Preoperative Window of Opportunity Study With Giredestrant (GDC-9545) or Tamoxifen in Premenopausal Women With Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative & Ki67≥10% Early Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer, Breast Cancer, Early-Onset
Sponsor: MedSIR

EU CT#: 2023-503565-36-00 
Study Code#: MEDOPP459 
CSP Version, Date: 3.0, 06-Nov-2023 
 
 
 
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Clinical Study Protocol (CSP) 
 
 
PREOPERATIVE WINDOW OF OPPORTUNITY STUDY WITH GIREDESTRANT (GDC-9545) 
OR TAMOXIFEN IN PREMENOPAUSAL WOMEN WITH ER[+]/HER2[-] & KI67 ≥10% EARLY 
BREAST CANCER  
(<The EMPRESS Study>) 
 
 
 
Study Code: MEDOPP459 
EU CT #: 2023-503565-36-00 
Clinicaltrials.gov #: NCT05659563 
 
Investigational Medicinal Product(s): Giredestrant (GDC-9545), tamoxifen 
CSP Version, Date: 3.0, 06-Nov-2023 
 
CSP Review History 
1. CSP version, date: 1.0, 27-Jan-2023 (Initial Submitted CSP Version) 
2. CSP version, date: 2.0, 27-Apr-2023 (Initial Approved CSP Version) 
3. CSP version, date: 3.0, 06-Nov-2023 
 
 
 
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SPONSOR’S SIGNATURE PAGE 
 
Study title: PREOPERATIVE WINDOW OF OPPORTUNITY STUDY WITH GIREDESTRANT 
(GDC-9545) OR TAMOXIFEN IN PREMENOPAUSAL WOMEN WITH ER[+]/HER2[-] & KI67 
≥10% EARLY BREAST CANCER (<The EMPRESS Study>) 
 
Study Code: MEDOPP459 <EMPRESS> 
 
CSP Version, Date: 3.0, 06-Nov-2023 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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KEY CONTACT DETAILS 
Sponsor 
Name: 
 
 
Contact Name:  
 
Address: 
 
 
Phone/Fax: 
 
 
E-mail: 
 
 
 
Sponsor’s Medical Scientist 
Name: 
 
 
Address: 
 
 
Phone: 
 
 
Fax:  
 
 
E-mail: 
 
 
 
Sponsor’s Safety Risk Management 
Name: 
 
Medica Scientia Innovation Research (MEDSIR) 
Address: 
 
Torre Glòries, Av. Diagonal 211, Planta 27, 08018 Barcelona (Spain) 
Phone: 
 
+ 34 932 214 135 
Fax:  
 
+ 34 932 992 382 
E-mail: 
 
EMPRESS_pharmacovigilance@medsir.org 
 
Study Principal Investigator 
Name: 
 
 
Email: 
 
 
Position:  
 
 
Institution: 
 
 
 
Study Co-Principal Investigator 
Name: 
 
 
Email: 
 
  
Position:  
 
 
Institution: 
 
 
 
 
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STEERING COMMITTEE 
Name 
Role 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DECLARATION OF INVESTIGATORS 
 
Study title: PREOPERATIVE WINDOW OF OPPORTUNITY STUDY WITH GIREDESTRANT 
(GDC-9545) OR TAMOXIFEN IN PREMENOPAUSAL WOMEN WITH ER[+]/HER2[-] & KI67 
≥10% EARLY BREAST CANCER (<The EMPRESS Study>) 
 
Study Code: MEDOPP459 
 
I have received, reviewed and understood the following: 
a) Clinical Study Protocol (CSP) Version, Date: 3.0, 06-Nov-2023. 
b) Investigator’s Brochure (IB) of giredestrant (GDC-9545) and Summary of Product 
Characteristics (SmPC) for tamoxifen with details of clinical and nonclinical data that are 
relevant to the study of the products in human subjects.  
 
I have been adequately informed about the development of the investigational products to 
date. I will confirm the receipt of updated IB and SmPCs. I have read this study protocol and 
agree that it contains all the information required to conduct the study. I agree to conduct the 
study as set out in this protocol. 
 
I fully understand that any changes instituted by the investigator(s) without previous 
agreement with the Sponsor would constitute a violation of the protocol, including any 
ancillary studies or procedures performed on study patients (other than those procedures 
necessary for the wellbeing of the patients). I am aware that I cannot deviate from or apply 
changes to the protocol without prior approval or the favorable opinion of the Institutional 
Review Board (IRB) or Ethics Committee (EC) and/or before Sponsor’s agreement to avoid 
immediate risk to the trial patients. If this occurs, I agree to inform the Sponsor as to the 
deviation or changes in writing and their reasons, as soon as possible. 
 
I will not enroll the first patient in the study until I have received approval from the appropriate 
IRB/EC and until all legal and regulatory requirements in my country have been fulfilled. 
 
The study will be conducted in accordance with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and its amendments, the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines 
(ICH E6(R2) GCP) and applicable regulations and laws. 
 
I agree to obtain, in the manner described in this protocol and in (ICH E6(R2) GCP), signed 
informed consent form (ICF) by the patient or witnessed verbal ICF to participate for all 
patients whose participation in this study is proposed to and before any patient’s study specific 
procedure is done. 
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 
I will ensure that the study drug(s) supplied by the Sponsor are being used only as described 
in this protocol and in the latest version of the IB. 
 
I am aware of the requirements for the correct reporting of safety events according to the 
protocol, and I commit to document and to report such events as required by the Sponsor 
and in accordance with Health Authority Regulatory requirements. 
 
I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of 
current laboratory accreditation, the name and address of the laboratory, and a list of normal 
values and ranges. 
 
I agree with the use of results of the study for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. 
 
I agree to keep all source documents and case report forms as specified in the relevant 
sections of this protocol. 
 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, 
sub-investigators and of any member of my study team (if requested) before the study starts, 
which may be submitted to regulatory authorities. 
 
I am aware of the possibility of being audited by the Sponsor or its delegate or inspected by 
regulatory authorities for the performance of this study. I will permit monitoring, auditing and 
inspection and provide direct access to source data/documents and reports for these 
purposes. 
 
Furthermore, I confirm herewith that the Sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes and 
for submission to Health Authorities worldwide. 
 
 
Name:  _____________________________________________________________________ 
 
Signature: _________________________ 
 
Date: __________________________ 
 
 
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CLINICAL STUDY PROTOCOL (CSP) SYNOPSIS 
CSP Title: 
Preoperative window of opportunity study with giredestrant (GDC-
9545) or tamoxifen in premenopausal women with ER[+]/HER2[-] & 
Ki67 ≥10% early breast cancer (EBC). 
CSP Short Title: 
The EMPRESS Study 
Study Code: 
MEDOPP459 
EU CT #: 
2023-503565-36-00 
Clinicaltrials.gov #: 
NCT05659563 
Trial Design:  
This is a multicenter, international, open-label, two-arms, one stage, 
phase II, window of opportunity, clinical trial. 
Investigational 
Medicinal Products:  
Giredestrant (GDC-9545), tamoxifen. 
Target Disease:  
ER[+]/HER2[-] & Ki67 ≥10% EBC. 
Patients:  
Women ≥18 years of age with well-defined premenopausal status and 
previously untreated histologically confirmed ER[+]/HER2[-] primary 
invasive adenocarcinoma of the breast with locally analyzed and 
centrally confirmed Ki67 ≥10%*, and tumor size ≥1.0 cm in longest 
diameter by ultrasound. Patients with distant metastatic disease are 
not eligible. 
Patients diagnosed with multifocal or multicentric breast cancer with at 
least one lesion ≥1.0 cm in the longest diameter by ultrasound 
(reference lesion) are also eligible if the largest tumor lesions have 
been histologically confirmed in the clinical evaluation and meet 
pathologic criteria for ER positivity and HER2 negativity. The reference 
lesion will be used to assess changes in tumor cell proliferation as 
measured by Ki67 expression.  
Patients must have an adequate organ function. Patients must agree 
to provide a primary tumor tissue sample and a blood sample obtained 
at baseline as well as a post-treatment tumor tissue and a blood 
sample (breast biopsy or from breast surgery, which will be performed 
either on the last day of treatment or the following day).  
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*Ki67 will be analyzed locally at the time of inclusion. Patients with 
basal Ki67 ≥20% will be assessed locally and centrally confirmed 
retrospectively and patients with 10-19% will be assessed centrally 
before inclusion.  
Number of patients:  92 
Selection criteria: 
Inclusion criteria 
Patients will be included in the study only if they meet ALL the following 
criteria: 
1. Signed Informed Consent Form (ICF) prior to beginning 
specific protocol procedures.  
2. Age ≥18 years at time of signing ICF.  
3. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0-1.  
4. Women with a well-determined premenopausal status as 
indicated in the protocol. 
5. Histologically confirmed invasive breast carcinoma, with all the 
following characteristics:  
a. Documented ER[+] tumor in accordance with American 
Society of Clinical Oncology (ASCO)/College of American 
Pathologists (CAP) guidelines (Allison et al., 2020), 
assessed locally and defined as ≥1% of tumor cells 
stained positive.  
b. Documented HER2[-] tumor in accordance with 2018 
ASCO/CAP guidelines (Wolff et al., 2018), assessed 
locally at baseline. 
Note: Diagnostic biopsy taken no more than 8 weeks prior to 
initiation of study treatment can be used as baseline.  
c. Ki67 score ≥10% analyzed locally and centrally confirmed 
(Nielsen et al., 2021).  
Note: Ki67 will be analyzed locally at the time of inclusion. 
Patients with basal Ki67 ≥20% will be assessed locally and 
centrally confirmed retrospectively and patients with 10-19% 
will be assessed centrally before inclusion.  
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d. Tumor size must be ≥1.0 cm in longest diameter by 
ultrasound as per Response Evaluation Criteria in solid 
Tumors (RECIST) criteria. 
Note: Patients with multifocal or multicentric breast cancer with at least 
one tumor lesion ≥1.0 cm in the longest diameter by ultrasound 
(reference lesion) are also eligible if the two largest tumor lesions have 
been histologically confirmed in the clinical evaluation and meet 
pathologic criteria for ER positivity and HER2 negativity. 
6. Willingness to provide a primary tumor tissue and blood 
sample obtained at baseline as well as a post-treatment tumor 
tissue and a blood sample (breast biopsy or breast surgery). 
7. Patient has adequate bone marrow, liver, and renal function:  
 
Hematological: absolute neutrophil count (ANC) ≥ 1.5 x 
109/L (1500/mL), platelet count ≥ 100.0 x109/L, and 
hemoglobin ≥ 9 g/dL (≥ 90g/L).  
Note: The blood counts are to meet the specified criteria without 
transfusion or growth factor support, unless it is clear that the bone 
marrow function is adequate and that any aberration has a clear and 
correctable cause, and the correction undertaken.  
 
Hepatic: total serum bilirubin ≤ 1.5’ institutional upper limit 
of normal (ULN) (patients with known Gilbert’s syndrome: 
≤ 3’ ULN); alkaline phosphatase (ALP) ≤ 2.5 times ULN; 
aspartate transaminase (AST) and serum alanine 
transaminase (ALT) ≤ 3’ times ULN.  
 
Coagulation: The international normalized ratio (INR) < 
1.5’ ULN and partial thromboplastin time (PTT or aPTT) < 
1.5’ ULN (except for patients receiving anticoagulation 
therapy). For patients receiving warfarin, a stable INR 
between 2 and 3 is required. For patients receiving 
heparin, PTT (or aPTT) between 1.5 and 2.5’ ULN (or 
patient value before starting heparin treatment) is 
required. If anticoagulation therapy is required for a 
prosthetic heart valve, stable INR between 2.5 and 3.5 is 
permitted.  
 
Renal: creatinine clearance ≥ 60 mL/min for patients with 
creatinine levels above institutional normal.  
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8. Negative serum pregnancy test result within 14 days prior to 
initiation of study treatment, and a negative urine pregnancy 
test within 24 hours prior to study treatment initiation.  
Note:  Premenopausal women age ≥18 years with premenopausal 
status defined as: estradiol (E2) in the premenopausal range 
(according to institution parameters) or patient has been menstruating 
regularly during the 6 months prior to randomization and has not used 
any form of hormonal contraception or any other hormonal treatments 
during this time. 
Women must remain abstinent and truly abstain from sexual activity 
(refrains from heterosexual intercourse) or use of locally recognized 
adequate methods of contraception (described as that with a failure 
rate <1%) during the length of the study, and to continue its use for 10 
days after the last dose of study treatment (for patients taking 
giredestrant) or 9 months following cessation of therapy (for patients 
in the tamoxifen arm). They must, as well, agree to refrain from 
donating eggs during the same period. 
Examples of non-hormonal contraceptive method with a failure rate of 
<1% per year (e.g. bilateral tubal ligation, male sterilization and copper 
intrauterine devices). The reliability of sexual abstinence should be 
evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the individual. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not adequate methods of contraception. 
9. Patients must be accessible for treatment and follow-up. 
10. Participants who are able and willing to swallow, retain, and 
absorb oral medication. 
Exclusion criteria:  
Any patient meeting ANY of the following criteria will be excluded from 
the study: 
1. Progesterone receptor (PgR)[+] and ER[-] patients. 
2. cT4 and/or cN2/3 and/or bilateral BC. 
3. Patients who have history of any prior (ipsilateral and/or 
contralateral) invasive breast cancer or Ductal carcinoma in 
situ (DCIS). Participants with a history of contralateral DCIS 
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treated by only local regional therapy at any time may be 
eligible. 
4. Evidence of metastatic disease. 
5. Previous systemic or local treatment for the primary breast 
cancer currently under investigation. 
6. History of any prior treatment with chemotherapy drugs, 
aromatase inhibitors (AIs), tamoxifen, selective estrogen 
receptor down regulator, or cyclin-dependent kinase 4 and 6 
inhibitors (CDK4/6i). 
7. Any invasive malignancy diagnosed within the previous 5 
years prior to screening in this study (other than basal cell 
carcinoma, cervical carcinoma in situ or contralateral DCIS). 
8. Known issues with swallowing oral medication, or inability or 
unwillingness to swallow oral medication. 
9. Participants who have a known clinically significant history of 
liver disease consistent with Child-Pugh Class B or C, 
including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C 
virus [HCV]), current alcohol abuse, cirrhosis, or positive test 
for viral hepatitis, as defined in the protocol. 
10. Active cardiac disease or history of cardiac dysfunction 
including any of the following: 
 
History or presence of symptomatic bradycardia or sick 
sinus syndrome. 
 
Resting heart rate <50 bpm at screening. 
 
History of angina pectoris, symptomatic pericarditis, 
myocardial infarction, or any cardiac arrhythmias (e.g., 
ventricular, 
supraventricular, 
nodal 
arrhythmias, 
or 
conduction abnormality) within 12 months prior to study 
entry. 
 
History of documented congestive heart failure (New York 
Heart Association Class II-IV) or cardiomyopathy. 
 
QT interval corrected through use of Fridericia’s formula 
(QTcF) >470 ms by at least three ECGs >30 minutes 
apart. 
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 
History of long or short QT syndrome, Brugada syndrome 
or known history of corrected QT interval prolongation, or 
torsades de pointes. 
 
History or presence of an abnormal ECG that is clinically 
significant in the investigator’s opinion. 
 
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 
cardiomyopathy, 
infiltrative 
cardiomyopathy, moderate-to-severe valve disease),, 
coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant 
electrolyte 
abnormalities 
(e.g., 
hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of long 
QT syndrome. 
11. Any serious medical condition or abnormality in clinical 
laboratory tests that, in the investigator's judgment, precludes 
the patient's safe participation in and completion of the study.  
12. Treatment with strong CYP3A4 inhibitors or inducers within 14 
days or 5 drug elimination half-lives (whichever is longer) prior 
to randomization.  
13. Active inflammatory bowel disease or chronic diarrhea, short 
bowel syndrome, or major upper gastrointestinal surgery 
including gastric resection. 
14. Participants who have a known allergy or hypersensitivity to 
any of the study drugs or any of their excipients. 
15. Participants who are pregnant or breastfeeding or intending to 
become pregnant during the study or within 10 days after the 
final dose of giredestrant (GDC-9545), or within 9 months after 
the final dose of tamoxifen.  
Note: Women of childbearing potential must have a negative serum 
pregnancy test result within 14 days prior to initiation of study treatment 
and a negative urine pregnancy test within 24 hours prior to study 
treatment initiation. 
16. Patients with renal dysfunction who require dialysis. 
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17. Participants who have had a serious infection requiring oral or 
IV antibiotics within 14 days prior to screening or other 
clinically significant infection (e.g., COVID-19) within 14 days 
prior to screening. 
Note: Participants who have fully recovered from serious or clinically 
significant infections at least 14 days prior to screening are eligible. If 
a participant exhibits signs or symptoms of potential COVID-19 
infection and there is a reasonable suspicion of exposure, 
investigators are to follow the American Society of Clinical Oncology 
2020 guidelines or institutional guidelines on testing. 
18. Participants who have had a major surgical procedure 
unrelated to breast cancer within 28 days prior to 
randomization. 
19. Participants who are unable or unwilling to comply with the 
requirements of the protocol in the opinion of the investigator.  
Study objectives:  
Primary objectives 
 
To assess changes in tumor cell proliferation as measured by 
Ki67 expression between baseline and post-treatment tumor 
biopsy samples by central assessment in patients with 
centrally confirmed Ki67 ≥10% (Arm A vs Arm B). 
Secondary objectives 
 
To measure complete cell cycle arrest (CCCA) in all arms, 
defined by Ki67 ≤2.7% in post-treatment sample.  
 
To analyze changes in ER and PgR levels, and molecular 
profiling using HTG.  
 
To evaluate toxicity according to National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v.5.0. 
 
 
 
 
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 
  
 
Study Endpoints: 
Primary endpoint 
 
Changes in tumor cell proliferation as measured by Ki67 
expression between baseline and post-treatment tumor biopsy 
samples by central assessment in patients with centrally 
confirmed Ki67 ≥10% (Arm A vs Arm B). 
Secondary endpoint 
 
CCCA in all arms, defined as the percentage of participants 
with centrally assessed Ki67 scores ≤2.7% stained nuclei 
upon treatment (post-treatment sample).  
 
Changes in markers (such as ER and PgR levels) and 
molecular profiling using HTG (PAM-like molecular test).  
 
Incidence and severity of adverse events (AEs), with severity 
determined in accordance with NCI-CTCAE v.5.0. 
 
 
  
 
Study treatment: 
Investigational Medicinal Products (IMPs) will be giredestrant (GDC-
9545) (test product) and tamoxifen (comparator).  
Eligible participants will be randomly assigned in a 1:1 ratio to either 
Arm A (treatment with giredestrant [GDC-9545]) or Arm B (treatment 
with tamoxifen).  
 
Giredestrant (GDC-9545): 30mg, orally (PO), daily (QD) on 
days 1-15.   
 
Tamoxifen: 20mg, PO, QD on days 1-15.   
Patients will be treated for a total of 15 days. 
Note: If post-treatment surgery or biopsy cannot be performed within 
+ 1 day from last day of treatment (15 days), treatment will be extended 
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to 16 days and surgery or biopsy will be performed on the following 
day. 
Study Procedures, 
Efficacy, and Safety 
Assessments: 
Screening period 
After signing the ICF and after confirming eligibility through the 
screening process, patients will be biopsied to confirm Ki67 score.   
Note: if a diagnostic biopsy was performed maximum 8 weeks prior to 
initiation of study treatment, it can be used as a baseline sample for 
the Ki67 assessment.     
Patient visits 
After confirming eligibility through the screening process, patients will 
be scheduled a visit for day 1 (D1) of treatment within 48 h after 
randomization. This visit must be scheduled as soon as possible upon 
reception of Ki67 score result (maximum 8 weeks between biopsy and 
the scheduled C1D1).  
In this first visit, medical history, including clinically significant 
diseases, surgeries, cancer history, and reproductive status will be 
recorded at baseline. In addition, all medications (e.g., prescription 
drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days 
prior to initiation of study treatment will be recorded. Also, for visit day 
1 (D1) of treatment, patients will be given the first dose of treatment 
and will be instructed how to take giredestrant (GDC-9545) or 
tamoxifen orally, daily at their homes during the following 14 days (D2 
to D15, to finalize a total of 15 days of treatment).  
Interruptions or delays due to any reason should be discussed with the 
medical monitor.  
To assess patient compliance with self-administration of study 
medication, site study staff will provide patients with detailed 
instructions and training for the handling and administration of study 
drugs. Patients will receive and should be instructed to complete a 
medication diary to record all relevant information during those days.  
A second biopsy will be collected at the end of treatment (EoT) after 
last dose of study treatment is taken by the patient. If post-treatment 
surgery or biopsy cannot be performed within + 1 day from last day of 
treatment (that is, on Day 15 or Day 15 +1), treatment will be extended 
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to 16 days and surgery or biopsy will be performed on the following 
day (be it Day 15 + 2 days). 
Patients will attend the clinic again for an end of study (EoS) visit 28 
days (+/- 3 days) after last dose of study treatment is taken.   
Assessments 
- 
Mandatory tumor tissue biopsy samples will be collected 
before the start of treatment (up to a maximum of 8 weeks 
before the first dose of study drug). If a diagnostic biopsy was 
performed maximum 8 weeks prior to study treatment 
initiation, it can be used as a baseline sample for the Ki67 
assessment. Additional biopsy will be taken at the EoT (+ 1 
day) after the last dose of study drug. If post-treatment surgery 
or biopsy cannot be performed within + 1 day from last day of 
treatment (15 days), treatment will be extended one extra day 
and patients will be able to have surgery or biopsy the 
following day (be it D15 + 2 days).  Mandatory liquid biopsy 
samples will be obtained before the start of treatment (up to a 
maximum of 14 days before the first dose of study drug) and, 
if possible, at the same timepoint as baseline hematological 
laboratory assessments. Post-study treatment liquid biopsy 
samples will be taken at the same timepoint, if possible, as 
post-study treatment tumor biopsies.  
- 
Visits scheduled for D1 and EoT will include an evaluation of 
vital signs (including: measurements of weight, respiratory 
rate, heart rate,  systolic and diastolic blood pressure while the 
patient is in a seated position, and temperature), physical 
examination (a complete physical examination should include 
the evaluation of head, eye, ear, nose, and throat; 
cardiovascular; dermatological; musculoskeletal; respiratory; 
gastrointestinal; and neurological systems), and analysis of 
laboratory results (including biochemical and hematological 
analysis, as well as pregnancy test). EoT visit will also include 
a review of the patient diary and new or worsened clinically 
significant abnormalities.  
- 
ECOG Performance status will be completed at screening and 
as specified in the schedule of activities. 
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- 
Known breast ultrasound result will be mandatory at screening 
(prior to randomization). 
- 
Baseline staging to document absence of metastatic disease 
should be performed as per institutional practice, in alignment 
with national guidelines and as clinically indicated, in patients 
where there may be a reasonable suspicion of advanced 
disease (e.g., clinically positive axillary lymph nodes, signs 
and symptoms). If performed, it must be within 28 days prior 
to randomization and reports of these examinations must be 
available. Examination type for tumor staging is at the 
discretion of the investigator and includes, for example, i.e. X-
ray, sonography, bone scan, CT, MRI, and/or PET-CT. 
- 
Single 12-lead ECGs will be obtained as outlined in the 
schedule of activities using an ECG machine that 
automatically calculates the heart rate and measures RR 
interval, QRS interval, QT interval, and QT interval corrected 
through use of Fridericia's formula (QTcF)/QT interval, PR 
duration. 
- 
The occurrence and maximum grade of side effects observed 
throughout the study will be listed and tabulated according to 
type and dose level. Any AEs that the investigator reports as 
unrelated to the drug will also be reported. In this study, side 
effects will be assessed according to the NCI-CTCAE v5.0.  
- 
Concomitant therapy (e.g. prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient will be collected in 
addition to protocol-mandated treatment from 7 days prior to 
initiation of study drug to treatment discontinuation or end of 
study visit. 
All assessments will be performed on the day of the specified visit 
unless a time window is specified (see Section 3.3.2). 
Safety follow-up 
All patients will be followed up for up to 28 days (+/- 3 days) after the 
last dose of the study treatment or discontinuation (regardless of the 
reason for discontinuation), in order to follow up toxicities and changes 
in concomitant medication. 
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Sample 
size 
and 
statistical methods: 
Primary analysis 
The analysis will compare absolute changes for Ki67 expression 
between the baseline and the post-treatment tumor biopsy samples by 
central assessment. 
Sample size 
The sample size was based on a superiority contrast between two 
study arms analyzed with a two-sided t-test set at 0.05 alpha level. We 
assumed a 70% mean in giredestrant (GDC-9545) Arm vs. 50% mean 
in tamoxifen with a 29% common standard deviation, according to the 
results observed in Dowsett M et al 2005. We planned 34 patients per 
arm to attain an 80% power.  
The final analysis will be conducted with unpaired Wilcoxon test 
because of the non-asymptotic distribution of data. We assumed that 
asymptotic efficiency of Wilcoxon test relative to the t-test, never falls 
below 0.86 (10.1214/aoms/1177728261). In addition, we expect a 10% 
dropout rate. So, 46 patients per arm will be finally recruited. We used 
the R software version 4.0.2. released on 2020-06-22 (“pwr”). 
Analysis methods 
The primary analysis will be conducted on the modified intention to 
treat (mITT) set which includes all randomly assigned patients that 
accomplish major selection criteria and underwent the appropriate 
assessment for central Ki67 values. We will use Wilcoxon unpaired 
test set at 0.05 alpha level. It includes treatment as a factor. The 
response variable is the change in tumor cell proliferation as measured 
by Ki67 expression between baseline and the post-treatment tumor 
biopsy samples by central assessment.  We propose declaring the 
superiority of giredestrant (GDC-9545) therapy if shown to be superior 
in this analysis. 
Supportive analysis for primary endpoint will be conducted in intention 
to treat set which includes all randomly assigned patients; and per 
protocol set which includes all randomly assigned patients without 
major protocol deviations. Missing values will be managed with last 
observation carried forward and multiple imputation methods for 
nonparametric and parametric methods, respectively. We will also 
analyze the primary endpoint with linear regression model adjusted by 
baseline Ki67 scores.  
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Secondary endpoints will be analyzed in the mITT set, comprised by 
all randomly assigned patients that accomplish major selection criteria 
(Central Ki67 ≥ 10%) with Ki67 evaluable values at baseline and after 
the treatment. Subjects will be analyzed according to treatment 
allocated. The mITT set will be used for primary and secondary 
efficacy analysis with parametric and non-parametric tests. 
 
The incidence and severity of AEs and safety parameters will be 
reported in safety analysis set. It includes all patients that received at 
least one dose of study drugs. We will summarize safety endpoints 
with frequencies and percentages per arm. 
Study calendar: 
Recruitment period: Estimated enrollment period will be 16 months. 
EoS will occur at 45 days (1.5 months) after last patient starts 
treatment unless premature termination of the study. 
 
 
 
 
 
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TABLE OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event  
AI 
Aromatase inhibitor 
ALT 
Alanine transaminase 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count  
ASCO 
American Society of Clinical Oncology  
AST 
Aspartate transaminase  
BC 
Breast Cancer  
BL 
Basal-like  
 
CAP 
College of American Pathologists  
CBR 
Clinical benefit rate 
  
CCCA 
Complete cell cycle arrest 
CDK4/6i 
Cyclin-dependent kinase 4 and 6 inhibitors 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval  
CRF 
Case report form 
CSP 
Clinical Study Protocol  
CSPV 
Clinical Safety and Pharmacovigilance 
CT 
Computed tomography 
  
CTCAE 
Common Terminology Criteria for Adverse Events 
DCIS 
Ductal carcinoma in situ 
DFS 
Disease free survival 
 
DoR 
Duration of response  
DSE 
Drug Safety Evaluation 
EBC 
Early breast cancer 
EC 
Ethics committee  
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ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EoS 
End of study  
EoT 
End of treatment  
ER 
Estrogen receptor 
  
ET 
Endocrine therapy 
FDA 
Food and Drug Administration  
FN 
Febrile neutropenia  
GCP 
Good clinical practice  
HIV 
Human immunodeficiency virus  
HER2 
Human Epidermal Growth Factor Receptor 2  
HR 
Hormone receptor, Hazard Ratio 
IB 
Investigator’s Brochure (IB)  
ICF 
Informed consent form  
HA 
Alternative hypothesis  
IDFS 
Invasive disease-free survival 
H0 
Null hypothesis  
IHC 
Immunohistochemistry  
ICH 
International Conference on Harmonization  
IMP 
Investigational medicinal product 
IRB 
Institutional review board  
ITT 
Intention-to-treat 
LDH 
Lactate dehydrogenase 
LHRH 
Luteinizing hormone-releasing hormone  
mITT 
Modified intention to treat 
MRI 
Magnetic resonance imaging  
NCCN 
National Comprehensive Cancer Network  
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events  
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NCI 
National Cancer Institute  
 
NET 
Neoadjuvant endocrine therapy 
NIS 
National Inpatient Sample  
NNT 
Number needed to treat  
OFS 
Ovarian function suppresion 
ORR 
Objective response rate  
OS 
Overall survival  
QD 
Once a day 
QoL 
Quality of life  
pCR 
Pathologic complete response  
PEPI 
Preoperative endocrine prognostic index 
PFS 
Progression-free survival  
PgR 
Progesterone receptor  
PO 
Orally 
PR 
Partial Response  
QT interval 
measure between Q wave and T wave in the heart’s 
electrical cycle 
QTcF 
Corrected QT interval using the Fridericia formula 
RECIST 
Response Evaluation Criteria In Solid Tumors  
RR 
Relative risk  
SAE 
Severe adverse effect  
SERD 
Selective estrogen receptor degrader 
SERM 
Selective estrogen receptor modulator 
SmPC 
Summary of product characteristics 
SoC 
Standard of care  
TPC 
Treatment of physician’s choice  
TtR 
Time to response  
UGT1A1 
Uridine diphosphate-glucuronosyl transferase 1ª1 
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ULN 
Upper limit of normal 
WoO 
Window of opportunity 
 
 
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TABLE OF CONTENTS 
SPONSOR’S SIGNATURE PAGE ................................................................................... 2 
KEY CONTACT DETAILS .............................................................................................. 3 
STEERING COMMITTEE ............................................................................................. 4 
DECLARATION OF INVESTIGATORS ............................................................................ 5 
CLINICAL STUDY PROTOCOL (CSP) SYNOPSIS ............................................................. 7 
TABLE OF ABBREVIATIONS ...................................................................................... 20 
TABLE OF CONTENTS .............................................................................................. 24 
LIST OF TABLES ....................................................................................................... 28 
1 
BACKGROUND ON HORMONE RECEPTOR-POSITIVE BREAST CANCER ................ 29 
1.1 
Hormone receptor-positive breast cancer .......................................................... 29 
1.2 
Treatment of hormone receptor-positive early breast cancer ............................. 29 
1.3 
Neoadjuvant endocrine treatment for ER-positive BC ........................................ 30 
1.4 
Rationale for Ki67 biomarker as primary endpoint ............................................. 31 
1.5 
Investigational agent : giredestrant (GDC-9545) ................................................. 33 
1.5.1 
Clinical overview of giredestrant (GDC-9545) .................................................................... 33 
1.6 
Rationale for developing a Window-of-Opportunity study in premenopausal 
patients with ER-positive/HER2-negative EBC ................................................................. 35 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 37 
3 
STUDY OVERVIEW ............................................................................................ 38 
3.1 
Study design ..................................................................................................... 38 
3.2 
Study treatment management .......................................................................... 40 
3.3 
Study schedule summary .................................................................................. 40 
3.3.1 
Screening phase .................................................................................................................. 40 
3.3.2 
Treatment Phase and End of Treatment visit ..................................................................... 41 
3.3.3 
Treatment and study discontinuation ................................................................................ 42 
3.3.4 
End of study visit................................................................................................................. 43 
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4 
PATIENT SELECTION .......................................................................................... 44 
4.1 
Target Study Population .................................................................................... 44 
4.2 
Inclusion criteria ............................................................................................... 44 
4.3 
Exclusion criteria ............................................................................................... 46 
5 
STUDY DRUG INFORMATION ............................................................................ 49 
5.1 
Formulation, packaging, and handling ............................................................... 49 
5.2 
Dosage, administration, and compliance ........................................................... 49 
5.3 
Study drug storage and drug accountability ....................................................... 50 
5.4 
Treatment compliance ...................................................................................... 51 
5.5 
Treatment modifications and discontinuation ................................................... 51 
5.6 
Medication errors and overdose ........................................................................ 52 
5.7 
General concomitant medication and additional assistance guidelines ............... 52 
5.8 
Prohibited therapies and medication ................................................................. 53 
5.8.1 
Interaction with other drugs .............................................................................................. 54 
6 
ASSESSMENTS AND STUDY PROCEDURES .......................................................... 55 
6.1 
Patient entry procedures................................................................................... 55 
6.1.1 
Informed consent ............................................................................................................... 55 
6.1.2 
Patient allocation ................................................................................................................ 55 
6.2 
Visit schedule ................................................................................................... 56 
6.3 
Demographic data and medical history .............................................................. 57 
6.4 
Tumor assessments ........................................................................................... 57 
6.4.1 
Ki67 score assessment ........................................................................................................ 57 
6.4.2 
Tumor imaging assessment by ultrasound ......................................................................... 57 
6.5 
Safety and tolerability assessments ................................................................... 58 
6.5.1 
Laboratory assessments ..................................................................................................... 58 
6.5.2 
Pregnancy and assessment of fertility ................................................................................ 58 
6.5.3 
Cardiac function monitoring ............................................................................................... 59 
6.5.4 
Physical examination .......................................................................................................... 60 
6.5.5 
Vital signs ............................................................................................................................ 60 
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6.5.6 
ECOG performance status .................................................................................................. 60 
6.6 
Tumor and blood samples ................................................................................. 61 
6.6.1 
Tumor tissue samples ......................................................................................................... 61 
6.6.2 
Blood samples ..................................................................................................................... 61 
6.7 
Patient discontinuation ..................................................................................... 62 
6.8 
Study and site discontinuation .......................................................................... 62 
7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .................................... 63 
7.1 
AEs definition ................................................................................................... 63 
7.1.1 
SAEs definitions .................................................................................................................. 64 
7.1.1.1 
Definition of life threatening .......................................................................................... 64 
7.1.1.2 
Definition of hospitalization ........................................................................................... 64 
7.1.1.3 
Definition of clinically/medically significant event ......................................................... 65 
7.1.1.4 
Cases of overdose, medication error, drug abuse, or drug misuse ................................ 65 
7.1.2 
AESIs for IMPs ..................................................................................................................... 66 
7.2 
Safety profile and management of AEs for IMPs ................................................ 66 
7.2.1 
AEs and SAE reporting and timeframe ............................................................................... 69 
7.2.2 
Expedited reporting to Health Authorities, Investigators, IRBs, and IECs .......................... 70 
7.2.3 
Other safety-related reports .............................................................................................. 70 
7.2.4 
Pregnancy reporting ........................................................................................................... 70 
8 
STATISTICAL CONSIDERATIONS ......................................................................... 72 
8.1 
Sample size ....................................................................................................... 72 
8.2 
Sample size ....................................................................................................... 72 
8.3 
Populations for Analyses ................................................................................... 72 
8.4 
Primary efficacy endpoint ................................................................................. 73 
8.5 
Missing data imputation methods ..................................................................... 74 
8.6 
Supportive analyses for primary efficacy endpoint ............................................. 74 
8.7 
Secondary and subgroup analyses ..................................................................... 76 
8.8 
Safety analysis .................................................................................................. 77 
8.9 
Exploratory analysis .......................................................................................... 77 
8.10 
Interim analyses ............................................................................................... 77 
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8.11 
Steering committee .......................................................................................... 78 
9 
ETHICAL CONSIDERATIONS ............................................................................... 79 
9.1 
Regulatory and ethics compliance ..................................................................... 79 
9.2 
IRBs/IECs .......................................................................................................... 79 
9.3 
Informed consent ............................................................................................. 79 
9.4 
Data protection ................................................................................................ 80 
10 SOURCE DOCUMENTATION, STUDY MONITORING AND QUALITY ASSURANCE ... 81 
10.1 
Source data documentation .............................................................................. 81 
10.2 
Study monitoring and source data verification ................................................... 82 
10.3 
Retention of records ......................................................................................... 82 
10.4 
Data quality assurance ...................................................................................... 83 
11 DATA MANAGEMENT ....................................................................................... 84 
11.1 
Data entry and management ............................................................................. 84 
11.2 
Data clarification .............................................................................................. 84 
11.3 
Data coding procedures .................................................................................... 84 
12 STUDY MANAGEMENT ..................................................................................... 85 
12.1 
Discontinuation of the study ............................................................................. 85 
12.2 
Changes to the protocol .................................................................................... 85 
12.3 
Publication policy protection of trade secrets .................................................... 85 
13 REFERENCES ..................................................................................................... 86 
 
 
 
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LIST OF TABLES 
Table 1. Clinical trials with neoadjuvant endocrine therapy in ER-positive BC. ................ 32 
Table 2. Ongoing clinical trials with giredestrant (GDC-9545) in BC. .................................. 34 
Table 3. Summary of objectives and endpoints of EMPRESS trial. ..................................... 37 
Table 4. ECOG performance status scale. .............................................................................. 60 
Table 5. Guidelines for Management of Patients Who Experience Adverse Events 
Associated with Giredestrant (GDC-9545). ............................................................................. 67 
Table 6. Planned analyses for the primary endpoint. ............................................................ 75 
 
Appendix 1: Schedule of study assessments and procedures ............................................ 92 
 
 
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1 
BACKGROUND ON HORMONE RECEPTOR-POSITIVE BREAST CANCER 
1.1 
Hormone receptor-positive breast cancer 
Breast cancer (BC) is the most commonly diagnosed cancer worldwide, with an estimated global 
incidence of 2.3 million new cases and almost 685,000 deaths in 2020 (IACR 2020). Notably, 
whereas the incidence of postmenopausal BC has stabilized in many higher-income countries, 
the incidence among premenopausal women under the age of 40 is increasing (Heer et al., 2020). 
Nearly 70% of all BC express the estrogen receptor (ER), which makes these tumors grow and 
progress in response to this hormone. Over the last decade, molecular characterization allowed 
the identification of Luminal A and Luminal B as the main molecular subtypes of ER-positive BC 
(TGCA 2012; Prat et al., 2013). Although it is not clear the difference between the two subtypes 
regarding endocrine therapy  sensitivity (Dunbier et al., 2011; Ellis et al., 2011), Luminal A tumors 
present a better prognosis at 5 to 10-year follow-up compared to the Luminal B subtype (TGCA 
2012; (Prat et al., 2016). 
1.2 
Treatment of hormone receptor-positive early breast cancer 
Endocrine therapy (ET) is regarded the mainstay for ER-positive/HER2-negative BC and should 
be considered for all patients with ER-positive early BC (EBC).  
In 1897, ovarian function suppression (OFS) was the first systemic therapy for cancer. In the 
1960s, ET by modulation of estrogen activity and/or synthesis appeared as key target for the 
treatment of ER-positive BC. In the 1970s, tamoxifen, a non-steroidal selective estrogen-receptor 
modulator (SERM), was approved by the Food and Drug Administration (FDA) as one of the first 
developed oral ET for women with ER-positive BC. Subsequently, aromatase inhibitors (AIs), 
which block the conversion of androgens into estrogens, were developed and commercialized. 
Currently, ET for EBC includes tamoxifen and aromatase inhibitors (AIs) with or without OFS. 
Despite the effectiveness of available therapies, many patients ultimately experience disease 
relapse or develop resistance to these agents (Angus et al., 2017). According to ESMO Clinical 
Practice Guidelines, all luminal-like tumors should be treated with ET. Addition of chemotherapy 
will depend on the amount of disease burden, individual risk of recurrence, presumed 
responsiveness to ET and patient preferences. 
Tamoxifen is the current adjuvant standard of care (SoC) for premenopausal patients with low-
risk (stages I-IIA and luminal A tumors) ER-positive EBC, where treatment duration is usually for 
5 to 10 years (Cardoso et al., 2019). Notably, 5 years of tamoxifen reduces their risk of death from 
breast cancer at 15 years by about one third (Early Breast Cancer Trialists’ Collaborative Group 
(EBCTCG) et al., 2011). 
 AIs for 5 years have demonstrated superiority over tamoxifen both in the advanced and early 
settings in postmenopausal patients. Compared to tamoxifen, AIs produce proportional reductions 
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in recurrence rates of about 30%. In premenopausal women, AIs are also considered in high-risk 
patients in combination with effective OFS  (Breast International Group (BIG) 1-98 Collaborative 
Group et al., 2005; Howell et al., 2005). 
In the SOFT and TEXT trials, AI plus OFS was compared to tamoxifen plus OFS in 
premenopausal women. In a combined updated analysis of these trials, at 12 and 13 years of 
median follow-up, a statistically significant 17% reduction of distant metastasis was observed, 
favoring AI with OFS (P = 0.03). However, overall survival did not significantly differ between the 
two clinical trials  (Francis, 2019; Francis et al., 2015). A recent meta-analysis comparing AI plus 
OFS or tamoxifen treatment in premenopausal women shows that AI plus OFS reduces the risk 
of breast cancer recurrence rather than tamoxifen, especially in patients with high-risk, without 
breast cancer mortality reduction (Bradley et al., 2022). In addition, for patients with high-risk 
node-positive EBC, the addition of the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) 
abemaciclib to ET for 2 years in the adjuvant setting significantly improved  invasive disease-free 
survival (IDFS) of patients (Johnston et al., 2020).  
However, these treatments are associated with short- and long-term side effects that determine 
the discontinuation of treatment.  Class side-effects of AIs are musculoskeletal symptoms, 
osteoporosis and bone fractures (Bradley et al., 2022; Breast International Group (BIG) 1-98 
Collaborative Group et al., 2005; Ea, 2007; Howell et al., 2005) while those of tamoxifen are 
thromboembolic disease and endometrial cancer (Fisher et al., 1998). OFS worsens tolerance 
and side effects to adjuvant ET due to induced early menopause. On the other hand, abemaciclib 
has been associated with diarrhea, fatigue, neutropenia, leucopenia, and nausea (Rugo et al., 
2021). 
In 2002, fulvestrant became the first-generation selective estrogen-receptor degraders (SERDs) 
to be used in advanced and metastatic BC (Osborne et al., 2002). SERDs have the potential to 
completely downregulate estrogen signaling by binding to, blocking and degrading Ers. In EBC, 
fulvestrant research was limited by the modest benefits over AI in advanced BC. However, 
preoperative studies provided consistent superiority in inhibition of the cell proliferation, defined 
by Ki67 marker, over tamoxifen in premenopausal patients (Dowsett, Nicholson, et al., 2005; 
Young et al., 2008).  
1.3 
Neoadjuvant endocrine treatment for ER-positive BC  
In EBC, neoadjuvant therapy has become one of the preferred treatment options. Its efficacy has 
been proven to be equivalent to adjuvant therapy, with some advantages such as the 
improvement of surgical resection and providing prognostic information. Whereas pathologic 
complete response (pCR) is associated with longer progression-free survival (PFS) and OS in the 
case of triple‐ negative and HER2‐ positive tumors, it is not a good prognostic biomarker in 
luminal breast cancer (Cortazar et al., 2014; Spring et al., 2020).  
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Some clinical trials have compared the benefit of neoadjuvant endocrine therapy (NET) versus 
four cycles of neoadjuvant chemotherapy in luminal breast cancer (Alba et al., 2012; Semiglazov 
et al., 2007). Semiglazov et al. shown that postmenopausal patients with ER-positive tumors 
treated with either NET (aromatase inhibitors) or chemotherapy had the same rate of overall 
objective response. In contrast, the GEICAM/2006-03 trial reported superior clinical benefit rates 
of neoadjuvant chemotherapy over NET in premenopausal and postmenopausal patients with 
ER-positive BC, especially in patients with a high proliferation rate (Ki67 > 10%). Nevertheless, a 
similar clinical response was observed between treatments in patients with a low proliferation rate 
(Ki67 < 10%), thereby suggesting that this group of patients could avoid chemotherapy in the 
adjuvant setting. To further support these data, a meta-analysis of prospective randomized clinical 
trials with at least one arm of NET (either monotherapy or dual therapy) shown similar response 
rates with NET than neoadjuvant chemotherapy but with substantially less toxicity  (Spring et al., 
2016).  
 NET is mainly used in patients in the preoperative treatment of ER-positive/HER2-negative BC 
who are eligible for neoadjuvant treatment but not for chemotherapy (Colomer et al., 2019). In 
postmenopausal women, NET with an AI (such as anastrozole, letrozole, or exemestane) is more 
effective than tamoxifen (Cataliotti et al., 2006; Eiermann et al., 2001; Ellis et al., 2011; Ellis & 
Ma, 2007). Although 3 (Cataliotti et al., 2006)and 4 (Eiermann et al., 2001; Ellis & Ma, 2007) 
months has been the standard treatment duration of NET, there is consensus that this length of 
treatment is insufficient to reach maximal tumor response. Non-randomized studies suggest that 
some tumors benefit from a longer duration (6-12 months) of NET (Carpenter et al., 2014; 
Llombart-Cussac et al., 2012; Spring et al., 2016).  
1.4 
Rationale for Ki67 biomarker as primary endpoint 
There has been a huge effort to find surrogate markers that can select a good prognosis 
population in patients treated with NET. Because anti-estrogen therapy mainly induces cell-cycle 
arrest, markers of tumor cell proliferation have been used to measure the in situ action of these 
drugs. In this scenario, Ki67 has emerged as a biomarker of efficacy after neoadjuvant treatment 
of luminal breast cancer. Ki67 is a nuclear antigen expressed by all proliferating cells between 
the late G1 and M phases of the cell cycle (Scholzen & Gerdes, 2000). There are three main 
studies showing that a lower Ki67 score in response to NET results in better long-term disease-
free recurrence outcomes, while high Ki67 levels predicts worse prognosis (Guerrero-Zotano & 
Arteaga, 2017).  
The IMPACT trial demonstrated that 2 and 12 weeks of neoadjuvant treatment with anastrozole 
significantly decreases Ki67 expression (76% and 82%, respectively) compared to tamoxifen 
alone (59% and 62%, respectively) or the combination of anastrozole plus tamoxifen (64% and 
61%, respectively), and was correlated with an increased recurrence-free survival. However, 
there were no significant differences in overall response. (Dowsett, Smith, et al., 2005; I. E. Smith 
et al., 2005).  
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In the P024 study, 16 weeks of neoadjuvant treatment with letrozole achieved a greater overall 
response rate (ORR) compared to tamoxifen (55% vs. 36%, respectively) and a significant 
reduction of Ki67 (87% vs. 75%, respectively) (Ellis & Ma, 2007). 
The ACOSOG Z1031 trial compared the efficacy of neoadjuvant exemestane, letrozole or 
anastrozole treatment for 16 to 18 weeks and shown that all three AIs produced an equivalent 
rate of Ki67 suppression, preoperative endocrine prognostic index (PEPI) score and there were 
no differences in surgical outcome (Ellis et al., 2011).  
The shorter 2-4 weeks period of NET has become a window of opportunity (WoO) for molecular-
based studies to provide early biological signals that may guide development in early and 
advanced settings. Notably, POETIC study was a phase III study showing that two weeks of 
neoadjuvant AI followed by standard adjuvant therapy was a safe treatment option and improved 
outcome in postmenopausal women with ER-positive EBC. The measurement of Ki67 levels at 
baseline and at 2 weeks treatment demonstrated that patients with low Ki67 levels (10%) had a 
lower risk of recurrence than patients with high Ki67 levels (>10%) (I. Smith et al., 2020). 
In this line, the phase II NEWEST  trials helped establish the optimal dose of fulvestrant 500 
versus 250 after 4 weeks of treatment on the bases of Ki67 levels and showed that 500mg dose 
achieved greater suppression of cell proliferation (Kuter et al., 2012). 
Table 1 summarizes clinical trials with NET for the treatment of postmenopausal women with ER-
positive BC and its impact to decrease Ki67 marker.  
Table 1. Clinical trials with neoadjuvant endocrine therapy in ER-positive BC.   
Clinical Trial  
Phase  Study  
% Ki67 decrease 
N/A 
II 
Neoadjuvant treatment of postmenopausal 
BC with anastrozole, tamoxifen, or both in 
combination: the Immediate Preoperative 
Anastrozole, tamoxifen, or Combined with 
tamoxifen (IMPACT) multicenter double-
blind randomized trial 
After 2 and 12 
weeks 
with 
anastrozole (76% 
and 
82%, 
respectively), 
tamoxifen 
(59% 
and 
62%, 
respectively), 
or 
combination 
treatment 
(64% 
and 
61%, 
respectively). 
N/A 
III 
Preoperative treatment of postmenopausal 
BC patients with letrozole: A randomized 
double-blind multicenter study (P024 trial) 
After 16 weeks 
with letrozole or 
tamoxifen 
(87% 
vs. 
75%, 
respectively). 
NCT00265759 
III 
A Randomized Phase III Trial Comparing 16 
to 18 Weeks of Neoadjuvant Exemestane 
(25 mg Daily), Letrozole (2.5 mg), or 
After 16-18 weeks 
with exemestane, 
letrozole 
or 
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Anastrozole (1 mg) in Postmenopausal 
Women With Clinical Stage II and III 
Estrogen Receptor Positive Breast Cancer 
(ACOSOG Z1031 trial) 
anastrozole 
(81,2%, 
87,1% 
and 
78%, 
respectively). 
NCT02338310 
III 
Trial of Perioperative Endocrine Therapy – 
Individualising Care (POETIC trial) 
After 2 weeks with 
anastrozole 
(75%). 
NCT00093002 
II 
A Randomized, Open-Label, Multicenter, 
Phase II Study Comparing the Effects on 
Proliferation 
and 
the 
Efficacy 
and 
Tolerability of Fulvestrant (FASLODEX®) 
500 mg With Fulvestrant (FASLODEX®) 
250 mg When Given as Neoadjuvant 
Treatment in Postmenopausal Women With 
Estrogen Receptor Positive Breast Cancer 
(T2, 3, 4b, N0-3, M0) (NEWEST trial) 
After 4 weeks with 
500mg or 250mg 
of 
fulvestrant 
(78.8% vs 47.4%, 
respectively). 
N/A: not applicable. 
1.5 
Investigational agent : giredestrant (GDC-9545) 
Giredestrant (GDC-9545) is a novel highly potent, orally available, second-generation SERD that 
is currently being developed for the treatment of patients with ER-positive BC. It binds with 
nanomolar affinity to both wild-type and mutant ESR1Y537S ER, encoded by the ESR1 gene, and 
decrease their protein levels by inducing their proteasome-mediated degradation, which greatly 
reduces the ER signaling pathway (Jhaveri et al., 2021; Liang et al., 2021). 
Giredestrant (GDC-9545) potently inhibits cell proliferation in vitro and exhibits a dose-dependent 
anti-tumor activity in several murine models, including cell lines and patients derived xenografts. 
In addition, it has shown excellent in vitro and in vivo safety and pharmacokinetic profiles. Notably, 
the effective doses ranged from 0.1 to 10mg/kg/day and were all well tolerated (Liang et al., 2021). 
1.5.1 
Clinical overview of giredestrant (GDC-9545) 
The study NCT03916744 was a phase I, open-label, multicenter trial of giredestrant (GDC-9545) 
to evaluate pharmacodynamics, pharmacokinetics, safety, and biologic activity of the drug in 
postmenopausal women with stage I-III operable ER-positive/HER2-negative untreated BC. 75 
patients were assigned to 15 (±2) days of treatment with giredestrant (GDC-9545) orally once 
daily (PO QD) at a dose of either 10, 30, or 100 mg followed by surgery. Tumor tissue samples 
were collected at baseline and at the end of treatment. The primary objective of the study was to 
measure changes in the Ki67 between pre- and post-treatment samples. Preliminary results from 
47 evaluated patients shown that 77% were classified as Luminal A and 23% Luminal B at 
baseline. Giredestrant (GDC-9545) treatment was well tolerated, no grade 4 or 5 adverse events 
(AEs) were reported and single serious grade 3 that appeared were unrelated to giredestrant 
(GDC-9545). In addition, it was biologically active at all doses. The post-treatment Ki67 reduction 
was 80% at 10 mg, 76% at 30mg and 80% at 100mg. Notably, 51% of tumors exhibited complete 
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cell cycle arrest (CCCA, Ki67 ≤2.7%) and the mean post-treatment proportional reductions of ER 
and PgR (progesterone receptor) H-scores were 71% (95% CI: 67–75) and 60% (95% CI: 51–
70), respectively (Moore et al., 2021). 
The phase II coopERA trial (NCT04436744) was a two arm, open-label, multicenter trial aimed at 
evaluating the efficacy, safety and pharmacokinetics of giredestrant (GDC-9545) plus palbociclib 
compared with anastrozole plus palbociclib in postmenopausal women with untreated ER-
positive/HER2-negative EBC. 221 patients with baseline Ki67 score ≥5% were randomized 1:1 to 
receive 14 days of anastrozole (1 mg, PO QD) or giredestrant (GDC-9545) (30 mg, PO QD) 
(window-of-opportunity phase, WoO) followed by 16 weeks (four 28-days cycles) of additional 
neoadjuvant palbociclib (125 mg, PO, D1-21) treatment prior to surgery. The primary objective of 
the study was to measure tumoral Ki67 changed between baseline and post-WoO samples. In 
ESMO Breast 2021, preliminary results were shown for 83/202 planned patients. Two-week 
relative Ki67 reduction was significantly greater with giredestrant (GDC-9545) than anastrozole 
(80% versus 67%, respectively) and a consistent Ki67 suppression was observed in patients with 
baseline Ki67 ≥20% (giredestrant (GDC-9545): 83% reduction; anastrozole: 71%) or <20% (65% 
vs 24%). After 14 days of treatment, 25% of tumors exhibited complete cell cycle arrest 
(secondary objective) with giredestrant (GDC-9545) versus 5% with anastrozole. Patients treated 
with giredestrant (GDC-9545) had fewer AEs than anastrozole.   
Table 2 summarizes ongoing clinical trials with giredestrant (GDC-9545) for the treatment of early 
or advanced hormonal receptor-positive BC. In addition, giredestrant (GDC-9545) is also being 
studied in the treatment of ER-positive/HER2-positive BC. 
Table 2. Ongoing clinical trials with giredestrant (GDC-9545) in BC.   
Clinical Trial  
Phase  
Study  
NCT03916744 
I 
A Phase I, Multicenter, Open-Label Preoperative, 
Short-Term Window Study of GDC-9545 in 
Postmenopausal 
Women 
With 
Stage 
I-III 
Operable, Estrogen Receptor-Positive Breast 
Cancer 
NCT03332797 
Ib/II 
Multicenter, Open-Label, Dose Escalation, Dose 
Expansion 
Study 
Evaluating 
the 
Safety, 
Pharmacokinetics, and Activity of GDC-9545 
Alone or in Combination With Palbociclib and/or 
LHRH Agonist in Patients With Locally Advanced 
or Metastatic Estrogen Receptor-Positive Breast 
Cancer 
NCT04802759 
 
Ib/II 
Open-Label, Multicenter, Randomized Umbrella 
Study Evaluating the Efficacy and Safety of 
Multiple Treatment Combinations in Patients With 
Breast Cancer (MORPHEUS-Breast Cancer) 
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NCT04436744 
II 
A Randomized, Multicenter, Open-Label, Two-
Arm, Phase II, Neoadjuvant Study Evaluating the 
Efficacy, Safety, and Pharmacokinetics of GDC-
9545 
Plus 
Palbociclib 
Compared 
With 
Anastrozole Plus Palbociclib for Postmenopausal 
Women With Estrogen Receptor-Positive and 
HER2-Negative Untreated Early Breast Cancer 
(coopERA trial) 
NCT04576455 
II 
Randomized, Open-Label, Multicenter Study 
Evaluating the Efficacy and Safety of GDC-9545 
Compared With Physician’s Choice of Endocrine 
Monotherapy in Patients With Previously Treated 
Estrogen 
Receptor-Positive, 
HER2-Negative 
Locally Advanced or Metastatic Breast Cancer 
(acelERA trial) 
NCT04961996 
 
III 
Randomized, Open-Label, Multicenter Study 
Evaluating the Efficacy and Safety of Adjuvant 
giredestrant Compared With Physician’s Choice 
of Adjuvant Endocrine Monotherapy in Patients 
With Estrogen Receptor-Positive, HER2-Negative 
Early Breast Cancer (lidERA trial) 
 NCT05306340 
 
III 
Randomized, Open-Label, Multicenter Study 
Evaluating the Efficacy and Safety of giredestrant 
Plus Everolimus Compared With Exemestane 
Plus Everolimus in Patients With Estrogen 
Receptor-Positive, 
HER2-Negative, 
Locally 
Advanced or Metastatic Breast Cancer (evERA 
trial) 
NCT05296798 
 
III 
Randomized, Open-Label Study Evaluating the 
Efficacy and Safety of giredestrant in Combination 
With Phesgo Versus Phesgo After Induction 
Therapy With Phesgo + Taxane in Patients With 
Previously Untreated HER2-Positive, Estrogen 
Receptor-Positive Locally-Advanced or Metastatic 
Breast Cancer (heredERA trial) 
NCT04546009 
 
III 
Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study Evaluating the Efficacy and 
Safety of GDC-9545 Combined With Palbociclib 
Compared 
With 
Letrozole 
Combined 
With 
Palbociclib in Patients With Estrogen Receptor-
Positive, HER2-Negative Locally Advanced or 
Metastatic Breast Cancer (persevERA trial) 
 
1.6 
Rationale for developing a Window-of-Opportunity study in premenopausal patients 
with ER-positive/HER2-negative EBC  
The reduction of Ki67 levels after NET has been shown to be a good marker of decreased tumor 
proliferation in postmenopausal patients (refer to Table 1). Although NET has also been studied 
in premenopausal patients with EBC, little is known about its impact on Ki67 marker. The NEST 
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clinical trial aimed at comparing the efficacy of NET versus neoadjuvant chemotherapy for 24 
weeks in premenopausal South Corean patients with ER-positive, HER2-negative, lymph node 
positive breast cancer. While better clinical responses were observed in patients receiving 
neoadjuvant chemotherapy, there were no differences in the Ki67 marker between the two 
treatment regimens (Kim et al., 2020).  
The WoO EMPRESS study aims at evaluating the changes in the Ki67 proliferation biomarker 
between baseline and post-treatment tumor samples of premenopausal ER-positive/HER2-
negative EBC patients (with centrally confirmed Ki67 ≥10%) treated for 15 days with either single 
agent giredestrant (GDC-9545) or tamoxifen. 
Strategically, the EMPRESS study aims to provide evidence on the biological superiority of 
giredestrant (GDC-9545) over tamoxifen in premenopausal EBC patients. Notably, a positive 
result may justify the development of future studies with giredestrant (GDC-9545) without OFS in 
this population. In addition, while a direct comparison of giredestrant (GDC-9545) treatment to a 
regimen combined with OFS in premenopausal women is not feasible due to the short period of 
treatment, an indirect comparison on Ki67 decrease at 15-days treatment could shed light as to 
whether giredestrant (GDC-9545) has the potential to decrease tumor cell proliferation in this 
patient population, in line with the results seen in postmenopausal patients treated with 
giredestrant (GDC-9545) (NCT03916744), letrozole (own series), and letrozole plus palbociclib 
(NCT03819010). 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are described in the Table 3.  
Table 3. Summary of objectives and endpoints of EMPRESS trial. 
PRIMARY OBJECTIVES  
PRIMARY ENDPOINT 
To assess changes in tumor cell proliferation as 
measured by Ki67 expression between baseline 
and post-treatment tumor biopsy samples by 
central assessment in patients with centrally 
confirmed Ki67 ≥10% (Arm A: giredestrant vs 
Arm B: tamoxifen). 
Changes in tumor cell proliferation as measured by 
Ki67 expression between baseline and post-
treatment 
tumor 
biopsy 
samples 
by 
central 
assessment in patients with centrally confirmed Ki67 
≥10% (Arm A: giredestrant vs Arm B: tamoxifen). 
SECONDARY OBJECTIVES  
SECONDARY ENDPOINTS  
 
To measure complete cell cycle arrest 
(CCCA) in all arms, defined by Ki67≤2.7% in 
post-treatment samples. 
 
 
CCCA in all arms, defined as the percentage of 
participants with centrally assessed Ki67 scores 
≤2.7% stained nuclei upon treatment (post-
treatment samples). 
 
To analyze changes in ER and PgR levels, 
and molecular profiling using HTG.   
 
Changes in markers (such as ER and PgR levels) 
and molecular profiling using HTG (PAM-like 
molecular test).   
 
To evaluate toxicity according to National 
Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) 
v.5.0.  
 
 
Incidence and severity of adverse events (AEs), 
with severity determined in accordance to NCI-
CTCAE v.5.0. 
Note: Patient safety and AEs will be evaluated using 
the NCI-CTCAE v.5.0. All AEs and serious adverse 
events (SAEs) will be assessed to determine the 
safety and tolerability of the treatment.  
 
 
 
 
 
  
 
 
 
 
 
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*Post-treatment sample should be collected after treatment, either on Day 15 or Day 15 + 1. If 
fresh post-treatment biopsy cannot be obtained within + 1 day from last day of treatment (that is 
on D15 or D15 +1), treatment will be extended to 16 days and post-treatment analyses will be 
done in surgery/biopsy sample obtained on the following day (be it D15 + 2 days). 
3 
STUDY OVERVIEW  
3.1 
Study design 
This is a multicenter, international, open-label, two-arms, one stage, phase II, window of 
opportunity, clinical trial aiming to assess changes in tumor cell proliferation as measured by Ki67 
expression between baseline and post-treatment (day 15) tumor biopsy samples by central 
assessment in premenopausal women with ER[+]/HER2[-] & Ki67 ≥10% early breast cancer 
(EBC).  
Note: if post-treatment surgery or biopsy cannot be performed within + 1 day from last day of 
treatment (that is, on day 15 or the day after), treatment will be extended to 16 days and patients 
will be able to have surgery or biopsy the following day (be it D15 + 2 days). 
After signing informed consent form (ICF) and confirmed eligibility, patients will be randomly 
assigned in a 1:1 ratio to receive either giredestrant (GDC-9545) 30 mg orally (PO) once a day 
(QD) or tamoxifen 20 mg PO QD as a single agent. 92 patients are expected to be enrolled in the 
study and treated for a total of 15 days.
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Figure 1 summarizes the EMPRESS study design. 
 
 
Figure 1. EMPRESS study design. Abbreviations: d: days; ER: Estrogen receptor; PgR: Progesterone receptor; PO: orally; QD: daily; R: randomization.
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3.2 
Study treatment management 
Eligible patients will be randomly assigned in a 1:1 ratio to either experimental Arm A (treatment 
with giredestrant (GDC-9545)) or control Arm B (treatment with tamoxifen). During the study 
treatment (a total of 15 days*), patients will receive either giredestrant (GDC-9545) 30 mg PO QD 
or tamoxifen 20 mg PO QD, both as a single agent.  
 
Arm A: giredestrant (GDC-9545): 30mg, PO, QD, on days 1-15.   
 
Arm B: tamoxifen: 20mg, PO, QD, on days 1-15.   
Giredestrant and tamoxifen can be taken with or without food at approximately the same time 
each day as per study treatment regimen.  
Patients will be treated for a total of 15 days and treatment will last until any of the situations 
described in Section 3.3.3. 
Dose delays and guidelines of management of the patients who experience adverse events 
associated with the study drugs are outlined in Section 7. 
*Note: if post-treatment surgery or biopsy cannot be performed within + 1 day from last day of 
treatment (that is, on D15 or D15+1), treatment will be extended to 16 days and patients will be 
able to have surgery or biopsy the following day (be it D15 + 2 days). 
3.3 
Study schedule summary 
The study will consist of a screening period of up to 28-day, a window-of-opportunity 15-day 
treatment phase, an End of Treatment visit (EoT) (+ 1 day after the final dose of study treatment) 
and an End of Study (EoS) visit (28 days +/- 3 days after the final dose of study treatment). 
3.3.1 
Screening phase 
During this phase, patient eligibility is determined, including the documentation of baseline 
characteristics. This phase will begin once the ICF is signed by the patient; procedures to be 
performed are described in Appendix 1: Schedule of study assessments and procedures.  
Patients must have histologically confirmed ER[+]/HER2[-] primary invasive adenocarcinoma of 
the breast with locally analyzed and centrally confirmed Ki67 ≥10% and tumor size ≥1.0cm in 
longest diameter by ultrasound.  
A Ki67 score ≥10% stained nuclei from the pre-treatment tumor tissue sample is required for 
eligibility. Ki67 score will be analyzed locally at the time of inclusion. Patients with basal Ki67 
≥20% will be assessed locally and centrally confirmed retrospectively and patients with 10-19% 
will be assessed centrally before inclusion. 
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To assess eligibility, HER2, ER and PgR status will be locally determined on the most recent 
tumor biopsy acquired at baseline prior to beginning of study treatment. 
All patients will be required to provide a pre-treatment tumor tissue sample and blood samples 
during screening, and a tumor biopsy sample and blood samples on Day 15 (+ 1 day) at the end 
of study treatment. If a diagnostic biopsy was performed maximum 8 weeks prior to initiation of 
study treatment, it can be used as a baseline sample for the Ki67 assessment. If post-treatment 
biopsy cannot be obtained within + 1 day from last day of treatment (15 days), treatment will be 
extended to 16 days and patients will be able to have surgery or biopsy the following day (be it 
D15 + 2 days). 
One re-screening is allowed for patients that were screening failure. Patients have to re-consent 
Informed Consent Form (ICF) before any study procedure is done. At re-screening, study 
assessments and procedures can be omitted if were performed during the initial screening period 
within the specified time frames. 
3.3.2 
Treatment Phase and End of Treatment visit 
The treatment phase is defined as the time between the study entry and the last dose of study 
treatment received within this trial. After confirming eligibility through the screening process, 
patients will be scheduled for visit day 1 (D1) of treatment within 48 h after randomization.  
In this first visit, medical history, including clinically significant diseases, surgeries, cancer history, 
and reproductive status will be recorded at baseline. In addition, all medications (e.g., prescription 
drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will be 
recorded. Also, in this first visit D1, patients will be given the first dose of treatment and will be 
instructed how to take giredestrant or tamoxifen orally, daily at their homes during the following 
14 days D2 to D15 (to finalize a total of 15 days of treatment).  
To assess patient compliance with self-administration of study medication, site study staff will 
provide patients with detailed instructions and training for the handling and administration of study 
drugs. Patients will receive and should be instructed to complete a medication diary to record all 
relevant information during those days.  
A second biopsy will be collected at the EoT (on day 15 or day 15 + 1), after last dose of study 
treatment is taken by the patient in the EoT visit. If a fresh post-treatment biopsy cannot be 
obtained within + 1 day from last day of treatment, treatment will be extended to 16 days and 
patients will be able to have surgery or biopsy the following day (be it D15 + 2 days). 
If a mandatory procedure described in the protocol falls on a bank holiday and/or weekend, this 
procedure should be performed on the day before or after the holiday (i.e. within a period of ± 2 
working days), with the exception of the post-treatment surgery or biopsy that must be performed 
on the last day of treatment or 1 day after last day of treatment. 
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All patients will be closely monitored for safety and tolerability during study treatment. Patients 
should be assessed for toxicity prior to any study treatment administration; dosing will occur only 
if the clinical assessment and local laboratory test values are acceptable. Refer to Section 7 for 
more information regarding toxicities.  
3.3.3 
Treatment and study discontinuation 
If at any time the constraints of this protocol are detrimental to the patient’s health and/or the 
patient no longer wishes to continue with the protocol therapy, the study treatment should be 
discontinued and the reason(s) for discontinuation documented in the clinical records of the 
patient and corresponding case report form (CRF). 
Patient’s study treatment may continue until one of the following criteria applies: 
 
Any medical condition or AEs that according to the protocol or in the judgment of the 
investigator may cause severe or permanent harm or which rule out continuation of study 
drug. 
Note: See detailed criteria for study treatment discontinuation due to toxicity in Section 
7. 
 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Disease progression per investigator’s assessment. 
 
Serious non-compliance with the study protocol. 
 
Death. 
 
Pregnancy during study treatment. 
 
Concomitant use of any other (non-protocol) anti-cancer therapy. 
 
Lost to follow-up. 
 
Patient withdraws consent. 
 
The study site or the Sponsor decides to close the study. 
All patients must return for the end of study visit 28 days (+/-3 days) after the final dose of study 
treatment regardless of the reason for treatment discontinuation. Patients who experience 
disease progression or unacceptable toxicity will be treated as per local practice after the EoS 
visit. If a patient discontinues treatment before the EoT visit (that is, before finalizing 15 days of 
treatment), the collection of tissue and blood samples will be discussed with the study medical 
monitor and will only be collected if feasible and as soon as possible (from a breast biopsy or 
breast surgery). 
Patients have the right to withdraw from the study at any time for any reason. Should a patient 
decide to withdraw, all efforts should be made to complete and report the observations as 
thoroughly as possible. The investigator should contact the patient or a responsible relative by 
telephone or through a personal visit to establish as completely as possible the reason for the 
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withdrawal. A complete final evaluation at the time of the patient’s withdrawal should be made 
with an explanation of why the patient is withdrawing from the study. Patients deciding to 
prematurely discontinue study treatment should be asked if they still can be contacted for further 
information. The outcome of that discussion should be documented in both the medical records 
and in the CRF. 
The investigator also has the right to withdraw patients from the study in the event of intercurrent 
illness, AEs, and treatment failure after a prescribed procedure, protocol violation, administrative 
reasons, or for other reasons. An excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. 
3.3.4 
End of study visit 
Patients will attend the clinic again for an EoS visit 28 days (+/- 3 days) after last dose of study 
treatment is taken.   
All AEs related to investigational medicinal product (IMP) will be followed up by the investigator 
until the event or its sequelae has resolved to baseline grade or better, the event is considered 
as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent. 
Every effort should be done to follow-up all serious adverse events considered to be related to 
study drug or trial-related procedures until an outcome can be reported.  
During the study period, resolution of adverse events (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data verification. All 
pregnancies reported during the study should be followed until pregnancy outcome.  
The EoS is defined as the last patient last visit, which takes place 28 days (+/- 3 days) after the 
last study dose is taken (or if patient ends treatment due to progression or any other reason listed 
in the previous section, or until premature termination of the study). This will be the last data 
collection point, and the last patient visit.   
In addition, the Sponsor reserves 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 seriousness of AEs in this or other studies indicates a potential health 
risk to patients. 
● 
Patient enrollment is unsatisfactory and/or excessively slow. 
● 
Data recording is inaccurate or incomplete. 
● 
Poor protocol adherence. 
● 
Non-compliance with the International Conference on Harmonization (ICH) guideline for 
Good Clinical Practice (GCP).  
 
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4 
PATIENT SELECTION 
Patient eligibility will be reviewed and documented by a suitable member of the investigator’s 
study team before the patients are enrolled in the study. This study can fulfil its objectives only if 
appropriate patients are enrolled. Patients must meet ALL the selection criteria. All relevant 
medical and non-medical conditions should be taken into consideration when deciding whether 
this protocol is suitable for a particular patient.  
4.1 
Target Study Population 
This study will enroll female patients ≥18 years of age with well-defined premenopausal status 
and 
previously 
untreated 
histologically 
confirmed 
ER[+]/HER2[-] 
primary 
invasive 
adenocarcinoma of the breast with locally analyzed and centrally confirmed Ki67 ≥10%*, and 
tumor size ≥1.0 cm in longest diameter by ultrasound (reference lesion). Patients with distant 
metastatic disease are not allowed. 
Well-define premenopausal status refers to women who have not reached the postmenopausal 
state because they are not permanently infertile due to prior bilateral oophorectomy, age ≥60 
years or age <60 years with amenorrhea for ≥12 months and estradiol and FSH levels in the 
postmenopausal range.   
Patients diagnosed with multifocal or multicentric breast cancer with at least one tumor lesion 
≥1.0 cm in the longest diameter by ultrasound (reference lesion) will be eligible for the study only 
if the two largest lesions have been histologically confirmed in the clinical evaluation and meet 
the pathologic criteria for ER positivity and HER2 negativity. The reference lesion will be used to 
assess changes in the tumor cell proliferation as measured by Ki67 expression. 
Patients must present an adequate organ function. Patients must agree to provide a primary 
tumor tissue sample and a blood sample during the diagnostic process (if the patient had a biopsy 
sample taken no longer than 8 weeks prior to initiation of study treatment, it can be used as 
baseline) and post-treatment tumor tissue and a blood sample (breast biopsy or breast surgery). 
*Ki67 will be analyzed locally at the time of inclusion. Patients with basal Ki67 ≥20% will be 
assessed locally and centrally confirmed retrospectively and patients with 10-19% will be 
assessed centrally before inclusion.  
4.2 
Inclusion criteria 
Patients must meet ALL the following inclusion criteria to be eligible for enrolment into the study: 
1. Signed Informed Consent Form (ICF) prior to beginning specific protocol procedures. 
2. Aged ≥ 18 years at time of signing ICF. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
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4. Women in a well-determined premenopausal status as indicated in the protocol Section 
4.1.  
5. Histologically confirmed invasive breast carcinoma, with all the following characteristics: 
a. Documented ER-positive tumor in accordance with American Society of Clinical 
Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et 
al., 2020), assessed locally and defined as ≥ 1% of tumor cells stained positive. 
b. Documented HER2-negative tumor in accordance with 2018 ASCO/CAP 
guidelines (Wolff et al., 2018), assessed locally at baseline. 
Note: Diagnostic biopsy taken no more than 8 weeks prior to initiation of study treatment 
can be used as baseline. 
c. Ki67 score ≥10% analyzed locally and centrally confirmed (Nielsen et al., 2021). 
Note: Ki67 will be analyzed locally at the time of inclusion. Patients with basal Ki67 ≥20% 
will be assessed locally and centrally confirmed retrospectively and patients with 10-19% 
will be assessed centrally before inclusion. 
d. Tumor size must be ≥1.0 cm in longest diameter by ultrasound as per Response 
Evaluation Criteria in solid Tumors (RECIST) criteria. 
Note: Patients with multifocal or multicentric breast cancer with a at least one tumor lesion 
≥1.0 cm in the longest diameter by ultrasound (reference lesion) are also eligible if the 
two largest lesions have been histologically confirmed in the clinical evaluation and meet 
pathologic criteria for ER positivity and HER2 negativity. 
6. Willingness to provide a primary tumor tissue and blood sample obtained at baseline as 
well as a post-treatment tumor tissue and blood samples (breast biopsy or from breast 
surgery). 
7. Patient has adequate bone marrow, liver, and renal function:  
 
Hematological: absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/mL), platelet 
count ≥ 100.0 x109/L, and hemoglobin ≥ 9 g/dL (≥ 90g/L).  
Note: The blood counts are to meet the specified criteria without transfusion or growth factor 
support, unless it is clear that the bone marrow function is adequate and that any aberration 
has a clear and correctable cause, and the correction undertaken.  
 
Hepatic: total serum bilirubin ≤ 1.5’ institutional upper limit of normal (ULN) (patients 
with known Gilbert’s syndrome: ≤ 3’ ULN); alkaline phosphatase (ALP) ≤ 2.5 times 
ULN; aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3’ 
times ULN.  
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 
Coagulation: The international normalized ratio (INR) < 1.5’ ULN and partial 
thromboplastin time (PTT or aPTT) < 1.5’ ULN (except for patients receiving 
anticoagulation therapy). For patients receiving warfarin, a stable INR between 2 and 
3 is required. For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5’ 
ULN (or patient value before starting heparin treatment) is required. If anticoagulation 
therapy is required for a prosthetic heart valve, stable INR between 2.5 and 3.5 is 
permitted.  
 
Renal: creatinine clearance ≥ 60 mL/min for patients with creatinine levels above 
institutional normal.  
8. Negative serum pregnancy test result within 14 days prior to initiation of study treatment 
and a negative urine pregnancy test within 24 hours prior to study treatment initiation. 
Note: Premenopausal women age ≥18 years with premenopausal status defined as: estradiol 
(E2) in the premenopausal range (according to institution parameters) or patient has been 
menstruating regularly during the 6 months prior to randomization and has not used any form of 
hormonal contraception or any other hormonal treatments during this time.  
Women must remain abstinent and truly abstains from sexual activity (refrains from heterosexual 
intercourse) or use of locally recognized adequate methods of contraception (described as that 
with a failure rate <1%) during the length of the study, and to continue its use for 10 days after 
the last dose of study treatment (for patients taking giredestrant) or 9 months following cessation 
of therapy (for patients in the tamoxifen arm).  They must, as well, agree to refrain from donating 
eggs during the same period of time.        
Examples of non-hormonal contraceptive method with a failure rate of <1% per year (e.g. bilateral 
tubal ligation, male sterilization and copper intrauterine devices). The reliability of sexual 
abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not adequate methods of contraception.  
9. Patients must be accessible for treatment and follow-up. 
10. Participants who are able and willing to swallow, retain, and absorb oral medication. 
4.3 
Exclusion criteria  
Patients will be excluded from the study if they meet ANY of the following criteria: 
1. Progesterone receptor (PgR)[+] and ER[-] patients. 
2. cT4 and/or cN2/3 and/or bilateral BC.  
3. Patients who have history of any prior (ipsilateral and/or contralateral) invasive BC or 
Ductal carcinoma in situ (DCIS). Participants with a history of contralateral DCIS treated 
by only local regional therapy at any time may be eligible. 
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4. Evidence of metastatic disease. 
5. Previous systemic or local treatment for the primary BC currently under investigation. 
6. History of any prior treatment with chemotherapy drugs, aromatase inhibitors (AIs), 
tamoxifen, selective estrogen receptor down regulator, or cyclin-dependent kinase 4 and 
6 inhibitors (CDK4/6i). 
7. Any invasive malignancy diagnosed within the previous 5 years prior to screening in this 
study (other than basal cell carcinoma, cervical carcinoma in situ or contralateral DCIS). 
8. Known issues with swallowing oral medication, or inability or unwillingness to swallow 
oral medication. 
9. Participants who have a known clinically significant history of liver disease consistent with 
Child-Pugh Class B or C, including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C 
virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis, as defined 
below:  
 
Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis 
B core antibody [HBcAb]) or HCV antibody. Unless required by local regulations, 
participants are not required to have HBV, or HCV assessments at screening if these 
assessments have not been previously performed. 
 
Participants who test positive for HBcAb are eligible only if test results are also 
positive for hepatitis B surface antibody and polymerase chain reaction is negative 
for HBV DNA Participants who are positive for HCV serology are eligible only if testing 
for HCV RNA is negative. 
10. Active cardiac disease or history of cardiac dysfunction including any of the following: 
 
History or presence of symptomatic bradycardia or sick sinus syndrome. 
 
Resting heart rate < 50 bpm at screening. 
 
History of angina pectoris, symptomatic pericarditis, myocardial infarction, or any 
cardiac arrhythmias (e.g.,ventricular, supraventricular, nodal arrhythmias, or 
conduction abnormality) within 12 months prior to study entry. 
 
History of documented congestive heart failure (New York Heart Association Class 
II-IV) or cardiomyopathy. 
 
QT interval corrected through use of Fridericia’s formula (QTcF) >470 ms by at least 
three ECGs >30 minutes apart. 
 
History of long or short QT syndrome, Brugada syndrome or known history of 
corrected QT interval prolongation, or torsades de pointes. 
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 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion. 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, left 
ventricular hypertrophic cardiomyopathy, infiltrative cardiomyopathy, moderate-to-
severe valve disease), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT 
syndrome. 
11. Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study.  
12. Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination 
half-lives (whichever is longer) prior to randomization.   
13. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major 
upper gastrointestinal surgery including gastric resection. 
14. Participants who have a known allergy or hypersensitivity to any of the study drugs or 
any of their excipients. 
15. Participants who are pregnant or breastfeeding or intending to become pregnant during 
the study or within 10 days after the final dose of giredestrant (GDC-9545), or within 9 
months after the final dose of tamoxifen.  
Note: Women of childbearing potential must have a negative serum pregnancy test result within 
14 days prior to initiation of study treatment and a negative urine pregnancy test within 24 hours 
prior to study treatment initiation. 
16. Patients with renal dysfunction who require dialysis. 
17. Participants who have had a serious infection requiring oral or IV antibiotics within 14 
days prior to screening or other clinically significant infection (e.g., COVID-19) within 14 
days prior to screening.   
Note: Participants who have fully recovered from serious or clinically significant infections at least 
14 days prior to screening are eligible. If a participant exhibits signs or symptoms of potential 
COVID-19 infection and there is a reasonable suspicion of exposure, investigators are to follow 
the American Society of Clinical Oncology 2020 guidelines or institutional guidelines on testing. 
18. Participants who have had a major surgical procedure unrelated to breast cancer within 
28 days prior to randomization.  
19. Participants who are unable or unwilling to comply with the requirements of the protocol 
in the opinion of the investigator.   
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5 
STUDY DRUG INFORMATION  
The investigational medicinal products (IMPs) for this study are giredestrant (GDC-9545) and 
tamoxifen. 
Complete description of the IMP will be documented in its respective Investigator Brochure (IB) 
and summary of product characteristics (SmPC), located in the Site/Investigator’s file. 
Summarized information is reported in this section. 
5.1 
Formulation, packaging, and handling 
Giredestrant (GDC-9545) will be supplied by the Sponsor as 30 mg capsules of GDC-9545 (free 
base equivalent), packaged in high-density polyethylene bottles with a plastic child‐resistant cap 
with induction seal and desiccant.  For information on the formulation of giredestrant (GDC-9545), 
see giredestrant’s (GDC-9545) IB. 
Tamoxifen will be supplied by each investigational site as 20 mg film-coated tablets. For 
information on the formulation of tamoxifen, see the SmPC local prescribing information.  
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.  
Refer to the giredestrant’s (GDC-9545) IB and the tamoxifen’s SmPC local prescribing information 
for more information on IMP handling, including preparation and storage, and accountability. 
5.2 
Dosage, administration, and compliance 
During the treatment phase, starting with Day 1, patients will be given the first dose of study 
treatment, which will be either giredestrant (GDC-9545) 30 mg (Arm A) or tamoxifen 20 mg (Arm 
B) in the clinic after the study assessments. Then, patients will be instructed how to take 
giredestrant (GDC-9545) or tamoxifen orally, daily at their homes during the following 14 days D2 
to D15 (to finalize a total of 15 days of treatment).  
Note: If post-treatment biopsy cannot be performed within + 1 day from last day of treatment (that 
is, on D15 or D15+1), treatment will be extended to a total of 16 days and patients will be able to 
have surgery the following day (be it D15 + 2 days). 
Giredestrant (GDC-9545) 30 mg PO QD and tamoxifen 20 mg PO QD should be taken orally with 
food at approximately the same time each day as per study treatment regimen. The capsule or 
tablet should be swallowed whole and should not be chewed, crushed, or opened. If a dose is 
missed, the dose should be made up unless the next dose is due within 6 hours (vomited doses 
should not be made up).  
To assess patient compliance with self-administration of study medication, site study staff will 
provide patients with detailed instructions and training for the handling and administration of study 
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drugs. Patients will receive and should be instructed to complete a medication diary to record all 
relevant information during those days. Patients will be instructed to bring all unused study 
medication and their medication diaries to the clinic at specified study visits (see schedule of 
assessments and activities).  
Compliance will be assessed by investigator site team staff (e.g. by counting returned 
capsules/tablets, clinic visit patient interview notes and reviewing patient diaries). 
Details on treatment administration should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF). Cases of overdose, medication errors, drug abuse or misuse, along 
with any associated adverse events should be reported in the eCRF.  
5.3 
Study drug storage and drug accountability  
The IMP giredestrant will be provided by the Sponsor. The IMP tamoxifen will be provided by 
each investigational site. 
The Investigator and other authorized personnel [e.g., pharmacist]) are responsible for safe and 
proper handling and storage of the study drug at the investigational site, for maintaining records 
of IMP delivery to the site, IMP inventory at the site, IMP use by each patient, and disposition or 
return of unused IMP, thus enabling reconciliation of all IMP received, and for ensuring that 
patients are provided with doses specified by the protocol. Only patients enrolled in the study may 
receive IMPs, and only authorized staff may supply or administer 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. Investigators and site staff are reminded to continuously monitor 
room storage temperatures and ensure that thermometers are working correctly as required for 
proper storage of investigational products. These may include thermometers for both the room 
and refrigerator storage. Any temperature excursions must be reported immediately to the 
Sponsor and documented. Once a deviation is identified, the IMP must be quarantined and not 
used until the Sponsor provides documentation of permission. Refer to the pharmacy manual 
and/or the giredestrant IB and the tamoxifen local prescribing information for information on IMP 
handling, including preparation and storage, and accountability. 
The study site should follow all instructions included with each shipment of IMP. The study site 
will acknowledge receipt of IMPs supplied by the Sponsor, using an Interactive Response 
Technology Platform 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. 
At the end of the trial, the Sponsor will provide instructions as to disposition of any unused IMP. 
If the Sponsor authorizes destruction at the trial site, the Investigator must ensure that the 
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materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by the Sponsor.  
The investigational site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and the destruction must be adequately documented.  
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. 
The investigational sites will be supplied with study drug according to the sites’ needs. The 
investigational site will acknowledge receipt of IMP and confirm the shipment condition and 
contents. Any damaged shipments will be replaced. IMPs must be stored according to their IB 
and/or local prescribing information.  
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from medication that 
needs to be dispensed. 
5.4 
Treatment compliance 
In the first visit D1, patients will be given the first dose of treatment and will be instructed how to 
take giredestrant (GDC-9545) or tamoxifen orally, daily at their homes during the following 14 
days D2 to D15 (to finalize a total of 15 days of treatment*). At the study visits, the medication 
diary as well as unused tablets or capsules and all containers or packaging (used or unused) of 
study treatment should be collected and reviewed for drug accountability. 
Treatment compliance will be defined as the number of capsules or tablets taken divided by the 
expected number of capsules or tablets and reported as a percentage. Capsules or tablets that 
are not returned will be considered to have been taken, unless otherwise specified in the patient’s 
diary and/or eCRF. Note that dosing eCRFs should be completed using the following prioritization: 
1) site pharmacy drug accountability logs (IMP disbursed minus IMP returned), 2) clinic visit 
patient interview notes, and 3) patient daily dosing diary. 
^Note: If post-treatment surgery or biopsy cannot be performed within + 1 day from last day of 
treatment (that is, D15 or D15+1), treatment will be extended to 16 days and surgery or biopsy 
will be performed on the following day (be it D15 + 2 days). This will be scheduled in advanced 
and determined with the investigator to ensure availability of patient. 
5.5 
Treatment modifications and discontinuation 
Safety and tolerability of all patients will be closely monitored throughout study treatment and the 
follow-up period using the US NCI-CTCAE version 5.0. Patients will be assessed in order to detect 
any side effects before administering new study treatment. Treatment will only be administered if 
clinical evaluation and local laboratory test results are acceptable.  
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Patients whose treatment is interrupted or permanently discontinued due to an AE, including 
abnormal laboratory value, must be followed until resolution or stabilization of the event, 
whichever comes first, which includes all study assessments appropriate to monitor the event. 
Treatment administration may be delayed assessing or treating AEs. 
Interruptions or delays due to any other reason should be discussed with the Medical Monitor. 
No dose modification will be permitted for giredestrant (GDC-9545) or tamoxifen. See Table 5. 
Guidelines for Management of Patients Who Experience Adverse Events Associated with 
Giredestrant (GDC-9545). In Section 7 for further details on management of AEs. 
Study treatment may be temporarily suspended in patients who experience toxicity considered 
related to study drug.  
5.6 
Medication errors and overdose  
An overdose is the administration of a drug in a quantity that is higher than the assigned dose.  
Cases of overdose, along with any associated AEs, should be reported as described in Section 
7. 
In the event of an overdose, the investigator should take the following steps: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any adverse event or serious adverse event and 
laboratory abnormalities until resolution. 
3. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor on the basis of clinical evaluation of the participant. 
5.7 
General concomitant medication and additional assistance guidelines 
Concomitant treatment and prior medication are defined as non-investigational medicinal product 
(non-IMP). Concomitant treatment includes any prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition 
to protocol-mandated treatment from 7 days prior to initiation of study drug to treatment 
discontinuation or end of study visit. 
Information on concomitant medication will include start date, end date, brand or generic name, 
route of administration, dose, and treatment indication. The following concomitant treatments 
are permitted during the study: 
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 
Symptomatic anti-emetics and anti-diarrheal therapy may be administered at the 
investigator’s discretion. 
 
Bone-sparing agents (e.g., bisphosphonates, denosumab for the treatment of 
osteoporosis/osteopenia) are allowed in the study provided patients are on stable doses 
for at least 4 weeks prior to randomization. 
 
Patients can be treated per standard of care except for use of any prohibited therapies. 
All concomitant medication and/or therapies should be documented in the patient’s eCRF. 
Cautionary therapies may include:  
 
Medications Associated with Bradycardia 
Investigators should use medical judgment and exercise caution when considering initiation of 
concomitant medication known to cause decreases in heart rate including, but not limited to, -
blockers and calcium channel antagonists. An alternative therapy should be used when possible.  
Patients on a stable dose of a -blocker or calcium channel antagonist for preexisting baseline 
conditions (e.g., hypertension) should be monitored closely in case dose modification is 
warranted. 
 
Herbal Therapies 
Herbal therapies not intended for the treatment of cancer may be used during the study at the 
discretion of the investigator and must be reported as concomitant therapy in the eCRF. 
Any medications deemed necessary to ensure patient safety and well-being may be administered 
at the discretion of the investigator with the exception of prohibited therapies contained in Section 
5.8. 
5.8 
Prohibited therapies and medication  
Use of the following concomitant therapies is prohibited during study treatment as described 
below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
during study treatment. 
 
Any concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or radiotherapy) 
is prohibited until after the end of study visit.  
 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate, oral contraception, hormone-eluting intrauterine 
devices, Gonadotropin-releasing hormone (GnRH) agonists and selective ER modulators 
(e.g., raloxifene) are prohibited until after the end of study visit. 
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 
Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination 
half-lives (whichever is longer) prior to randomization. Note: this includes consumption 
of grapefruit, grapefruit juice, grapefruit supplements, or Seville oranges (potent CYP3A 
inhibitors) within 3 days prior to randomization. 
 
Potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or 
bupropion). 
The investigator should consult the prescribing information in giredestrant’s (GDC-9545) IB and 
tamoxifen’s SmPC for information on prohibited therapies and recommended dose adjustments 
for concomitant medications. Giredestrant DDI study (GP44001) suggests that giredestrant is a 
moderately sensitive CYP3A substrate. It is advised that investigators consider alternatives to the 
concomitant use of moderate CYP3A inducers with giredestrant or giredestrant combination 
treatment. If this is not possible or there are no suitable alternatives, co-administration with 
moderate CYP3A inducers should be generally limited to short term use (approximately 30 days). 
Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active 
tamoxifen metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, 
fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during 
tamoxifen treatment. Patients with rare hereditary problems of galactose intolerance, the Lapp 
lactase deficiency or glucose-galactose malabsorption should not take tamoxifen. 
In addition, the investigator should contact the study Medical Monitor if questions arise regarding 
medications not listed above. Enrolled patients who subsequently require the use of any 
prohibited therapies must be discontinued from study treatment. 
5.8.1 
Interaction with other drugs  
Interaction of giredestrant (GDC-9545) with other medicinal products and other forms of 
interaction  
Giredestrant is a moderately sensitive CYP3A substrate. Co-administration giredestrant with the 
strong CYP3A inhibitors and inducers should be avoided. Refer to the giredestrant’s (GDC-9545) 
IB for a complete summary of safety information and DDIs. 
Interaction of tamoxifen with other medicinal products and other forms of interaction  
When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase 
in anticoagulant effect may occur. Where such co-administration is initiated, careful monitoring of 
the patient is recommended.  
As tamoxifen is metabolized by cytochrome P450 3A4, care is required when co-administering 
with drugs, such as rifampicin, known to induce this enzyme as tamoxifen levels may be reduced. 
The clinical relevance of this reduction is unknown. Therefore, is recommended to avoid the 
coadministration of tamoxifen and CYP3A inhibitors/inducers.  
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Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma 
levels of one of the more active forms of the drug, i.e., endoxifen, has been reported in the 
literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI 
antidepressants (e.g. paroxetine) in some studies.  
As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 
inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever 
possible be avoided. 
6 
ASSESSMENTS AND STUDY PROCEDURES  
6.1 
Patient entry procedures 
6.1.1 
Informed consent 
Written informed consent from the patient (or the patient’s legally authorized representative) must 
be signed and dated before her participation in the study and before performing any study specific 
procedure. Patients will be informed as to the nature of the study drug and will receive pertinent 
written information regarding the study objectives, possible benefits, and potential AEs. They will 
also receive information on the follow-up procedures and possible risks they will be exposed to. 
The informed consent form will also inform patients about how biological samples will be obtained 
and collected and its legal implications. A copy of the signed ICF must be provided to the patient 
or the patient’s legally authorized representative. Patients have the right to voluntarily withdraw 
from the study at any time for any reason, and this will not affect any future medical treatment the 
patient will receive. 
6.1.2 
Patient allocation  
The following steps must be taken before registering patients to this study: 
1. Completion of patient eligibility checklist by the investigational site, once checked all 
selection criteria. For patients with locally determined basal Ki67 between 10% and 19%, 
after receiving central Ki67 score result. 
Note for Ki67 selection criteria: Ki67 will be analyzed locally at the time of inclusion. For 
patients with basal Ki67 ≥20% according to local analysis, Ki67 ≥10% will be centrally 
confirmed retrospectively after inclusion. For patients with basal Ki67 levels between 10% 
and 19% according to local analysis, Ki67 ≥10% will need to be centrally confirmed before 
inclusion. 
2. Registration of patient in the Sponsor’s study database. 
3. Randomization using Sponsor’s study database. 
Confirmation of patient allocation using Sponsor study database:  
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Each patient will be identified with a unique patient number (UPN) for this study obtained from 
eCRF. All data will be recorded with this identification number on the appropriate eCRFs. 
Confirmation of patient’s eligibility for study participation will be recorded on the eCRF by the 
investigational site and verified by the study medical monitor prior to inclusion (all screening data 
needs to be completed 48h prior to randomization to allow enough time for medical monitor 
review). The investigator is responsible for safeguarding patient information (i.e., age, name, 
address, telephone number, social security number, and study identification number), ensuring 
access to this information by Health Authorities if necessary. These records will remain 
confidential for the period of time stipulated by current legislation. 
Randomization 
Premenopausal women with ER[+]/HER2[-] and Ki6 ≥10% early breast cancer will be randomized 
in a 1:1 ratio to giredestrant (GDC-9545) or tamoxifen arms.  
Randomization will be accomplished using an automated web randomization system (eCRF 
provided by the Sponsor). The system contains the randomization schedule. At the screening 
visit, the investigative site will obtain the patient number from the eCRF and will contact 
randomization system (online). The site will enroll the patient by indicating minimal information 
sufficient to distinguish one patient from another and receive the patient identity (ID) number. At 
the baseline visit, the system will associate that patient with the next available treatment on the 
randomization schedule and provide the randomization number. 
Refer to the separate study manual for instructions for study entry, patient ID assignments, and 
randomization procedures. 
6.2 
Visit schedule 
After confirming eligibility through the screening process as indicated above, patients will be 
scheduled for baseline visit at day 1 (D1) of treatment within 48 h after randomization.  
All screening tests and evaluations must be completed within the protocol scheduled time 
windows and reviewed to confirm that patients meet all eligibility criteria within 28 days prior to 
the first administration of study medication (dosing). The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
The study will consist of a screening period of up to 28-day, a window-of-opportunity 15-day 
treatment phase, an EoT visit (+ 1 day) and an EoS visit (28 days +/- 3 days after the final dose 
of study treatment). If post-treatment biopsy cannot be obtained within + 1 day from last day of 
treatment (15 days), treatment will be extended to 16 days and surgery or biopsy may be 
performed on the following day (be it D15 + 2 days). 
Assessments scheduled for day 1 (before treatment) must be performed within 48 hours prior to 
study treatment administration, unless otherwise indicated in the schedule of assessments, to 
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confirm to the patient if treatment can be followed up. If a mandatory procedure described in the 
protocol falls on a bank holiday and/or weekend, this procedure should be performed on the day 
before or after the holiday (i.e. within a period of ± 2 working days), except for the time window 
for the End of Treatment visit tumor biopsy that should be collected at Day 15 (+ 1 day). If post-
treatment biopsy cannot be performed within + 1 day from last day of treatment (that is, on D15 
or D15+1), treatment will be extended to 16 days and surgery or biopsy will be performed the day 
after. 
The summary of study assessments is included in Appendix 1: Schedule of study 
assessments and procedures. 
6.3 
Demographic data and medical history 
Demographic data include age, sex, and self-reported race/ethnicity. Medical history comprises 
clinically significant diseases, surgical interventions, history of cancer (including prior 
antineoplastic treatments and procedures), history of smoking, alcoholism, drug addiction, as well 
as any medications (i.e., prescribed drugs, over-the-counter drugs, medicinal plants, homeopathic 
remedies, or food supplements) used by the patient in the 7 days prior to screening visit. 
6.4 
Tumor assessments 
Assessment of primary tumor and regional lymph nodes must be performed by physical 
examination at screening and prior to administration of study treatment.  
Patients must have histologically confirmed ER[+]/HER2[-] primary invasive adenocarcinoma of 
the breast with locally analyzed and centrally confirmed Ki67 ≥10% and tumor size ≥1.0cm in 
longest diameter by ultrasound. 
6.4.1 
Ki67 score assessment 
A Ki67 score ≥10% stained nuclei from the pre-treatment tumor tissue sample is required for 
eligibility. Ki67 score will be analyzed locally at the time of inclusion. For patients with basal Ki67 
≥20% according to local analysis, Ki67 ≥10% will be centrally confirmed retrospectively after 
inclusion. For patients with basal Ki67 levels between 10% and 19% according to local analysis, 
Ki67 ≥10% will need to be centrally confirmed before randomization. 
To assess eligibility, HER2, ER, PgR will be locally determined on the most recent tumor biopsy 
acquired at baseline prior to beginning of study treatment. 
6.4.2 
Tumor imaging assessment by ultrasound  
Breast ultrasound and axillary node lymph status assessment should be performed according to 
institutional practice and result must be known at screening to assess eligibility and tumor size 
prior to randomization. 
All known sites of disease must be documented at screening. Baseline staging to document 
absence of metastatic disease should be performed as per institutional practice, in alignment with 
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national guidelines, in patients where there may be a reasonable suspicion of advanced disease 
(e.g., clinically positive axillary lymph nodes, signs and symptoms). If done, it must be performed 
within 28 days prior to randomization and reports of these examinations must be available at site. 
Examination type for tumor staging is at the discretion of the investigator and can include i.e. X-
ray, sonography, bone scan, CT, MRI, and/or PET-CT scan.   
Patients diagnosed with multifocal or multicentric breast cancer will be eligible for the study if the 
two largest lesions meet pathologic criteria for ER positivity and HER2 negativity and at least one 
tumor lesion measures ≥ 1cm in the longest diameter by ultrasound (reference lesion) and this 
one meets the histologic inclusion criteria of Ki67 score ≥10% as described in Section 6.4.1. 
6.5 
Safety and tolerability assessments 
6.5.1 
Laboratory assessments 
Laboratory tests will be performed in accordance with local standard treatment and clinical 
indications before treatment administration. These values should include: hematological test 
(hemoglobin, hematocrit, red blood cell count, platelet count, WBC and differential count [ANC, 
lymphocytes, monocytes, eosinophils and basophils, and other cells]); coagulation (INR, PTT (or 
aPTT)); chemistry panel (serum or plasma): sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total bilirubin (if total bilirubin is 2xULN, also 
direct bilirubin), AST, ALT, ALP, urate and LDH; fasting lipid panel: cholesterol, LDL cholesterol, 
HDL cholesterol, and triglycerides (after ≥ 8 hours of fasting); urinalysis, including dipstick (pH, 
specific gravity, glucose, protein, ketones, and blood) and microscopic examination (sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, and bacteria), FSH and estradiol. Urinalysis should 
be performed as clinically indicated during study treatment. 
6.5.2 
Pregnancy and assessment of fertility 
Premenopausal status is defined as estradiol (E2) in the premenopausal range (according to 
institution parameters) or patient has been menstruating regularly during the 6 months prior to 
randomization and has not used any form of hormonal contraception or any other hormonal 
treatments during this time. 
All patients must undergo a serum pregnancy test at screening to confirm eligibility in the trial and 
within 14 days prior to initiation of study treatment (with result available prior to dosing), and a 
urine pregnancy test (with results available prior to dosing) within 24 hours prior to study treatment 
initiation.  
All patients must remain abstinent and truly abstains from sexual activity (refrains from 
heterosexual intercourse) or use of locally recognized adequate methods of contraception 
(described as that with a failure rate <1%) during the length of the study, and to continue its use 
for 10 days after the last dose of study treatment (for patients taking giredestrant) or 60 days 
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following cessation of therapy (for patients in the tamoxifen arm). They must, as well, agree to 
refrain from donating eggs during the same period. 
Examples of non-hormonal contraceptive method with a failure rate of <1% per year are bilateral 
tubal ligation, male sterilization and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods 
of contraception. 
An additional pregnancy test is indicated in the EoT visit and in the EoS visit, when a urine 
pregnancy test should be performed. 
In case of pregnancy during study treatment or within 10 days after the last dose of study 
treatment (for patients taking giredestrant) or 60 days following cessation of therapy (for patients 
in the tamoxifen arm), the patient must permanently stop study treatment immediately and/or 
withdraw from the trial, and the pregnancy must be reported on the Clinical Trial Pregnancy Form 
as specified in Section 7.2.4. 
6.5.3 
Cardiac function monitoring 
Cardiac function monitoring consists of a standard 12-lead ECG, and cardiac signs or symptoms 
collection. All patients must have a standard 12-lead ECG in screening period, maximum 48h 
before start of treatment dose, in the EoT visit and in the EoS visit. The same method should be 
used throughout the study for each patient, and preferably performed and assessed by the same 
assessor. 
Single 12-lead ECGs will be obtained as outlined in the schedule of activities using an ECG 
machine that automatically calculates the heart rate and measures RR interval, QRS interval, QT 
interval, and QT interval corrected through use of Fridericia's formula (QTcF)/QT interval, PR 
duration.  
Lead placement should be as consistent as possible. ECG recordings must be performed after 
the participant has been resting in a supine position. All ECGs are to be obtained prior to other 
medical procedures scheduled at that same time (e.g., vital sign measurements, blood draws). 
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 all ECG reports. Copies of ECG 
tracings (paper or digital) will be kept as part of the participant's permanent study file at the site. 
Any morphologic waveform changes or other ECG abnormalities must be documented on the 
eCRF. ECG measurement may be performed by an MN professional but reviewed and assessed 
by the investigator. 
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Any patient who develops clinical signs or symptoms of cardiac failure should undergo a standard 
12-lead ECG, LVEF measurement, and cardiac enzyme assessment.  
6.5.4 
Physical examination 
Assessment of primary tumor and regional lymph nodes must be performed by physical 
examination at screening and prior to administration of study treatment.  
A complete physical examination should also include an examination of head, eyes, ears, nose, 
and throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, digestive, 
genitourinary, and neurological systems. Changes to abnormalities identified during the baseline 
period should be recorded at all subsequent physical examinations. New or worsening 
abnormalities should be recorded as AEs, if applicable. 
6.5.5 
Vital signs 
These will include the measurement of height (only during screening), weight, respiratory rate, 
heart rate, blood pressure, and body temperature. Abnormal or significant changes in vital signs 
from baseline should be recorded as AEs, if appropriate. 
6.5.6 
ECOG performance status 
Performance status will be determined using the ECOG performance status scale (see Table 4). 
Wherever possible, the patient’s performance status should always be assessed by the same 
personnel throughout the study. 
Table 4. ECOG performance status scale.  
Grade  
Scale 
0  
Fully active, able to carry on all pre-disease performance without restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, i.e., light housework, office work.  
2  
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours.  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair.  
5 
Dead. 
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http://www.ecog.org/general/perf_stat.html 
6.6 
Tumor and blood samples 
All patients will be required to provide a pre-treatment tumor tissue sample and blood samples 
during screening, and a tumor biopsy sample and a blood sample on Day 15 (+ 1-2 days) at the 
end of study treatment. 
6.6.1 
Tumor tissue samples 
Mandatory biopsy samples will be collected before the start of treatment (up to a maximum of 8 
weeks before the first dose of study drug). If a diagnostic biopsy was performed maximum 8 
weeks prior to initiation of study treatment, it can be used as a baseline sample for the Ki67 
assessment. Additional biopsy will be taken at the EoT (+ 1 day) after the last dose of study drug. 
Note: if post-treatment biopsy cannot be obtained within + 1 day from last day of treatment (on 
D15 or D15+1), treatment will be extended to 16 days and patients will be able to have surgery 
or biopsy the following day (be it D15 + 2 days). 
Tumor samples obtained are to be collected as tumor paraffin embedded block (two formalin fixed 
paraffin-embedded blocks [FFPE]). Tumor tissue samples must be of good quality based on total 
and viable tumor content: Samples must contain a minimum of 500 viable tumor cells that 
preserve cellular context and tissue architecture. Samples collected via resection, core-needle 
biopsy (at least three cores, embedded in a single paraffin block), punch, or forceps biopsy are 
acceptable. 
Note: Details regarding Ki67 staining can be found in the separate laboratory manual.  
Note II: Samples must contain a minimum of 500 viable tumor cells. In the event of containing 
less cells (but as long as there’s a minimum of 350 viable cells), the case can be discussed with 
the medical monitor and a second FFPE block can be sent to the Sponsor’s designated central 
laboratory.  
These samples will be used for assessing study co-primary endpoints referring to changes in 
tumor cell proliferation as measured by Ki67 expression between baseline and day 15 post-
treatment tumor biopsy samples by central assessment in patients with centrally confirmed Ki67 
≥10% (Arm A vs Arm B), and other secondary endpoints as indicated in the protocol. 
6.6.2 
Blood samples 
Mandatory liquid biopsies will be taken before the start of study treatment (up to a maximum 14 
days before the first dose of the study drug) and, if possible, at the same timepoint as baseline 
hematological laboratory assessments,  and at the EoT (+ 1 day after the last dose of study drug, 
which will be D15, D15+1, D16+1). Post-study treatment liquid biopsy samples will be taken at 
the same timepoint, if possible, as post-study treatment tumor biopsies. 
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These samples will be used to perform a plasma endocrine panel with samples pre- and post-
therapy. Please refer to the study laboratory manual for more information. 
Since the identification of new markers that correlate with disease activity and the efficacy or 
safety of treatment is rapidly developing, the definitive list of analyses remains to be determined. 
6.7 
Patient discontinuation 
Patients have the right to withdraw from the study at any time for any reason. The investigator 
also has the right to withdraw patients from the study in the event of intercurrent illness, AEs, and 
treatment failure after a prescribed procedure, protocol violation, administrative reasons, or for 
other reasons. An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Should a patient decide to withdraw, all efforts should be made to complete and report the 
observations as thoroughly as possible. Although the patient has no obligation to provide the 
reasons for his/her voluntary withdrawal, the investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as completely as possible 
the reason for the withdrawal. 
A complete final evaluation at the time of the patient’s discontinuation from the study should be 
made. The principal specific reason for the removal of a patient from the study must be clearly 
stated in his/her medical records and will be recorded on the CRF. 
In the case that the patient decides to prematurely discontinue study treatment, he/she should be 
asked if he/she can still be contacted for further information. The outcome of that discussion 
should be documented in both the medical records and in the CRF. 
6.8 
Study and site discontinuation 
The Sponsor reserves 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 seriousness of AEs in this or other studies indicates a potential health 
risk to patients. 
 
Patient enrollment is unsatisfactory. 
 
Data recording is inaccurate or incomplete. 
 
Excessively slow recruitment. 
 
Poor protocol adherence. 
 
Non-compliance with the International Conference on Harmonization (ICH) guideline for 
Good Clinical Practice (GCP).  
 
 
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7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording protocol-defined AEs, SAEs and non-
serious adverse events of special interest (AESIs); measurement of protocol-specified 
hematology, clinical chemistry, measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug(s). 
7.1 
AEs definition 
An AE is any untoward medical occurrence in a clinical study subject/patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with his/her 
treatment. An AE can therefore be any unfavorable and/or unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, regardless of whether it is considered related to the medicinal 
(investigational) product. 
The causal relationship between an AE and the IMP will be defined as below: 
Not related: The temporal association between the adverse event and the IMP makes a causal 
relationship unlikely, or the subject/patient’s clinical state or the study procedure/conditions 
provide a sufficient explanation for the adverse event. 
Related: The temporal association between the adverse event and the IMP makes a causal 
relationship possible and the subject/patient’s clinical state or the study procedure/conditions do 
not provide a sufficient explanation for the adverse event. 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP drugs. 
The descriptions and grading scales found in the revised NCI-CTCAE v 5.0 will be utilized for all 
toxicity reporting. A copy of the CTCAE v 5.0 can be downloaded from the CTEP website 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refe
rence_5x7.pdf). 
The intensity (severity) of an AE will be recorded as one of the following but also CTCAE Grade 
will be recorded: 
 
Mild - Easily tolerated and does not interfere with normal daily activities, CTCAE 
Grade 1. 
 
Moderate - Causes some interference with daily activities, intervention or treatment 
may be needed. CTCAE Grade 2. 
 
Severe - Normal daily activities are substantially impaired, hospitalization and/or 
intervention or treatment is required, CTCAE Grade 3 or 4. 
 
Fatal - Death, CTCAE Grade 5. 
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 
Not applicable (clinically significant and asymptomatic laboratory test abnormalities 
or abnormal assessments, for which no CTCAE grading guidance is applicable but 
which are considered as AEs). 
A mild, moderate or severe AE may or may not be serious (see definition below). These terms 
are used to describe the intensity of a specific AE. However, a severe AE (such as severe 
headache) may be of relatively minor medical significance and is not necessarily serious. For 
example, nausea lasting several hours may be rated as severe, but may not be clinically serious. 
Fever of 39°C that is not considered severe may become serious if it prolongs hospital discharge 
by a day. Seriousness rather than severity serves as a guide for defining regulatory reporting 
obligations. 
7.1.1 
SAEs definitions 
Per definition, a SAE is defined as any adverse event that either: 
 
results in death (i.e., the AE actually causes or leads to death), 
 
is life threatening (i.e., the AE, in the view of the investigator, places the subject/patient 
at immediate risk of death when it occurs), 
 
requires inpatient hospitalization or prolongation of existing hospitalization, 
 
results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person ability to conduct normal life functions), 
 
is a congenital anomaly/birth defect (in a neonate/infant born to a mother exposed to the 
investigational product(s). 
7.1.1.1 
Definition of life threatening 
An AE is life threatening if the subject/patient was at immediate risk of death from the event as it 
occurred, i.e. does not include an event that might have caused death if it had occurred in a more 
serious form. For instance, drug induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening even though drug-induced hepatitis can be fatal. 
7.1.1.2 
Definition of hospitalization 
AEs requiring hospitalization should be considered serious. In general, hospitalization signifies 
that the subject/patient has been detained (usually involving an overnight stay) at the hospital or 
emergency ward for observation and/or treatment which would not have been appropriate at the 
study site. When in doubt as to whether hospitalization occurred or was necessary, the AE should 
be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, need not to be notified according to immediate reporting criteria. If anything untoward is 
reported during any procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
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7.1.1.3 
Definition of clinically/medically significant event 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject/patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Clinically/medically significant events MUST be reported as SAEs. 
In this clinical trial and as defined in this protocol, SAEs and hospitalizations unequivocally and 
solely related to established tumor disease progression will NOT be treated as SAEs for reporting 
obligations. 
SAEs, if brought to the attention of the Investigator at any time after the cessation of the study 
treatment and considered by the Investigator to be possibly related to the study treatment (so, in 
fact serious adverse reactions), will be reported to the Sponsor. 
7.1.1.4 
Cases of overdose, medication error, drug abuse, or drug misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse (hereafter 
collectively referred to as "special situations") are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher than 
the assigned dose. 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher than 
the assigned dose. 
 
Medication error:  accidental deviation in the administration of a drug, including 
accidentally omitted doses. In some cases, a medication error may be intercepted prior 
to administration of the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm. 
 
Drug misuse:  intentional deviation in the administration of a drug that does not qualify as 
drug abuse. In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the participant. 
Special situations are not in themselves AEs but may result in AEs.  Each AE associated with a 
special situation should be recorded separately on the Adverse Event eCRF.  If the associated 
adverse event fulfils seriousness criteria or qualifies as an adverse event of special interest, the 
event should be reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event). 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 
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accidental overdose and one entry to report the headache. The "Accidental overdose" and 
"Medication error" boxes would need to be checked for both entries. 
In the event of an overdose, the investigator should follow the steps described in Section 5.6.  
7.1.2 
AESIs for IMPs 
AESIs must be reported by the Investigator to the Sponsor expeditiously (see Section 7.2.1 for 
reporting instructions), regardless of their seriousness (i.e., no more than 24 hours after 
learning of the event). AESIs for giredestrant 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 
Table 5. Guidelines for Management of Patients Who Experience Adverse Events 
Associated with Giredestrant (GDC-9545). in Section 7.2). 
● 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product. 
This term applies only when a contamination of the study drug is suspected.  
● 
Grade ≥3 hepatitis or elevations in AST or ALT. 
● 
Grade ≥3 acute kidney injury, creatinine increases, or renal toxicity. 
● 
Grade ≥2 bradycardia. 
● 
Grade ≥2 thromboembolic events. 
7.2 
Safety profile and management of AEs for IMPs 
AEs will be collected from the first study-mandated procedure until the End of Study visit to be 
done 28 days (± 3 days) after the last day of study treatment. All study subjects/patients will be 
carefully monitored for the occurrence of AEs during this period. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. Any additional 
events that fall outside this definition should also be reported separately. 
All AEs must be recorded in the CRF. The investigator should follow each adverse event until the 
event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow-up, or the patient withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
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Table 5. Guidelines for Management of Patients Who Experience Adverse Events 
Associated with Giredestrant (GDC-9545). 
Adverse Reaction 
Event action to be taken 
Elevation of hepatic transaminases  
General guidance  
 
If patient presents with jaundice, coagulopathy, abdominal pain, or 
other symptoms suggestive of hepatic toxicity, perform liver 
function tests with additional evaluation per institutional guidelines.  
 
If hepatic enzymes are elevated with no obvious malignant cause 
found, consult with hepatologist.  
 
Treat patient with hepatic enzyme elevation according to local 
standard of care. 
Grade 1 or 2 
 
Continue giredestrant (GDC-9545).  
 
Rule out alternative etiologies (e.g., disease progression, 
concomitant medications, or biliary obstruction).  
 
Treat patient according to local standard of care. 
Grade 3 
 
Permanently discontinue giredestrant (GDC-9545).  
 
Consult with hepatologist. 
Grade 4 or meets   
criteria as defined 
by Hy’s Law* 
 
Permanently discontinue giredestrant (GDC-9545).  
 
Consult with hepatologist. 
Gastrointestinal events (nausea, vomiting, diarrhea) 
General guidance 
 
Monitor closely for GI symptoms. If patient presents with nausea, 
vomiting, or diarrhea, manage according to local standard of care, 
including use of anti-diarrheal agents and supportive care such as 
hydration and dietary modification as appropriate.  
 
Infectious or alternate etiologies should be ruled out. 
Grade 2 
 
Manage and treat according to local standard of care. If persistent 
despite appropriate medical therapy, withhold giredestrant (GDC-
9545) until resolution to Grade ≤ 1. 
Grade ≥ 3 
 
Withhold giredestrant (GDC-9545) until event resolves to Grade ≤ 
1.  
 
Manage and treat patient according to local standard of care.  
 
Consider consulting with gastroenterologist.  
 
Resume giredestrant (GDC-9545) at full dose once the event 
resolves to Grade ≤ 1.  
 
If adverse event is recurring and patient cannot tolerate treatment, 
then permanently discontinue giredestrant (GDC-9545). 
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Adverse Reaction 
Event action to be taken 
Venous thromboembolic events (including pulmonary embolism) 
General guidance 
 
Advise patient to seek immediate medical attention if they become 
aware of any symptoms of PE or DVT, such as acute onset of 
chest pain, shortness of breath, or swelling in extremities. 
Grade ≥ 2 
 
Withhold giredestrant (GDC-9545) until patient is stable.  
 
Manage and treat patient according to local standard of care.  
 
Resume giredestrant (GDC-9545) at full dose once the patient is 
stable.  
 
Permanently discontinue giredestrant (GDC-9545) for recurrent 
thromboembolic events. 
Bradycardia 
General guidance 
 
Monitor patient closely for symptomatic bradycardia. 
Grade 1 
 
Continue giredestrant (GDC-9545).  
 
Continue to monitor patient per schedule of activities. 
 
If heart rate falls below 40 bpm, withhold giredestrant (GDC-9545) 
until heart rate returns to > 40 bpm and patient remains 
asymptomatic. 
Grade 2 
 
Withhold giredestrant (GDC-9545) and consult with cardiologist.  
 
Resume giredestrant (GDC-9545) at full dose once the event 
improves to Grade ≤ 1 and the heart rate returns to >40 bpm.  
 
For recurrent Grade 2 bradycardia, permanently discontinue 
giredestrant (GDC-9545).  
Grade ≥ 3 
 
Permanently discontinue giredestrant (GDC-9545) and consult with 
cardiologist. 
Renal toxicity or increased creatinine 
Grade 1 or 2 
 
Continue giredestrant (GDC-9545).  
 
Manage patient according to local standard of care. 
Grade ≥ 3 
 
Permanently discontinue giredestrant (GDC-9545).  
 
Manage patient according to local standard of care.  
 
Consult with nephrologist. 
Non-hematologic toxicity 
Grade 1 or 2 
 
Continue giredestrant (GDC-9545).   
 
Rule out alternative etiologies. 
Grade 3 
 
Withhold giredestrant (GDC-9545) until symptoms resolve to Grade 
≤ 1, and then resume giredestrant (GDC-9545) at full dose. 
Grade 4 
 
Permanently discontinue giredestrant (GDC-9545). 
DVT = deep vein thrombosis; GI = gastrointestinal; PE= pulmonary embolism; ULN = 
upper limit of normal.  
*The finding of an elevated ALT or AST (> 3xULN) in combination with either an elevated total bilirubin (> 2xULN) 
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). 
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7.2.1 
AEs and SAE reporting and timeframe 
Reporting requirements will comply with all EU safety reporting requirements as detailed in 
“Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on 
clinical trials on medicinal products for human use, repealing Directive 2001/20/EC”. 
The investigator is responsible for ensuring that all adverse events (see Section 7.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness, severity and causality. 
During the study period, resolution of adverse events (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data verification. 
The investigator or investigator’s team will report all protocol defined SAEs and AESIs to the 
Sponsor (MEDSIR) no later than 24 hours of any site study team staff becoming aware of the 
event as follows: 
 
The full details of the SAE and/or AESI should be collected and fully documented using 
the SAE form and sent to MEDSIR. 
 
Follow-up information, copies of the results of any tests, the outcome of the event plus 
the investigator’s opinion of IMP relationship to the SAE(s) and AESI(s), and other 
document when requested and applicable, will accompany the SAE form as available on 
the day of reporting or provided as soon as possible thereafter. 
 
The original SAE Report Form and the fax confirmation sheet from the Sponsor must be 
kept with the CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MEDSIR) 
according to the reporting instructions provided by MEDSIR at the site initiation visit and filed in 
the Investigator’s File. 
All SAEs must be reported to Drug Safety Evaluation (DSE) Clinical Safety and 
Pharmacovigilance (CSPV) team address: EMPRESS_sae@medsir.org. 
SAEs and AESIS will be followed until resolved, a stable outcome or baseline condition is 
reached, subject/patient is lost to follow-up or dies. 
As Sponsor, MEDSIR will be responsible for ensuring that events are reported within the 
mandated timeframe to the EMA and other Competent Authorities, Institutional Review Boards 
/Institutional Ethics Committees (IRBs/IECs) and investigator(s), as necessary and in accordance 
with all applicable guidelines, approved directives, and regulations. All safety reporting local 
regulatory requirements will be followed. 
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7.2.2 
Expedited reporting to Health Authorities, Investigators, IRBs, and IECs 
To determine reporting requirements for single SAE cases, MEDSIR (as Sponsor) or its designee 
will assess the expectedness of these events using the following reference documents: 
- Current IMP SmPC/IB. 
MEDSIR (as Sponsor) or its designee 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. 
Within 7 calendar days after being notified of the event, MEDSIR (as Sponsor) or its designee will 
report unexpected fatal or life-threatening events associated with the use of the study drug to the 
regulatory agencies and competent authorities, to the investigators and IRBs/IECs. MEDSIR (as 
Sponsor) or its designee will report other unexpected SAEs associated with the use of the study 
medication to the appropriate competent authorities (according to local guidelines), investigators, 
and central IRBs/IECs by a written safety report within 15 calendar days of notification. All safety 
expedited reports will be reported in accordance to all regulatory reporting obligations (including 
timelines) and local regulatory requirements. 
7.2.3 
Other safety-related reports 
As Sponsor, MEDSIR will assess constantly the benefit/risk rate of the trial, that means a 
continuous evaluation of the safety profile of the drugs under investigation will be done using all 
available information. MEDSIR will provide the regulatory agencies and competent authorities 
and the investigators with any relevant information that may affect the benefit/risk rate of the trial. 
An annual Development Safety Update Report (DSUR safety report) for IMP will be prepared and 
distributed by MEDSIR or its designee in accordance with all regulatory reporting obligations and 
local regulatory requirements. 
In order to ensure the correct and necessary exchange of safety related information between 
MEDSIR (as Sponsor) and Roche (as the owner of the IMP), a project specific Safety Data 
Exchange Agreement will be established and signed between both companies. 
MEDSIR or its designee will report any finding of noncompliance (as failure to follow any 
applicable regulation or institutional policies that govern human subjects’ research) and/or serious 
noncompliance (as noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants) 
according to any reporting obligation and local regulatory requirements. 
7.2.4 
Pregnancy reporting 
Irrespective of the treatment received by the subject/patient, any subject/patient’s or 
subject/patient’s partner pregnancy occurring during study treatment or within 10 days after the 
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last dose of study treatment (for patients taking giredestrant) or 60 days following cessation of 
therapy (for patients in the tamoxifen arm) must be reported within 24 hours of investigator’s 
knowledge of the event. 
Patients will be instructed to immediately inform the investigator if they become pregnant during 
the study or within 28 days after the final dose of study drug. 
Pregnancies will be treated as SAEs and the investigator will complete a Clinical Trial Pregnancy 
Reporting Form and forward it to the Sponsor according to the reporting instructions provided by 
MEDSIR at the site initiation visit and filed in the Investigator’s File. The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  
The subject/patient will be asked to provide follow-up information on the outcome of the 
pregnancy, including premature termination should the case arise and on the infant until 12 
months of life. Spontaneous miscarriage and congenital abnormalities will also be reported as 
SAEs. Follow-up queries may be sent, asking for further information, if required for a 
comprehensive assessment of the case. 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined at 12 months of the infant’s life. 
Additional follow-up information on any IMP -exposed pregnancy and infant will be requested at 
specific time points (i.e., after having received the initial report, at the end of the second trimester, 
two weeks after the expected date of delivery, and at 3, 6, and 12 months of the infant’s life). 
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).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event). 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. 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study drug 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
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8 
STATISTICAL CONSIDERATIONS  
8.1 
Sample size 
A total of 92 patients will be enrolled in this trial and randomized 1:1 in the arm A with giredestrant 
(GDC-9545) (n=46) and the arm B with tamoxifen (n=46), with an expected accrual time of 
approximately 16 months and an additional 0.5 months for follow-up from end of accrual until 
EoT. EoS will be 28 days (+/- 3 days) after last dose of study treatment is taken. 
8.2 
Sample size 
The analysis will compare absolute changes for Ki67 expression between baseline score and the 
evaluation after  the treatment. The sample size was based on a superiority contrast between two 
study arms analyzed with a two-sided t-test set at 0.05 alpha level. We assumed a 70% mean in 
giredestrant (GDC-9545) Arm vs. 50% mean in tamoxifen with a 29% common standard deviation, 
according to the results observed (Dowsett, Smith, et al., 2005). We planned 34 patients per arm 
to attain an 80% power.  
The final analysis will be conducted with unpaired Wilcoxon test because of the non-asymptotic 
distribution of data. We assumed that asymptotic efficiency of Wilcoxon test relative to the t-test, 
never falls below 0.86 (Jr & Lehmann, 1956). In addition, we expect a 10% dropout rate. So, 46 
patients per arm will be finally recruited. We used the R software version 4.0.2. released on 2020-
06-22 (“pwr”). 
8.3 
Populations for Analyses 
Modified intention to treat (mITT) set 
All randomly assigned patients that accomplish major selection criteria (Central Ki67 ≥ 10%), with 
≥ 14 days of treatment*, and the central Ki67 evaluated at baseline and at most on the day after 
the completion of treatment Subjects will be analyzed according to treatment allocated. The mITT 
set will be used for primary and secondary efficacy analysis. 
* One day of deviation from the 15 days of treatment indicated for the main objective will be 
accepted. 
Intention-to-treat (ITT) analysis set  
All patients randomized. Subjects will be analyzed according to treatment allocated. The ITT set 
will be used for supportive efficacy analyses. 
Per protocol analysis (PP) set 
All randomly assigned patients that accomplish major selection criteria, with Ki67 evaluable 
values at baseline and after the treatment, with a minimum exposure to the drugs assigned in the 
randomized arm, and without major protocol deviations. Criteria for determining the “per protocol” 
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group assignment would be established by the Steering Committee before the statistical analysis 
begins. Subjects will be analyzed according to treatment received. The PP set will be used for 
supportive efficacy analyses. This analysis will only occur if this set differs by ≥ 10% from the 
mITT set. 
Safety analysis set 
Includes all patients who received at least one dose of the study drug. Subjects will be analyzed 
according to treatment received. The safety set will be used for analyses of safety endpoints. 
 
 
 
 
8.4 
Primary efficacy endpoint 
The change in tumor cell proliferation as measured by Ki67 expression between baseline and the 
post-treatment tumor biopsy samples by central assessment. 
The primary analysis will be done for the mITT analysis set. We only will analyse observed valid 
cases (observed-cases method).  
The global null hypothesis is that the giredestrant (GDC-9545) does not differ from tamoxifen 
treatment group in the mean percentage of absolute difference in Ki67 between baseline score 
and after the treatment. The alternative hypothesis is that the giredestrant (GDC-9545) differs 
from the tamoxifent treatment group.  
The test of the null hypothesis is based on a two-sided Wilcoxon unpaired test set at 0.05 alpha 
level. It includes treatment as a factor. The response variable is the absolute difference in Ki67 
score after the treatment. We propose declaring the superiority of giredestrant (GDC-9545) 
therapy if shown to be superior in this analysis. 
We will estimate the 95% confidence intervals (CI) for the mean and median of absolute difference 
between baseline and the post treatment evaluation in each study arm. The 95% confidence 
intervals (CI) for the mean and median difference between treatments are estimated by the T-
Test and Hodges–Lehmann estimator, respectively.  
Individual baseline and post-treatment Ki67 scores will be summarized with dot plots linking with 
a line the observations of the same patient. Absolute and relative change between baseline and 
post-treatment will be summarized with waterfall and bar plots. 
 
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8.5 
Missing data imputation methods 
The values of Ki67 could be missing for patients without valid analytic values or withdrawal. 
Missing values for primary endpoint will be managed with three methods: 
a) Observed case imputation: Only observed valid cases are analyzed. 
b) Last observation carried forward: Missing value are replaced by the last value observed before. 
c) The standard multiple imputation performed in three steps: (1) the imputation of non-monotone 
missing data using MCMC. A total of 10 complete datasets are generated within this step; (2) the 
imputation of monotone missing data with regression models; (3) the calculation of endpoint 
estimates, standard errors and p-values for each dataset; and (4) the combination of all dataset 
results by Rubin’s rules. 
8.6 
Supportive analyses for primary efficacy endpoint 
The primary endpoint analysis will be repeated for the PP and ITT set as described in the previous 
section. For ITT analysis the missing values for Ki67 after the treatment are imputed with baseline 
Ki67 scores based on the last observation carried forward principle (0 score in absolute difference 
of Ki67). For PP analysis only observed valid cases will be analysed. 
Additionally, the following supportive analyses will be performed (Table 6. Planned analyses for 
the primary endpoint.): 
a) The Ki67 score after two weeks of treatment will be adjusted by baseline Ki67 scores. The 
analysis will be done for the mITT, ITT and PP analysis set (as appropriate). We only will analyse 
observed valid cases for mITT and PP analysis set. Alternatively, the missing management 
method for ITT analysis will be the multiple imputation. 
The test of the null hypothesis is based on a linear regression model which includes treatment as 
a factor and baseline Ki67 score as covariate. The response variable is the Ki67 score after the 
treatment. Because of the non-asymptotic distribution of data, power transformations will be 
conducted with response and covariate. The transformed values of the Ki67 score are assumed 
to be a linear function of the treatment as: 
Y = β0 + β1X1 +  β2X2  
where 
Y = The Ki67 score after the treatment, 
β0 denotes intercept, 
β1 denotes the treatment effect, 
X1 refers to the treatment groups (Giredestrant (GDC-9545) and tamoxifen), 
β2 denotes the Ki67 baseline score effect, 
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X2 refers to the Ki67 baseline score. 
The parameterization method is based on a reference group (tamoxifen). The p-values and 95% 
CI are estimated by the Wald method. The 95% CI will be also reported back transformed.  
b) The relative percentage of change between baseline and the post treatment evaluation in each 
patient will be calculated using the baseline and post-treatment scores divided by baseline scores 
per 100. The 95% CI for the arithmetic and geometric mean in each arm will be estimated with T-
Test.  
The geometric mean will be estimated using the log values for the relative percentage of change. 
The log-transformation is designed for non-negative values, so we will add a constant to the 
individual values of relative percentage change before applying the transformation. The 95% CI 
for the geometric mean will be reported back transformed using the anti-log scale and subtracting 
the constant. The analysis will be done for the mITT, ITT and PP analysis set (as appropriate). 
We only will analyse observed valid cases for mITT and PP analysis set. Alternatively, the missing 
management method for ITT analysis will be the multiple imputation. 
Table 6. Planned analyses for the primary endpoint. 
ID 
Set 
Analysis sets 
Main 
estimate 
and 
(Imputation Method) 
Type of analysis 
1 
mITT 
Patients excluded:  
-Central Ki67 < 10% or not 
evaluable at baseline. 
-<14 days of treatment. 
-Without the Ki67 central 
evaluation at baseline and 
after at most on the day after 
the completion of treatment.  
Central Ki67 score 
Difference 
between 
baseline and post treatment 
evaluation. 
(Observed case) 
Primary 
-Willcoxon unpaired  
-95% CI T-test 
-95% CI HL 
2 
ITT 
All patients randomized 
regardless of IEs are included 
(Treatment policy strategy). 
Central Ki67 score 
Difference 
between 
baseline and post treatment 
evaluation. 
(Last observation carried 
forward) 
Supportive 
-Willcoxon unpaired 
-95% CI T-test 
-95% CI HL 
3 
PP 
Patients excluded:  
-Central Ki67 < 10% or not 
evaluable at baseline. 
-Without the Ki67 central 
evaluation after the treatment 
-Patients with other major 
deviations in accordance 
steering committee. 
Central Ki67 score 
Difference 
between 
baseline and post treatment 
evaluation. 
(Observed case) 
Supportive 
-Willcoxon unpaired 
-95% CI T-test 
-95% CI HL 
4 
mITT 
See above ID nr. 1 
Central Ki67 score 
Ki67 
score 
after 
the 
treatment 
adjusted 
by 
baseline score. 
-Box-cox transformation 
(Observed case) 
Supportive 
-Linear 
regression 
(Wald test) adjusted by 
baseline scores 
5 
ITT 
See above ID nr. 2 
Central Ki67 score 
Ki67 
score 
after 
the 
treatment 
adjusted 
by 
baseline score. 
Supportive 
-Linear 
regression 
(Wald test) adjusted by 
baseline scores 
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ID 
Set 
Analysis sets 
Main 
estimate 
and 
(Imputation Method) 
Type of analysis 
-Box-cox transformation 
(Multiple imputation) 
6 
PP 
See above ID nr. 3 
Central Ki67 score 
Ki67 
score 
after 
the 
treatment 
adjusted 
by 
baseline score. 
-Box-cox transformation 
(Observed case) 
Supportive 
-Linear 
regression 
(Wald test) adjusted by 
baseline scores 
7 
mITT 
See above ID nr. 1 
Central Ki67 score 
% 
of 
change 
between 
baseline and post treatment 
evaluation. 
(Observed case) 
Supportive 
-95% CI for arithmetic 
and geometric means in 
each arm 
8 
ITT 
See above ID nr. 2 
Central Ki67 score 
% 
of 
change 
between 
baseline and post treatment 
evaluation. 
(Multiple imputation) 
Supportive 
-95% CI for arithmetic 
and geometric means in 
each arm 
9 
PP 
See above ID nr. 3 
Central Ki67 score 
% 
of 
change 
between 
baseline and post treatment 
evaluation. 
(Observed case) 
Supportive 
-95% CI for arithmetic 
and geometric means in 
each arm 
CI: Confidence interval; HL: Hodges–Lehmann method; ITT: Intention to treat; mITT: Modified 
intention to treat; PP: Per protocol. 
8.7 
Secondary and subgroup analyses  
The secondary efficacy endpoints will be done for the mITT analysis set. We only will analyse 
observed valid cases.  
For quantitative measures (Ki67, ER, PR, and other molecular markers) the mean, median, 
geometric mean, standard deviation, interquartile range, and range will be reported as appropriate 
per study arm and visit. Summary statistics for the absolute and relative change between baseline 
and post-treatment will be also reported. 
Individual baseline and post-treatment scores in quantitative measures will be summarized with 
dot plots linking with a line the observations of the same patient. Absolute and relative change 
between baseline and post-treatment will be summarized with waterfall and bar plots.  
The difference between baseline and post-treatment evaluation will be compared in each arm 
with Wilcoxon paired test. We will estimate the 95% confidence intervals (CI) for the mean and 
median.  
The difference between study arms at baseline and after the treatment will be compared with 
Wilcoxon unpaired test. We will estimate the 95% confidence intervals (CI) for the mean and 
median difference between treatments with T-Test and Hodges–Lehmann estimator, respectively. 
The comparison of quantitative score after two weeks of treatment in each arm will be adjusted 
by baseline scores based on linear regression. Power transformations will be deliberated.   
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For qualitative measures (CCCA [Ki67≤2.7%] after the treatment) we will calculate the number 
and proportion of patient achieving the cut-off criterion. We will estimate the proportions with the 
95% Pearson-Clopper confidence intervals. The between arms comparison will be conducted with 
logistic regression models. Factor estimates, odds ratios, corresponding 95% confidence 
intervals, and p-value will be presented. P-values and 95% confidence intervals will be based on 
Wald test. 
The comparison of primary and secondary endpoints between patient and molecular 
characteristics will be conducted if considered appropriate. The quantitative endpoints will be 
analyzed with linear regression based on Wald test. The binary endpoints will be analyzed with 
logistic regression models. Factor estimates, odds ratios, corresponding 95% confidence 
intervals, and p-value for applicable test statistics will be presented. P-values and 95% confidence 
intervals will be based on Wald test.  
For all secondary analyses, we will use two-sided p-values with alpha ≤ 0.05 level of significance 
and 95% confidence intervals. 
8.8 
Safety analysis 
Safety date will be analyzed in safety analysis sets. All safety measures will be described in each 
arm. We will summarize adverse events and adverse events of special interest, premature 
withdrawal from study medication, laboratory parameters, exposure to study medication, 
concomitant medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ class 
(SOC) and within each SOC, by the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Additional summaries by frequency tables will also be provided for the AEs. 
Patients who died will be listed together with the cause of death. 
Laboratory parameters, hematology and biochemistry, will be presented in shift tables of NCI-
CTCAE grade at baseline versus worst grade during treatment. 
Other safety variables, such as exposure to study medication, ECOG performance status, 
concomitant medications, vital signs, and physical examination, will be analyzed in a similar way. 
Frequency tables will summarize the exposure of study medication. 
 
 
 
  
8.10 Interim analyses 
No interim analyses are planned 
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8.11 Steering committee 
A Steering Committee will be established for this study. It will be composed by the study site 
investigators, the Sponsor’s Medical Monitor, the Scientific Global Coordinator, and additional 
physicians with experience in experimental therapy management. 
Steering Committee meetings are scheduled to review the available safety of the first patient 
enrolled at each cohort who have completed treatment period, and every 6 months thereafter until 
communication of the study results. The Steering Committee will meet to review, discuss, and 
evaluate all the gathered feasibility, safety, and efficacy data. In case of any arising a concern, 
these meetings can also be called at any time at request of a participating investigator or the 
Sponsor study team. At these meetings, the Sponsor and the participating investigators must 
reach a consensus on feasibility, efficacy, and safety data. The Sponsor will prepare minutes from 
these meetings and circulate them to each investigator for comment prior to finalization. 
Each study site investigator will monitor patient’s data for serious toxicities on an ongoing basis. 
 
 
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9 
ETHICAL CONSIDERATIONS  
9.1 
Regulatory and ethics compliance  
The study will be performed and reported in accordance with the guidelines of the International 
Conference on Harmonization (ICH), and the ethical principles laid down in the Declaration of 
Helsinki. The study will be also compliance with European Directive 2001/20/EC and any 
applicable local regulations. 
9.2 
IRBs/IECs 
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments, informed consent forms, study subject 
information sheets, and advertising materials. The IRB/IEC must also be contacted in the event 
of any major protocol violation or any SAE. 
It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate 
and timely information is provided at all phases during the study. 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly informing 
the IRB/EC/CA of any protocol amendments (approval is required before implementation of 
substantial amendments). 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB/EC/CA all unanticipated problems involving risk 
to human patients. Some IRBs/ECs/CA may want prompt notification of all SAEs, whereas others 
require notification only about events that are serious, assessed to be related to study treatment, 
and are unexpected. Investigators may receive written 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 regulatory requirements and with the policies and 
procedures established by their IRB/EC/CA and archived in the site’s study file. 
9.3 
Informed consent 
For each study subject, written informed consent will be obtained prior to any protocol related 
activities. As part of this procedure, the study site Investigator or designee must explain orally and 
in writing the nature, duration, and purpose of the study, and the action of the drugs in such a 
manner that the study subject is aware of the potential risks, inconveniences, or adverse effects 
that may occur. The study subject should be informed that he/she is free to withdraw from the 
study at any time. The subject will receive all information that is required by local regulations and 
ICH guidelines. 
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The Consent Form must be signed and dated by the patient or the patient’s legally authorized 
representative before her participation in the study. The case history or clinical records for each 
patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative, if applicable. 
All signed and dated Consent Forms must remain in each patient’s study file and must be 
available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to procedures 
outlined in the informed consent or when new information becomes available that may affect the 
willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall document the 
informed consent process and that written informed consent was obtained for the updated/revised 
Consent Form for continued participation in the study. The final revised IRB/EC-approved 
Informed Consent Form must be provided to the Sponsor for regulatory purposes. 
9.4 
Data protection 
The Sponsor will ensure the confidentiality of patient’s medical information in accordance with all 
applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of such data 
[95/46/EC] confirms herewith compliance to Directive 95/46/EC in all stages of Data 
Management. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, the Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 
 
 
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10  SOURCE 
DOCUMENTATION, 
STUDY 
MONITORING 
AND 
QUALITY 
ASSURANCE 
10.1 Source data documentation 
Source data refers to all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). 
Source documents are original documents, data, and records (i.e., hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial). 
Sponsor’s Quality Assurance group may assist in assessing whether electronic records generated 
from computerized medical record systems used at investigational sites can serve as source 
documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the purposes of 
clinical research (as opposed to general clinical practice), applicable hardcopy source documents 
must be maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
At a minimum, source documentation must be available to substantiate subject identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study receipt/dispensing/return records; study administration information; and date of 
completion and reason. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records) in order to ensure data 
completeness and accuracy as required by study protocol. The Investigator and/or site staff must 
make CRFs and source documents of subjects enrolled in this study available for inspection by 
MEDSIR or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as required 
by regulations, officials of the regulatory health authorities (i.e., FDA, EMEA, and others), and/or 
ECs/IRBs. The Investigator and study site staff must comply with applicable privacy, data 
protection, and medical confidentiality laws for use and disclosure of information related to the 
study and enrolled subjects. 
The patient must also allow access to the patients’ medical records. Each patient should be 
informed of this prior to the start of the study. 
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10.2 Study monitoring and source data verification 
Study progress will be monitored by MEDSIR or its representative (i.e., a CRO) as frequently as 
necessary to ensure: 
That the rights and well-being of human subjects are protected; 
- the reported trial data are accurate, complete, and verifiable from the source documents; and 
- the conduct of the trial is in compliance with the current approved protocol/amendment(s), GCP, 
and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be identified in a handout located in 
the Investigator Site File. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original records, laboratory reports, medical records, subject diaries) in order to ensure 
data completeness and accuracy as required by study protocol. The Investigator and/or site staff 
must make CRFs and source documents of subjects enrolled in this study available for inspection 
by the Sponsor or its representative at the time of each monitoring visit. 
10.3 Retention of records 
Investigators must retain all study records required by the applicable regulations in a secure and 
safe facility. The Investigator must consult a Sponsor representative before disposal of any study 
records and must notify the Sponsor of any change in the location, disposition, or custody of the 
study files. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. “Essential documents” are defined as 
documents that individually and collectively permit evaluation of the conduct of a trial and the 
quality of the data produced. These documents should be retained for a longer period, however, 
if required by the applicable e regulatory requirements or by an agreement with the Sponsor. The 
CHMP requires retention for the maximum period of time permitted by the institution, but not less 
than 15 years (ICH E6, 4.9.5). It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained (ICH E6, 
5.5.12). 
The study site Investigator must not dispose of any records relevant to this study without either 
(1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect 
such records. The study site Investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study. Such documentation is subject to inspection by the Sponsor and the FDA and/or EMA 
(or respective individual EU country regulatory authorities). 
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These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
10.4 Data quality assurance 
During and/or after completion of the study, quality assurance auditor (s) named by the MEDSIR 
or the regulatory authorities may wish to perform on-site audits. The Investigators will be expected 
to cooperate with any audit and provide assistance and documentation (including source data) as 
requested. 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical 
study (i.e., CRFs and other pertinent data) provided that patient confidentiality is respected. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor’s audit plans, this study 
may be selected for audit by representatives from the Sponsor’s (or designee’s) Quality 
Assurance Department. Inspection of site facilities (i.e., pharmacy, drug storage areas, 
laboratories) and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP (ICH E6), and applicable country regulatory requirements. 
 
 
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11 DATA MANAGEMENT 
11.1 Data entry and management 
In this study, all data will be entered onto CRFs in a timely fashion by the Investigator and/or the 
Investigator’s dedicated site staff. 
The Investigator must review data recorded in the CRF to verify their accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the conclusion of the 
study, the occurrence of any protocol violations will be identified and recorded as part of the 
clinical 
database. After these actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and will become available for statistical data analysis. 
11.2 Data clarification 
As part of the conduct of the trial, MEDSIR may have questions about the data entered by the 
site, referred to as queries. The monitors and the Sponsor are the only parties that can generate 
a query. 
11.3 Data coding procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries as described in the Data Management Plan. 
 
 
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12  STUDY MANAGEMENT 
12.1 Discontinuation of the study 
MEDSIR reserves the right to discontinue the study for safety or administrative reasons at any 
time. Should the study be terminated and/or the site closed for whatever reason, all investigational 
drugs pertaining to the study must be returned to MEDSIR. Any actions required to assess or 
maintain study subject safety will continue as required, in spite of termination of the study. 
12.2 Changes to the protocol 
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by MEDSIR, the Scientific Global Coordinator, the study site 
Investigator, and the IRB/IE/CA before implementation. This requirement for approval should in 
no way prevent any immediate action from being taken by the study site Investigator or MedSIR 
in the interests of preserving the safety of all subjects included in the trial. If an immediate change 
to the protocol is felt to be necessary by the study site Investigator and is implemented for safety 
reasons, MEDSIR should be notified as soon as possible (within 24 hours if possible) and the 
IRB/IEC/CA should be informed as necessary. 
12.3 Publication policy protection of trade secrets 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without prior written permission 
from the Scientific Global Coordinator and MEDSIR However, authorized regulatory officials, the 
Scientific Global Coordinator or the study site Investigator, and MEDSIR personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All clinical 
investigational drug, patient bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by Scientific Global 
Coordinator or the study site Investigator and MEDSIR. 
The Sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts 
will be made with full collaboration of principal Investigators and in accordance with the current 
guidelines of Good Publication Practice. 
The Sponsor must be notified of any intent to publish data collected from the study and prior 
approval from Sponsor must be obtained prior to publication. 
 
 
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Appendix 1: Schedule of study assessments and procedures 
Study Period 
Screening 
Period* 
Treatment Period** 
End of 
Treatment 
visit** 
Post-Treatment End of Study 
visit 
Day 
-28 to -1 day 
Baseline 
(Day 1) 
Days 2-15 
Day 15 (+ 1 
day) 
28 days (+/- 3 days) after last 
dose of study treatment 
Informed Consent Form1 
 
x 
 
 
 
 
Demographic data and medical 
history2 
x 
 
 
 
 
ECOG performance status 
x 
x 
 
x 
x 
Weight and vital signs3 
x 
x 
 
x 
x 
ER, PgR and HER2 status4 
x 
 
 
 
 
Ki67 score assessment5, 14 
x 
 
 
x 
 
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Study Period 
Screening 
Period* 
Treatment Period** 
End of 
Treatment 
visit** 
Post-Treatment End of Study 
visit 
Day 
-28 to -1 day 
Baseline 
(Day 1) 
Days 2-15 
Day 15 (+ 1 
day) 
28 days (+/- 3 days) after last 
dose of study treatment 
Breast ultrasound and axillary 
lymph node status6 
x 
 
 
x (as clinically indicated) 
Tumor staging as per institutional 
practice7 
x 
 
 
 
 
Complete physical examination 
(breast and regional lymph nodes 
examination)8 
x 
x 
 
x 
x 
AE reporting9 
x 
x 
x 
x 
x 
Concomitant medication 
reporting10 
x 
x 
x 
x 
x 
12-Lead ECG11 
x 
x 
 
x 
x 
Laboratory assessments12 
X 
x 
 
x 
x 
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Study Period 
Screening 
Period* 
Treatment Period** 
End of 
Treatment 
visit** 
Post-Treatment End of Study 
visit 
Day 
-28 to -1 day 
Baseline 
(Day 1) 
Days 2-15 
Day 15 (+ 1 
day) 
28 days (+/- 3 days) after last 
dose of study treatment 
Pregnancy test13 
X 
x 
 
x 
x 
Tissue and blood samples 
collection14 
x 
 
 
x 
 
Viral serology15 
x 
 
 
 
 
Treatment administration16 
 
x 
x 
(administered 
at home) 
x 
 
Medication diary17 
 
x 
 
x 
 
Post-study anticancer therapy 
 
 
 
 
x  
 
*Screening period: all screening data needs to be completed 48h prior to randomization to allow enough time for medical monitor review. 
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**Treatment period and EoT visit: After confirming eligibility through the screening process as indicated above, patients will be scheduled for baseline visit at 
Day 1 of treatment within 48 h after randomization. If post-treatment surgery or biopsy cannot be performed within + 1 day from last day of treatment (that is, on 
Day 15 or the immediate day after [Day 15+1]), treatment will be extended to a total of 16 days and patients will be able to have surgery or biopsy the following 
day (be it Day 15 + 2). 
1. 
Informed Consent Form: Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 
1 may be used; such tests do not need to be repeated for screening, unless otherwise indicated. 
2. 
Demographic data and Medical history: Complete medical history and demographics (including age, gender, and ethnic origin). All medications taken in 
the last 28 days prior to enrolment will be collected. 
3. 
Weight and vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse rate, and body 
temperature (oral, axillary, or tympanic temperature). 
4. 
ER, PR and HER2 status: Local confirmation of ER[+] (<= 500 cell count) and HER2[-] status based on local testing on the most recent analyzed biopsy. 
5. 
Ki67 score assessment: Ki67 will be analyzed locally at the time of inclusion. For patients with basal Ki67 ≥20% according to local analysis, Ki67 ≥10% 
will be centrally confirmed retrospectively after inclusion. For patients with basal Ki67 levels between 10% and 19% according to local analysis, Ki67 ≥10% 
will need to be centrally confirmed before inclusion. Ki67 will be analyzed centrally on the post-treatment biopsy. 
6. 
Breast ultrasound and axillary node status: Breast and axillary ultrasound should be performed according to institutional practice and result must be 
known at screening to assess eligibility and tumor size prior to randomization, and then as clinically indicated. 
7. 
Tumor staging as per institutional practice: Baseline staging to document absence of metastatic disease should be performed as per institutional practice, 
in alignment with national guidelines, in patients where there may be a reasonable suspicion of advanced disease (e.g., clinically positive axillary lymph 
nodes, signs and symptoms). If done, it must be performed within 28 days prior to randomization and reports of these examinations must be available at 
site. Examination type for tumor staging is at the discretion of the investigator and can include i.e. X-ray, sonography, bone scan, CT, MRI, and/or PET-CT 
scan.   
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8. 
Complete physical examination: including complete evaluation of the breast primary tumor and regional lymph nodes and evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  
9. 
AE reporting: 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 with grading according to the NCI–CTCAE v.5.0 criteria. After initiation of study drug, all adverse events will be reported 
until 28 days (EoS) after the final dose of study treatment. After this period, 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. 
10. 
Concomitant medication reporting: Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until end of study visit.  
11. 
12-lead ECG: Patients should be resting in a supine position for at least 10 minutes prior to ECG recording. All ECGs will be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws). All patients must have a standard 12-lead ECG in screening period, 
maximum 48h before start of treatment dose, in the EoT visit and in the EoS visit. 
12. 
Laboratory assessments: These values should include: hematological test (hemoglobin, hematocrit, red blood cell count, platelet count, WBC and 
differential count [ANC, lymphocytes, monocytes, eosinophils and basophils, and other cells]); coagulation (INR, PTT (or aPTT)); chemistry panel (serum 
or plasma): sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin (if total bilirubin is 
2xULN, also direct bilirubin), AST, ALT, ALP, urate and LDH; fasting lipid panel: cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (after ≥ 8 
hours of fasting); urinalysis, including  dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and microscopic examination (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, and bacteria), FSH and estradiol. Baseline (Day 1, prior to initiation of study treatment) laboratory assessments are 
not required if the screening assessments were performed at within 14 days prior to initiation of study treatment. 
13. 
Pregnancy test: Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment and 
a negative urine pregnancy test within 24 hours prior to study treatment initiation. An additional pregnancy test is indicated in the EoT visit and in the EoS 
visit, when a urine pregnancy test should be performed. 
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14. 
Tissue and blood samples collection: Mandatory tumor tissue biopsy samples will be collected before the start of treatment (up to a maximum of 8 weeks 
before the first dose of study drug). If a diagnostic biopsy was performed maximum 8 weeks prior to initiation of study treatment, it can be used as a baseline 
sample for the Ki67 assessment. A fresh post-study treatment biopsy will be obtained on Day 15 (+ 1 day). A fresh post-study treatment biopsy will be 
obtained on D15 (+1 day). If post-treatment surgery cannot be performed within + 1 day from last day of treatment (that is, on D15 or D15+1), treatment will 
be extended to 16 days and surgery or biopsy can be performed on the following day. At both timepoints the most recent tumor biopsy from the patient 
should be obtained when available. Mandatory liquid biopsy samples will be obtained before the start of study treatment (up to a maximum of 14 days before 
the first dose of study drug) and, if possible, at the same timepoint as baseline hematological laboratory assessments. Post-study treatment liquid biopsy 
samples will be taken at the same timepoint, if possible, as post-study treatment tumor biopsies. 
15. 
Viral serology: Human Immunodeficiency Virus, Hepatitis B surface Antigen (HBsAg), total Hepatitis B core Antibody (HBcAb), Hepatitis C Virus antibody; 
additional tests for Hepatitis B Virus DNA or Hepatitis C Virus RNA will be required to confirm eligibility. 
16. 
Treatment administration: Patients will receive either giredestrant (GDC-9545) 30 mg, PO, QD on days 1-15 – Arm A - or tamoxifen – Arm B - 20mg, PO, 
QD on days 1-15. Treatment on Day 1 will be administered at the clinic. If post-treatment surgery or biopsy cannot be performed within + 1 day from last 
day of treatment (that is, on Day 15 or Day 15+1), treatment will be extended to 16 days so that surgery or biopsy can be performed on the following day. 
17. 
Medication diary: Patients will receive a medication diary and should be instructed to complete the medication diary each day (Day 1 to Day 15, or Day 16 
if applicable). The medication diary and unused capsules or tablets in their bottles should be collected and reviewed at the EoT visit for drug accountability.
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