(relative to start of IV infusion for 
Treatment B) b 
 
 
Pre-
dose 
0 0.25 0.5 0.58 0.67 
1 
1.5 
2 
2.5 
3 
4 
5 
6 
8 
12 
24 
Adverse event monitoring p 
 
Prior and concomitant medications q 
 
Study drug administration r 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples for GDC-9545 PK s 
 
 
X 
 
Xt 
Xt 
Xt 
Xt 
X 
X 
X 
Xu 
X 
X 
Xu 
X 
X 
X 
X 
Confinement in the clinic 
 
 
 
 
 


    
 
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Study Procedures 
Study days in each period 
Follow-Up 
Phone Call 
 
3 
4 
5 
6 
7 
8v 
14 to 16w 
Time after study drug dosing (hours) – 
(relative to start of IV infusion for 
Treatment B) b 
48 
72 
96 
120 
144 
168 
 
Limited physical examination g 
 
 
 
 
 
Xx 
 
12-lead safety ECG 
 
 
 
 
 
Xx 
 
Vital signs i 
 
 
 
 
 
Xx 
 
Laboratory safety tests j 
 
 
 
 
 
Xx 
 
Urinalysis k 
 
 
 
 
 
Xx 
 
Adverse event monitoring p 
 
Prior and concomitant medications q 
 
Plasma samples for GDC-9545 PK s 
X 
X 
X 
X 
X 
Xy 
 
Confinement in the clinic 
 
 
0.25 hours = 15 minutes, 0.5 hours = 30 minutes, 0.58 hours = 35 minutes; 0.67 hours = 40 minutes 
a Admission to the clinical unit (Period 1 only).  Subjects will be resident in the clinical unit for 28 to 29 consecutive nights that will cover all 3 treatment periods. 
Eligibility will be reassessed at admission/pre-dose. 
b All assessments will be timed and performed relative to the start of dosing 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days before initiation 
of study treatment. 
d Period 1 only 
e Update only (Period 1 only). 
f 
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems. 
g Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated. 
h Periods 1, 2 and 3 
i 
Includes pulse rate, and systolic and diastolic blood pressure while the subject is in a supine position, and oral temperature at all time points. 


    
 
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Reporting and Analysis Plan GP42662(QSC204283) Final v1.0  
 
                                 
 
 
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j 
Hematology includes white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit (packed cell volume), mean cell hemoglobin, mean 
cell hemoglobin concentration, mean cell volume, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes).  
Chemistry panel (serum) includes magnesium, sodium, potassium, chloride, glucose, fasting glucose, urea, creatinine, creatine kinase, total protein, albumin, 
phosphate (inorganic), calcium, total bilirubin, direct bilirubin (only if total is elevated), alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma glutamyl transferase (GGT), and bicarbonate.  Creatinine clearance will be estimated at screening from serum creatinine 
using the Cockcroft-Gault equation for eligibility purposes.  Coagulation panel includes international normalized ratio (INR), activated partial thromboplastin 
time (APTT), thrombin time and prothrombin time (PT). 
k Includes pH, specific gravity, glucose, protein, ketones, blood, bilirubin, leukocytes, nitrites, urobilinogen. Microbiology and/or microscopic urinalysis 
examination, at the discretion of the Investigator based on urinalysis results (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
l 
Amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, phencyclidine, and 
tricyclic anti-depressants. 
m HBsAg, HCV Antibody, HIV Antibody for all subjects. 
n Estradiol and FSH for post-menopausal female subjects only. 
o All subjects must have a negative highly sensitive serum pregnancy test result at screening and a negative highly sensitive urine pregnancy test at 
admission. 
p After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should 
be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  All deaths that occur during the 
protocol-specified adverse event reporting period (see protocol Section 5.3.1), regardless of relationship to study drug, must be recorded on the Adverse 
Event eCRF and immediately reported to the Sponsor (see protocol Section 5.4.2).  Deaths that occur after the adverse event reporting period should be 
reported as described in protocol Section 5.6.  In addition, the Sponsor should be notified if the Investigator becomes aware of any serious adverse event that 
is believed to be related to prior study drug treatment (see protocol Section 5.6). 
q Medication (e.g., prescription drugs, over-the-counter drugs, HRT, vaccines, topical medications, herbal or homeopathic remedies, nutritional supplements) 
used by a subject in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until discharge from the study. 
r Treatment B will be administered intravenously over 30 minutes (as an infusion). For Treatment B only, to assess tolerability of the IV administration, the first 
subject will be dosed as a sentinel; then, at least 4 hours later, the second subject will be dosed only if there are no acute safety findings for the first subject. 
If the first two subjects tolerated the IV dose, in the opinion of the Principal Investigator and Medical Monitor, the remaining subjects will be dosed. The third 
subject will be dosed at least 20 hours after the second subject (i.e., at least 24 hours after the first subject). All subsequent dosing of the IV formulation will 
be staggered by at least 15 minutes. For Treatments C and D, all subjects will be dosed as a single cohort. 
s See Appendix 4 for detailed schedule.  Permissible time windows for PK sampling and other assessments are: pre-dose, ≤1 hour before dosing; 0.25 to 
0.5 hours post-dose, ±2 minutes; 0.58 to 1 hour, ±5 minutes; 1.5 to 8 hours, ±15 minutes; 12 to 24 hours, ±30 minutes; 48 to 168 hours, ±4 hours. 
t 
Treatment B (IV dose only). 0.5 hours sample to be taken immediately after IV administration (i.e., 30 minutes after the start of the IV administration) 
u Treatments C and D (oral doses) only. 
v Discharge from clinical unit in Period 3 only. The same procedures are to be performed at early termination/withdrawal as at discharge.  


    
 
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w Follow-up telephone call at 13 to 15 days post-final dose. 
x Period 3 only; safety discharge assessments will be performed at the time of actual discharge/early termination from the clinical unit 
y Periods 1, 2 and 3. In Period 3, PK blood samples to be collected at 168 hours post-dose or at time of actual discharge/early termination if earlier.