A PHASE I, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF ARV-471 (PF-07850327), A SINGLE AGENT IN JAPANESE PARTICIPANTS WITH ER+/HER2-LOCALLY ADVANCED OR METASTATIC BREAST CANCER
Phase: PHASE1
Conditions: Breast Neoplasms
Sponsor: Pfizer

ARV-471 (PF-07850327) 
Protocol C4891016 
Protocol Amendment 2, 21 Oct 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Oncology Clinical Protocol Template (01 March 2021) 
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Title Page 
A PHASE I, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY AND PHARMACOKINETICS OF ARV-471 
(PF-07850327), A SINGLE AGENT IN JAPANESE PARTICIPANTS WITH 
ER+/HER2-LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
 
Study Intervention Number: 
Study Intervention Name: 
US IND Number: 
PF-07850327 
ARV-471 
NA 
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Protocol Number: 
C4891016 
Phase: 
1 
Brief Title: Phase 1 Safety, Tolerability and Pharmacokinetics Study With ARV- 
471 (PF-07850327) in Japanese Participants With ER+/HER2- Locally Advanced or 
Metastatic BC 
 
 
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must be promptly notified. 

ARV-471 (PF-07850327) 
Protocol C4891016 
Protocol Amendment 2, 21 Oct 2022 
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CT02-GSOP Oncology Clinical Protocol Template (01 March 2021) 
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Document History 
 
Document 
Version Date 
Amendment 2 
21 Oct 2022 
Amendment 1 
25 Mar 2022 
Original protocol 
09 Feb 2022 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 
Protocol Amendment Summary of Changes Table 
Amendment 2 (21-October-2022) 
Overall Rationale for the Amendment: The protocol was amended mainly to incorporate 
newly available data following the Investigator Brochure (v. 4.0) update. 
 
Section # and Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Non- 
substantial 
2.2.4. Clinical Overview of 
ARV-471 
2.3. Benefit/Risk 
Assessment 
Updated the safety, PK 
and efficacy of 
ARV-471 in 
participants with 
locally advanced or 
metastatic ER+HER2- 
breast cancer in Study 
ARV-471-mBC-101 
and in healthy 
volunteers in 
ARV-471-CPhm-103 
To align with 
updated IB 
Substantial 
1.2. Schema 
2.2.5. Rationale of dose 
selection in Phase 1 study in 
Japan 
Updated the starting 
dose to 200 mg QD 
based on the data from 
Part B in Study 
ARV-471-mBC-101 
To align with the 
RP3D of 
ARV-471 
Substantial 
4.1. Overall Design 
4.3. Justification for Dose 
6.1. Study Intervention(s) 
Administered 

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Section # and Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Non- 
substantial 
6.5.1. Dose 
Interruption/Reductions 
9.3.2. Primary 
Endpoint(s)/Estimand(s)/An 
alysis 
9.5. Sample Size 
Determination 
5.2. Exclusion Criteria 
Exclusion Criteria 6 
6.8.2. Proton Pump 
Inhibitors 
10.8. Appendix 8: 
Prohibited Concomitant 
Medications That May 
Result in DDI 
Updated the prohibited 
drugs 
To align with 
updated IB 
Substantial 
5.3.2. Other Considerations 
Deleted the Other 
Considerations 
To align with 
updated IB 
Substantial 
1.3. Schedules of Activities 
Table 1 and Table 2 
Corrected the visit 
window on Day 1 of 
Cycle 2 and beyond in 
Table 1 and at Cycle 2 
and 3 Day 1 in Table 2 
To incorporate 
changes/clarifica 
tions specified in 
the PACL (24 
Jun 2022) 
Non- 
substantial 
6.4. Study Intervention 
Compliance 
Updated not to be 
mandatory to retrieve 
the investigational 
drugs at every visit 
To incorporate 
changes/clarifica 
tions specified in 
the PACL (24 
Jun 2022) 
Non- 
substantial 
8.2.6. Pregnancy Testing 
10.9.3.1. Laboratory Testing 
Removed the reference 
to collection of the 
pregnancy test result 
on the CRF 
To incorporate 
changes/clarifica 
tions specified in 
the PACL (24 
Jun 2022) 
Non- 
substantial 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 9 
LIST OF FIGURES .................................................................................................................... 9 
1. PROTOCOL SUMMARY ................................................................................................... 10 
1.1. Synopsis ......................................................................................................................... 10 
1.2. Schema ........................................................................................................................... 19 
1.3. Schedule of Activities .................................................................................................... 20 
2. INTRODUCTION ................................................................................................................ 27 
2.1. Study Rationale .............................................................................................................. 27 
2.2. Background .................................................................................................................... 27 
2.2.1. Breast Cancer .................................................................................................... 27 
2.2.2. PROTAC® and ARV-471 ................................................................................. 28 
2.2.3. Nonclinical overview of ARV-471 ................................................................... 29 
2.2.4. Clinical Overview of ARV-471 ........................................................................ 29 
2.2.5. Rationale of dose selection in Phase 1 study in Japan ...................................... 33 
2.3. Benefit/Risk Assessment ............................................................................................... 33 
2.3.1. Risk Assessment ............................................................................................... 36 
2.3.2. Benefit Assessment ........................................................................................... 39 
2.3.3. Overall Benefit/Risk Conclusion ...................................................................... 39 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................................ 39 
4. STUDY DESIGN ................................................................................................................. 40 
4.1. Overall Design ............................................................................................................... 40 
4.2. Scientific Rationale for Study Design ........................................................................... 41 
4.2.1. Choice of Contraception/Barrier Requirements ................................................ 42 
4.2.2. Collection of Retained Research Samples ......................................................... 42 
4.3. Justification for Dose ..................................................................................................... 42 
4.3.1. Dose Limiting Toxicity Definition .................................................................... 44 
4.4. End of Study Definition ................................................................................................. 46 
5. STUDY POPULATION ...................................................................................................... 46 
5.1. Inclusion Criteria ........................................................................................................... 46 
5.2. Exclusion Criteria .......................................................................................................... 48 

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5.3. Lifestyle Considerations ............................................................................................... 51 
5.3.1. Contraception ................................................................................................... 51 
5.4. Screen Failures ............................................................................................................. 52 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 52 
6.1. Study Intervention(s) Administered .............................................................................. 52 
6.1.1. Administration .................................................................................................. 52 
6.2. Preparation, Handling, Storage and Accountability ..................................................... 53 
6.2.1. Preparation and Dispensing .............................................................................. 54 
6.3. Measures to Minimize Bias: Randomization and Blinding .......................................... 54 
6.3.1. Allocation to Study Intervention ...................................................................... 54 
6.3.2. Storage ............................................................................................................. 55 
6.4. Study Intervention Compliance .................................................................................... 55 
6.5. Dose Modification ........................................................................................................ 55 
6.5.1. Dose Interruption/Reductions ........................................................................... 56 
6.6. Continued Access to ARV-471 After the End of the Study ......................................... 57 
6.7. Treatment of Overdose ................................................................................................. 57 
6.8. Concomitant Therapy ................................................................................................... 58 
6.8.1. Prohibited Medications/Therapy ...................................................................... 58 
6.8.2. Proton Pump Inhibitors .................................................................................... 58 
6.8.3. H2 Receptor Antagonists or Antacids .............................................................. 58 
6.8.4. Supportive Care ................................................................................................ 59 
6.8.5. Hematopoietic Growth Factors and Transfusions ............................................ 59 
6.8.6. Antidiarrheal, Antiemetic Therapy .................................................................. 59 
6.8.7. Corticosteroids ................................................................................................. 59 
6.8.8. Surgery and Radiotherapy ................................................................................ 59 
7. DISCONTINUATION OF ARV-471 AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 60 
7.1. Discontinuation of ARV-471 ........................................................................................ 60 
7.2. Participant Discontinuation/Withdrawal From the Study ............................................ 61 
7.2.1. Withdrawal of Consent .................................................................................... 61 
7.3. Lost to Follow-Up ........................................................................................................ 61 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 62 

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8.1. Efficacy Assessments .................................................................................................... 63 
8.1.1. Tumor Response Assessments .......................................................................... 63 
8.2. Safety Assessments ........................................................................................................ 63 
8.2.1. Physical Examinations ...................................................................................... 63 
8.2.2. Vital Signs ......................................................................................................... 64 
8.2.3. Electrocardiograms ............................................................................................ 64 
8.2.4. Echocardiograms ............................................................................................... 65 
8.2.5. Clinical Safety Laboratory Assessments ........................................................... 65 
8.2.6. Pregnancy Testing ............................................................................................. 65 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting ........................ 66 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ............. 66 
8.3.2. Method of Detecting AEs and SAEs ................................................................. 68 
8.3.3. Follow-Up of AEs and SAEs ............................................................................ 68 
8.3.4. Regulatory Reporting Requirements for SAEs ................................................. 68 
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, 
and Occupational Exposure .................................................................................... 68 
8.3.6. Cardiovascular and Death Events ...................................................................... 71 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .................................................................................... 71 
8.3.8. Adverse Events of Special Interest ................................................................... 71 
8.3.9. Medical Device Deficiencies ............................................................................ 72 
8.3.10. Medication Errors ............................................................................................ 72 
8.4. Pharmacokinetics ........................................................................................................... 73 
CCI 
 
8.5.1. Specified Genetics ............................................................................................. 74 
8.5.2. Retained Research Samples for Genetics .......................................................... 74 
CCI  
 
CCI 
 
CCI 
 
8.7. Immunogenicity Assessments ....................................................................................... 75 
8.8. Health Economics .......................................................................................................... 75 
9. STATISTICAL CONSIDERATIONS ................................................................................. 76 

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9.1. Statistical Hypotheses .................................................................................................... 76 
9.1.1. Estimands .......................................................................................................... 76 
9.2. Analysis Sets .................................................................................................................. 76 
9.3. Statistical Analyses ........................................................................................................ 77 
9.3.1. General Considerations ..................................................................................... 77 
9.3.2. Primary Endpoint(s)/Estimand(s)/Analysis ....................................................... 77 
9.3.3. Secondary Endpoint(s)/Estimands Analysis ..................................................... 77 
CCI 
 
9.3.5. Other Safety Analyses ....................................................................................... 81 
9.3.6. Other Analysis(es) ............................................................................................. 82 
9.4. Interim Analyses ............................................................................................................ 82 
9.5. Sample Size Determination ........................................................................................... 82 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................... 83 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ...................... 83 
10.1.1. Regulatory and Ethical Considerations ........................................................... 83 
10.1.2. Financial Disclosure ........................................................................................ 84 
10.1.3. Informed Consent Process .............................................................................. 85 
10.1.4. Data Protection ................................................................................................ 86 
10.1.5. Committees Structure ...................................................................................... 86 
10.1.6. Dissemination of Clinical Study Data ............................................................. 86 
10.1.7. Data Quality Assurance ................................................................................... 87 
10.1.8. Source Documents .......................................................................................... 89 
10.1.9. Study and Site Start and Closure ..................................................................... 89 
10.1.10. Publication Policy ......................................................................................... 90 
10.1.11. Sponsor’s Qualified Medical Personnel ........................................................ 91 
10.2. Appendix 2: Clinical Laboratory Assessments ............................................................ 92 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ............................................................................ 94 
10.3.1. Definition of AE .............................................................................................. 94 
10.3.2. Definition of an SAE ....................................................................................... 95 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the 
Active Collection Period ........................................................................................ 97 

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10.3.4. Reporting of SAEs ....................................................................................... 100 
10.4. Appendix 4: Contraceptive and Barrier Guidance .................................................... 101 
10.4.1. Male Participant Reproductive Inclusion Criteria ....................................... 101 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................... 101 
10.4.3. Woman of Childbearing and Non-Childbearing Potential ........................... 102 
10.4.4. Contraception Methods ................................................................................ 103 
CCI 
 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ........... 105 
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ....................................... 107 
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI ........... 109 
10.8.1. CYP3A inhibitors/inducers .......................................................................... 109 
10.8.2. Drugs Known to Predispose to Torsade de Pointes or QT interval 
prolongation ........................................................................................................ 110 
10.8.3. Substrates of Transporters ............................................................................ 111 
10.8.4. PPI ................................................................................................................ 111 
10.9. Appendix 9: Alternative Measures During Public Emergencies .............................. 112 
10.9.1. Eligibility ..................................................................................................... 112 
10.9.2. Telehealth Visits ........................................................................................... 112 
10.9.3. Alternative Facilities for Safety Assessments .............................................. 113 
10.9.4. Study Intervention ........................................................................................ 114 
10.9.5. Home Health Visits ...................................................................................... 114 
10.9.6. Adverse Events and Serious Adverse Events............................................... 115 
10.9.7. Efficacy Assessments ................................................................................... 115 
10.9.8. Independent Oversight Committees ............................................................. 115 
10.10. Appendix 10: Bone Marrow Reserve in Adults ..................................................... 116 
10.11. Appendix 11: RECIST (Response Evaluation Criteria In Solid Tumors) 
version 1.1 Guidelines ................................................................................................... 118 
10.12. Appendix 12: ECOG Performance Status* ............................................................ 123 
10.13. Appendix 13: Protocol Amendment History .......................................................... 124 
10.14. Appendix 14: Abbreviations ................................................................................... 127 
11. REFERENCES ................................................................................................................ 131 

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LIST OF TABLES 
Table 1. 
Schedule of Activities ........................................................................................... 20 
Table 2. 
Schedule of PK and ECG Assessment .................................................................. 25 
Table 3. 
Preliminary PK Data of ARV-471-mBC-101 Part A (Data Snapshot of 06 
Jun 2022) ............................................................................................................... 31 
Table 4. 
DLT Criteria .......................................................................................................... 45 
Table 5. 
Dose Levels ........................................................................................................... 56 
Table 6. 
Dose Reduction ..................................................................................................... 56 
Table 7. 
Definition of Plasma Pharmacokinetic Parameters for ARV-471 and 
ARV-473 ............................................................................................................... 79 
Table 8. 
Detection Probability of Over MTD ..................................................................... 83 
Table 9. 
Core Lab Tests....................................................................................................... 92 
Table 10. List of CYP3A Inhibitors/Inducers ...................................................................... 110 
Table 11. List of Drugs Known to Predispose to Torsade de Pointes ................................. 110 
Table 12. List of P-gp Sensitive Substrates ......................................................................... 111 
Table 13. List of Proton Pump Inhibitors ............................................................................ 111 
 
 
LIST OF FIGURES 
Figure 1. A Schematic Diagram of PROTAC (ARV-471) ................................................... 28 

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Phase 1 Safety, Tolerability and Pharmacokinetics Study With ARV-471 
(PF-07850327) in Japanese Participants With ER+/HER2- Locally Advanced or 
Metastatic BC 
Rationale 
ARV-471 is a PROteolysis-TArgeting Chimera (PROTAC®) hetero-bifunctional small 
molecule that induces active degradation of ER. ARV-471 is being developed for the 
treatment of patients with ER+/HER2- locally advanced or mBC. ARV-471 works by 
recruiting an E3 ligase to ubiquitinate ER which results in its subsequent degradation through 
the proteasome, a large, multi-subunit protein complex that degrades ubiquitinated proteins 
into small peptides. Such “active” degradation results in improved knockdown of tumor ER 
relative to fulvestrant in xenograft mouse models and produces TGI in vivo both as a single 
agent and in combination with palbociclib. Unlike fulvestrant, which is administered via IM 
injections, ARV-471 is orally administered. Further, in early preclinical studies, ARV-471 
has demonstrated greater ER degradation compared to other oral SERDs in clinical 
development, such as AZD9496 and RAD19011. 
Currently, ARV-471 is being evaluated in one Phase 1/2 study (Study ARV-471-mBC-101). 
The study is an FIH, open-label, 2-part, sequential group, 3+3 dose escalation (Part A), and 
cohort expansion (Part B) of single agent ARV-471 and a Phase 1b investigation of 
ARV-471 in combination with palbociclib to evaluate the safety and tolerability of ARV-471 
(Part C), either as a single agent or in combination with palbociclib, in participants with 
locally advanced or mBC. The study will also characterize the first dose and steady-state PK 
profile, assess preliminary antitumor activity, PD effects on exploratory biomarkers and the 
safety of ARV-471 at the RP2D. 
As of 06 June 2022, 78 participants have been treated in Part A in Study 
ARV-471-mBC-101. No DLTs have been reported and MTD has not been reached with 
ARV-471 monotherapy across total daily doses of 30 mg to 700 mg. The majority of TRAEs 
are Grade 1 or 2 in severity, with TRAEs in ≥10% of participants limited to nausea (25.6%), 
fatigue (21.8%), constipation (12.8%), arthralgia, decreased appetite, hot flush, and vomiting 
(10.3% each). Four participants experienced 6 Grade 3 TRAEs; headache lasting 1 day, 
asymptomatic amylase increased and lipase increased, nausea and asymptomatic ECG QT 
prolongation, and venous embolism that occurred after a minor procedure (bone biopsy). 
The participant with Grade 3 venous embolism was the only participant who discontinued 
ARV-471 due to a TRAE. In addition, evidence of clinical benefit has been observed in this 
heavily treated population, with a 36.2% CBR among 25 of 69 evaluable participants and a 
8.6% ORR with 5 of 58 response-evaluable participants having confirmed PRs in Part A. 
The purpose of this study is to confirm safety and tolerability at the RP3D of ARV-471 in 
Japanese participants with ER+/HER2- locally advanced or mBC. Since no DLTs had been 
reported across 30 mg to 700 mg total daily doses in Part A in Study ARV-471-mBC-101 

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and 200 mg QD was selected as the RP3D of ARV-471 from Part B, it is considered 
adequate to evaluate safety and tolerability at the RP3D, 200 mg QD in Phase 1 study in 
Japanese participants. 
Objectives, Endpoints, and Estimands 
 
Objectives 
Endpoints 
Estimands 
Primary: 
Primary: 
Primary: 
• To evaluate the safety and 
tolerability of ARV-471 at the 
RP3D 
First cycle DLTs 
The primary estimand for 
incidence of DLTs is DLT 
rate estimated based on data 
from DLT-evaluable 
participants during the DLT 
evaluation period which is the 
first cycle of treatment (ie, 28 
days) after the first dose of 
study intervention. 
Secondary: 
Secondary: 
Secondary: 
• To evaluate the overall safety 
profile 
• AEs as characterized by type, 
frequency, severity (as graded by 
NCI CTCAE version 5.0), timing, 
seriousness, and relationship to 
study drug 
• Laboratory abnormalities as 
characterized by type, frequency, 
severity (as graded by NCI CTCAE 
version 5.0), and timing 
NA 
• 
To characterize the 
single-dose and multiple-dose 
PK of ARV-471 and 
ARV-473 (an epimer of 
ARV-471) 
The following PK parameters will be 
assessed when applicable after a 
single dose and after multiple doses: 
single dose: AUCtau, AUClast, Cmax, 
Tmax, t½, MRCmax, and MRAUCtau 
multiple doses; AUCtau, AUClast, Cmax, 
Cmin, Ctrough, CL/F*, Tmax, Vz/F*, Rac, 
t½, t½eff, MRCmax, and MRAUCtau 
NA 
* ARV-471 only 
Vz/F and t½ for single dose and multiple 
doses will be calculated only if data 
permit. 
• To explore preliminary 
antitumor activity 
Antitumor activity of ARV-471 will 
be assessed by evaluating the 
following: 
• ORR per RECIST version 1.1 
• CBR based on the summation of 
CRs, PRs and SD of 24 weeks 
duration or longer 
• Time to event endpoints: PFS, 
DOR 
NA 

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Overall Design 
Brief Summary 
This study is a single-countiy, non-randomized, open-label, Phase 1 study. This study will 
evaluate the safety, tolerability, PK, and preliminary efficacy of ARV-471 as monotherapy in 
Japanese paiiicipants with ER+/HER2- locally advanced or mBC. 
One dose level of ARV-471, 200 mg QD which has been detennined as the RP3D for 
monotherapy in the FIH study (Study ARV-471-mBC-101) conducted outside Japan, will be 
investigated. Six pa1iicipants will receive ARV-471 at 200 mg QD. If none or 1 pa1iicipant 
experience DLT during the first cycle (1 Cycle= 28 days), ARV-471, 200 mg QD will be 
considered tolerable as monotherapy in Japanese participants. lf2 participants experience 
DLT, the investigator and the sponsor should discuss the safety and tolerability based on the 
available data, and then under the agreement between the investigator and the sponsor, an 
additional 3 paiiicipants at the same dose level, up to a total of 9 paiiicipants, will be emolled 
to fmiher investigate the safety and tolerability of ARV-471 as monotherapy in Japanese 
paiiicipants. If no DLT is reported in an additional 3 participants, 200 mg QD will be 
considered tolerable in Japanese pa1iicipants. IfDLT is observed in 33% of pa1iicipants at 
200 mg QD, the investigation at the next lower dose level may be explored. 
Number of Participants 
Six paiiicipants will be emolled to evaluate DLT and an additional 3 paiiicipants may be 
emolled depending on the number of paiiicipants with DLTs (total up to 9 paiiicipants). 
Paiiicipants who fail to complete at least 75% of study dmg ti·eatinent in Cycle 1 for reasons 
other than DLT are considered not to be DLT-evaluable and will be replaced. If 2 DLTs 
occur in 6 paiiicipants, the investigator and the sponsor should discuss the safety and 
tolerability based on the available data, and then under the agreement between the 
investigator and the sponsor, it may be allowed to emoll an additional 3 paiticipants at the 
- 
Objectives - 
Endpoints 
- 
Estimands 
■ 
■ 

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same dose level. Thus, the actual sample size may depend on the underlying dose toxicity 
profile. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
assignment to study intervention. A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study activity. Potential participants 
who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled. 
Study Population and Specific Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria are listed below: 
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study: 
Age and Sex: 
1. Participants (women and men) at least 20 years of age at the time of signing the 
informed consent. 
• 
Postmenopausal women due to surgical or natural menopause, defined by at least 
1 of the following criteria: 
o Age ≥60 years. 
o Age <60 years and cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; and 
follicle-stimulating hormone level within the laboratory’s reference range for 
postmenopausal females. 
o Documented bilateral oophorectomy with surgery at least 2 months prior to start 
of study treatment. 
o Medically confirmed ovarian failure. 
 
• 
Pre- or perimenopausal women or men may be enrolled if treated with a GnRH 
analogue for at least 4 weeks prior to Cycle 1 Day 1. If a participant has received 
GnRH analogue, they must remain on it for the duration of the trial. 
• 
Refer to Section 10.4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Type of Participant and Disease Characteristics: 

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2. Histological or cytological diagnosis of ER+/HER2- advanced breast cancer that is 
metastatic, recurrent, or locally advanced unresectable breast cancer. 
• 
ER+ disease must be documented by IHC per ASCO/CAP Guidelines2. 
• 
HER2- disease must be documented by either IHC or in-situ hybridization per 
ASCO/CAP guidelines3. 
3. Participants who are resistant to standard therapy or for which no standard therapy is 
available or have received; 
• 
at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or 
advanced/metastatic). However, the number of prior cytotoxic chemotherapy 
regimen in the locally advanced or metastatic setting must be no more than 3 
regimens. 
All such therapy must be discontinued at least 14 days prior to enrollment. 
Informed Consent: 
4. Capable of giving signed informed consent as described in Section 10.1, which 
includes compliance with the requirements and restrictions listed in the ICD and in this 
protocol. 
Other Inclusion criteria: 
5. ECOG PS 0 or 1 (Section 10.12). 
6. Adequate Bone Marrow or Coagulation Function, defined as (with no transfusion of 
blood products or use of hematopoietic growth factors in the 28 days prior to 
enrollment): 
a. ANC ≥1,500/mm3 or ≥1.5 x 109/L; 
b. Platelets ≥100,000/mm3 or ≥100 x109/L; 
c. Hemoglobin ≥9 g/dL; 
d. aPTT ≤1.25× ULN and INR ≤1.25. 
7. Adequate Renal Function, defined as an estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution. 
8. Adequate Liver Function, defined as: 
a. Total bilirubin ≤1.5 x ULN (<3 x ULN in a participant with documented Gilbert’s 
syndrome); 

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b. AST and ALT ≤2.5 x ULN if there is NO liver metastasis; ≤5.0 x ULN if there is 
liver metastasis. 
9. Participants with brain metastases must meet all the following conditions: 
a. Have completed their planned course of treatment; 
b. Have recovered from the acute effects of radiation therapy or surgery prior to first 
dose of drug; 
c. Have discontinued high dose corticosteroid treatment for these metastases for at 
least 4 weeks; 
d. Are neurologically stable as judged by the investigator; 
e. Participants who are diagnosed with a CNS metastasis during the screening period 
must also meet these criteria. 
10. Resolution of acute effects of any prior therapy to either baseline severity or CTCAE 
version 5.0 Grade ≤1 (except for AEs not constituting a safety risk in the investigator’s 
judgment). 
11. Participants must agree and be capable of taking oral medication without crushing, 
dissolving, or chewing tablets. 
12. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Participants with any other active malignancy within 3 years prior to enrollment, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the cervix, Bowen’s disease. 
2. Participants sustaining major surgery defined as a complex procedure performed under 
regional or general anesthesia with a recovery period of at least 4 weeks prior to study 
enrollment. 
3. Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of 
ARV-471. 
4. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 

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participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
5. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to 
>25% of the bone marrow (see Section 10.10 Bone Marrow Reserve in Adults). 
Palliative radiation for the alleviation of pain due to bone metastasis will be allowed 
during the study. 
Prior/Concomitant Therapy: 
6. Concurrent administration of medications, foods or herbal supplements that are strong 
inhibitors or inducers of CYP3A4 and drugs with a known risk of causing Torsade de 
Pointes or QT interval prolongation. Prior use of strong CYP3A inhibitors and drugs 
with a known risk of causing Torsade de Pointes or QT interval prolongation must be 
stopped 7 days before enrollment and strong CYP3A inducers must be stopped 14 days 
before enrollment. Refer to Sections 6.8 Concomitant Therapy and 10.8 (Appendix 
8). 
7. Prior treatment with ARV-471. 
8. Systemic anticancer therapy chemotherapy or endocrine therapy within 14 days prior to 
study entry (6 weeks for mitomycin C or nitrosoureas). If the last immediate anticancer 
treatment contained an antibody-based agent(s) (approved or investigational), then an 
interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) prior to 
receiving the study intervention treatment is required. 
9. Participants who have initiated therapy with bone-modifying agents (bisphosphonates, 
denosumab, or similar) within 14 days of enrollment (participants who are receiving 
bone-modifying agents are eligible for this study provided the bone-modifying agent 
was started more than 14 days prior to study enrollment). 
10. Previous high-dose chemotherapy requiring stem cell rescue. 
Prior/Concurrent Clinical Study Experience: 
11. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry. A participant may be eligible even if they are in the follow-up phase of an 
investigational study as long as they haven’t received treatment in the study for 
5 half-lives of the agents. 
Diagnostic Assessments: 
12. Serum pregnancy test (for females of childbearing potential) positive at screening 
and/or a breastfeeding participant (including females who are currently breastfeeding 
or intend to temporarily interrupt breastfeeding). 

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13. Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but 
not limited to) HBV, HCV, and known HIV or AIDS-related illness. Comments 
regarding specific circumstances follow. 
a. COVID-19/SARS-CoV-2: This protocol excludes participants with active 
infections, as noted above. While SARS-CoV-2 testing is not mandated for entry 
into this protocol, testing should follow local clinical practice standards. If a 
participant has a positive test result for SARS-CoV-2 infection, is known to have 
asymptomatic infection or is suspected of having SARS-CoV-2, he/she is excluded. 
b. HIV: In equivocal cases, participants whose viral load is negative may be eligible. 
HIV seropositive participants who are otherwise healthy and at low risk for 
AIDS-related outcomes could be considered eligible. Potential eligibility for a 
specific HIV positive protocol candidate should be evaluated and discussed with the 
sponsor prior to any screening, based on current and past CD4 and Tcell counts, 
history (if any) of AIDS defining conditions (eg, opportunistic infections), and 
status of HIV treatment. Also, the potential for drug-drug interactions will be taken 
into consideration. 
c. HBV: 
• Participants with active, uncontrolled bacterial, fungal, or viral infection, 
including HBsAg positive. 
• Participants with positive HBsAb and positive HBcAb are allowed to 
participate in the study if they have negative HBV DNA test at screening but 
HB viral load should be monitored for re-activation every 12 weeks. 
• Participants with HBsAb positive who get vaccinated with HBV are exempted 
from the testing of HB viral load. 
• Participants who test positive for HBV viral load at any time during the study 
will interrupt administration of ARV-471, and should be considered for 
consultation with a hepatologist and initiation of antiviral therapies (eg, 
nucleoside antagonist) in accordance with the JSH Guidelines for the 
management of Hepatitis B Virus infection. 
d. HCV: 
• Positive HCV antibody is indicative of infection but may not necessarily render 
a potential candidate ineligible, 
(https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf). 
14. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that 
may affect participant safety or interpretation of study results (eg, baseline 
QTcF>470 ms, complete LBBB, signs of an acute or indeterminate age myocardial 

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infarction, ST-T interval changes suggestive of active myocardial ischemia, second or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the 
baseline uncorrected QTcF is >470 ms, this interval should be rate corrected using the 
Fridericia method and the resulting QTcF should be used for decision making and 
reporting. QTcF exceeds 470 ms, or QRS complex exceeds 120 ms, the ECG should 
be repeated 2 more times and the average of the 3 QTcF or QRS complex values 
should be used to determine the participant’s eligibility. Computer interpreted-ECGs 
should be over-read by a physician experienced in reading ECGs before excluding 
participants. Cases must be discussed in detail with the sponsor to judge eligibility. 
15. Any of the following in the previous 12 months: myocardial infarction, long QT 
syndrome, Torsade de Pointes, clinically important atrial or ventricular arrhythmias 
(including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious 
conduction system abnormalities (eg, bifascicular block [defined as right bundle branch 
and left anterior or posterior hemiblock], 3rd degree AV block), unstable angina, 
coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart 
Association class III or IV, cerebrovascular accident, transient ischemic attack, 
symptomatic pulmonary embolism, and/or other clinical significant episode of 
thrombo-embolic disease. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, 
atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial 
fibrillation). If a participant has a cardiac rhythm device/pacemaker placed and QTcF 
>470 ms, the participant may be considered eligible. Participants with cardiac rhythm 
device/pacemaker must be discussed in detail with the sponsor to judge eligibility. 
16. History of symptomatic cardiac valve disease. Participants with mitral valve prolapse 
which is asymptomatic or not associated with clinically significant sequalae (eg, mitral 
regurgitation) are eligible. Any case of mitral valve prolapse must be discussed with 
the sponsor prior to enrollment to confirm eligibility. 
17. Active inflammatory gastrointestinal disease, chronic diarrhoea, known diverticular 
disease or previous gastric resection or lap band surgery. 
Other Exclusions: 
18. Investigator site staff or Pfizer employees directly involved in the conduct of the study, 
site staff otherwise supervised by the investigator, and their respective family members. 
Intervention Groups and Duration 
ARV-471 will be administered orally QD with food, in continuous dosing over 28-day 
cycles. A participant may continue treatment at the discretion of the investigator until a 
treatment discontinuation criterion is met (see Section 7.1). 
All treatment-related Grade 3 AEs should have their dose interrupted until return to Grade ≤1 
or baseline. Study drug may be resumed using the modification guidelines in Table 6. 
All treatment-related Grade 4 AEs should have their study treatment discontinued. 

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or 
► 
 
Following dosing intenuption or cycle delay due to toxicity, the study intervention dose may 
need to be reduced when ti·eatment is resumed. Dose reduction of study intervention by 
1 dose level (see Table 5) will be allowed depending on the type and severity of toxicity 
encountered. Pa1ticipants requiring more than 1 dose reduction will be discontinued from the 
ti·eatment and entered into the Follow-up phase, unless othe1wise agreed between the 
investigator and the sponsor. 
Data Monitoring Committee or Other Independent Oversight Committee: No 
Statistical Methods 
The prima1y endpoint of this study is first cycle DLT. The occunence ofDLTs observed in 
the dosing coho1t in Japanese population is used to confnm the tolerability of the RP3D that 
was detennined in Study ARV-471-mBC-101 conducted outside Japan. The target DLT rate 
is 33%. If a propo1tion of observed DLTs in this study is less than 33%, the tolerability of 
the RP2D in Japanese population is considered to be confmned. AEs constituting DLTs will 
be listed. Confmnation of the tolerability of the RP2D will be perfo1med using the DLT 
evaluable set (see Section 9.2). 
1.2. Schema 
 
Q!,!in 28 days 
 
 
 
0/6 
1/6 1-----..•l_2_o_o_m_g_Q_D_is 
_, 
. 
tolerable 
 
 
 
m:..Iiu 28 days 
 
 
6 pa !: ; nts----. 
2_16_ 
 
 
 
 
_,I  scuss between Em; '•;i :: : nal,-,: ---►....  21_9  , 
;  
 
  ;a  
 
200mgQD 
!J1vt tigator and .   
, , 
Sp so..- 
200 mg QD 
'•,- 
··,,,_ 
' 
?:316 
-------------"4  Explore one lower 
 
: 
May consider 
exploring one 
.... 
 
_, May c,onsider 
dose level 
lower dose level 
 
 
exploring one 
lowerdose level 
0 

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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed infonnation on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the paiiicipant. 
Table 1. 
Schedule of Activities 
 
Visit Identifier 
Abbreviations used in this table may be found in 
Section 10.14 (Appendix 14). 
Screening 
( 28 days 
p1·ior 
C1D1)1 
Study Treatment Period 
1 Cycle = 28 days 
EOT/Withdrawal2 
Follow-up3 
Cycle 14 
Cycle 2 and 
bevond4 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
22 
Day 1 
Day 
15 
Visit Window 
NA 
NA 
(±2) 
(±2) 
NA 
(±2) 
Cycle 
(±2) 
2: 
(+2) 
Cycle 
3+: 
(±2) 
Info1med consent5 
X 
Medical history6 
X 
Eligibility Criteria and Registration7 
X 
Clinical Evaluation 
PE8 
X 
X 
Brief PE8 
X 
X 
X 
X 
X 
X 
Hei'4it 
X 
Weight 
X 
X 
X 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOGPS 
X 
X 
X 
X 
X 
Treatment 
ARV-47110 
X 
X 
X 
X 
X 
X 
X 
X 
Disease assessments 

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Visit Identifier 
Abbreviations used in this table may be found in 
Section 10.14 (Appendix 14). 
Screening 
( 28 days 
p1·ior 
C1D1)1 
Study Treatment Period 
1 Cycle = 28 days 
EOT/Withdrawal2 
Follow-up3 
Cycle 14 
Cycle 2 and 
bevond4 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
22 
Day 1 
Day 
15 
Visit Window 
NA 
NA 
(±2) 
(±2) 
NA 
(±2) 
Cycle 
2: 
(+2) 
Cycle 
3+: 
(±2) 
(±2) 
CT/MRI scans11 
X 
Every 8 weeks from ClDl, then every 12 weeks from C7Dl 
(±7 davs) 
X 
Bone scan12 
X 
Safety Assessments 
Serious and nonserious AE monitoring13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatment(s) 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology15 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry16 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation17 
X 
X 
X 
X 
Thyroid function18 
X 
Viral disease assessment19 
X 
Urinalvsis20 
X 
X 
X 
Electrocardiogram 
X 
Refer to Table 2 
Echocardiogram21 
X 
Pregnancy test22 and contraception check23 
X 
X 
X 
X 
X 
PK assessments 
Blood sample for ARV-471 
Refer to Table 2 
PD or phannacogenomic assessments 
Tumor biopsy (optional) 24 
X 
X 
X 
■ 
 
Footnotes for Schedule of Activities 

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1. 
Screening: To be completed within 28 days prior to start of study treatment. 
 
2. 
EOT/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of study drug and prior to initiation of any new 
antitumor therapy. Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks [as applicable] 
for disease assessments). 
 
3. 
Follow-up: At least 28 days, and no more than 35 days after discontinuation of study drug treatment, participants will return to undergo review of pregnancy 
test, contraception check, prior/concomitant medications, ECOG PS, brief PE, and assessment for AEs and SAEs. Participants continuing to experience 
toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the 
clinical judgment of the investigator, that no further improvement is expected. 
 
4. 
Day relative to start of ARV-471 (Day 1). 
 
5. 
Informed consent must be obtained prior to any study specific procedures (see Section 10.1.3). 
 
6. 
Medical history includes history of disease process other than the cancer under study (active or resolved) and concurrent illness, prior treatments and any 
current medical treatments for any condition. 
 
7. 
Eligibility Criteria and Registration: Participant number assigned by the sponsor (see Section 5.1 and 5.2). 
 
8. 
PE must be performed within 48 hours prior to a scheduled visit. A full PE is required at Screening and EOT/Withdrawal visits. There is no need to repeat 
PE if screening assessment is within 4 days of Cycle 1 Day 1. A brief PE should be performed at other visits as indicated. A brief PE will be symptom 
directed exam and assessment for emergent toxicities or changes from prior visits (see Section 8.2.1). 
 
9. 
Vital Signs includes temperature, BP, respiratory rate and pulse rate. BP and pulse rate should be recorded in the sitting or semi-recumbent position after 5 
minutes of rest (recommended same position should be used throughout the study). On in-clinic dosing days, vital signs should be measured prior to dosing 
(pre-dose) (see Section 8.2.2). 
 
10. ARV-471 will be administered orally once daily with food during each 28-day cycle. On days of scheduled clinic visits, ARV-471 should be undertaken in 
the clinic (ie, not at home). Time of dose should be recorded in the source documents and eCRF. On Day 1, 2, 15 and 16, participants will be provided a 
light meal prior to their ARV-471 dose given in the clinic. On other clinic visit days participants will also take a light meal prior to their ARV-471 dose 
given in the clinic. Participants will self-dose as described above, except for doses that will be administered in the clinic (see Section 6.1.1). 
 
11. CT/MRI scans will be performed within 28 days prior to Cycle 1 Day 1 and will include all known or suspected disease regions. Scans obtained as part of 
standard of care before consent was signed are acceptable if obtained within 28 days prior to Cycle 1 Day 1. Imaging will include chest, abdomen, and 
pelvis CT or MRI scans (same modality should be used throughout the study). If MRI is performed for the abdomen and pelvis examinations at baseline, 
then at least a non-contrast CT of the chest must be performed as well. CT or MRI scans to be done every 8 weeks (±7 days) from the date of first dose 
(Cycle 1 Day 1), for the first 24 weeks of study treatment, then every 12 weeks (±7 days) thereafter. Scans should be performed independent of dose 

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delays. Tumor assessments will continue until radiographically and/or clinically (ie, for photographed or palpable lesions) documented disease progression 
as per RECIST version 1.1, study drug discontinuation (for participants who discontinued treatment for reasons other than RECIST-defined disease 
progression), initiation of new anticancer therapy, or discontinuation of participant from overall study participation (eg, death, participant's request, lost to 
follow-up, study terminated by sponsor), whichever occurs first. Given the exploratory nature of the study, confirmation of response (CR or PR) is 
preferred (see Section 10.11). Tumor assessments should be repeated at the EOT/Withdrawal visit if more than 8 weeks or 12 weeks (as applicable) have 
passed since the last evaluation. 
 
12. Bone scans must be performed in all participants at baseline within 28 days prior to Cycle 1 Day 1. Scans obtained as part of standard of care before 
consent was signed are acceptable if obtained within 28 days prior to Cycle 1 Day 1. Bone scans performed >28 to 45 days prior to enrollment as part of 
clinical care unrelated to this study may be acceptable pending discussion with the sponsor. For participants with bone lesions identified only by bone scan 
at baseline, additional studies (eg, X-ray, CT scan with bone windows or MRI) must be performed of these lesions at baseline and for follow-up 
assessments. 
 
13. Serious and nonserious AE monitoring: From the time the participant provides informed consent through and including a minimum of 28 calendar days 
after the last study drug administration (active collection period). If the participant begins a new anticancer therapy, the period for recording non-serious 
AEs on the eCRF ends at the time the new treatment is started. However, any SAEs related to study treatment occurring during the active collection period 
must still be reported to the sponsor or designee and recorded in the eCRF, irrespective of any intervening treatment (see Section 8.3.1 and 8.3.3). 
 
14. All concomitant medications, over-the-counter, and non-drug supportive interventions should be recorded in the eCRF including supportive care drugs; eg, 
anti-emetic treatment and prophylaxis, palliative radiotherapy on study is permitted (eg, skeletal administration for mBC), drugs used to treat AEs or 
chronic diseases, and non-drug supportive interventions (eg, transfusions). 
 
15. Hematology: There is no need to repeat on Cycle 1 Day 1 if screening assessment is performed within 3 days prior to that date. Assessments performed at 
each subsequent visit should be performed within 2 days prior to dosing. See Section 10.2 for more information. 
 
16. Chemistry: There is no need to repeat on Cycle 1 Day 1 if screening assessment is performed within 7 days prior to that date. See Section 10.2 for more 
information. 
 
17. Coagulation: There is no need to repeat on Cycle 1 Day 1 if screening assessment is performed within 3 days prior to that date. See Section 10.2 for details. 
 
18. Thyroid function: ie, TSH. 
 
19. Viral disease assessment: HBsAg, HBcAb, HBsAb, HCVAb, and HIV testing to be conducted by local laboratory when required by local regulations or if 
warranted by participant history. 
 
20. Urinalysis: Local urine dipstick testing is acceptable. There is no need to repeat on Cycle 1 Day 1 if screening assessment is performed within 7 days prior 
to that date. See Section 10.2 for more information. 

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21. Repeat as clinically indicated (refer to Section 8.2.4). 
 
22.  Pregnancy test: A serum pregnancy test will be conducted on all women of childbearing potential at Screening. Urine pregnancy tests will be done on 
study. If a mine test cannot be confinned as negative (eg, an ambiguous result), a serum pregnancy test is required. 
 
23. Contraception check: The investigator or qualified designee will discuss with the pa1ticipant the need to use 1 highly effective contraception method 
consistently and coITectly and document such conversation in the pa1ticipant's cha11. In addition, the investigator or qualified designee will instruct the 
participant to call illllllediately if one selected contraception method is discontinued, or if pregnancy is known or suspected of the participant or the 
participant's partner. Male pa1ticipants who are able to father children will need to affum that they meet the criteria for the coITect use of2 of the selected 
methods of contraception (see Section 10.4). 
 
 
 
An EOT/Withdra:wal biopsy should only be perfo1med if a 
screening biopsy was perfo1med and an on-treatment biopsy was NOT performed at Cycle 2 Day 1 or before Cycle 2. This EQT/Withdrawal biopsy should 
be performed while the pa1ticipant is still on study drug. 
 
25. 
 
 
26. 

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Pharmacokinetic Sampling and ECG 
Table 2. 
Schedule of PK and ECG Assessment 
 
Visit Identifier 
Study Treatment Pe1iod 
1 Cvcle = 28 davs 
EOT/Withdrnwal1 
Cycle 1 
Cvcle 2 and 3 
Dav 1 
Day2 
Day8 
Dav15 
Dav 16 
Dav22 
Dav 1 
Dav 15 
Visit Window 
NA 
NA 
(±2) 
(±2) 
NA 
(±2) 
Cycle 2: 
(+2) 
Cycle 3: 
(±2) 
(±2) 
PK2,3 
Pre-dose (if dosing day) 
X 
X (24hours) 
X 
X 
X (24 hours) 
X 
X 
X 
x5 
1hour 
X 
X 
2hours 
X 
X 
4hours 
X 
X 
6hours 
X 
X 
8hours 
X 
X 
12 hours (optional)4 
X 
X 
Electrocardiogram6 
Pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
x5 
4hours (±25 min) 
X 
X 
6 or 8 homs (±45 min) 
X 
X 
Footnotes for Schedule of PK and ECG Assessment 
1. EQT/Withdrawal: visit to be perfo1med as soon as possible but no later than 4 weeks from the last dose of study drng and prior to initiation of any new 
antitumor therapy. 
2.  On Days 1, 2, 15 and 16, the pa1ticipant will be provided a light meal after the pre-dose sample prior to their ARV-471 dose in the clinic. All pa1ticipants 
will be hospitalized for PK sampling and ECG assessment during Day 1 to 2 and Day 15 to 16 in the first cycle of dosing of ARV-471. 
 
3. With regard to serial PK sampling on Cycle 1 Days 1 and 15, samples should be collected within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample). For pre-dose samples on Cycle 1 Days 2, 8, 16 and 22, Cycle 2 Days 1 and 15, and Cycle 3 Days 1 and 15, pre-dose samples collected 
within 24 hours± 10% (ie,2 hours and 24 minutes) after the dose administration on the day prior to the pre-dose PK sampling AND collected prior to 
administration of ARV-471 on that day (for pre-dose PK samples) will be considered protocol compliant (refer to Section 8.4). 

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4. Collection of PK sample at 12 hours is optional. 
 
5. A single time point assessment can be collected if the participant does not receive study treatment on this visit. 
 
6. Standard 12 Lead ECG: ECGs will be collected at times specified in the SoA. The Screening ECG will be a single 12-lead ECG. At all other times, at each 
time point, 3 consecutive 12 lead ECGs (triplicate) will be performed approximately 2 minutes apart to determine mean QTcF interval. All 12 lead ECGs 
should be confirmed by a qualified individual at the institution. When coinciding with blood sample draws for PK, ECG assessment should preferably be 
performed prior to blood sample collection, such that the blood sample is collected at the nominal time. If the mean QTcF is prolonged (≥60 msec from the 
baseline and >500 msec), the ECGs should be re-evaluated by a qualified individual at the institution for confirmation. Additional triplicate ECGs may be 
performed as clinically indicated (refer to Section 8.2.3). 

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2. INTRODUCTION 
ARV-471, a PROteolysis-TArgeting Chimera (PROTAC®) hetero-bifunctional small 
molecule is currently being investigated in patients with ER+/HER2- locally advanced or 
mBC. 
2.1. Study Rationale 
The purpose of this study is to confirm safety and tolerability at the RP3D of ARV-471 in 
Japanese participants with ER+/HER2- locally advanced or mBC. 
2.2. Background 
2.2.1. Breast Cancer 
In Japan, breast cancer is the fourth leading cause of cancer death in women, with 
approximately 15,500 people expected to die with breast cancer in 2020. It is estimated that 
approximately 92,300 women were newly diagnosed with breast cancer, which is the first 
incidence in all cancers in 20204. Regarding men, it is estimated that approximately 700 
people were newly diagnosed with breast cancer, which is <1% in all breast cancer in 20204. 
Treatment options for advanced breast cancer or mBC depend on many different factors, 
including whether the tumors express ER and/or progesterone receptor or HER2. The 
standard of care for women with mBC is endocrine therapy, chemotherapy and/or targeted 
therapy alone or in combination. Patients with ER+/HER2- mBC are treated with endocrine 
therapy, sometimes in combination with targeted drugs such as CDKi. In patients with 
aggressive disease or whose disease continues to progress on endocrine therapy, 
chemotherapy may be prescribed. 
The current standard of care for patients with ER+/HER2- mBC is endocrine therapy ± CDKi 
or mTOR inhibitor. Endocrine therapies include ovarian ablation or suppression (for 
premenopausal women), tamoxifen (a selective ER modulator, SERM), aromatase inhibitors, 
and fulvestrant (a selective ER downregulator, SERD). Metastatic BC remains incurable, 
and sequencing of endocrine therapies is the recommended approach for the treatment of 
ER+ breast cancer. The addition of targeted agents including CDKi and mTOR inhibitors to 
a backbone of endocrine therapy further improves patient outcomes. 
Fulvestrant is considered a cornerstone component of ER-targeted endocrine regimens in the 
advanced disease setting, and works via an indirect mechanism of protein degradation, 
resulting in destabilization of ER. Single agent fulvestrant is dosed at 500 mg IM on Days 1, 
15, and 29 and once monthly thereafter. Efficacy of fulvestrant was established by 
comparison to the selective aromatase inhibitor anastrozole in 2 randomized, controlled 
clinical trials in postmenopausal women with locally advanced or mBC5. All participants 
had progressed after previous therapy with an antiestrogen or progestin for breast cancer in 
the adjuvant or advanced disease setting. In both trials, eligible participants with measurable 
and/or evaluable disease were randomized to receive either fulvestrant 250 mg IM once a 
month (28 days + 3 days) or anastrozole 1 mg orally once a day. Results of the trials, after a 
minimum follow-up duration of 14.6 months, ruled out inferiority of fulvestrant to 

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anastrozole. There was no statistically significant difference in OS between the 2 treatment 
groups after a follow-up duration of 2 years or more. A third study compared fulvestrant 
500 mg dose to fulvestrant 250 mg dose. Results of this study after a minimum follow-up 
duration of 18 months showed that PFS was statistically significantly superior with 
fulvestrant 500 mg versus fulvestrant 250 mg (6.5 months versus 5.4 months, respectively). 
There was no statistically significant difference in OS between the 2 treatment groups (25.1 
months for fulvestrant 500 mg and 22.8 months for fulvestrant 250 mg). ORR were similar; 
the RR for the 500 mg dose was 13.8 % (95% CI 9.7%-18.8%) and for the 250 mg dose was 
14.6% (95% CI 10.5%-19.4%)5. 
2.2.2. PROTAC® and ARV-471 
A new technology termed PROTAC, proteolysis targeting chimera, has been developed for 
inducing the protein degradation by a targeting molecule. This technology takes advantage 
of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces 
a hybrid molecule to specifically knock down a targeted protein. PROTAC is composed of a 
short peptide that binds to E3 ubiquitin ligase and a small molecule that binds to target 
protein followed by polyubiquitination and proteasome degradation of target6. 
ARV-471 is a PROTAC small molecule that induces active degradation of ER. ARV-471 is 
being developed for the treatment of patients with ER+/HER2- locally advanced or mBC. 
ARV-471 works by recruiting an E3 ligase to ubiquitinate ER which results in its subsequent 
degradation through the proteasome, a large, multi-subunit protein complex that degrades 
ubiquitinated proteins into small peptides (Figure 1). 
Figure 1. A Schematic Diagram of PROTAC (ARV-471) 
 
Such “active” degradation results in improved knockdown of tumor ER relative to fulvestrant 
in xenograft mouse models and produces TGI in vivo both as a single agent and in 

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combination with palbociclib. Unlike fulvestrant, which is administered via IM injections, 
ARV-471 is orally administered. Further, in early preclinical studies, ARV-471 has 
demonstrated greater ER degradation compared to other oral SERDs in clinical development, 
such as AZD9496 and RAD19011. 
2.2.3. Nonclinical overview of ARV-471 
Please refer to ARV-471 IB Section 5 for nonclinical details. 
2.2.4. Clinical Overview of ARV-471 
Currently, ARV-471 is being evaluated in one Phase 1/2 study (Study ARV-471-mBC-101). 
 Study ARV-471-mBC-101 
2.2.4.1.1. Study design 
Study ARV-471-mBC-101 (ClinicalTrials.gov Identifier: NCT04072952) is a Phase 1/2 FIH, 
open-label, 2-part, sequential group, 3+3 dose escalation (Part A), and cohort expansion (Part 
B) of single agent ARV-471 and a Phase 1b investigation of ARV-471 in combination with 
palbociclib to evaluate the safety and tolerability of ARV-471 (Part C), either as a single 
agent or in combination with palbociclib, in participants with locally advanced or mBC. The 
study will also characterize the first dose and steady state PK profile, assess preliminary 
antitumor activity, PD effects on exploratory biomarkers, and the safety of ARV-471 at the 
RP2D. The study consists of 3 parts: 
 
• 
Part A – Phase 1 Dose Escalation aims to enroll up to 75 participants to determine the 
MTD and/or RP2D of ARV-471 as monotherapy. ARV-471 will be administered orally 
QD or BID with food for 28-day cycles. 
 
• 
Part B – Phase 2 Cohort Expansion aims to enroll approximately 60 participants. Two 
single agent RP2D and schedules of ARV-471 at 200 mg QD and 500 mg QD. 
Participants will receive ARV-471 orally at the RP2D with food for 28-day cycles. 
 
• 
Part C – Phase 1b Combination ARV-471 + palbociclib aims to enroll up to 
approximately 55 participants to determine the safety and recommended dose of 
ARV-471 in combination with palbociclib. Part C will include 3 dose-escalation levels 
for ARV-471 in combination with palbociclib: 200 mg QD (Cohort C1), 400 mg QD 
(Cohort C2), and 500 mg QD (Cohort C3). The starting dose of palbociclib in the 
approved dose and regimen, 125 mg once daily for 21 days followed by 7 days off 
treatment to complete a 28-day cycle. 
As of 06 June 2022, 78 participants have been treated across 7 dose level cohorts in Part A 
using a once daily administration schedule [N=3 at 30 mg; N=3 at 60 mg; N=9 at 100 mg; 
N=7 at 120 mg; N=7 at 180 mg; N=8 at 200 mg; N=15 at 360 mg; N=22 at 250 mg 
BID/500 mg QD; and N=4 at 700 mg QD]. The sponsor evaluated 2 potential RP2D 
candidates of 200 mg QD and 500 mg QD in Part B and 200 mg QD was selected as the 
RP3D of ARV-471 from Part B. As of 06 June 2022, an additional 71 participants have been 

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treated in the current 200 mg QD or 500 mg QD dose cohort in Part B and 27 participants 
have been treated in Part C. 
2.2.4.1.2. Pharmacokinetics and Product Metabolism 
Blood samples for PK evaluation were collected from mBC participants receiving ARV-471. 
A chiral bioanalytical LC-MS/MS method was used for analysis of ARV-471 and ARV-473 
for Parts A, B and C of Study ARV-471-mBC-101. ARV-473 is an epimer of ARV-471 with 
ER antagonistic but no degradation activity, and was formed to a limited extent in animals 
and humans although it is not thought to be formed via enzymatic conversion. PK parameter 
values for ARV-471 + ARV-473 are also reported. PK analyses were performed using 
noncompartmental analysis methods for Parts A and C. Preliminary PK data from Part A of 
Study ARV-471-mBC-101 were available from dose levels ranging from 30 mg to 700 mg 
administered either as QD or BID. Preliminary results indicated dose-dependent increases in 
Cmax and AUCtau for ARV-471, ARV-473, and ARV-471 + ARV-473 up to 500 mg total 
daily dose administered either as 250 mg BID or 500 mg QD on both Day 1 and Day 15 (see 
Table 3). The median Tmax ranged from 4 to 7 hours across the dose levels. Geometric mean 
ARV-471 AUCtau is 7324 ng•h/mL on Day 15 at 60 mg QD (N=3) and has exceeded the 
nonclinical efficacious range associated with TGI (AUCinf = 5717 ± 2353 ng•h/mL, single 
30 mg/kg in mice). Following 200 mg QD dosing (N=8), a geometric mean Rac based on 
AUCtau of 1.7 was observed between Day 1 and Day 15. The mean effective t1/2 at steady 
state (t½eff) ranged from 23 to 33 hours. The ratio of ARV-473/ARV-471, based on AUCtau, 
on Cycle 1 Day 15 is 32%. These preliminary findings are similar to those observed 
exposures of ARV-473 relative to ARV-471 (≥26%) in toxicology studies in dogs and rats. 

 
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Table 3. 
Preliminary PK Data of ARV-471-mBC-101 Part A (Data Snapshot of 06 Jun 2022) 
 
 
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2.2.4.1.3. Safety 
As of 06 June 2022, a total of 176 participants have received at least 1 dose of ARV-471 in 
Parts A, B and C. 
Regardless of study drug attribution and grade, TEAEs were observed in 157 of the total 176 
participants treated with ARV-471 in the ongoing trial (all parts). Please refer to ARV-471 
IB Section 6.5 for details. 
2.2.4.1.3.1. Part A – Dose Escalation (n=78) 
The most common TEAEs (regardless of attribution to study drug) observed in ≥10% of 
participants, listed in decreasing order of frequency, were: fatigue (33.3%), nausea (33.3%), 
constipation (30.8%), arthralgia (17.9%), vomiting (17.9%), back pain (16.7%), diarrhoea 
(16.7%), headache (16.7%), decreased appetite (15.4%), AST increase (14.1%), hot flush 
(14.1%), hyperglycaemia (12.8%), pain in extremity (12.8%), insomnia (11.5%), ALT 
increased (10.3%), and dizziness (10.3%). 
A total of 13 participants (16.7%) experienced TEAEs of Grade ≥3 severity. The Grade 3 
TEAEs that occured in 1 participant each were nausea, stomatitis, arthralgia, fatigue, AST 
increased, electrocardiogram QT prolonged, amylase increased, blood alkaline phosphatase 
increased, lipase increased, headache, presyncope, embolism, venous embolism, procedural 
pain, humerus fracture, acute kidney injury, and malignant pleural effusion. Grade 3 
hypertension occurred in 2 participants. The Grade 4 TEAEs of hypoglycaemia, neutrophil 
count decreased, and neutropenia occurred in 1 participant each. The Grade 5 TEAE of 
cardiac arrest occurred in 1 participant and was unrelated to ARV-471. 
A total of 54 of 78 participants (69.2%) had at least 1 TEAE considered potentially related to 
ARV-471. The most commonly reported TRAEs observed in ≥10%, listed in decreasing 
order of frequency were nausea (25.6%), fatigue (21.8%), constipation (12.8%), arthralgia 
(10.3%), decreased appetite (10.3%), hot flush (10.3%), and vomiting (10.3%). Four 
participants (5.1%) experienced 6 Grade 3 TRAEs: headache lasting 1 day, asymptomatic 
amylase increased and lipase increased, nausea and asymptomatic electrocardiogram QT 
prolonged, and venous embolism that occurred after a minor procedure (bone biopsy). There 
were no Grade 4 or Grade 5 TRAEs reported. 
2.2.4.1.3.2. Part B – Dose Expansion (n=71) 
A total of 62 of the 71 participants (87.3%) reported at least 1 TEAE, and the most 
commonly reported TEAEs observed in ≥10% of participants, listed in decreasing order of 
frequency, include fatigue (39.4%), nausea (21.1%), constipation (16.9%), arthralgia 
(16.9%), AST increased (12.7%), decreased appetite (11.3%), headache (11.3%), and back 
pain (11.3%). 
A total of 16 participants (22.5%) experienced a total of 23 TEAEs of Grade ≥3 severity. 
The Grade 3 TEAEs that occurred in 1 participant each were intestinal obstruction, muscular 
weakness, AST increased, ALT increased, blood alkaline phosphatase increased, 
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cholangitis, neutropenia, spinal cord compression, upper gastrointestinal haemorrhage, 
fatigue, pyrexia, back pain, and decreased appetite. The Grade 3 TEAE of anaemia was 
reported in 2 participants. The Grade 4 TEAEs of hyperbilirubinaemia, hypercalcaemia and 
hepatic haemorrhage were reported in 1 participant each. A Grade 5 TEAE of acute 
respiratory failure was reported in 1 patient, after that participant presented with progressive 
malignant pleural effusion. 
A total of 51 participants (71.8%) experienced at least 1 TRAE, and the most commonly 
reported TRAEs observed in ≥10% of participants were fatigue (33.8%), nausea (16.9%), and 
arthralgia (12.7%). Five participants (7.0%) experienced 6 TRAEs, with severity of 
Grade ≥3, including Grade 3 events of electrocardiogram QT prolonged, thrombocytopenia, 
neutropenia, decreased appetite, and fatigue. There was 1 Grade 4 TRAE of 
hyperbilirubinaemia. There were no Grade 5 TRAEs reported. 
2.2.4.1.3.3. Part C – Phase 1b Dose Escalation of Combination of ARV-471 + palbociclib 
(n=27) 
A total of 24 of 27 participants (88.9%) reported at least 1 TEAE. The most common TEAEs 
observed in ≥20% of participants, include neutrophil count decreased (51.9%), fatigue 
(44.4%), neutropenia (37.0%), platelet count decreased (33.3%), anaemia (29.6%), nausea 
(25.9%), cough (22.2%), diarrhoea (22.2%), and white blood cell decreased (22.2%). 
2.2.5. Rationale of dose selection in Phase 1 study in Japan 
Two single agent RP2D of ARV-471 at 200 mg QD and 500 mg QD were selected from Part 
A and 200 mg QD was selected as the RP3D of ARV-471 from Part B in the FIH study 
(Study ARV-471-mBC-101) conducted outside Japan (see detail in Section 4.3). The RP3D, 
200 mg QD will be investigated in the Phase 1 study in Japanese participants. No DLTs had 
been reported across 30 mg to 700 mg total daily doses in Study ARV-471-mBC-101. It is 
considered adequate to evaluate safety and tolerability at the RP3D, 200 mg QD in Phase 1 
study in Japanese participants. If DLT is observed in ≥33% of participants at 200 mg QD, 
the investigation at the next lower dose level may be explored. 
2.3. Benefit/Risk Assessment 
ARV-471 may potentially benefit patients with locally advanced or mBC whose disease has 
progressed on currently approved standard of care agents. Preclinical and clinical data 
demonstrate that ARV-471 is a potent, selective, orally bioavailable degrader of ER, 
effectively lowers ER levels in tumors, and therefore it is anticipated to provide improved 
efficacy when compared to standard-of-care agent, fulvestrant. 
Preclinical toxicology studies performed in rats and dogs with ARV-471 using QD oral 
administration showed it was well tolerated in both 7- and 28-day studies. The NOAELs for 
daily oral administration of ARV-471 to rats and dogs for 28 days were the highest dose of 
100 mg/kg/day and 90 mg/kg/day, respectively. Based on the studies, potential adverse 
effects may include changes consistent with the pharmacologic activity of ARV-471 as an 
ER degrader, and similar to effects observed with other agents that target ER (eg, fulvestrant) 
when administered in healthy animals. These included reversible changes in the female 

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■ 
■ 
reproductive tissues such as increased ovaiy weight and occunence of ovai·ian cysts and 
corpus hemonhagicum, and uterine and cervical atrophy. Findings in the testis, epididymis, 
and prostate of male animals were consistent with effects seen in male animals dosed with 
ER inhibitors for at least 1 month and also showed si s of reversibili . An additional 
finding consisted of 
unaccompanied by changes to the 
findings seen in 
(1) had no observed i 
act on the clinic s 
s   of  the  anir 
not accompanied by any other changes in 
and 
and-- 
(2) were observed in only- 
at 
and were also observed in control 
animals; and (3) did not increase m frequency or severity with increasing dose or exposure 
level or duration of dosing. Overall, it is not expected that the fmdings listed above should 
impact clinical studies with ARV-471 for the treatment of ER+/HER2- paiticipants with 
locally advanced or mBC. 
As of 06 June 2022, 78 pa1ticipants have been treated in Part A in Study 
ARV-471-mBC-101. No DLTs have been reported and MID has not been reached with 
ARV-471 monotherapy across total daily doses of 30 mg to 700 mg. The majority ofTRAEs 
ai·e Grade 1 or 2 in severity. The participant with Grade 3 venous embolism was the only 
patient who discontinued ARV-471 due to a TRAE. In addition, evidence of clinical benefit 
has been observed in this heavily treated population, with a 36.2% CBR among 25 of 69 
evaluable paiticipants and a 8.6% ORR with 5 of 58 response-evaluable paiiicipants having 
confinned PRs. 
QT Prolongation: 
In the subsequent 3-month toxicity study in dogs, ARV-471 when administered at 90 
mg/kg/day resulted in an approximate 13 msec prolongation of QT/QTc intervals on study 
Day 85 (nonadverse) associated with comparative exposure mai·gins to the 200 mg clinical 
dose of approximately 5.8x and 5.9x for AUC and Cmax, respectively. Both single- and 
repeat-dose studies up to Day 28 were negative for this effect at higher or equivalent 
dose/exposures, respectively. Neither ARV-471 nor ARV-473 inhibit the hERG channel in 
vitro at concentrations greater than 100 times those of clinical relevance. Overall, a potential 
concentration and time dependent impact on QT interval in the dog was observed. 
Concentration-QTc modeling analysis of clinical data revealed a concentration-dependent 
increase in QTcF. Based on the model, a QTcF change from baseline is predicted to be 
6.8 msec (90% CI: 5.7, 7.9) at the geometric mean Cmax for the sum of ARV-471 and 
ARV-473 (1,091 ng/mL) at steady-state after 200 mg QD dosing, while a QTcF change is 
predicted to be 14.7 msec (90% CI: 12.3, 17.1) at the geometric mean Cmax (2,360 ng/mL) 
after 500 mg QD dosing. 
From the ongoing ARV-471-mBC-101 study, as of 06 Jun 2022, 13 paiticipants repo1ied 
TEAEs of electrocardiogram QT prolonged (12 pa1iicipants had TRAEs and in 1 paiiicipant 
the AE was considered as not related to ARV-471 per investigator). 

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Based on the categorical analysis of ECG data from 149 participants in Study 101 Part A and 
Part B (data cutoff date of 06 Jun 2022), 3 participants experienced a QTcF >500 msec (1 of 
each at 180 mg, 200 mg, and 500 mg daily dose) and 4 participants had QTcF change from 
baseline >60 msec (1 at 200 mg, 2 at 500 mg and 1 at 700 mg daily dose). 
No Grade 4/5 QT prolonged events have been reported of the 13 reported prolonged QTc 
events. 
The Sponsor had an external cardiology expert evaluate the records of the participants with 
ECG abnormalities. The review concluded that of the 13 participants who reported QTc 
prolonged events, only 2 participants had a true diagnosis of QTc prolongation, of which low 
potassium and concomitant medications were confounding factors. The cardiologist 
concluded that due to the relatively low incidence of true treatment emergent ECG QTc 
abnormalities in the ARV-471-mBC-101 study, which had alternative explanations, ARV- 
471 does not adversely affect the ECG. 
All events will continue to be monitored and participants will be excluded from ARV-471 
trials if taking medications that are either known to prolong the QT interval or are associated 
with a risk of Torsades de Pointes, within 7 days prior to first study dose in all studies (until 
analyses of data from future studies are available). Concomitant use of such medications with 
ARV-471 will also be prohibited unless utilized with caution to treat a drug-related AE when 
no alternative is available. Protocols will include a list of drugs (adapted from 
https://crediblemeds.org/) that are associated with known QT risk. 
TEAE of electrocardiogram QT prolonged has been identified to be of potential risk based on 
nonclinical findings, concentration-QTc modeling demonstrating concentration-dependent 
increases in QTcF, and from clinical data from Study ARV-471-mBC-101 Parts A, B and C. 
Additional potential adverse effects of ARV-471 may be similar to those observed with 
ER-degrading agents such as fulvestrant, and include nausea, bone pain, arthralgia, headache, 
back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal 
pain, cough, dyspnea, and constipation. The most common laboratory abnormalities with 
fulvestrant were increased hepatic enzymes (ALT, AST, and ALP5. Participants will be 
monitored closely throughout study participation. The sponsor will immediately notify the 
investigator of any additional safety or toxicology information which becomes available 
during the study. 
More detailed information about ARV-471 is provided in the IB, which is the SRSD for this 
study. 

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2.3.1. Risk Assessment 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) ARV-471 
QT prolongation 
Potential risk based on nonclinical findings. 
Concentration-QTc modeling analysis revealed a 
concentration-dependent increase in QTcF in a 
dose range of 30 mg to 700 mg total daily dose. 
Thirteen participants were reported with non- 
serious AE of QT interval prolongation in the 
ongoing FIH study (ARV-471-mBC-101); for 12 
participants the event was considered related as 
per investigators. Per an external cardiology 
consultant review, only 2 participants had a true 
diagnosis of QTc prolongation, of which low 
potassium and concomitant medications were 
confounding factors. 
Clinical safety not yet fully characterized. 
Participants will be monitored for QT interval changes 
with ECG monitoring at screening and during the study. 
Participants at high risk of QT prolongation as per 
Exclusion criteria #14 and 15 are excluded from 
participation in the study (see Section 5.2). 
Concomitant drugs predisposing to Torsade de Pointes or 
QT prolongation are prohibited as per Section 10.8. 
Study intervention will be temporarily interrupted, 
reduced, or permanently discontinued based on severity of 
the events occurred (see Section 6.5.1). 
Venous embolism (VE) 
Potential risk based on metastatic cancer setting 
and known class effect with ET (SERM, SERD, 
AI). 
One Grade 3 related serious VE case, with 
confounding factors of obesity, diabetes and 
immobility due to recent biopsy procedure, and a 
Grade 3 serious embolism case assessed as 
unlikely related to ARV-471 by the investigator, 
were reported in the Study ARV-471-mBC-101. 
Participants with a history of clinically significant 
thromboembolic or cerebrovascular events are excluded 
from participation in the study as per Exclusion criteria 
#15 (see Section 5.2). 
Coagulation tests will be performed at screening and will 
be repeated on treatment. Suspicious of VE should be 
investigated, per local standard practice (eg, D-Dimer, 
fibrinogen, imaging). 
Study intervention will be temporarily interrupted, 
reduced, or permanently discontinued based on severity of 
the events occurred (see Section 6.5.1). 
DDI 
The potential for DDIs exists with ARV-471. In 
vitro assessment indicates CYP3A4 as the 
principal isoform responsible for CYP-mediated 
metabolism of ARV-471. Drugs that are 
inhibitors of CYP3A4 may increase the exposure 
Medications known to strongly induce or inhibit CYP3A4, 
or act as a sensitive P-gp substrate are prohibited (see 
Section 10.8). 
The concomitant use of PPIs with ARV-471 is not 
recommended. If PPI treatment is required, ARV-471 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
of ARV-471, whereas drugs that are inducers of 
CYP3A4 may reduce the exposure of ARV-471. 
ARV-471 is also an in vitro inhibitor of P-gp and 
in vitro weak inhibitor of BCRP. BCRP 
substrates, rosuvastatin and sulfasalazine, may be 
used because safety risk is low. 
Studies conducted in fasted dogs and rats showed 
a pH effect on absorption when administered with 
famotidine (lowered PK at neutral pH). Elevated 
gastric pH may reduce ARV-471 absorption. 
intake with a moderate-fat meal (400-800 calories, 
approximately 35% fat) is recommended. H2 receptor 
antagonists or local antacids may be used, but should be 
staggered. Administer ARV-471 ≥2 hours before or after 
antacids. Administer ARV-471 ≥2 hours before or 10-12 
hours after H2 receptor antagonists (see Section 6.8). 
Study Procedures 
CT or MRI procedures for tumor 
assessments 
CT scans expose the participant to a small dose of 
radiation. The contrast dye used with the CT scan 
may cause pain or burning when injected. 
The dye may worsen kidney function for those 
with kidney disease or are dehydrated. The dye 
may cause an allergic reaction. MRI risks include 
possible reactions to metals due to magnets, loud 
noises from the machine causing hearing issues, 
increase in body temperature during long MRIs, 
and claustrophobia. 
Only experienced professionals will conduct the CT or 
MRI procedures. The participant will be asked about 
allergies to the contrast dye. Medical history will be 
reviewed for kidney disease, and information will be 
provided to minimize dehydration. If possible, an open 
MRI can be used for those experiencing claustrophobia. 
The participant may be offered earplugs and/or 
headphones to minimize the noise. 
Blood draws for PK, biomarker, blood 
chemistry, hematology, coagulation 
evaluations andCCI  
The risks associated with blood collection 
commonly include discomfort, pain, redness and 
swelling and/or bruising where the blood is taken 
from the participant’s arm. Sometimes bleeding 
can occur at the place where blood is drawn. 
Fainting and infection are rare occurrences 
associated with blood collection. 
Only experienced professionals will conduct the blood 
draws. 
Pre- and post-treatment tumor biopsies 
(optional) 
The risks associated with biopsies include pain or 
discomfort during the biopsy, including slight, 
stinging pain when a local anesthetic is injected by 
needle to numb the area, pressure and dull pain 
where the biopsy needle is inserted, discomfort 
from lying still for an extended time, and soreness 
at the biopsy site. Other risks can include 
bleeding, swelling, scarring, bruising, nerve 
To reduce these risks, the site of the biopsy will be 
anesthetized and sterile techniques will be used. 

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damage and infection, which can be life 
threatening or fatal in rare cases. 
Other 
The COVID-19 pandemic may pose risks to 
study participation 
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a study 
procedure at a study facility. 
Use of telehealth, home health, etc will be utilized in the 
study to minimize potential exposure of trial participants to 
SARS-CoV-2 (see Section 10.9). 

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2.3.2. Benefit Assessment 
In general, nonclinical toxicity studies have shown that ARV-471 is safe and well tolerated. 
And in initial data from participants with ARV-471 across multiple doses in FIH 
monotherapy study (n=78), most TRAEs were low grade, and no clear dose-dependent AEs 
were identified. 
2.3.3. Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to study participants, the potential 
risks identified in association with ARV-471 are justified by the anticipated benefits that may 
be afforded to participants with ER+/HER2- locally advanced or mBC. 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
 
Objectives 
Endpoints 
Estimands 
Primary: 
Primary: 
Primary: 
• To evaluate the safety and 
tolerability of ARV-471 at the 
RP3D 
First cycle DLTs 
The primary estimand for 
incidence of DLTs is DLT 
rate estimated based on data 
from DLT-evaluable 
participants during the 
DLT-evaluation period which 
is the first cycle of treatment 
(ie, 28 days) after the first 
dose of study intervention. 
Secondary: 
Secondary: 
Secondary: 
• To evaluate the overall safety 
profile 
• AEs as characterized by type, 
frequency, severity (as graded by 
NCI CTCAE version 5.0), timing, 
seriousness, and relationship to 
study drug 
• Laboratory abnormalities as 
characterized by type, frequency, 
severity (as graded by NCI CTCAE 
version 5.0), and timing 
NA 
• 
To characterize the 
single-dose and multiple-dose 
PK of ARV-471 and 
ARV-473 (an epimer of 
ARV-471) 
The following PK parameters will be 
assessed when applicable after a 
single dose and after multiple doses: 
single dose: AUCtau, AUClast, Cmax, 
Tmax, t½, MRCmax, and MRAUCtau 
multiple doses; AUCtau, AUClast, Cmax, 
Cmin, Ctrough, CL/F*, Tmax, Vz/F*, Rac, 
t½, t½eff, MRCmax, and MRAUCtau 
NA 
* ARV-471 only 
Vz/F and t½ for single dose and multiple 
doses will be calculated only if data 
permit. 

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- 
 
4. STUDY DESIGN 
4.1. Overall Design 
This study is a single-countiy, non-randomized, open-label, Phase 1 study. This study will 
evaluate the safety, tolerability, PK, and preliminary efficacy of ARV-471 as monotherapy in 
Japanese paiiicipants with ER+/HER2- locally advanced or mBC. 
One dose level of ARV-471, 200 mg QD which has been detennined as the RP3D as 
monotherapy in the FIH study (Study ARV-471-mBC-101) conducted outside Japan will be 
investigated. Six paiiicipants will receive ARV-471 at 200 mg QD. If none or 1 participant 
experience DLT dming the first cycle (1 Cycle= 28 days), ARV-471, 200 mg QD will be 
considered tolerable as monotherapy in Japanese pa1iicipants. lf2 pa1iicipants experience 
DLT, the investigator and the sponsor should discuss the safety and tolerability based on the 
available data, and then under the agreement between the investigator and the sponsor, an 
additional 3 paiiicipants at the same dose level, up to a total of 9 participants, will be enrolled 
to fmiher investigate the safety and tolerability of ARV-471 as monotherapy in Japanese 
paiiicipants. If no DLT is repo1ied in an additional 3 pa1iicipants, 200 mg QD will be 
considered tolerable in Japanese paiiicipants. IfDLT is observed in 33% of pa1iicipants at 
200 mg QD, the investigation at the next lower dose level may be explored. 
Objectives 
Endpoints 
Estimands 
• To explore prelimina1y 
antitumor activity 
- 
Antitumor activity of ARV-471 will 
be assessed by evaluating the 
following: 
• ORR per RECIST version 1.1 
• CBR based on the sUllllllation of 
CRs, PRs and SD of 24 weeks 
duration or longer 
• Time to event endpoints: PFS, 
DOR 
NA 
■ 
■ 

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Paiiicipants who are inadequate to evaluate DLT (incomplete Cycle 1; fail to complete at 
least 75% of study drng ti·eatment in Cycle 1 for reasons other than DLT) must be replaced to 
adequately assess the safety of ARV-471. 
Note: "Enrolled" means a pa1iicipant's, or their legally authorized representative's, agreement 
to participate in a clinical study following completion of the info1med consent process and 
assignment to study intervention. A paiiicipant will be considered enrolled if the info1med 
consent is not withdrawn prior to paiiicipating in any study activity. Potential participants 
who ai·e screened for the pmpose of detennining eligibility for the study, but do not 
paiiicipate in the study, are not considered enrolled. 
In order to ensure paiiicipant safety, an interval of at least 1 day shall separate ti·eatment 
initiation for the first paiticipant and ti·eatment initiation for the second paiiicipant. 
A paiiicipant may continue ti·eatment at the discretion of the investigator until a ti·eatment 
discontinuation criterion is met (see Section 7.1). 
Paiiicipants who have evidence of radiographic disease progression may be considered for 
continued study therapy provided the investigator has detennined that they are still benefiting 
from study therapy; this must be reviewed and approved by the sponsor. 
 
4.2. Scientific Rationale for Study Design 
The pmpose of this Phase 1 study is to evaluate the safety, tolerability, PK, and prelimina1y 
efficacy of ARV-471 as monotherapy in Japanese pa1iicipants with ER+/HER2- locally 
advanced or mBC. A target toxicity rate defined by DLT of <33% has u-aditionally been 
considered acceptable in the oncology field. The study with enrolhnent of 6 paiiicipants will 
allow for a reasonable number of treated paiiicipants to assess the safety, tolerability and PK 
of ARV-471 in Japanese paiiicipants. 
 

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4.2.1. Choice of Contraception/Barrier Requirements 
ARV-471 is known to cause risk for severe manifestations of developmental toxicity in 
humans or suspected on the basis of the intended pharmacology. Therefore, the use of a 
highly effective method of contraception is required (see Section 10.4). 
ARV-471 is not genotoxic. However, nonclinical studies suggest risk for severe 
manifestations of developmental toxicity at relevant clinical exposures for ARV-471. 
Therefore, the use of a highly effective method of contraception is required (see Section 
10.4). 
Studies to evaluate the development toxicity of ARV-471 have not been conducted. 
Therefore, the use of a highly effective method of contraception is required (see Section 
10.4). 
4.2.2. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
4.3. Justification for Dose 
Two single agent RP2D of ARV-471 at 200 mg QD and 500 mg QD were selected from Part 
A and 200 mg QD was selected as the RP3D of ARV-471 from Part B in the FIH study 
(Study ARV-471-mBC-101) conducted outside Japan. The RP3D, 200 mg QD, will be 
investigated in this study. 
As of 06 June 2022, 176 participants have been treated in Study ARV-471-mBC-101 (Part A, 
n=78; Part B; n=71, Part C, n=27). ARV-471 has been well tolerated across total daily doses 
of 30 mg to 700 mg, without any DLTs observed. Most TRAEs were Grades 1 or 2. The 
MTD has not been reached, and the maximum administered dose was 700 mg total daily dose 
(administered 400 mg/300 mg BID) in Part A. 
Two single agent ARV-471 doses at 200 mg QD and 500 mg QD were selected as the RP2D 
based on a review of PK, PD, safety and efficacy data from Part A in Study 
ARV-471-mBC-101. Two RP2Ds are being investigated in Part B in Study 
ARV-471-mBC-101 to further assess the activity of ARV-471. 
The rationale for the selection of 2 RP2Ds is as follows: 
200 mg QD 
The 200 mg QD dose was selected as the RP2D based on a review of data from Part A in 
Study ARV-471-mBC-101 available as of 10 Feb 2021. At that time, a total of 38 
participants had been treated with ARV-471 as monotherapy in Part A of the study. Doses 
received had been: 30 mg QD, n=3; 60 mg QD, n=3; 120 mg QD, n=7; 180 mg QD, n=7, 
360 mg QD, n=14; and 250 mg BID, n=4. ARV-471 had been well tolerated at all doses 
tested, and reported safety data were as follows: 

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 
No DLT or treatment-related SAEs had occurred at doses up to and including 180 mg 
QD. 
 
One treatment-related SAE occurred at the 360 mg QD dose level, a Grade 3 
thromboembolic event. No DLT, additional treatment-related SAE or Grade 3/4 
treatment-related events had been reported among the 13 participants who had completed 
at least 1 cycle of ARV-471 at 360 mg QD. 
 
The majority of reported AEs had been Grade 1. Grade 2 TRAEs had been reported at 
doses of 120 mg and higher. The only Grade 2 TRAE to occur in more than 1 
participant was nausea (n=2). 
 
Preliminary PK, PD and efficacy data from the first 20 participants treated at doses up to 
360 mg QD were as follows: 
o 
ARV-471 demonstrates dose-related PK, with doses of 60 mg QD and above 
resulting in exposures that far exceed the efficacious threshold for tumor regression 
in preclinical models. 
o 
Based on data from the first 3 dose levels (30 mg-120 mg), significant ER 
degradation (up to 90% with an average of 62%) was observed in participant tumor 
biopsies, which exceeds the 40%-50% degradation reported for fulvestrant. 
Degradation of both wild-type ER and ESR1-mutant proteins was observed7,8. 
o 
A confirmed PR (with 51% shrinkage in tumor burden) was observed in a 
participant who received ARV-471 at 120 mg QD, and who was heavily pretreated 
with multiple lines of endocrine therapy and prior CDK4/6. 
o 
Shrinkage of measurable lesions was observed in 71% (10/14) of evaluable 
participants, and occurred across multiple dose levels. 
o 
The CBR (defined as SD persisting ≥24 weeks, or a best response of confirmed CR 
or PR) was 42% (5/12) among evaluable participants up to 180 mg, which exceeds 
the CBR (<20%) reported for fulvestrant in a similar population. Clinical benefit 
was also observed across dose levels. 
500 mg QD 
As of 13 April 2021, the dose escalation has proceeded through 30 mg QD, 60 mg QD, 
120 mg QD, 180 mg QD, 360 mg QD, and 500 mg total daily dose in Part A in Study 
ARV-471-mBC-101, and has almost completed the 700 mg total daily dose level. Data that 
support the selection of 500 mg QD as a RP2D are as follows: 
 
No DLTs have been reported with ARV-471 monotherapy among the 45 participants 
treated in dose escalation and cohort expansion at doses up to 250 mg BID (500 mg total 
daily dose). In addition, 2 participants have received the 700 mg total daily dose for 
more than 28 days with no DLT. 

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 
The majority of TRAEs are Grade 1 in severity, with TRAEs in ≥10% of participants 
limited to nausea, fatigue and arthralgia. 
 
Except for 1 participant in the 360 mg cohort who discontinued study treatment due to a 
Grade 3 thromboembolic event that was assessed as possibly related to treatment, there 
have been no additional Grade 3 TRAEs or treatment discontinuations due to toxicity. 
 
PK results indicated dose-related increase in exposure (Cmax and AUC) up to 500 mg 
dose level. 
 
The NOAEL in the most sensitive species in nonclinical toxicology studies (female rat) 
was 100 mg/kg/day, which is equivalent to a human dose of approximately 960 mg. 
Refer to the IB for details. 
 
ARV-471 efficacy in participant-derived xenograft models was dose proportional. 
No clinically meaningful exposure-response relationship was observed for any safety and 
efficacy endpoints between the two RP2Ds, except that there is potential risk of QTc 
prolongation especially in the higher dose group of 500 mg QD based on a 3-month dog 
toxicology study, concentration-QTc modeling analysis results and preliminary observed 
dose-dependent increases in QTcF at higher doses of ARV-471 in monotherapy Parts A and 
B of Study ARV-471-mBC-101. Model-predicted QTcF change from baseline was 6.8 msec 
(90% CI: 5.7 msec, 7.9 msec) after 200 mg QD and 14.7 msec (90% CI: 12.3 msec, 
17.1 msec) after 500 mg QD, respectively, using the observed geometric mean Cmax for the 
sum of ARV-471 and ARV-473. No DLTs had been reported across 30 mg to 700 mg total 
daily doses in Study ARV-471-mBC-101. Based on the totality of the data and benefit-risk 
profile, the 200 mg QD dose has been selected for the RP3D for the planned Phase 3 ARV- 
471 monotherapy study. It is considered adequate to evaluate safety and tolerability at the 
RP3D, 200 mg QD in Phase 1 study in Japanese participants. 
In the study, dose escalation beyond 200 mg QD is not planned. If DLT is observed in ≥33% 
of participants at 200 mg QD, the investigation at the next lower dose level may be explored. 
4.3.1. Dose Limiting Toxicity Definition 
For purposes of tolerability decisions, a DLT is defined as any AE or abnormal laboratory 
value which are related to ARV-471 and assessed as unrelated to disease, disease 
progression, intercurrent illness or concomitant medications/therapies occurring during the 
first 28 days of treatment that meets at least 1 of the criteria listed in Table 4. A participant is 
classified as DLT-evaluable if he/she experiences a DLT or in the absence of a DLT, receives 
at least 75% of the planned dose intensity of study intervention during the DLT window. If a 
participant does not meet these criteria, he/she may be replaced. All safety information 
including AEs that have occurred in the participants who were excluded from the DLT 
evaluation will be considered in the assessment of tolerability. AEs that are clinically 
significant and considered to be related to the study intervention that occur after the DLT 
observation period will be reviewed in context of all safety data available. That review may 

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result in re-evaluation of the dosing level. Severity of AEs will be graded according to 
CTCAE v5.0. 
 
 
Table 4. 
DLT Criteria 
 
Hematological DLTs 
• Prolonged myelosuppression, defined as CTCAE Grade ≥3 hematologic parameters (ANC <1000/mm3, 
platelet count <50,000/mm3, or hemoglobin <8 g/dL) in a bone marrow with <5% blasts and no evidence 
of leukemia or abnormal dysplasia, that lasts longer than 28 days from the point of detection. 
• Grade ≥3 neutropenia with infection. 
• Grade 4 neutropenia lasting >5 days. 
• Febrile neutropenia (defined as an ANC <1.0×109/L with a single temperature of >38.3℃ or 101°F, or a 
sustained temperature of ≥38.0℃ or 100.4°F for more than 1 hour). 
• Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion (defined as requiring 
hospitalization, urgent medical intervention or transfusion). 
• Grade 4 thrombocytopenia. 
• Any toxicity requiring dose interruption for ≥14 days will be considered a DLT. Any AE attributed to 
ARV-471 detected within the DLT evaluation period requiring dose interruption for ≥14 days extending 
beyond the end of the DLT evaluation period and to post-DLT evaluation period will also be considered a 
DLT. 
• Grade 3 leukopenia or neutropenia less than 28 days unaccompanied by fever or infection will NOT be 
considered a DLT. 
• Grade 3 thrombocytopenia of less than 28 days without clinical evidence of bleeding will NOT be 
considered a DLT. 
• Anemia not requiring transfusion will NOT be considered a DLT. 
• Any isolated Grade 3 lymphopenia of any duration will NOT be considered a DLT. 
Non-Hematologic DLTs 
• Grade ≥3 toxicities are DLT. Those that have not been maximally treated and the following AEs will not 
be considered as DLTs: 
o Grade 3 nausea/vomiting/diarrhoea or Grade 4 vomiting/diarrhoea lasting <72 hours in the absence of 
maximal medical therapy. 
o 
Grade 3 fatigue lasting less than 7 days. 
• Hy‘s Law (concomitant ALT or AST elevation of ≥3×ULN and total bilirubin elevation of ≥2×ULN 
without a clear alternative etiology) is considered a DLT. 
• Grade ≥3 electrolyte abnormality that lasts >72 hours, unless the participant has clinical symptoms, in 
which case all Grade ≥3 electrolyte abnormality regardless of duration should count as a DLT. 
• Grade ≥3 amylase or lipase elevation NOT associated with symptoms or clinical manifestations of 
pancreatitis is NOT considered a DLT. 
• QTcF prolongation: Any Grade ≥3 QT prolongation must be considered a DLT. The participant must also 
be evaluated by cardiology and discontinued from the study and study drug. 
• Any AE attributed to ARV-471 requiring dose interruption for ≥14 days will be considered a DLT. Any 
AE attributed to ARV-471 detected within the DLT evaluation period requiring dose interruption for ≥14 
days extending beyond the end of the DLT evaluation period and to post-DLT evaluation period will also 
be considered a DLT. 
• Any death not clearly due to the underlying disease or extraneous causes. 
Clinically important or persistent toxicities (eg, toxicities responsible for significant dose delay) that are not 
included in the above criteria may also be considered a DLT following review by the investigators and the 
sponsor. To be considered a DLT, the AE must represent a clinically significant shift from baseline and must 
be considered at least likely related to ARV-471 by the investigator or sponsor. 

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4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Participants (women and men) at least 20 years of age at the time of signing the 
informed consent. 
• 
Postmenopausal women due to surgical or natural menopause, defined by at least 
1 of the following criteria: 
o Age ≥60 years. 
o Age <60 years and cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; and 
follicle-stimulating hormone level within the laboratory’s reference range for 
postmenopausal females. 
o Documented bilateral oophorectomy with surgery at least 2 months prior to start 
of study treatment. 
o Medically confirmed ovarian failure. 
 
• 
Pre- or perimenopausal women or men may be enrolled if treated with an GnRH 
analogue for at least 4 weeks prior to Cycle 1 Day 1. If a participant has received 
GnRH analogue, they must remain on it for the duration of the trial. 
• 
Refer to Section 10.4 for reproductive criteria for male (Section 10.4.1) and 
female (Section 10.4.2) participants. 

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Type of Participant and Disease Characteristics: 
2. Histological or cytological diagnosis of ER+/HER2- advanced breast cancer that is 
metastatic, recurrent, or locally advanced unresectable breast cancer. 
• 
ER+ disease must be documented by IHC per ASCO/CAP Guidelines2. 
• 
HER2- disease must be documented by either IHC or in-situ hybridization per 
ASCO/CAP guidelines3. 
3. Participants who are resistant to standard therapy or for which no standard therapy is 
available or have received; 
• 
at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or 
advanced/metastatic). However, the number of prior cytotoxic chemotherapy 
regimen in the locally advanced or metastatic setting must be no more than 3 
regimens. 
All such therapy must be discontinued at least 14 days prior to enrollment. 
Informed Consent: 
4. Capable of giving signed informed consent as described in Section 10.1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
Other Inclusion criteria: 
5. ECOG PS 0 or 1 (Section 10.12). 
6. Adequate Bone Marrow or Coagulation Function, defined as (with no transfusion of 
blood products or use of hematopoietic growth factors in the 28 days prior to 
enrollment): 
a. ANC ≥1,500/mm3 or ≥1.5 x 109/L; 
b. Platelets ≥100,000/mm3 or ≥100 x109/L; 
c. Hemoglobin ≥9 g/dL; 
d. aPTT ≤1.25× ULN and INR ≤1.25. 
7. Adequate Renal Function, defined as an estimated creatinine clearance ≥60 mL/min 
as calculated using the method standard for the institution. 
8. Adequate Liver Function, defined as: 

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a. Total bilirubin ≤1.5 x ULN (<3 x ULN in a participant with documented 
Gilbert’s syndrome); 
b. AST and ALT ≤2.5 x ULN if there is NO liver metastasis; ≤5.0 x ULN if there is 
liver metastasis. 
9. Participants with brain metastases must meet all the following conditions: 
a. Have completed their planned course of treatment; 
b. Have recovered from the acute effects of radiation therapy or surgery prior to 
first dose of drug; 
c. Have discontinued high-dose corticosteroid treatment for these metastases for at 
least 4 weeks; 
d. Are neurologically stable as judged by the investigator; 
e. Participants who are diagnosed with a CNS metastasis during the screening 
period must also meet these criteria. 
10. Resolution of acute effects of any prior therapy to either baseline severity or CTCAE 
version 5.0 Grade ≤1 (except for AEs not constituting a safety risk in the 
investigator’s judgment). 
11. Participants must agree and be capable of taking oral medication without crushing, 
dissolving, or chewing tablets. 
12. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Participants with any other active malignancy within 3 years prior to enrollment, 
except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in 
situ of the cervix, Bowen’s disease. 
2. Participants sustaining major surgery defined as a complex procedure performed 
under regional or general anesthesia with a recovery period of at least 4 weeks prior 
to study enrollment. 
3. Known or suspected hypersensitivity or severe allergy to active ingredient/excipients 
of ARV-471. 

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4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
5. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to 
>25% of the bone marrow (see Section 10.10 Bone Marrow Reserve in Adults). 
Palliative radiation for the alleviation of pain due to bone metastasis will be allowed 
during the study. 
Prior/Concomitant Therapy: 
6. Concurrent administration of medications, foods or herbal supplements that are strong 
inhibitors or inducers of CYP3A4 and drugs with a known risk of causing Torsade de 
Pointes or QT interval prolongation. Prior use of strong CYP3A inhibitors and drugs 
with a known risk of causing Torsade de Pointes or QT interval prolongation must be 
stopped 7 days before enrollment and strong CYP3A inducers must be stopped 14 
days before enrollment. Refer to Sections 6.8 Concomitant Therapy and 10.8 
(Appendix 8). 
7. Prior treatment with ARV-471. 
8. Systemic anticancer therapy chemotherapy or endocrine therapy within 14 days prior 
to study entry (6 weeks for mitomycin C or nitrosoureas). If the last immediate 
anticancer treatment contained an antibody-based agent(s) (approved or 
investigational), then an interval of 28 days or 5 half-lives (whichever is shorter) of 
the agent(s) prior to receiving the study intervention treatment is required. 
9. Participants who have initiated therapy with bone-modifying agents 
(bisphosphonates, denosumab, or similar) within 14 days of enrollment (participants 
who are receiving bone-modifying agents are eligible for this study provided the 
bone-modifying agent was started more than 14 days prior to study enrollment). 
10. Previous high-dose chemotherapy requiring stem cell rescue. 
Prior/Concurrent Clinical Study Experience: 
11. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry. A participant may be eligible even if they are in the follow-up phase of 
an investigational study as long as they haven’t received treatment in the study for 
5 half-lives of the agents. 
Diagnostic Assessments: 
12. Serum pregnancy test (for females of childbearing potential) positive at screening 
and/or a breastfeeding participant (including females who are currently breastfeeding 
or intend to temporarily interrupt breastfeeding). 

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13. Participants with active, uncontrolled bacterial, fungal, or viral infection, including 
(but not limited to) HBV, HCV, and known HIV or AIDS-related illness. Comments 
regarding specific circumstances follow. 
a. COVID-19/SARS-CoV-2: This protocol excludes participants with active 
infections, as noted above. While SARS-CoV-2 testing is not mandated for entry 
into this protocol, testing should follow local clinical practice standards. If a 
participant has a positive test result for SARS-CoV-2 infection, is known to have 
asymptomatic infection or is suspected of having SARS-CoV-2, he/she is 
excluded. 
b. HIV: In equivocal cases, participants whose viral load is negative may be 
eligible. HIV seropositive participants who are otherwise healthy and at low risk 
for AIDS-related outcomes could be considered eligible. Potential eligibility for 
a specific HIV positive protocol candidate should be evaluated and discussed 
with the sponsor prior to any screening, based on current and past CD4 and Tcell 
counts, history (if any) of AIDS defining conditions (eg, opportunistic 
infections), and status of HIV treatment. Also, the potential for drug-drug 
interactions will be taken into consideration. 
c. HBV: 
• Participants with active, uncontrolled bacterial, fungal, or viral infection, 
including HBsAg positive. 
• Participants with positive HBsAb and positive HBcAb are allowed to 
participate in the study if they have negative HBV DNA test at screening but 
HB viral load should be monitored for re-activation every 12 weeks. 
• Participants with HBsAb positive who get vaccinated with HBV are exempted 
from the testing of HB viral load. 
• Participants who test positive for HBV viral load at any time during the study 
will interrupt administration of ARV-471, and should be considered for 
consultation with a hepatologist and initiation of antiviral therapies (eg, 
nucleoside antagonist) in accordance with the JSH Guidelines for the 
management of Hepatitis B Virus infection. 
d. HCV: 
• Positive HCV antibody is indicative of infection but may not necessarily 
render a potential candidate ineligible, 
(https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf). 
14. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities 
that may affect participant safety or interpretation of study results (eg, baseline 

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QTcF>470 ms, complete LBBB, signs of an acute or indeterminate age myocardial 
infarction, ST-T interval changes suggestive of active myocardial ischemia, second or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the 
baseline uncorrected QTcF is >470 ms, this interval should be rate corrected using the 
Fridericia method and the resulting QTcF should be used for decision making and 
reporting. QTcF exceeds 470 ms, or QRS complex exceeds 120 ms, the ECG should 
be repeated 2 more times and the average of the 3 QTcF or QRS complex values 
should be used to determine the participant’s eligibility. Computer interpreted ECGs 
should be over-read by a physician experienced in reading ECGs before excluding 
participants. Cases must be discussed in detail with the sponsor to judge eligibility. 
15. Any of the following in the previous 12 months: myocardial infarction, long QT 
syndrome, Torsade de Pointes, clinically important atrial or ventricular arrhythmias 
(including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious 
conduction system abnormalities (eg, bifascicular block [defined as right bundle 
branch and left anterior or posterior hemiblock], 3rd degree AV block), unstable 
angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart 
Association class III or IV, cerebrovascular accident, transient ischemic attack, 
symptomatic pulmonary embolism, and/or other clinical significant episode of 
thrombo-embolic disease. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, 
atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial 
fibrillation). If a participant has a cardiac rhythm device/pacemaker placed and QTcF 
>470 ms, the participant may be considered eligible. Participants with cardiac rhythm 
device/pacemaker must be discussed in detail with the sponsor to judge eligibility. 
16. History of symptomatic cardiac valve disease. Participants with mitral valve prolapse 
which is asymptomatic or not associated with clinically significant sequalae (eg, 
mitral regurgitation) are eligible. Any case of mitral valve prolapse must be 
discussed with the sponsor prior to enrollment to confirm eligibility. 
17. Active inflammatory gastrointestinal disease, chronic diarrhoea, known diverticular 
disease or previous gastric resection or lap band surgery. 
Other Exclusions: 
18. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 

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correct use. At time points indicated in the SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart 
(participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception) considering that their risk for pregnancy may have changed since 
the last visit. In addition, the investigator or designee will instruct the participant to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the participant or partner. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. 
For the purposes of this protocol, study intervention refers to ARV-471. 
6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
ARV-471 
Type 
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
100 mg 
Dosage Level(s) 
200 mg 
Route of Administration 
Oral 
Use 
Experimental 
IMP or NIMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Refer to the product specific IP manual. 
Packaging and Labeling 
Study intervention will be provided in a high-density 
polyethylene bottle with child-resistant cap. Each bottle will be 
labeled as required per country requirement. 
Current/Former Name(s) or Alias(es) 
NA 
 
6.1.1. Administration 
ARV-471 will be administered orally QD with food, in continuous dosing over 28-day 
cycles. 

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A participant may continue treatment at the discretion of the investigator until a treatment 
discontinuation criterion is met (see Section 7.1). Participants who have evidence of 
radiographic disease progression may be considered for continued study therapy provided the 
investigator has determined that they are still benefiting from study therapy; this must be 
reviewed and approved by the sponsor. 
Participants will swallow tablet whole, and will not manipulate or chew tablet prior to 
swallowing. 
A cycle is defined as 28 days, regardless of missed doses or dose delays. 
Participants should be instructed to take their medication in the morning at approximately the 
same time each day and to not take more than the prescribed dose at any time. 
If a participant misses a day of treatment, he/she must be instructed not to “make it up” but to 
resume subsequent doses the next day as prescribed. 
If a participant vomits any time after taking a dose, he/she must be instructed not to “make it 
up” but to resume subsequent doses the next day as prescribed. 
If a participant inadvertently takes 1 extra dose during a day, the participant should not take 
the next dose of ARV-471. 
6.2. Preparation, Handling, Storage and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business. 
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual. 

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4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
5. Study interventions should be stored in their original containers. 
6. Site staff will instruct participants on the proper storage requirements for takehome 
study intervention. 
7. See the IP manual for storage conditions of the study intervention. 
8. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. 
9. All study intervention that is taken home by the participant, both used and unused, 
must be returned to the investigator by the participant. Returned study intervention 
must not be redispensed to the participants. 
10. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual. 
6.2.1. Preparation and Dispensing 
A qualified staff member will dispense the study intervention in the bottles provided, in 
quantities appropriate according to the SoA. A second staff member will verify the 
dispensing. The participant should be instructed to maintain the product in the bottle, as 
appropriate provided throughout the course of dosing and return the bottle, as appropriate to 
the site at the next study visit. 
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Study Intervention 
Participants will be enrolled to the study after participants have given their written informed 
consent and have completed the necessary baseline (screening visit) assessments. The site 
staff will email a complete Registration Form to the designated sponsor study team member 
or designee. The sponsor will assign a participant ID number and supply this number to the 
site. The participant ID number will be used on all study-related documentation at the site. 

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No participant will receive study intervention until the investigator or designee has 
received the following information in writing from the sponsor: 
• 
Confirmation of the participant’s enrollment; 
• 
Specification of the dose level for that participant and; 
• 
Permission to proceed with dosing the participant. 
Study intervention will be dispensed at the study visits summarized in the SoA. 
Returned study intervention must not be redispensed to the participants. 
6.3.2. Storage 
ARV-471 should be stored and shipped at 2°C to 8°C (36°F to 47°F), in a dry place, away 
from direct sunlight. Do not freeze. 
6.4. Study Intervention Compliance 
On days of scheduled visits, study drug treatment should be withheld and taken while in the 
clinic (ie, not at home) under the supervision of study staff. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
Participants will self-dose as described above, with the exception of doses that will be 
administered at the clinic. 
At each visit, prior to dispensing additional study treatment, study center personnel will 
assess compliance by review of the previously dispensed ARV-471 study treatment in its 
respective bottle. Participants will be required to return all bottles and remaining tablets of 
ARV-471, as well as the completed participant diary for drug accountability and 
documentation of food consumption. Study treatment bottles with unused study treatment 
may be returned to the participants for continued use. Participants are to complete 
participant diary daily during study participation. Participants exhibiting poor compliance as 
assessed by tablet counts should be counseled on the importance of good compliance to the 
study dosing regimen. Noncompliance is defined as taking less than 75% due to reasons 
other than toxicity or more than 120% of assigned study drug during any evaluation period 
(visit to visit). Deviation(s) from the prescribed dosage regimen should be recorded in the 
CRF. 
A record of the number of ARV-471 tablets dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions, will also 
be recorded in the CRF. 
6.5. Dose Modification 
Every effort should be made to administer study intervention on the planned dose and 
schedule. In the event of significant toxicity, dosing may be delayed and/or reduced as 

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described below. In the event of multiple toxicities, dose modification should be based on 
the worst toxicity observed. Participants are to be instructed to notify investigators at the 
first occurrence of any adverse symptom. In addition to dose modifications, investigators are 
encouraged to employ best supportive care according to local institutional clinical practices. 
Toxicities potentially related to study intervention should be managed according to the dose 
modifications described in Table 5 and Table 6. 
6.5.1. Dose Interruption/Reductions 
All treatment-related Grade 3 AEs should have their dose interrupted until return to Grade ≤1 
or baseline. Study drug may be resumed using the modification guidelines below (see 
Table 6). 
All treatment-related Grade 4 AEs should have their study treatment discontinued (see 
Table 6). 
No specific dose adjustments are recommended for Grade 1 or 2 treatment-related toxicity. 
However, investigators should always manage their participants according to their medical 
judgment based on the particular clinical circumstances. 
Participants experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the 
next lower dose level once recovery to Grade ≤1 or baseline is achieved. 
Following dosing interruption or cycle delay due to toxicity, the study intervention dose may 
need to be reduced when treatment is resumed. Dose reduction of study intervention by 1 
dose level (see Table 5) will be allowed depending on the type and severity of toxicity 
encountered. Participants requiring more than 1 dose reduction will be discontinued from the 
treatment and entered into the Follow-up phase, unless otherwise agreed between the 
investigator and the sponsor. All dose modifications/adjustments must be clearly 
documented in the participant's source notes and CRF. 
Table 5.  Dose Levels 
 
Dose Level 
ARV-471 
 
Starting 
200 mg/d 
-1 
100 mg/d 
 
Participants experiencing a DLT may resume dosing at the next lower dose level (if 
applicable) once adequate recovery is achieved, and in the opinion of the investigator and 
sponsor, the participant is benefiting from therapy. 
 
Table 6. 
Dose Reduction 
 
Related Grade 3a AEs 
ARV-471 Dose Modificationb 
 
First Dose Reduction 
Reduce by 1 dose levelc, d 
Second Dose Reduction 
Discontinue ARV-471 
 
Related Grade 4 AE 
Discontinue ARV-471e 
 

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Table 6. 
Dose Reduction 
 
Related Grade 3a AEs 
ARV-471 Dose Modificationb 
 
a. Grade 3 AEs not requiring dose reduction: 
Grade 3 fatigue lasting <7 days; 
Grade 3 lymphopenia lasting <72 hours; 
Grade 3 nausea/vomiting/diarrhoea lasting <72 hours in the absence of maximal medical therapy. 
b. See Table 5. 
c. Depending on the nature of the toxicity and the rapidity of recovery following dose interruption, 
resumption of the same dose may be considered after the first instance of the related Grade 3 AE. 
d. If the participant has demonstrated significant benefit, the AE was rapidly reversible, and redosing is not 
expected to pose a significant risk to the participant, dose re-escalation of ARV-471 may be considered 
after consultation with the sponsor. 
e. If the participant has demonstrated significant benefit, the AE was rapidly reversible, and redosing is not 
expected to pose a significant risk to the participant, resumption of ARV-471 at a reduced dose may be 
considered dependent on the nature of the Grade 4 AE after consultation with the sponsor. 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. 
ARV-471 treatment should be permanently discontinued for any dosing interruption lasting 
>28 days with the following exceptions: 
o 
Dosing interruptions >28 days that occur for non-drug-related reasons may be 
allowed if approved by the sponsor. Prior to re-initiating treatment in a participant 
with a dosing interruption lasting >28 days, the sponsor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted. 
6.6. Continued Access to ARV-471 After the End of the Study 
No intervention will be provided per protocol to study participants beyond the end of the 
study. 
6.7. Treatment of Overdose 
For this study, any dose of ARV-471 that is ≥150% of the planned dose within a 24-hour 
time period will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator or qualified designee should: 
1. Contact the medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of ARV-471 (whichever is 
longer). 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 

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4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
5.  Obtain a blood sample for PK analysis within 7 days from the date of the last dose of 
ARV-471 if requested by the sponsor (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 based on the clinical evaluation of the participant. 
6.8. Concomitant Therapy 
All prior and concomitant treatments, received by participants from screening and up to 28 
days after the last dose of study treatment, or up to the start of new anticancer therapy, 
including supportive care drugs (eg, anti-emetic treatment and prophylaxis), drugs used to 
treat AEs or chronic diseases, and non-drug supportive interventions (eg, transfusions) will 
be recorded on the CRF. Concomitant medications for AEs and SAEs should follow 
respective guidance for the AE and SAE reporting period. Only subsequent anticancer 
therapy initiated after end of study treatment(s) will be reported at the follow-up visits. 
Concomitant treatment considered necessary for the participant’s well-being may be given at 
discretion of the treating physician. 
Palliative radiotherapy on study is permitted (eg, skeletal administration for mBC), but 
should be discussed with the sponsor prior to initiation. Bisphosphonates and RANKL 
inhibitors are allowed. Paracetamol/acetaminophen at doses of ≤2 g/day is permitted for use 
any time during the study. Herbal supplements and Chinese herbal medicines are not 
permitted, if the ingredients are unknown or included ingredients may have potential DDI 
(refer to Section 10.8). Other concomitant medications may be considered on a case-by-case 
basis by the investigator in consultation with the sponsor, as necessary. 
6.8.1. Prohibited Medications/Therapy 
Other therapies with known anticancer effects are prohibited during study participation. 
Ovarian suppression therapy with GnRH agonists is not considered anticancer therapy and is 
allowed. 
Medications which are not allowed in this study refer to Section 10.8. 
6.8.2. Proton Pump Inhibitors 
Co-administration of gastric acid-reducing agents may reduce ARV-471 absorption. The 
concomitant use of PPIs with ARV-471 is not recommended. If PPI treatment is required, 
ARV-471 intake with a moderate-fat meal (400-800 calories, approximately 35% fat) is 
recommended. Refer to Section 10.8 for examples of drugs that are PPIs. 
 
6.8.3. H2 Receptor Antagonists or Antacids 
H2 receptor antagonists (eg, cimetidine, famotidine, etc.) or local antacids (eg, aluminum 
hydroxide, calcium carbonate, bismuth subsalicylate, etc.) may be used, but should be 

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staggered. Administer ARV-471 ≥2 hours before or after antacids. Administer ARV-471 ≥2 
hours before or 10-12 hours after H2 receptor antagonists. 
6.8.4. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to the specific supportive care product Prescribing 
Information or the current ASCO guidelines. 
6.8.5. Hematopoietic Growth Factors and Transfusions 
Primary prophylactic use of colony stimulating factors is not permitted during the first 28 
days of Cycle 1, but they may be used to treat treatment-emergent neutropenia or 
participants experienced DLT in Cycle 1 as indicated by the current ASCO guidelines9 or 
Japanese package insert. During the screening window (ie, 28 days prior to Day 1), 
Granulocyte colony stimulating factors are not permitted to qualify a participant with low 
WBC counts. 
Packed red blood cell and platelet transfusions should be administered only if clinically 
indicated. These treatments are not permitted during the first 28 days of Cycle 1, but may be 
used for participants experienced DLT in Cycle 1. 
6.8.6. Antidiarrheal, Antiemetic Therapy 
Primary prophylaxis beyond the first cycle is at the investigator’s discretion. The choice of 
the prophylactic drug as well as the duration of treatment is up to the investigator with 
sponsor approval assuming there is no known or expected DDI and assuming the drug is not 
included in the Concomitant Therapy section (Section 6.8). 
6.8.7. Corticosteroids 
Chronic systemic corticosteroid use (prednisone >10 mg/day or equivalents) for palliative or 
supportive purposes is not permitted. Acute emergency administration, topical applications, 
inhaled sprays, eye drops, or local injections of corticosteroids are allowed. 
6.8.8. Surgery and Radiotherapy 
Caution is advised for any surgical procedures during the study. The appropriate interval of 
time between surgery and ARV-471 required to minimize the risk of impaired wound healing 
and bleeding has not been determined. Postoperatively, the decision to reinitiate ARV-471 
treatment should be based on a clinical assessment of satisfactory wound healing and 
recovery from surgery. Palliative radiotherapy to specific sites of disease will be permitted if 
considered medically necessary by the treating physician. All attempts will be made to rule 
out progressive disease in the event of increased localized pain. 

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7. DISCONTINUATION OF ARV-471 AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of ARV-471 
It may be necessary for a participant to permanently discontinue ARV-471. Reasons for 
permanent discontinuation of study intervention may include the following: 
• Objective disease progression; 
• Global deterioration of health status requiring discontinuation; 
• Unacceptable toxicity; 
• Pregnancy; 
• Significant protocol violation; 
• Lost to follow-up; 
• Participant refused further treatment; 
• Study terminated by sponsor; 
• Death; 
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for safety follow-up. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up for any further evaluations that need to 
be completed. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
See Section 10.9.4 for guidance for participants with active or presumed SARS-CoV-2 
infection. 
Follow-Up: 
At least 28 calendar days, and no more than 35 calendar days after discontinuation of study 
intervention, participants will return to undergo review of concomitant treatments, brief 
physical examination, ECOG PS and assessment for AEs and SAEs. Participants continuing 
to experience AEs at this point following discontinuation of treatment will continue to be 
followed at least every 4 weeks until resolution or determination, in the clinical judgment of 
the investigator, that no further improvement is expected. 

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7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study may include: 
• Refused further study procedures; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law. 
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for/attend a 
required study visit: 

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• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible.Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 

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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
During the COVID-19 pandemic, please refer to Section 10.9 for safety and efficacy 
assessments. 
8.1. Efficacy Assessments 
8.1.1. Tumor Response Assessments 
Tumor assessments will include all known or suspected disease sites. Imaging will include 
contrast enhanced chest, abdomen and pelvis computed tomography or MRI scans; brain 
computed tomography or MRI scan for participants with known or suspected brain 
metastases; bone scan and/or bone x-rays for participants with known or suspected bone 
metastases. For participants with known computed tomography contrast allergy, a non 
contrast computed tomography of the chest with contrast enhanced abdominal and pelvic 
MRI can be used. The same imaging technique used to characterize each identified and 
reported lesion at baseline will be employed in the following tumor assessments. 
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the SoA, whenever disease progression is suspected 
(eg, symptomatic deterioration), and at the time of withdrawal from treatment (if not done in 
the previous 8 weeks or 12 weeks [as applicable]). Assessment of response will be made 
using RECIST version 1.1 (see Section 10.11). 
All participants’ files and radiologic images must be available for source verification. 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues. 
8.2.1. Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
A brief physical examination will include, at a minimum, assessments of skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
PE may be conducted by a physician, trained physician's assistant, or nurse practitioner as 
acceptable according to local regulation. 

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Height and weight will also be measured and recorded as per the SoA. For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface. Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains. They must also remove the contents of their pockets and remain 
still during measurement of weight. 
ECOG PS will also be measured and recorded as per the SoA. ECOG performance scale is 
available in Section 10.12. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Section 10.3) must be reported according to the processes in 
Section 8.3.1 to 8.3.3. 
8.2.2. Vital Signs 
Oral, tympanic, axillary or skin temperature, pulse rate, respiratory rate, and BP will be 
assessed. 
BP and pulse rate measurements will be assessed in a sitting or semi-recumbent position (the 
same position should be maintained throughout the study) with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
BP and pulse rate measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
rate and 3 BP measurements (3 consecutive BP readings will be recorded at intervals of at 
least 1 minute). The average of the 3 BP readings will be recorded on the CRF. 
8.2.3. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR, QT, and QTcF intervals and QRS 
complex. For ECG machines that do not report QTcF, calculation of QTcF from QT and 
HR, for example using online tools, is permitted. Alternative lead placement methodology 
using torso leads (eg, Mason-Likar) should not be used given the potential risk of 
discrepancies with ECGs acquired using standard limb lead placement. All scheduled ECGs 
should be performed after the participant has rested quietly for at least 5 minutes in a supine 
position. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >500 msec; or b) an 
absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator); or c) QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 

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if QTcF intervals do not return to less than the criteria listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Section 10.7. 
8.2.4. Echocardiograms 
A screening echocardiogram is required with special attention to valvular structure and 
function. A multigated acquisition scan is not sufficient. An echocardiogram should be 
repeated as clinically indicated. 
8.2.5. Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical safety laboratory tests to be performed and the SoA 
for the timing and frequency. All protocol-required laboratory assessments, as defined in 
Section 10.2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
See Section 10.6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury. 
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 

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commenced and a second negative pregnancy test result will be required at the baseline visit 
prior to the participant’s receiving the ARV-471. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In 
such cases, the participant must be excluded if the serum pregnancy result is positive. 
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant 
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records. 
Confirm that the participant is adhering to the contraception method(s) required in the 
protocol. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Section 10.3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant/ legally 
authorized representative will be questioned about the occurrence of AEs in a nonleading 
manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention. 

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Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form. 
 Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in Section 
10.3. The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment. Note that a switch to a commercially available version of the study intervention is 
considered as a new anticancer therapy for purposes of SAE reporting. 
 Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period. Note that a switch to a 
commercially available version of the study intervention is considered as a new anticancer 
therapy for the purposes of SAE reporting. 

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8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Section 10.3. 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 

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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
 Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
• A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation or skin 
contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 30 days after 
the last dose. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 

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completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
• Spontaneous abortion including miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
 Exposure During Breastfeeding 
An EDB occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental EDB 
is a female family member or healthcare provider who reports that she is 
breastfeeding after having been exposed to the study intervention by ingestion, 
inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental 
exposure, the exposure information does not pertain to the participant enrolled in the study, 

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so the information is not recorded on a CRF. However, a copy of the completed CT SAE 
Report Form is maintained in the investigator site file. 
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accord with authorized use. However, 
if the infant experiences an SAE associated with such a drug, the SAE is reported together 
with the EDB. 
 Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file. 
8.3.6. Cardiovascular and Death Events 
Not applicable. 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
The following DREs are common in participants with ER+/HER2- locally advanced or mBC 
and can be serious/life threatening: 
• Disease progression 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE. These events will be recorded on the 
corresponding CRF page in the participant’s CRF within the appropriate time frame. 
Note: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
• The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 
• The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.8. Adverse Events of Special Interest 
Not applicable. 

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 Lack of Efficacy 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE. 
8.3.9. Medical Device Deficiencies 
Not applicable. 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report Form to 
Pfizer Safety Within 24 Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
Medication errors include, but are not limited to: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
• 
The administration of expired study intervention; 
• The administration of an incorrect study intervention; 
• The administration of an incorrect dosage; 
• The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 

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applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.4. Pharmacokinetics 
Blood samples (4 mL) to provide a minimum of 1.5 mL for measurement of plasma 
concentrations of ARV-471 and ARV-473, will be collected into appropriately labeled tubes 
as specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. 
All efforts will be made to obtain the samples at the exact nominal time relative to dosing. 
However, the exact time of the sample collection will always be noted on the CRF. If a 
scheduled blood sample collection on and after Cycle 2 (except for Cycle 1) cannot be 
completed for any reason, the missed sample time may be re-scheduled with agreement of 
the clinical investigator, participant, and sponsor. 
With regard to serial PK sampling on Cycle 1 Days 1 and 15, samples obtained within 10% 
of the nominal time (eg, within 6 minutes of a 60-minute sample) relative to dosing will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. 
For pre-dose samples on Cycle 1 Days 2, 8, 16 and 22, Cycle 2 Days 1 and 15, and Cycle 3 
Days 1 and 15, pre-dose samples collected within 24 hours ± 10% (ie, 2 hours and 24 
minutes) after the dose administration on the day prior to the pre-dose PK sampling AND 
collected prior to administration of ARV-471 on that day (for pre-dose PK samples) will be 
considered protocol compliant. Participants must be instructed to withhold their daily dose 
of study drugs on PK sampling days until the pre-dose PK sample collection has been 
completed. The actual date and time (24-hour clock time) of the sample collection and the 
most recent dosing date and time before and after each collection will be recorded on the 
CRF. The actual times may change, but the number of samples will remain the same. The 
date of missing dose should be also be recorded in the CRF. 
Ctrough at steady state is defined as the pre-dose concentration that meets the following 
dose-compliant acceptance criteria: 
 Participants must have received 6 consecutive days at the same dose of ARV-471 once 
daily prior to the pre-dose PK sampling; 
 PK samples must have been collected 24 hours ± 10% after the dose administered the 
day prior to the pre-dose PK sampling. 

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Samples collected for measurement of plasma concentrations of ARV-471 and ARV-473 will 
be analyzed using a validated analytical method in compliance with applicable SOPs. All 
samples still within the known stability of the analyte of interest at the time of receipt by the 
bioanalytical laborato1y will be analyzed. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and repo1ted to the sponsor. 
On a case-by-case basis, the sponsor may make a detennination as to whether sample 
integrity has been compromised. 
As part of understanding the PK of the investigational product, samples may be used for 
metabolic identification and/or evaluation of the bioanalytical method, as well as for other 
internal explorato1y purposes. These data.will not be included in the CSR. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be infonned of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
 
 
 
 
 

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I 
 
 
 
 
8.7. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
8.8. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
·- 
I 

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9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypotheses 
There are no statistical hypotheses in this study so that no formal statistical testing will be 
performed. 
9.1.1. Estimands 
 DLT 
The estimand is defined by the following attributes: 
Population: participants who receives at least 1 dose and classified as DLT-evaluable, ie, 
participants who experiences a DLT or in the absence of a DLT, receives at least 75% of the 
planned dose intensity of study intervention during the DLT window. 
Endpoint: occurrence of DLTs at first cycle. For the definition of DLTs, see Section 4.3.1. 
Treatment condition: Participants who fail to complete at least 75% of study drug treatment 
in Cycle 1 for reasons other than DLT (eg, logistical or technical reasons, non-DLT-related 
dose delays) are considered not to be DLT-evaluable and will be replaced. 
Population-level summary: DLT rate defined as the number of DLT-evaluable participants 
with DLTs in the DLT-evaluation period divided by the number of DLT-evaluable 
participants in the DLT-evaluation period. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined. 
 
Participant Analysis Set 
Description 
Full Analysis Set (FAS) 
All enrolled participants who have been assigned to treatment. 
Participants are analyzed according to the treatment they were 
assigned. 
Safety Analysis Set 
(SAS) 
All enrolled participants who receive at least 1 dose of study 
intervention. Unless otherwise specified the safety analysis set will be 
the default analysis set used for all analyses. 
DLT Evaluable Set 
All enrolled participants who receive at least 75% of the planned dose 
intensity of study treatment and either experienced DLT or do not have 
major protocol deviations during the DLT observation period. 
PK Parameter Set 
All enrolled participants treated who do not have protocol deviations 
influencing PK assessment, and have sufficient information to estimate 
at least 1 of the PK parameters of interest. 

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Participant Analysis Set 
Description 
PK Concentration Set 
All enrolled participants who are treated and have at least 1 analyte 
concentration above the lower limit of quantitation. 
Response Evaluable Set 
All enrolled participants who received at least one dose of study 
treatment and had adequate baseline disease assessment. Participants 
who discontinued early or died will be included. 
PD/Biomarker Analysis 
Set(s) 
The PD/Biomarker analysis population is defined as all enrolled 
participants with at least 1 of the PD/Biomarkers evaluated at pre 
and/or post dose. 
9.3. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
9.3.1. General Considerations 
The data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, PK 
measurements, and biomarker measurements. 
9.3.2. Primary Endpoint(s)/Estimand(s)/Analysis 
The first cycle DLT is the primary endpoint of this study. The occurrence of DLTs observed 
in the dosing cohort in Japanese population is used to confirm the tolerability of the RP3D 
that was determined in Study ARV-471-mBC-101 conducted outside Japan. The target DLT 
rate is 33%. If a proportion of observed DLTs in this study is less than 33%, the tolerability 
of the RP3D in Japanese population is considered to be confirmed. AEs constituting DLTs 
will be listed. Confirmation of the tolerability of the RP3D will be performed using the DLT 
evaluable set. 
If there is either no or 1 DLT in 6 participants, the tolerability of the RP3D is confirmed. If 2 
of 6 participants experience DLT, an additional 3 participants can be enrolled or the next 
lower dose level can be explored to further investigate the safety and tolerability of ARV-471 
as monotherapy in Japanese participants. If no DLT is reported in an additional 3 
participants, the RP3D will be considered tolerable in Japanese participants. If DLT is 
observed in ≥33% of participants at 200 mg QD, the investigation at the next lower dose 
level may be explored. 
9.3.3. Secondary Endpoint(s)/Estimands Analysis 
 Adverse Events 
AEs will be graded by the investigator according to the NCI CTCAE version 5.0 and coded 
using MedDRA. AE data will be reported in tables and listings. Summaries of AE by 
appropriate MedDRA terms, toxicity grade, and seriousness and relationship to study 
treatment will be presented, as well as summaries of AEs leading to death and premature 
withdrawal from study treatment. The number and percentage of participants who 

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experienced any AE, SAE, TRAE, and treatment related SAE will be summarized according 
to worst toxicity grades. The summaries will present AEs on the entire study period. 
Listings of DLTs and deaths will be provided. 
 Laboratory Test Abnormalities 
The number and percentage of participants who experienced laboratory test abnormalities 
will be summarized according to worst toxicity grade observed for each laboratory assay. 
The analyses will summarize laboratory tests on the entire study period. For laboratory tests 
without CTCAE grade definitions, results will be categorized as normal, abnormal, or not 
done. 
 Pharmacokinetic Analysis 
The concentrations of ARV-471 and ARV-473 will be summarized by descriptive statistics 
(n, mean, standard deviation, CV, median, minimum, maximum, geometric mean and 
geometric CV) by cycle, day and nominal time. Individual participant, median and mean 
profiles of the concentration-time data will be plotted by cycle and day (single dose and 
steady state) using nominal times. Individual, median and mean profiles will be presented on 
both linear-linear and log-linear scales. 
All the concentration data will be listed but the concentrations deviated more than 10% from 
the planned time will not be included in summarization. 
Plasma PK parameters for ARV-471 and ARV-473 following multiple dose administration 
will be derived from the concentration-time profiles using noncompartmental methods as 
data permit. The PK parameters to be assessed in this study, their definition, and method of 
determination are outlined in Table 7. In all cases, actual PK sampling times will be used in 
the derivation of PK parameters. The single-dose PK parameters on Day 1 in Cycle 1 and 
steady-state PK parameters on Day 15 in Cycle 1 will be summarized descriptively (n, mean, 
standard deviation, CV, median, minimum, maximum, geometric mean and geometric CV) 
by cycle and day. 
Ctrough at steady state will be summarized descriptively (n, mean, standard deviation, CV, 
median, minimum, maximum, geometric mean and geometric CV) by cycle and day. Ctrough 
at steady state will be plotted by cycle and day, and also plotted using a box whisker plot by 
cycle and day. Ctrough at steady state is defined as the pre-dose concentration that meets the 
following dose-compliant acceptance criteria: 
 Participants must have received 6 consecutive days at the same dose of ARV-471 once 
daily prior to the pre-dose PK sampling; 
 PK samples must have been collected 24 hours ± 10% after the dose administered the 
day prior to the pre-dose PK sampling. 

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el 
 
Table 7. 
Definition of Plasma Pharmacokinetic Parameters for ARV-471 and 
ARV-473 
Parameter 
Day 1 (D1) or 
Day 15 (D15) 
Definition 
Method of Determination 
Cmax 
D1 & D15 
Maximum observed plasma 
concentration 
Observed directly from data 
Tmax 
D1 & D15 
Time to reach Cmax 
Observed directly from data as time 
of first occurrence 
AUClast 
D1 & D15 
Area under the plasma 
concentration-time curve from 
time zero to the time of the last 
quantifiable concentration 
(Clast) 
AUCtau 
D1 & D15 
Area under the plasma 
concentration-time curve from 
time zero to time tau (τ), the 
dosing interval, where tau = 24 
hours (QD dosing) 
Cmin 
D15 
Lowest concentration observed 
during the dosing interval 
Ctrough 
D15c 
Pre-dose plasma concentration 
during multiple dosing 
Linear/Log trapezoidal method 
 
 
 
 
Linear/Log trapezoidal method 
 
 
 
Observed directly from data 
Observed directly from data 
t½a 
D1 & D15 
Terminal elimination half-life 
Loge(2)/kel, where k d was the 
terminal phase rate constant 
calculated by a linear regression of 
the log-linear concentration-time 
curve. 
t½eff 
D15 
Effective half-life (t½eff) based 
t½eff=tau*ln2/ln[Rac/(Rac-1)] 
CL/Fb 
D15 
on Rac 
Apparent clearance 
Dose/AUCtau 
Vz/Fa,b 
D15 
Apparent volume of 
distribution 
c 
Dose/(AUCtau*kel ) 
MRCmax 
D1 & D15 
ARV-473 to ARV-471 ratio 
Cmax for ARV-473/Cmax for ARV-471 
for Cmax 
MRAUCtau 
D1 & D15 
ARV-473 to ARV-471 ratio 
for AUCtau 
AUCtau for ARV-473/ AUCtau for 
ARV-471 
Rac 
D15 
Accumulation ratio based on 
AUCtau,D15 /AUCtau,D1 
AUC (observed) 
a. If data permit. 
b. ARV-471 only. 
c. Ctrough will be evaluated on Days 15, 16 and 22 of Cycle 1 and Days 1 and 15 of Cycle 2 and 3, if data permit. 
d. The terminal phase rate constant, kel, is estimated as the absolute value of the slope of a linear regression during the 
terminal phase of the natural-logarithm (ln) transformed concentration-time profile. Terminal half-life and other 
parameters based on kel should only be reported when the terminal phase is well characterized. The detailed criteria 
considered will be included in the SAP. 
 
 Antitumor activities 
The response evaluable set will be used for all response-related analysis. Tumor response 
will be presented in the form of participant data listings that include, but are not limited to, 
tumor type, tumor response at each visit, and BOR. In addition, progression date, death date, 

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date of first response and last assessment date, and date of last contact will be listed. A 
summary of tumor response and BOR based on RECIST version 1.1 will also be presented. 
The detailed analyses will be described in the SAP. 
 
Best Overall Response 
BOR will be assessed based on RECIST version 1.1. 
ORR is defined as the percentage of participants with a BOR of CR and PR. The ORR and 
its exact 95% CI will be summarized using Wilson's score methodology. 
The CBR is defined as the percentage of pa1iicipants with BOR of CR, PR and SD of 24 
weeks duration or longer. The CBR and its exact 95% CI will be summarized using 
Wilson's score methodology. 
For analyses of ORR and CBR, paiiicipants with confmned and unconfnmed responses will 
be included as responders. A summaiy table ofBOR will also be provided. For these 
analyses, confnmed and unconfnmed responses will be summai·ized separately. 
Progression Free Survival 
PFS is the time from the first date of the study intervention to the date of the first 
documentation of progression, or death due to any cause. Progression is defined as the 
appeai·ance of local, regional or distant disease of the same type after CR or progression of 
pre-existing lesions. The Kaplan-Meier method will be used to analyze PFS. A data listing 
of PFS will be provided. 
Duration of Response 
DOR is defined for participants with confnmed objective response (as defined above in 
overall response) as the time from the first documentation of objective tumor response to the 
first documentation of objective tumor progression or to death due to any cause, whichever 
occurs first. The Kaplan-Meier method will be used to analyze DOR, if appropriate. A data 
listing of DOR will be provided. DOR for participants with unconfmned objective response 
will also be summai·ized sepai·ately. 
 

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9.3.5. Other Safety Analyses 
All safety analyses will be performed on the safety population. 
AEs, ECGs, BP, pulse rate, cardiac monitoring results, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants. Any clinical laboratory, ECG, BP, and pulse rate abnormalities of potential 
clinical concern will be described. Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. 
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported. 
 Electrocardiogram Analyses 
Changes from baseline for the ECG parameters QT interval, HR, QTcF, PR interval, and 
QRS complex will be summarized by treatment and time. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
≥450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
 
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point for summarization and categorical analysis. If any of the 
3 individual ECG tracings at each time point has a QTcF value >500 ms, but the mean of the 
triplicates is not >500 ms, the data from the participant’s individual tracing will be described 
in a safety section of the CSR in order to place the >500 ms value in appropriate clinical 
context. Changes from baseline will be defined as the change between the postdose QTcF 
value and the average of the timematched baseline triplicate values on Day 1, or the average 
of the predose triplicate values on Day 1. 
In addition, an attempt will be made to explore and characterize the relationship between 
exposure and QT interval length using a PK/PD modeling approach. If a PK/PD relationship 
is found, the impact of participant factors (covariates) on the relationship will be examined. 

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The analysis of ECG results will be based on participants in the SAS with baseline and 
on-treatment ECG data. Baseline ECG is defined as the most recent ECG prior to Cycle 1 
Day 1 dosing. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates. Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will QTcF using standard conection factors (ie, Fridericia's [default conection], 
Bazett's, and possibly a study-specific factor, as appropriate). Data will be summarized and 
listed for QT interval, HR, RR interval, PR interval, QRS complex, QTcF, and by dose. 
Individual QT intervals will be listed by time and dose. The most appropriate correction 
factor will be selected and used for the following analyses of centrnl tendency and outliers 
and used for the study conclusions. Descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be used to summarize the absolute value of the QTc 
interval and changes from baseline in QTc after treatment, by dose and time point. Details of 
additional analysis (if any) will be specified in SAP. 
 
9.4. Interim Analyses 
No fonnal interim analysis will be conducted for this study. As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK/PD modeling, and/or suppo1iing clinical 
development. 
9.5. Sample Size Determination 
Six paiiicipants will be enrolled to evaluate DLT and an additional 3 paiiicipants may be 
enrolled depending on the number of paiiicipants with DLTs (total up to 9 paiiicipants). 
Paiiicipants who fail to complete at least 75% of study dmg treatment in Cycle 1 for reasons 
other than DLT are considered not to be DLT-evaluable and will be replaced. If 2 DLTs 
occur in 6 paiiicipants, the investigator and the sponsor should discuss the safety and 
tolerability based on the available data, and then under the agreement between the 
investigator and the sponsor, it may be allowed to enroll an additional 3 pa1iicipants at the 
same dose level. Or, if DLT is observed in 2 of 6 paiiicipants at 200 mg QD, the 
investigation at the next lower dose level may be explored. Thus, the actual sample size may 
depend on the underlying dose toxicity profile. The RP3D is considered intolerable in 
Japanese paiiicipants if 33% DLTs are observed in this study. Although the sample size is 
not based on any statistical considerations, the sample size of 6 pa1iicipants would have 
57.98% chance to declai·e that the RP3D determined in Study ARV-471-mBC-101 has 

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exceeded the MTD for Japanese participants if the true DLT rate for Japanese participants is 
30% and over (Table 8). Similarly, the sample size of 6 would have 76.67% and 89.06% 
chance to detect probability of over MTD if the true DLT rate is 40% and 50%, respectively. 
Table 8. 
Detection Probability of Over MTD 
 
Number of 
DLTs 
Observed 
True DLT Rate 
Total 
Sample 
Size 
Total 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
0.4 
0.45 
0.5 
6 
0-1 
96.72 
88.57 
77.65 
65.54 
53.39 
42.02 
31.91 
23.33 
16.36 
10.94 
2 
3.05 
9.84 
17.62 
24.58 
29.66 
32.41 
32.80 
31.10 
27.80 
23.44 
≥3 
0.22 
1.59 
4.73 
9.89 
16.94 
25.57 
35.29 
45.57 
55.85 
65.63 
9a 
2b 
2.62 
7.17 
10.82 
12.58 
12.51 
11.12 
9.01 
6.72 
4.62 
2.93 
≥3b 
0.44 
2.67 
6.80 
11.99 
17.15 
21.30 
23.79 
24.39 
23.17 
20.51 
Detection 
Probability of 
Over MTD with 
Sample Size of 6 
3.28 
11.43 
22.35 
34.46 
46.61 
57.98 
68.09 
76.67 
83.64 
89.06 
Detection 
Probability of 
Over MTD with 
Sample Size of 
Up to 9a 
0.66 
4.25 
11.53 
21.88 
34.09 
46.86 
59.08 
69.95 
79.02 
86.13 
a: An additional 3 participants will be allowed based on agreement between the investigator and sponsor only 
if 2 DLTs occur in the initial 6 participants. If 3 or more DLTs occur in the initial 6 participants, it is 
considered as over MTD and not allowed an additional participants. 
b: The sum of 2 DLTs that occurred in the initial 6 participants and the DLT that occurred in an additional 3 
participants. 
 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 

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The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• 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. 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations. 
 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP that the investigator becomes 
aware of. 
10.1.2. Financial Disclosure 
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 

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10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his/her legally authorized representative and answer 
all questions regarding the study. The participant or his/her legally authorized representative 
should be given sufficient time and opportunity to ask questions and to decide whether or not 
to participate in the trial. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH GCP guidelines, privacy and 
data protection requirements, where applicable, and the IRB/EC or study center. 
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant or his or her legally authorized representative must be informed that his/her 
personal study-related data will be used by the sponsor in accordance with local data 
protection law. The level of disclosure must also be explained to the participant or his or her 
legally authorized representative. 
The participant or his or her legally authorized representative must be informed that his/her 
medical records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities. 
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD. 
Participants or his or her legally authorized representative must be reconsented to the most 
current version of the ICD(s) during their participation in the study. 
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative. 
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 28 days from the previous ICD signature date. 

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10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
10.1.5. Committees Structure 
 Data Monitoring Committee 
This study will not use a DMC. 
10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in participants) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 

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EudraCT 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov. 
Documents within marketing authorization packages/submissions 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015. 
Data sharing 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data available from these trials 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information redacted. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
10.1.7. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 

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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties. 
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
Monitoring details describing strategy, including the definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality, such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 

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10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the Clinical 
Monitoring Plan, which is maintained by the sponsor. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, the ICH GCP guidelines, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines; 

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• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
If the sponsor decides to terminate the study for a reason unrelated to the safety of study 
intervention(s), participants may continue to receive study intervention(s) per the 
investigator’s judgement and protocol-specified safety assessments will continue to be 
performed for these participants until the end of study as defined in Section 4.4. The 
following non-safety-related study procedures and assessments may be stopped upon written 
notification from the sponsor: 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 

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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
10.1.11. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Pfizer internal system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an ECC at the time of informed 
consent. The ECC contains, at a minimum, (a) protocol and study intervention identifiers, 
(b) participant’s study ID number, (c) site emergency phone number active 24 hours/day, 7 
days per week, and (d) Pfizer Call Center number. 
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number 
is not intended for use by the participant directly; if a participant calls that number directly, 
he or she will be directed back to the investigator site. 

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10.2. Appendix 2: Clinical Laboratory Assessments 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues. 
 
Table 9. 
Core Lab Tests 
 
Hematology 
Coagulation 
Pregnancy Test 
Notes 
Hemoglobin 
PT or INR 
For female participants of 
childbearing potential, on 
serum or urine (to be 
specified in the protocol 
Database should be 
constructed to allow 
capture of differential 
counts as percent and 
absolute values but only 
one or the other should be 
used by the site to collect 
data. Results will be 
reported as absolute 
values after conversion 
and graded according to 
the CTCAE criteria 
Platelets 
PTT or aPTT 
WBC 
Absolute Neutrophils 
Serology 
Absolute Lymphocytes 
HBV* 
Absolute Monocytes 
HCVAb* 
Urinalysis 
Absolute Eosinophils 
HIV/HIVAb* 
Urine dipstick: pH, 
Glucose, Protein, Blood, 
Ketones, Nitrites, 
Leukocyte esterase, 
Urobilinogen, Urine 
bilirubin 
For urine protein, if 
dipstick shows urine 
protein ++ or above, 
perform 24-hour urine 
protein test. 
Only if urine dipstick is 
positive for blood, 
protein, nitrates or 
leukocyte esterase, 
perform microscopy 
(Reflex Testing). 
Absolute Basophils 
Endocrinology 
Chemistry 
TSH 
ALT 
AST 
Alk Phos 
Sodium 
Potassium 
Magnesium 
Chloride 
Total Calcium 
Total Bilirubin** 
BUN or Urea 
Creatinine 
Uric Acid 
Glucose (non-fasted) 
Albumin 
Phosphorus or Phosphate 
CK 
Amylase 

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Table 9. 
Core Lab Tests 
 
Lipase 
* HBsAg, HBsAb, HBcAb, HBV DNA, HCVAb, and HIV/HIVAb to be conducted by local laboratory where 
required by local regulations or if warranted by participant history 
**For Hy’s law potential cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, PT/INR, 
and ALP. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting 
10.3.1. Definition of AE 
 
 
 
Events Meeting the AE Definition 
• 
 Any abno1mal laborato1y test results (hematology, clinical chernistiy, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abno1mal laboratory test results that meet any of the conditions below must be 
recorded as an AE: 
• 
Is associated with accompanying symptoms; 
• 
Requires additional diagnostic testing or medical/surgical intervention; 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drng tl'eatment, or other therapy. 
• 
 Exacerbation of a chronic or intennittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the staii of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected DDI. 
• 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be repo1ied as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-haiming intent. Such overdoses should be repo1ied regardless of 
sequelae. 
• 
An AE is any untoward medical occmTence in a paiiicipant or clinical study 
paiticipant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• 
 Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnonnal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
AE Definition 

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Events NOT Meeting the AE Definition 
• 
 Any clinically significant abnonnal laborato1y findings or other abnonnal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the paiiicipant's condition. 
• 
 The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
paiiicipant's condition. 
• 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
 Situations in which an untoward medical occunence did not occur (social and/or 
convenience admission to a hospital). 
• 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the staii of the study that do not worsen. 
• 
 Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF. Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be repo1ied as AEs. 
10.3.2. Definition of an SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed below: 
a.  Results in death 
b. Is life-threatening 
The te1m "life-threatening" in the definition of "serious" refers to an event in which 
the paiiicipant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe. 
C. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the pa1iicipant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician's office or 
outpatient setting. Complications that occur during hospitalization ai·e AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether "hospitalization" occmTed or was necessaiy, the 
AE should be considered serious. 

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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect. 
f. Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious. 
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
• Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Severity section). 

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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting 
 
The table below summarizes the requirements for recording AEs on the CRF and for 
repo1iing SAEs on the CT SAE Repo1i Fo1m to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Repo1i Fo1m for repo1iing of SAE infonnation is not 
the same as the AE page of the CRF. When the same data are collected, the fonns must 
be completed in a consistent manner. AEs should be recorded using concise medical 
tenninology and the same AE te1m should be used on both the CRF and the CT SAE 
Repo1i Fo1m for repo1iing of SAE infonnation. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs/SAEs associated 
with EDP or breastfeeding 
Note: Instances of EDP or 
All instances of EDP are 
repo1ied (whether or not 
there is an associated 
SAE)* 
EDB not associated with an AllinStances ofEDBare 
AE or SAEarenot captured  repo1ied (whether or not 
in the CRF. 
there is an associated 
S 
)\. ** 
AE1 
Environmental or 
None. Exposure to a study The exposure (whether or 
non-pa1iicipant is not 
 not there is an associated 
collected on the CRF. 
AE or SAE) must be 
repo1ied.*** 
occupational exposure 
to the product under 
study to a 
non-pa1iicipant (not 
involving EDP or EDB). 
* 
EDP (with or without an associated AE or SAE): any pregnancy infonnation is reported to 
Pfizer Safety using CT SAE Repo1t Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Repo1t Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Fo1m which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational 

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exposure are reported to Pfizer Safetv usin the CT SAE Report F01m. 

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•  When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laborato1y repo1is, and diagnostic 
repo1is) related to the event. 
• The investigator will then record all relevant AE or SAE info1mation in the CRF. 
• It is not acceptable for the investigator to send photocopies of the paiiicipant's 
medical records to Pfizer Safety in lieu of completion of the CT SAE Repo1i 
Fonn/AE or SAE CRF page. 
• There may be instances when copies of medical records for ce1iain cases are 
requested by Pfizer Safety. In this case, all pa1iicipant identifiers, with the 
exception of the paiticipant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
•  The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical info1mation. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Severity 
The investigator will make an assessment of severity for each AE repo1ied during the 
study and assign it to 1 of the categories listed below (as defined by the NCI CTCAE 
system). An event is defined as "serious" when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
GRADE Clinical Description of Severity 
- 
1 
MILDAE 
2 
MODERATEAE 
3 
>-- 
4 
SEVEREAE 
LIFE-THREATENING; urgent intervention indicated 
5 
DEATH RELATED TO AE 
 
 
• 
The investigator is obligated to assess the relationship between study 
intervention and each occmTence of each AE or SAE. The investigator will use 
clinical judgment to dete1mine the relationship. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, 
evidence, and/or ai·guments to suggest a causal relationship, rather than a 
relationship cannot be rnled out. 
Assessment of Causality 

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• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
 
• 
The investigator will also consult the IB and/or product infonnation, for 
marketed products, in his/her assessment. 
• 
For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality. 
 
• 
There may be situations in which an SAE has occmTed and the investigator has 
minimal infonnation to include in the initial repo1t to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor. 
 
• 
The investigator may change his/her opinion of causality in light of follow-up 
infonnation and send an SAE follow-up repo1t with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when detennining regulato1y 
repo1ting requirements. 
• 
 If the investigator does not know whether or not the study intervention caused 
the event, then the event will be handled as "related to study intervention" for 
repo1ting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and repo1t 
such an assessment in the dedicated section of the CT SAE Repo1t Fo1m and in 
accordance with the SAE repo1ting requirements. 
 
 
 
 
 
• 
 The investigator is obligated to perfonn or anange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laborato1y tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers. 
• 
New or updated info1mation will be recorded in the originally submitted 
documents. 
Follow-Up of AEs and SAEs 

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10.3.4. Reporting of SAEs 
 
 
• 
The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the infonnation. 
• 
The primaiy mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool. 
• 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electrnnic system as soon as the data 
become available. 
• 
After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entiy of new data or changes to existing data. 
• 
If a site receives a repo1t of a new SAE from a study paiticipant or receives 
updated data on a previously repo1ted SAE after the electi·onic data collection 
tool has been taken off-line, then the site can repo1t this infonnation on a paper 
SAE fonn (see next section) or to Pfizer Safety by telephone. 
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool 
• 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Repo1t Fo1m pages within the designated 
repo1ting time frames. 
. 
-i service. 
com .er 
acceptable with a copy of the CT SAE Report Fonn sent by overnight mail or 
• 
Facsiinile ti·ansinission of the CT SAE Repo1t Fo1m is the prefened method to 
ti·ansinit this info1mation to Pfizer Safety. 
• 
In circumstances when the facsiinile is not working, notification by telephone is 
SAE Reporting to Pfizer Safety via CT SAE Report Form 

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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 30 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
• Is not a WOCBP (see definitions below in Section 10.4.3). 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 30 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention. 

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• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, as described below during the 
intervention period and for at least 30 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). In addition, a second effective method of contraception, as 
described below, must be used. The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing and Non-Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
2. Postmenopausal female: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition, 
• A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
 
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contraception or HRT. When there is a high FSH level, it should be confirmed 
that there is no other medical cause. 
• A female on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
Highly Effective Methods That Have Low User Dependency 
1. Intrauterine device. 
2. Bilateral tubal occlusion. 
3. Vasectomized partner. 
• A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
1. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent: 
• Male or female* condom with or without spermicide*; 
• Cervical cap*, diaphragm*, or sponge with spermicide*; 
• A combination of male condom with either cervical cap*, diaphragm*, or sponge 
with spermicide* (double-barrier methods). 
* not approved in Japan. 

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I 
 
I 
 
I 
 
I 
 
I  
 
I 
 
I 
 
I 
 
 
 
 

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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.” 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 × 
ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an ALP value <2 × ULN or not 
available. 
For participants with baseline AST OR ALT OR TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on which 
values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 

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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and ALP. Consideration should also be given to drawing a 
separate tube of clotted blood and an anticoagulated tube of blood for further testing, as 
needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 

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10.7. Appendix 7: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AE 
• 
Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• 
New PR interval prolongation >280 ms. 
• 
New prolongation of QTcF to >480 ms (absolute) or by ::::60 ms from baseline. 
• 
New-onset ati·ial flutter or fibrillation, with conu-olled venti·icular RR: ie, rate 
<120 bpm. 
• 
New-onset type I second-degree (Wenckebach) AV block of>30 seconds' duration. 
• 
 Frequent PVCs, ti·iplets, or sho1t intervals (<30 seconds) of consecutive venti·icular 
complexes. 
ECG Findings That May Qualify as Serious AE 
• 
QTcF prolongation >500 ms. 
• 
New ST-T changes suggestive of myocardial ischemia. 
• 
New-onset LBBB (QRS >120 ms). 
• 
New-onset right bundle branch block (QRS >120 ms). 
• 
Symptomatic bradycardia. 
• 
Asystole: 
• 
In awake, symptom-free paiticipants in sinus rhythm, with documented periods of 
asystole ::::3.0 seconds or any escape rate <40 bpm, or with an escape rhythm that 
is below the AV node. 
• 
In awake, symptom-free paiticipants with au-ial fibrillation and bradycai·dia with 
1 or more pauses of at least 5 seconds or longer. 
• 
Au-ial flutter or fibrillation, with rapid venti·icular RR: rapid= rate >120 bpm. 
• 
Sustained supraventi·icular tachycardia (rate>120 bpm) ("sustained"= sho1t duration 
with relevant symptoms or lasting>1 minute). 
• 
Venti·icular rhythms >30 seconds' duration, including idioventi·icular rhythm (HR 
<40 bpm), accelerated idioventi·icular rhythm (HR >40 bpm to <l 00 bpm), and 

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monomorphic/polymo1phic ventricular tachycardia (HR >100 bpm (such as torsades 
de pointes)). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heaii block. 
ECG Findings That Qualify as SAEs 
• 
Change in pattern suggestive of new myocardial infai·ction. 
• 
Sustained ventriculai·tachyaiThythmias (>30 seconds' duration). 
• 
Second- or third-degree AV block requiring pacemaker placement. 
• 
Asystolic pauses requiring pacemaker placement. 
• 
Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• 
Ventricular fibrillation/flutter. 
• 
 At the discretion of the investigator, any atThythmia classified as an adverse 
expenence. 
The enumerated list of major events of potential clinical concem are recollllllended as "ale1ts" or 
notifications from the core ECG laborato1y to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 

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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI 
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgement on the ongoing 
participation of any participant with prohibited medication use during the study. 
These lists of drugs prohibited for potential DDI concerns with the IMP may be revised 
during the course of the study with written notification from sponsor, to include or exclude 
specific drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs). 
10.8.1. CYP3A inhibitors/inducers 
The concurrent use of the following treatments is prohibited throughout the duration of the 
active treatment phase. 
• CYP3A accounted for 85% of the CYP metabolism of ARV-471 based on in vitro 
data. Co-administration with drugs that are strong CYP3A inhibitors and inducers 
may change the plasma concentrations of ARV-471 in humans. 
• The concurrent use of strong CYP3A inhibitors/inducers is prohibited throughout the 
duration of the active treatment phase. Additionally, the concurrent use of herbal 
supplements and Chinese herbal medicines are not permitted, if the ingredients are 
unknown or included ingredients may have potential DDI such as strong CYP3A 
inducers or inhibitors. 
Prior use of medications, food, herbal supplements, Chinese herbal medicines that are strong 
inhibitors of CYP3A must be stopped 7 days before enrollment. Strong inducers of CYP3A 
must be stopped 14 days before enrollment. 
 
Examples of prohibited concomitant medications are provided below. 
This is not an all-inclusive list (examples including, but not limited to the drugs provided 
below). 
Site staff should consult with the sponsor or designee with any questions regarding potential 
DDI. 
Investigators should consult the product prescribing information for any other medication 
used throughout the duration of the active treatment phase for information regarding 
medication that is prohibited for concurrent use. 

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Table 10.  List of CYP3A Inhibitors/Inducers 
 
Drug Category Drugs 
Strong CYP3A 
inhibitors* 
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir, 
elvitegravir, josamycin, indinavir, itraconazole, ketoconazole, lopinavir, 
lonafamib, mibefradil, mifepristone, nefazodone, nelfinavir, paritaprevir 
and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, 
saquinavir, telaprevir, troleandomycin, tipranavir, telithromycin, 
voriconazole, grapefmit, grapefmit juice or any product containing 
izrapefmit 
Strong CYP3A 
inducers* 
apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, 
mitotane, phenvtoin, rifampin, rifapentine and St.  John's WOii 
* Dmg-Dmg Interaction Database (DIDB, 2022) provided by University of Washington and Food and Dmg 
Administration listings (FDA, 2020) as sources: 
 
• 
DIDB10: https://www.drnginteractionsolutions.org/ 
 
• 
 FDA11: https://www.fda.gov/drngs/drng-interactions-labeling/dmg-development-and-drng- 
interactions-table-substrates-inhibitors-and-inducers 
 
10.8.2. Drugs Known to Predispose to Torsade de Pointes or QT interval prolongation 
The relationship between ARV-471 concentration and QT/QTc interval is unknown. 
Regarding the detailed info1mation, refer to Section 2.3. Concunent use of ARV-471 with 
diugs of known risk of causing Torsade de Pointes or QT interval prolongation is prohibited 
throughout the duration of the active treatment phase. 
This is not an all-inclusive list (examples including, but not limited to the diugs provided 
below). 
Table 11.  List of Drugs Known to Predispose to Torsade de Pointes 
 
Drug Category 
Drugs 
Drugs known 
aclambicin, amiodarone, anagrelide, arsenic trioxide, astemizole*, 
to predispose to 
Torsade de 
azithromycin, bepridil, cesium chloride*, chloroquine, chlorpromazine, 
chlorprothixene*, cilostazol, ciprofloxacin, cisapride*, citalopram, 
Pointes* 
clarithromycin, disopyramide, dofetilide*, domperidone, donepezil, 
dronedarone*, droperidol, erythromycin, escitalopram, flecainide, 
fluconazole, gatifloxacin*, grepafloxacin*, halofantrine*, haloperidol, 
hydi·oquinidine*, hydi·oxychloroquine, ibogaine*, ibutilide*, 
levofloxacin, levomepromazine (methotrimeprazine), levomethadyl*, 
levosulpiride*, meglumine antimoniate*, mesoridazine*, methadone, 
moboce1iinib*, moxifloxacin, nifekalant, ondansetron, oxaliplatin, 
papaverine HCl (intra-corona1y), pentamidine, pimozide, probucol, 
procainamide, quinidine, roxithromycin, se1iindole*, sevoflurane, 
sotalol, sparfloxacin*, sulpiride, sultopride, terfenadine*, terlipressin*, 
terodiline* thioridazine*. vandetanib 
*Dmgs are not launched or was removed from Japan market (gatifloxacin: ophthalmic chug is only launched) 

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Adapted from crediblemeds.org (organization that curates the University of Arizona Cancer Center for 
Education and Research on Therapeutics database: “Risk Categories for Drugs that Prolong QT & induce 
TdP-Known Risk of TdP”. 
See website for current list: https://crediblemeds.org/index.php/druglist 
 
10.8.3. Substrates of Transporters 
ARV-471 is an in vitro inhibitor of P-gp and BCRP. Treatment with ARV-471 has potential 
for increasing exposure of concomitant medications that are substrates for P-gp and BCRP 
transporters. P-gp substrates should be used with caution. BCRP substrates, rosuvastatin and 
sulfasalazine, may be used because safety risk is low. 
This is not an all-inclusive list (examples including, but not limited to the drugs provided 
below). 
Table 12. List of P-gp Sensitive Substrates 
 
Drug Category 
Drugs 
P-gp sensitive 
substrates* 
dabigatran etexilate, digoxin/digitoxin, fexofenadine 
* Drug-Drug Interaction Database (DIDB, 2022) provided by University of Washington and Food and Drug 
Administration listings (FDA, 2020) as sources: 
 
• 
DIDB10: https://www.druginteractionsolutions.org/ 
 
• 
FDA11: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- 
interactions-table-substrates-inhibitors-and-inducers 
 
10.8.4. PPI 
Co-administration of PPIs may reduce ARV-471 absorption. The concomitant use of PPIs 
with ARV-471 is not recommended. 
This is not an all-inclusive list (examples including, but not limited to the drugs provided 
below). 
Table 13. List of Proton Pump Inhibitors 
 
Drug Category 
Drugs 
Proton pump inhibitors 
(PPIs)* 
esomeprazole, lansoprazole, omeprazole, rabeprazole, pantoprazole**, 
dexlansoprazole** 
* Refer to corresponding concomitant drugs USPIs or local product prescribing information. 
** Drugs are not launched in Japan. 

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10.9. Appendix 9: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic in Japan and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.9.1. Eligibility 
While SARS-CoV-2 testing is not mandated for this study, local clinical practice standards 
for testing should be followed. A participant should be excluded if he/she has a positive test 
result for SARS-CoV-2 infection, is known to have asymptomatic infection, or is suspected 
of having SARS-CoV-2. Participants with active infections are excluded from study 
participation as per Exclusion Criterion 13a. When the infection resolves, the participant 
may be considered for re-screening. 
10.9.2. Telehealth Visits 
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the SoA or unscheduled 
visits. Telehealth visits may be used to continue to assess participant safety and collect data 
points. Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit: 
• Review and record study intervention(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.3. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Section 10.4 and Section 10.9.3.1 of this appendix regarding 
pregnancy tests. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 

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10.9.3. Alternative Facilities for Safety Assessments 
 Laboratory Testing 
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations. 
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory: 
• Hematology; 
• Chemistry; 
• Coagulation; 
• Urinalysis; 
• Pregnancy test; 
• Endocrinology; 
• Serology. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records. Confirm that the participant is adhering to the contraception 
method(s) required in the protocol. 
 Imaging 
If the participant is unable to visit the study site for safety imaging assessment(s), the 
participant may visit an alternative facility to have the safety imaging assessment(s) 
performed. Qualified study site personnel must order, receive, and review results. 
 Electrocardiograms and Echocardiogram 
If the participant is unable to visit the study site for ECGs and echocardiogram, the 
participant may visit an alternative facility to have the ECGs and echocardiogram performed. 
Qualified study site personnel must order, receive, and review results. 

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10.9.4. Study Intervention 
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered. 
ARV-471 may be shipped by courier to study participants if permitted by local regulations 
and in accordance with storage and transportation requirements for the ARV-471. Pfizer 
does not permit the shipment of ARV-471 by mail. The tracking record of shipments and the 
chain of custody of ARV-471 must be kept in the participant’s source documents/medical 
records. 
The following is recommended for the administration of ARV-471 for participants who have 
active confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion) SARS-CoV-2 infection: 
• For symptomatic participants with active SARS-CoV-2 infection, ARV-471 should 
be delayed for at least 14 days from the start of symptoms. This delay is intended to 
allow the resolution of symptoms of SARS-CoV-2 infection. 
• Prior to restarting treatment, the participant should be afebrile for 72 hours, and 
SARS-CoV-2-related symptoms should have recovered to Grade ≤1 for a minimum 
of 72 hours. Notify the study team when treatment is restarted. 
• Continue to consider potential drug-drug interactions as described in Section 6.8 for 
any concomitant medication administered for treatment of SARS-CoV-2 infection 
10.9.5. Home Health Visits 
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the participant’s location, rather than an in-person study visit at the site. The 
following may be performed during a home health visit: 
• PE; 
• Vital Signs (including height and weight); 
• ECOG; 
• Safety laboratory blood draws (including hematology, chemistry, coagulation, 
endocrinology, serology); 
• Urinalysis; 
• Blood draw for PK and PD; 
• ECGs, if available; 

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• Also all assessments included in Section 10.9.2 Telehealth Visits. 
10.9.6. Adverse Events and Serious Adverse Events 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided. Temporary discontinuation of the study 
intervention may be medically appropriate until the participant has recovered from 
COVID-19. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study sponsor. 
10.9.7. Efficacy Assessments 
Please contact the sponsor should a participant need to use alternative measures for efficacy 
assessments. A plan will be devised in discussion with the sponsor and investigator. 
10.9.8. Independent Oversight Committees 
This is an open-label, non-randomized Phase 1 study. This study will not use a DMC. 

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10.10. Appendix 10: Bone Marrow Reserve in Adults 
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol. 5, 255-258, 196112 
Marrow Distribution of the Adult 
 
SITE 
MARROW 
wt. (g) 
FRACTION 
RED 
MARROW 
AGE 40 
RED 
MARROW 
wt. (g) 
AGE 40 
% TOTAL 
RED MARROW 
CRANIUM 
Head: 
Cranium 
Mandible 
136.6 
AND 
165.8 
0.75 
124.3 
13.1 
13.1 
MANDIBLE 
16.4 
0.75 
12.3 
Upper Limb Girdle: 
2 Humerus, 
head & neck 
2 Scapulae 
2 Clavicles 
86.7 
HUMERI, 
26.5 
0.75 
20.0 
8.3 
8.3 
SCAPULAE, 
CLAVICLES 
67.4 
0.75 
50.5 
21.6 
0.75 
16.2 
Sternum 
Ribs: 
1 pair 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
39.0 
0.6 
23.4 
2.3 
82.6 
10.2 
All 0.4 
4.1 
12.6 
5.0 
16.0 
6.4 
STERNUM 
18.6 
7.4 
AND 
23.8 
9.5 
7.9 
10.2 
RIBS 
23.6 
9.4 
25.0 
10.0 
24.0 
9.6 
21.2 
8.5 
16.0 
6.4 
11.2 
4.5 
4.6 
1.8 
Sacrum 
194.0 
0.75 
145.6 
13.9 
PELVIC 
BONES 
2 os coxae 
310.6 
0.75 
233.0 
22.3 
36.2 
FEMUR 
2 Femoral head 
and neck 
53.0 
0.75 
40.0 
3.8 

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Marrow Distribution of the Adult (cont’d) 
 
SITE 
MARROW 
wt. (g) 
FRACTION 
RED MARROW 
AGE 40 
RED 
MARROW 
wt. (g) 
AGE 40 
% TOTAL 
RED MARROW 
Vertebrae 
35.8 
(Cervical): 
1 
6.6 
All 0.75 
5.0 
2 
8.4 
6.3 
3 
5.4 
4.1 
3.4 
4 
5.7 
4.3 
5 
5.8 
4.4 
6 
7.0 
5.3 
7 
8.5 
6.4 
Vertebrae 
147.9 
(Thoracic): 
1 pair 
10.8 
All 0.75 
8.1 
2 
11.7 
8.8 
3 
11.4 
8.5 
4 
12.2 
9.1 
VERTEBRAE 
5 
13.4 
10.1 
14.1 
28.4 
6 
15.3 
11.5 
7 
16.1 
12.1 
8 
18.5 
13.9 
9 
19.7 
14.8 
10 
21.2 
15.9 
11 
21.7 
16.3 
12 
25.0 
18.8 
Vertebrae 
114.1 
(Lumbar): 
1 pair 
27.8 
All 0.75 
20.8 
2 
29.1 
21.8 
10.9 
3 
31.8 
23.8 
4 
32.1 
24.1 
5 
31.4 
23.6 
TOTAL 
1497.7 
1045.7 
100.0 
100.0 

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10.11. Appendix 11: RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–24713. 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
• 
Lesions that can be accurately measured in at least one dimension. 
• 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm). 
• 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
• 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
• 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
• 
Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 
• 
Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment. 
Normal sites 
• 
Cystic lesions: Simple cysts should not be considered as malignant lesions and 
should not be recorded either as target or non-target disease. Cystic lesions thought 
to represent cystic metastases can be measurable lesions, if they meet the specific 
definition above. If non-cystic lesions are also present, these are preferred as target 
lesions. 

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• 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments 
All sites of disease must be assessed at baseline. Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randomization and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
non-evaluable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements. Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded. The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
• 
If two target lesions coalesce the measurement of the coalesced mass is used. If a 
large target lesion splits, the sum of the parts is used. 
• 
Measurements for target lesions that become small should continue to be recorded. 
If a target lesion becomes too small to measure, 0 mm should be recorded if the 
lesion is considered to have disappeared; otherwise a default value of 5 mm should 
be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease. Measurements are not required but rather 
assessments will be expressed as CR, Non-CR/Non-PD, PD, NE. Multiple non-target lesions 
in one organ may be recorded as a single item on the CRF (eg, ‘multiple enlarged pelvic 
lymph nodes’or ‘multiple liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible. If not, 
subsequent objective statuses might be non-evaluable. 

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Target Disease 
1. CR: Complete disappearance of all target lesions with the exception of nodal disease. 
All target nodes must decrease to normal size (short axis <10 mm). All target lesions 
must be assessed. 
2. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of 
all target measurable lesions. The short diameter is used in the sum for target nodes, 
while the longest diameter is used in the sum for all other target lesions. All target 
lesions must be assessed. 
3. SD: Does not qualify for CR, PR or Progression. All target lesions must be assessed. 
Stable can follow PR only in the rare case that the sum increases by less than 20% 
from the nadir, but enough that a previously documented 30% decrease no longer 
holds. 
4. PD: 20% increase in the sum of diameters of target measurable lesions above the 
smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy), with a minimum absolute increase of 5 mm. 
5. NE: Progression has not been documented, and 
• One or more target measurable lesions have not been assessed; or 
• One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure); or 
• One or more target lesions were excised or irradiated. 
Non-target disease 
6. CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
7. Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
8. PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy. In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 
9. NE: Progression has not been determined and one or more non-target sites were not 
assessed or assessment methods were inconsistent with those used at baseline. 

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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. 
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
• 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate. If no disease is identified, objective status is CR. 
• 
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression 
Participants requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status. Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Objective Response Status at Each Evaluation 
 

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If the protocol allows enrollment of participants with only non-target disease, the following 
table will be used: 
Objective Response Status at each Evaluation for Participants with Non-Target Disease 
 
Best Overall Response 
The BOR is the best response recorded from the randomization until disease progression or 
death due to any cause. This is derived from the sequence of objective statuses. Objective 
statuses are not considered after objective progression is documented or after start of the first 
anticancer treatment post discontinuation of protocol treatment. BOR for each participant 
will be derived as one of the following categories. 
• 
CR: At least one objective status of CR documented before progression. 
• 
PR: At least one objective status of PR documented before progression. 
• 
SD: At least one objective status of stable documented at least 8 weeks after 
randomization date and before progression but not qualifying as CR, PR. 
• 
PD: Objective status of progression within 16 weeks of randomization, not 
qualifying as CR, PR or SD. 
• 
NE: Progression not documented within 16 weeks after randomization and no other 
response category applies. 

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10.12. Appendix 12: ECOG Performance Status*14 
 

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10.13. Appendix 13: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. The Protocol Amendment Summary of Changes Table 
for past amendments can be found below: 
 
Document 
Version Date 
Summary and Rationale for Changes 
Amendment 1 
25 Mar 2022 
1.3. Schedules of Activities 
Table 1 and Table 2 
8.4. Pharmacokinetics 
9.3.3.3. Pharmacokinetic Analysis 
Table 8 
• 
Corrected the visit at Day 21 to Day 22 in 
Cycle 1. 
Rationale: Correction 
4.2.1. Choice of Contraception/Barrier 
Requirements 
• 
Added that ARV-471 is not genotoxic. 
Rationale: Genotoxicity study results are 
required for considering contraception 
duration based on the guideline (Guidance for 
Industry, Oncology Pharmaceuticals: 
Reproductive Toxicity Testing and Labeling 
Recommendations). 
4.3.1. Dose Limiting Toxicity Definition 
• 
Added that all safety information including 
AEs that have occurred in the participants 
who were excluded from the DLT evaluation 
will be considered in the assessment of 
tolerability. 
Rationale: To incorporate changes requested 
by the PMDA following the review of the 
original final protocol dated 09 February 
2022. 
Table 5. DLT Criteria 

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Document 
Version Date 
Summar  and Rationale for Chan es 
• 
 Clarified the DLT definition of Grade 3 
toxicities in Non-Hematologic DLTs. 
• 
 Clarified that any AE attributed to ARV-471 
detected within DLT evaluation period 
requiring dose inte1n1ption for14 days 
extending beyond the end of the DLT 
evaluation period and to post-DLT evaluation 
period will also be considered a DLT. 
Rationale: To incorporate changes requested 
by the PMDA following the review of the 
original final protocol dated 09 Febrnaiy 
2022. 
5.2. Exclusion Criteria #12 
• 
Added the breastfeeding paiiicipant (including 
females who ai·e cunently breastfeeding or 
intend to temporai·ily intenupt breastfeeding). 
Rationale: To incorporate changes requested 
by the PMDA following the review of the 
original final protocol dated 09 Febrnaiy 
2022. 
8.3.5.1. Exposme Dming Pregnancy 
• 
 Updated the data collection period for details 
of the pregnancy from 90 days to 30 days after 
the last dose. 
Rationale: To align with the contraception 
period. 
 
I 

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Document 
Version Date 
10.4.1. Male Paiiicipant Reproductive Inclusion 
Criteria 
10.4.2. Female Paiiicipant Reproductive Inclusion 
Criteria 
• 
Updated the contrnception requirements 
period from at least 90 days to 30 days after 
the last dose of study intervention in both 
male and female paiiicipants. 
Rationale: Alignment of the criteria with the 
ARV-471 program level protocol 
10.4.4. Contrnception Methods 
• 
Removed the ho1monal contraception 
methods. 
Rationale: Honnonal contraception methods 
ai·e not applicable for patients with breast 
cancer. 
In addition, other clai·ifications, administrative, 
and typographical modifications were made. 
09 Feb 2022 
NA 

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10.14. Appendix 14: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
AE 
adverse event 
AI 
Aromatase inhibitor 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma-concentration curve 
AUClast 
area under the plasma concentration-time curve from time zero to 
the time of the last quantifiable concentration 
AUCtau 
area under the plasma concentration-time curve from time zero to 
time tau 
AV 
atrioventricular 
BCRP 
Breast Cancer Resistance Protein 
BID 
twice daily 
BOR 
best overall response 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAP 
College of American Pathologists 
CBR 
clinical benefit response 
CDC 
Centers for Disease Control and Prevention 
CDK4/6 
Cyclin-Dependent Kinase 4/6 
CDKi 
CDK4/6 inhibitors 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
lowest concentration observed during the dosing interval 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 

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Abbreviation 
Term 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CCI 
Ctrough 
pre-dose plasma concentration during multiple dosing 
CV 
coefficient of variation 
CXDX 
Cycle X Day X 
CYP 
cytochrome P-450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRE 
disease related events 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
EDP 
exposure during pregnancy 
EDTA 
ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
EOT 
end of treatment 
ER 
estrogen receptor 
CCI 
ET 
endocrine therapy 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GnRH 
gonadotropin-releasing hormone 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HER2 
human epidermal growth factor receptor 2 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 

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Abbreviation 
Term 
HIVAb 
human immunodeficiency virus antibody 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ID 
identification 
IHC 
immunohistochemistry 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IP manual 
investigational product manual 
IPAL 
Investigational Product Accountability Log 
IRB 
institutional review board 
JSH 
Japan Society of Hepatology 
LBBB 
left bundle branch block 
LC-MS/MS 
liquid chromatograph-tandem mass spectrometry 
LFT 
liver function test 
mBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NA 
not applicable 
NCI 
National Cancer Institute 
NE 
Non-evaluable 
NIMP 
non-investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic(s) or progressive disease 
PE 
physical examination 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
PR 
partial response 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PROTAC 
PROteolysis-TArgeting Chimera 
PS 
performance status 
PT 
prothrombin time 

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Abbreviation 
Term 
PTT 
partial thromboplastin time 
PVC 
premature ventricular contraction/complex 
QD 
once daily 
QRS 
time from the beginning of the Q wave to the end of the S wave in 
the electrocardiogram 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
QTL 
quality tolerance limit 
Rac 
accumulation ratio based on AUC (observed) 
RANKL 
Receptor Activator of Nuclear Factor Kappa B Ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
CCI 
RP2D 
recommended phase 2 dose 
RP3D 
recommended phase 3 dose 
RR 
response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SERD 
selective estrogen receptor degrader/downregulator 
SERM 
selective estrogen receptor modulator 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
t½eff 
effective half-life based on accumulation ratio 
TBili 
total bilirubin 
TdP 
Torsades de Pointes 
TEAE 
treatment-emergent adverse event 
TGI 
tumor growth inhibition 
Tmax 
time to reach maximum concentration 
TME 
tumor microenvironment 
TRAE 
treatment-related adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VE 
venous embolism 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 

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1 

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