Clinical trial NCT05538312
Conditions: Healthy
Sponsor: Pfizer
Start date: 2023-02-23; Completion date: 2023-05-22
Enrollment: 12 participants; Allocation: NA; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to understand if a strong CYP3A4 inhibitor (itraconazole) affects how ARV-471 is processed and eliminated in healthy adults.

All participants in this study will receive one dose of ARV-471 alone by mouth in Period 1. In Period 2, everyone will receive itraconazole by mouth once a day for multiple days. Participants will also receive one dose of ARV-471 by mouth. The levels of ARV-471 in Period 1 will be compared to the levels of ARV-471 in Period 2 to determine if the CYP3A4 inhibitor affects how ARV-471 is processed differently in healthy adults.

Detailed description:

Arms: arm 1: vepdegestrant administered as a single dose in Period 1 and Period 2. Itraconazole administered once a day for 11 days in Period 2.
Interventions: intervention 1: vepdegestrant intervention 2: Itraconazole
Intervention descriptions: intervention 1: Participants will receive a single dose of vepdegestrant by mouth in Period 1 and Period 2, with a washout period of at least 10 days between doses of vepdegestrant intervention 2: Participants will receive itraconazole by mouth once a day for 11 days in Period 2.

Protocol documents:
Prot_000.pdf: 
ARV-471 (PF-07850327) 
Protocol C4891009 
Final Protocol Amendment 2, 12 January 2023 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022) 
Page 1 
 
 
 
 
 
Title Page 
AN INTERVENTIONAL, PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD 
STUDY TO ESTIMATE THE EFFECT OF MULTIPLE DOSES OF ITRACONAZOLE ON 
THE PHARMACOKINETICS OF SINGLE DOSE ARV-471 IN THE FED CONDITION 
IN HEALTHY ADULT MALES, AND FEMALES OF NONCHILDBEARING 
POTENTIAL 
 
Study Intervention Number: 
PF-07850327 
Study Intervention Name: 
ARV-471 
US IND Number: 
N/A 
EudraCT Number: 
2022-003282-38 
ClinicalTrials.gov ID: 
N/A 
Pediatric Investigational Plan Number: 
N/A 
Protocol Number: 
C4891009 
Phase: 
1 
Brief Title: Phase 1, Open-label, Fixed Sequence, 2-Period Study to Estimate the Effect 
of Multiple Doses of Itraconazole on the Pharmacokinetics of Single Dose ARV-471 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Protocol C4891009 
Final Protocol Amendment 2, 12 January 2023 
PFIZER CONFIDENTIAL 
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Document History 
 
Document 
Version Date 
Amendment 2 
12 January 2023 
Amendment 1 
21 October 2022 
Original protocol 
20 July 2022 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
change letter(s). 
Protocol Amendment Summary of Changes Table 
Amendment 2 (12 January 2023) 
Overall Rationale for the Amendment: Responses to regulatory queries warranted protocol 
amendments. 
 
Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
1.3. Schedule of 
Activities Table 
3. PK, ECG, BP, 
and PR Sampling 
Schema for 
Period 1 and 
Table 4. PK, 
ECG, BP, and 
PR Sampling 
Schema for 
Period 2 
12-Lead ECG 
measurement at 4 hours 
post-dose was changed to 
6 hours post-dose 
The 6-hour timepoint 
more closely aligns with 
the observed ARV-471 
Tmax range in patients 
and healthy volunteers. 
Nonsubstantial 
4.3. Justification 
for Dose 
Table 9 and Table 10 
were reformatted and 
safety exposure margins 
were updated. In-text 
exposure margins were 
updated to correspond 
with changes in the 
tables. 
Tables were made more 
comprehensive by 
replacing point estimates 
with a range of predicted 
safety exposure margins. 
Nonsubstantial 
4.2. Scientific 
Rationale for 
Study Design - 
Males 
Safety exposure margins 
were updated in Table 5. 
In-text exposure margins 
were updated to 
correspond with changes 
in the table. 
Table 5 was made more 
comprehensive by 
replacing point estimates 
with a range of predicted 
safety exposure margins. 
Nonsubstantial 
10.9. Appendix 
9: Overview of 
GLP Safety 
Pharmacology 
and Toxicology 
Testing Program 
Table formatting was 
updated and additional 
studies were included. 
CRO contact 
information was 
removed and date of 
Updates were made to 
comply with Clinical 
Trials Facilitation and 
Coordination Group 
guidelines. 
Nonsubstantial 


ARV-471 (PF-07850327) 
Protocol C4891009 
Final Protocol Amendment 2, 12 January 2023 
PFIZER CONFIDENTIAL 
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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
for ARV-471 
(PF-07850327) 
completion of the final 
report was added. 
1.1. Synopsis 
Regulatory 
Agency 
Identification 
Number(s) 
US IND number was 
removed. 
This study will be 
conducted in Belgium and 
not submitted under the 
US IND. 
Nonsubstantial 
Title Page 
US IND Number 
US IND number was 
removed. 
This study will be 
conducted in Belgium and 
not submitted under the 
US IND. 
Nonsubstantial 
10.10 Appendix 
10: 
Abbreviations 
Added abbreviations to 
the list. 
Added abbreviations 
relative to this 
amendment. 
Nonsubstantial 


ARV-471 (PF-07850327) 
Protocol C4891009 
Final Protocol Amendment 2, 12 January 2023 
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 9 
1. PROTOCOL SUMMARY ................................................................................................... 10 
1.1. Synopsis ................................................................................................................... 10 
1.2. Schema..................................................................................................................... 14 
1.3. Schedule of Activities .............................................................................................. 15 
2. INTRODUCTION ................................................................................................................ 22 
2.1. Study Rationale ........................................................................................................ 22 
2.2. Background .............................................................................................................. 22 
2.2.1. Nonclinical Pharmacology .......................................................................... 22 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 22 
2.2.3. Nonclinical Safety ....................................................................................... 23 
2.2.4. Clinical Overview ....................................................................................... 24 
2.3. Benefit/Risk Assessment ......................................................................................... 26 
2.3.1. Risk Assessment ......................................................................................... 27 
2.3.2. Benefit Assessment ..................................................................................... 29 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 29 
3. OBJECTIVES AND ENDPOINTS ...................................................................................... 29 
4. STUDY DESIGN ................................................................................................................. 29 
4.1. Overall Design ......................................................................................................... 29 
4.2. Scientific Rationale for Study Design ...................................................................... 30 
4.2.1. Choice of Contraception/Barrier Requirements .......................................... 34 
4.2.1.1. Females ...................................................................................... 34 
4.2.1.2. Males ......................................................................................... 34 
4.2.2. Collection of Retained Research Samples ................................................... 35 
4.3. Justification for Dose ............................................................................................... 35 
4.4. End of Study Definition ........................................................................................... 38 
5. STUDY POPULATION....................................................................................................... 38 
5.1. Inclusion Criteria ..................................................................................................... 39 
5.2. Exclusion Criteria .................................................................................................... 39 
5.3. Lifestyle Considerations .......................................................................................... 42 
5.3.1. Contraception .............................................................................................. 42 


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5.3.2. Meals and Dietary Restrictions ...................................................................42 
5.3.3. Caffeine, Alcohol, and Tobacco ..................................................................43 
5.3.4. Activity .......................................................................................................44 
5.4. Screen Failures .........................................................................................................44 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..................................44 
6.1. Study Intervention(s) Administered .........................................................................44 
6.1.1. Administration .............................................................................................45 
6.2. Preparation, Handling, Storage, and Accountability ...............................................45 
6.2.1. Preparation and Dispensing .........................................................................47 
6.3. Assignment to Study Intervention ...........................................................................47 
6.4. Blinding ...................................................................................................................47 
6.4.1. Blinding of Participants ...............................................................................47 
6.4.2. Blinding of Site Personnel ...........................................................................47 
6.4.3. Blinding of the Sponsor ..............................................................................47 
6.5. Study Intervention Compliance ...............................................................................47 
6.6. Dose Modification ...................................................................................................48 
6.7. Continued Access to Study Intervention After the End of the Study ......................48 
6.8. Treatment of Overdose ............................................................................................48 
6.9. Prior and Concomitant Therapy ...............................................................................48 
6.9.1. Rescue Medicine .........................................................................................49 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................49 
7.1. Discontinuation of Study Intervention .....................................................................49 
7.1.1. COVID-19 ...................................................................................................49 
7.2. Participant Discontinuation/Withdrawal From the Study .......................................49 
7.2.1. Withdrawal of Consent ...............................................................................50 
7.3. Lost to Follow-up ....................................................................................................50 
8. STUDY ASSESSMENTS AND PROCEDURES ................................................................51 
8.1. Administrative and Screening Procedures ...............................................................51 
8.1.1. Screening Procedures ..................................................................................52 
8.2. Efficacy Assessments ..............................................................................................53 
8.3. Safety Assessments ..................................................................................................53 


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8.3.1. Physical Examinations ................................................................................ 53 
8.3.2. Vital Signs ................................................................................................... 53 
8.3.2.1. Blood Pressure and Pulse Rate .................................................. 53 
8.3.3. Electrocardiograms ...................................................................................... 54 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 55 
8.3.5. COVID-19 Specific Assessments ............................................................... 55 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 55 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 56 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 56 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF .................... 57 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 57 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 57 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 57 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 58 
8.4.5.1. Exposure During Pregnancy ...................................................... 58 
8.4.5.2. Exposure During Breastfeeding ................................................. 60 
8.4.5.3. Occupational Exposure .............................................................. 60 
8.4.6. Cardiovascular and Death Events ................................................................ 60 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 60 
8.4.8. Adverse Events of Special Interest ............................................................. 60 
8.4.8.1. Lack of Efficacy ........................................................................ 61 
8.4.9. Medical Device Deficiencies ....................................................................... 61 
8.4.10. Medication Errors ...................................................................................... 61 
8.5. Pharmacokinetics ..................................................................................................... 62 
8.5.1. Plasma for Analysis of ARV-471 and ARV-473 ........................................ 62 
8.5.2. Derivation of Pharmacokinetic Parameters ................................................. 63 
8.6. Genetics ................................................................................................................... 64 
8.6.1. Specified Genetics ....................................................................................... 64 
8.6.2. Retained Research Samples for Genetics .................................................... 64 
8.7. Biomarkers ............................................................................................................... 64 
8.7.1. Specified Gene Expression (RNA) Research .............................................. 64 


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8.7.2. Specified Protein Research ..........................................................................64 
8.7.3. Specified Metabolomic Research ................................................................65 
8.7.4. Retained Research Samples for Biomarkers ................................................65 
8.8. Immunogenicity Assessments..................................................................................65 
8.9. Health Economics ....................................................................................................65 
9. STATISTICAL CONSIDERATIONS .................................................................................65 
9.1. Statistical Hypothesis ..............................................................................................65 
9.2. Analysis Sets ............................................................................................................65 
9.3. Statistical Analyses ..................................................................................................66 
9.3.1. Pharmacokinetic Analyses ..........................................................................66 
9.3.2. Safety Analyses ...........................................................................................66 
9.3.2.1. Electrocardiogram Analyses ......................................................67 
9.3.3. Other Analyses ............................................................................................67 
9.4. Interim Analyses ......................................................................................................67 
9.5. Sample Size Determination .....................................................................................68 
10. SUPPORTING  DOCUMENTATION  AND  OPERATIONAL 
CONSIDERATIONS...........................................................................................................69 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................69 
10.1.1. Regulatory and Ethical Considerations .....................................................69 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .........................................................................69 
10.1.2. Financial Disclosure ..................................................................................70 
10.1.3. Informed Consent Process ........................................................................70 
10.1.4. Data Protection ..........................................................................................71 
10.1.5. Committees Structure ................................................................................71 
10.1.5.1. Data Monitoring Committee ....................................................71 
10.1.6. Dissemination of Clinical Study Data .......................................................71 
10.1.7. Data Quality Assurance .............................................................................72 
10.1.8. Source Documents.....................................................................................74 
10.1.9. Study and Site Start and Closure ...............................................................74 
10.1.10. Publication Policy ...................................................................................75 
10.1.11. Sponsor’s Medically Qualified Individual ..............................................76 
10.1.12. Transfer of Obligations Statement ...........................................................76 


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10.2. Appendix 2: Clinical Laboratory Tests ..................................................................77 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................................78 
10.3.1. Definition of AE ........................................................................................78 
10.3.2. Definition of an SAE .................................................................................79 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ............................................................................80 
10.3.4. Reporting of SAEs ....................................................................................84 
10.4. Appendix 4: Contraceptive and Barrier Guidance .................................................86 
10.4.1. Male Participant Reproductive Inclusion Criteria ....................................86 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................86 
10.4.3. Woman of Childbearing Potential .............................................................86 
10.4.4. Contraception Methods .............................................................................87 
10.5. Appendix 5: Genetics ............................................................................................89 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ........90 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines .............................................92 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ..............................................................................92 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ................92 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities ...................................................................................................92 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ....................................93 
10.9. Appendix 9: Overview of GLP Safety Pharmacology and Toxicology 
Testing Program for ARV-471 (PF-07850327) .........................................................95 
10.10. Appendix 10: Protocol Amendment History .......................................................98 
10.11. Appendix 11: Abbreviations ..............................................................................101 
11. REFERENCES .................................................................................................................105 


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LIST OF TABLES 
Table 1. 
Period 1: ARV-471 Alone .........................................................................15 
Table 2. 
Period 2: ARV-471 in the Presence of Itraconazole .................................17 
Table 3. 
PK, ECG, BP, and PR Sampling Schema for Period 1 .............................20 
Table 4. 
PK, ECG, BP, and PR Sampling Schema for Period 2 .............................21 
Table 5. 
Exposure Margin Determination for Testicular Toxicity in Rat and 
Dog Toxicity Studies ................................................................................33 
Table 6. 
Summary of Plasma ARV-471 AUCinf (h*ng/mL) by Treatment 
(Fed/Fasted) in Study ARV-471-CPhm-103............................................35 
Table 7. 
Mechanistic static DDI model predictions of the effect of steady- 
state itraconazole (200 mg QD) on the PK of ARV-471 ...........................36 
Table 8. 
Repeat Dose Toxicity Study ARV-471 Exposure Margins in Male 
and Female Rats ........................................................................................37 
Table 9. 
Repeat Dose Toxicity Studies Exposure Margins in Male and 
Female Beagle Dogs ..................................................................................38 
Table 10. 
Definitions of PK Parameters ....................................................................63 
Table 11. 
Safety QTcF Assessment ..........................................................................67 
Table 12. 
Confidence Interval Estimation of PK Endpoints for Bioavailability .......68 
Table 13. 
Protocol-Required Safety Laboratory Assessments ..................................77 
Table 14. 
Adults (18 Years and Above)—2021 CKD-EPI Equations18 ............................ 92 
Table 15. 
Overview of GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) .....................................................95 
Table 16. 
Facilities for GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) .....................................................96 


ARV-471 (PF-07850327) 
Protocol C4891009 
Final Protocol Amendment 2, 12 January 2023 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: An Interventional, Phase 1, Open-Label, Fixed Sequence, 2-Period Study to 
Estimate the Effect of Multiple Doses of Itraconazole on the Pharmacokinetics Of Single 
Dose ARV-471 in the Fed Condition in Healthy Adult Males, and Females of 
Nonchildbearing Potential 
Brief Title: Phase 1, Open-label, Fixed Sequence, 2-Period Study to Estimate the Effect of 
Multiple Doses of Itraconazole on the Pharmacokinetics of Single Dose ARV-471 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
N/A 
EudraCT Number: 
2022-003282-38 
ClinicalTrials.gov ID: 
N/A 
Pediatric Investigational Plan Number: 
N/A 
Protocol Number: 
C4891009 
Phase: 
1 
 
Rationale: 
Itraconazole and its primary metabolite (hydroxy-itraconazole) are specific strong inhibitors 
of CYP3A. Since ARV-471 is a substrate for CYP3A, concomitant administration of 
multiple doses of itraconazole along with ARV-471 may lead to increased systemic exposure 
of ARV-471. The objective of this study is to estimate the effect of multiple doses of 
itraconazole on the PK of ARV-471. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
• 
To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a single 
oral 200 mg dose of ARV-471. 
Primary: 
• Plasma AUCinf and Cmax of ARV-471 and ARV-473, as 
data permits (AUClast if AUCinf cannot be estimated). 
Secondary: 
• 
To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a single 
oral 200 mg dose of ARV-471. 
• Plasma AUClast, Tmax, t1/2, CL/F and Vz/F of ARV-471 
and ARV-473, as data permits. 
• 
To evaluate the safety and tolerability of a single 
oral 200 mg dose of ARV-471 administered to 
healthy participants in the absence and presence of 
multiple doses of itraconazole under fed conditions. 
• Safety laboratory tests, physical examination, vital 
signs, electrocardiograms, concomitant medication and 
adverse event monitoring. 
 
Overall Design: 
This is a Phase 1, open-label, 2-period, fixed-sequence crossover study to estimate the effect 
of multiple doses of the strong CYP3A inhibitor, itraconazole, on the pharmacokinetics of 


ARV-471 (PF-07850327) 
Protocol C4891009 
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ARV-471 and its epimer, ARV-473, in healthy male and female participants of 
nonchildbearing potential. 
Number of Participants: 
Approximately 12 participants will be enrolled in the study. 
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 after screening. 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, unless otherwise specified by the 
protocol. 
Study Population: 
Key inclusion and exclusion criteria are listed below: 
Inclusion Criteria 
Participants must meet all the following key inclusion criteria to be eligible for enrollment 
into the study: 
1. Healthy male and/or female participants of non-childbearing potential who are overtly 
healthy as determined by medical evaluation including medical history, physical 
exam, laboratory tests, vital signs and standard 12-lead ECGs and are between the 
ages of 18 and 65 years, inclusive at the time of signing the ICD. 
2. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg. 
3. Evidence of a personally signed and dated informed consent document indicating that 
the participant has been informed of all pertinent aspects of the study. 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
2. Pregnant female participants, breastfeeding female participants, female participants of 
childbearing potential. 


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3. Male participants with partners currently pregnant; fertile male participants who are 
unwilling or unable to use a highly effective method of contraception. 
4. Use of prescription or non-prescription medications, including vitamins, herbal and 
dietary supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products within 7 days prior to the first dose of 
study intervention with the exception of: 
• Moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 
half-lives (whichever is longer) prior to the first dose of study intervention 
• Moderate/potent CYP3A inhibitors which are prohibited within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. 
5. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
6. A positive urine drug test or alcohol breath test at discretion of investigator. 
7. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. 
8. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results. 
9. AST or ALT level >1.0 × ULN. 
10. Total bilirubin level >1.0 × ULN; participants with a history of Gilbert’s syndrome 
may have direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin level is ≤ ULN. 
11. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. 
12. History of use of tobacco or nicotine-containing products in excess of the equivalent 
of 5 cigarettes/day or 2 chews of tobacco/day. 
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. Known hypersensitivity or previous adverse events associated with azole antifungals 
or any of the formulation components of ARV-471. 
15. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
16. Renal impairment as defined by an eGFR<60 mL/min/1.73m2. 


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Study Arms and Duration: 
The study will consist of 2 periods; Period 1 = single dose of ARV-471 alone and Period 2 = 
multiple doses of itraconazole + single dose of ARV-471. A washout period of at least 
10 days must occur between the 2 successive single doses of ARV-471 in this study. 
Following administration of ARV-471 in each period, participants will undergo serial PK 
sampling. 
 
Study Intervention(s) 
Intervention Name 
ARV-471 (PF-07850327) 
Itraconazole 
Type 
Drug 
Drug 
Dose Formulation 
Tablet 
Oral Solution 
Unit Dose Strength(s) 
100 mg 
10 mg/mL 
Dosage Level(s) 
200 mg 
200 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Experimental treatment to assess an endpoint 
IMP or NIMP/AxMP 
IMP 
NIMP/AxMP 
Sourcing 
Provided centrally by the sponsor 
Sourced locally by the trial site 
Packaging and Labeling 
Study intervention will be provided in 
high-density polyethylene bottle with 
child resistant cap. Each bottle will be 
labeled as required per country 
requirement. 
Study intervention (20 mL itraconazole 10 
mg/mL oral solution) will be dispensed from 
commercial Sporanox® into oral syringes. 
Current/Former Names 
or Aliases 
ARV-471 
(PF-07850327) 
Itraconazole (Sporanox®) 
 
Statistical Methods: 
A sample size of 12 PK evaluable participants who have at least 1 of the ARV-471/ARV-473 
PK parameters of primary interest (AUCinf or Cmax) is expected to provide 90% CIs for the 
difference between treatments of CCI  and CCI  on the natural log scale for AUCinf 
and Cmax, respectively, with 80% coverage probability. 


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ARV-471 and ARV-473 PK parameters following a single dose administration of ARV-471 
will be derived from the ARV-471 and ARV-473 plasma concentration versus time profiles 
using non-compartmental methods as data permit. ARV-471 and ARV-473 PK parameters 
(primary endpoints: AUCinf and Cmax; secondary endpoints: AUClast, Tmax, t1/2, CL/F, and 
Vz/F) will be summarized descriptively by treatment. Individual participant parameters for 
AUCinf, AUClast and Cmax will be plotted by treatment and overlaid with geometric mean. 
ARV-471 and ARV-473 concentrations will be listed and summarized descriptively by PK 
sampling time and treatment. Summary profiles (means and medians) of concentration versus 
time data will be plotted by treatment on linear and semi log scale. Individual participant 
concentration versus time profiles will also be presented. 
Natural log transformed ARV-471 and ARV-473 AUCinf (if data permit), AUClast and Cmax 
will be analyzed using a mixed effect model with treatment as a fixed effect and participant 
as a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Treatment A 
(ARV-471 given alone) is the Reference Treatment while Treatments B (ARV-471 given 
after multiple doses of itraconazole) is the Test Treatment. 
Ethical Considerations: 
Participants are not expected to receive any clinical benefit. Participants contribute to the 
process of developing a new therapy for the treatment of patients with ER+/HER2- breast 
cancer. 
1.2. Schema 
Not applicable. 


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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 information on each procedure and 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 participant. 
 
Table 1. 
Period 1: ARV-471 Alone 
 
Visit Identifier 
Abbreviations used in 
this table may be 
found in Appendix 11. 
Screen 
Period 1 
Early 
Discontinuation 
Notes 
Days Relative to Day 
1 
Day - 
28 to 
Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 3 Day 
4 
Day 
5 
Day 6 
• 
All screening should be done ≤28 days before the first dose. 
• 
Day relative to start of study intervention (Period 1 Day 1). 
*: At PI discretion, participant are allowed to remain in CRU from D-1 Period 1 until D12 of 
Period 2. In that case, discharge assessments of Period 1 described below will not be performed. 
Informed consent 
X 
• 
Informed consent should be obtained prior to undergoing any study-specific procedures. 
• 
See Section 10.1.3 for additional information. 
CRU confinement 
X 
X 
X 
X 
X 
Participants will be admitted to the CRU on the day prior to ARV-471 dosing (Day -1 of 
Period 1) and may be kept at the CRU through at least Day 4 of Period 1 at the discretion of the 
investigator. Follow-up visit activities (if necessary) will be performed at the discretion of the 
principal investigator, if there is an unresolved AE(s) at discharge, or in the case of an early 
discontinuation. These activities may include physical examination, safety laboratory, 
contraception check, single 12-lead ECG and supine blood pressure and pulse rate. 
Outpatient Visit 
X 
X 
X 
Outpatient visit required only if participant is discharged on Day 4. 
Inclusion/exclusion 
criteria 
X 
X 
See Sections 5.1 and 5.2 for details. 
Medical/medication 
history 
X 
X 
Medical history will include but not limited to a history of prior drug, alcohol, and tobacco use, 
as well as blood donation within prior 60 days. Medical history will be recorded at Screening 
and updated on Day -1 of Period 1 only. 
Physical exam 
X 
X 
A full PE, without genitourinary evaluation will be performed by trained medical personnel at 
the investigator site at Screening or Day -1 of Period 1 only (height and weight must be 
obtained at Screening to obtain BMI for eligibility criteria). A limited PE may be performed at 
other designated time points at the discretion of the investigator. Only weight needs to be 
recorded thereafter. See Section 8.3.1 for details. 
Blood pressure and 
pulse rate 
X 
X 
X 
X 
Obtain supine BP and PR following at least a 5 minute rest in a supine position. Refer to 
Table 3 for BP and PR measurements. 


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Table 1. 
Period 1: ARV-471 Alone 
 
Visit Identifier 
Abbreviations used in 
this table may be 
found in Appendix 11. 
Screen 
Period 1 
Early 
Discontinuation 
Notes 
Days Relative to Day 
1 
Day - 
28 to 
Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 3 Day 
4 
Day 
5 
Day 6 
• 
All screening should be done ≤28 days before the first dose. 
• 
Day relative to start of study intervention (Period 1 Day 1). 
*: At PI discretion, participant are allowed to remain in CRU from D-1 Period 1 until D12 of 
Period 2. In that case, discharge assessments of Period 1 described below will not be performed. 
Safety laboratory 
X 
X 
X 
X* 
X 
Safety laboratory assessments including urinalysis, hematology, and chemistry will be 
performed at the indicated time-points. Additional safety laboratory assessments may be 
performed at any time at the discretion of the investigator. Participants must abstain from all 
food and drink (except water) at least 4 hours prior to any safety laboratory evaluations. 
12-Lead ECG 
X 
X 
X 
X* 
X 
Refer to Table 3 for single 12-lead ECG collections. 
Demography 
X 
Demographics will include participant, race, ethnicity, age, and gender during the screening 
visit. 
Contraception check 
X 
X 
X* 
X* 
X* 
X 
On Screening, Day -1 and on Day 4 (or any day that coincides with discharge), the investigator 
or their designee will discuss with the participant and their partner the need to use highly 
effective contraception consistently and correctly according to contraception guidelines. If 
participants are discharged on Day 4, the contraception check will be done at each outpatient 
visit. 
FSH 
X 
Will be performed at screening for postmenopausal (amenorrheic for at least 12 consecutive 
months with no alternative pathological or physiological cause) female participants only. 
Urine drug testing 
X 
X 
Urine drug (mandatory) and alcohol breath and blood test (at discretion of investigator) will be 
performed at Screening and on Day -1. These tests may be performed at any other time at the 
discretion of the investigator. 
HIV, HBsAg, HBsAb, 
HBcAb, HCVAb 
X 
HBsAb may be routinely tested or only if HBsAg and/or HBcAb are positive. HBsAb due to 
vaccination is permissible 
COVID-19 related 
measures 
X 
X 
X 
X 
X 
X 
X 
X 
Performed according to CRU procedure. 
ARV-471 
administration 
X 
On Period 1 Day 1, participants will be given a high fat, high calorie meal at approximately 30 
minutes prior to ARV-471 dosing. The high fat, high calorie breakfast will be consumed within 
a 20-minute period, with the study drug administered within approximately 10 minutes after 
completion of the meal. Administration of 200 mg ARV-471 will occur with approximately 240 
mL of water followed by at least 4 hours fast post dosing. A washout period of at least 10 days 
must occur between the 2 successive single doses of ARV-471 in this study 
Retained Research 
Samples for Genetics 
(Prep D1) 
X 
Prep D1 Retained Research Samples for Genetics: If not collected on the designated collection 
day, collect at the next available time point when biospecimens are being collected in 
conjunction with a participant visit. See Section 8.6.2. 


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Table 1. 
Period 1: ARV-471 Alone 
 
Visit Identifier 
Abbreviations used in 
this table may be 
found in Appendix 11. 
Screen 
Period 1 
Early 
Discontinuation 
Notes 
Days Relative to Day 
1 
Day - 
28 to 
Day -2 
Day 
-1 
Day 
1 
Day 
2 
Day 3 Day 
4 
Day 
5 
Day 6 
• 
All screening should be done ≤28 days before the first dose. 
• 
Day relative to start of study intervention (Period 1 Day 1). 
*: At PI discretion, participant are allowed to remain in CRU from D-1 Period 1 until D12 of 
Period 2. In that case, discharge assessments of Period 1 described below will not be performed. 
CRU discharge 
X 
Follow-up visit activities (if necessary) will be performed at the discretion of the principal 
investigator, if there is an unresolved AE(s) at discharge, or in the case of an early 
discontinuation. These activities may include physical examination, safety laboratory, 
contraception check, single 12-lead ECG and supine blood pressure and pulse rate. 
Serious and 
nonserious AE 
monitoring 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
X 
See Section 8.4.3 for AE and SAE assessments. 
 
 
Table 2. 
Period 2: ARV-471 in the Presence of Itraconazole 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 11. 
Period 2 
F/U 
Early 
Discontinuation 
Notes 
Days Relative to Day 1 
Day -1 
Day 1-4 
Day 5 
Day 6- 
11 
Day 12 
28-35 
Days 
• 
Day relative to start of study intervention (Period 2 Day 1). 
• 
Follow-up may occur via telephone contact and must occur 28 to 35 
days after administration of the final dose of study intervention. 
*: At PI discretion, participant are allowed to remain in CRU from D-1 
Period 1 until D12 of Period 2. In that case, admission assessment for Period 
2 describe below will not be performed. 
CRU confinement 
X 
→ 
→ 
→ 
X 
Participants will be admitted to the CRU on the day prior to itraconazole 
dosing (Day -1) and will be kept at the CRU through Day 12 of Period 2 at 
the discretion of the investigator. Follow-up visit activities (if necessary) will 
be performed at the discretion of the principal investigator, if there is an 
unresolved AE(s) at discharge, or in the case of an early discontinuation. 
These activities may include physical examination, safety laboratory, 
contraception check, single 12-lead ECG and supine blood pressure and pulse 
rate. 


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Table 2. 
Period 2: ARV-471 in the Presence of Itraconazole 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 11. 
Period 2 
F/U 
Early 
Discontinuation 
Notes 
Days Relative to Day 1 
Day -1 
Day 1-4 
Day 5 
Day 6- 
11 
Day 12 
28-35 
Days 
• 
Day relative to start of study intervention (Period 2 Day 1). 
• 
Follow-up may occur via telephone contact and must occur 28 to 35 
days after administration of the final dose of study intervention. 
*: At PI discretion, participant are allowed to remain in CRU from D-1 
Period 1 until D12 of Period 2. In that case, admission assessment for Period 
2 describe below will not be performed. 
Blood pressure and pulse 
rate 
X 
Obtain supine BP and PR following at least a 5 minute 
rest in a supine position. Refer to Table 4 for BP and PR measurements. 
Safety laboratory 
X 
X (Day 4 
only) 
X 
X 
Safety laboratory assessments including urinalysis, hematology, and 
chemistry will be performed at the indicated time-points. Additional safety 
laboratory assessments may be performed at any time at the discretion of the 
investigator. Participants must abstain from all food and drink (except water) 
at least 4 hours prior to any safety laboratory evaluations. 
12-Lead ECG 
X 
X (Day 6 
only) 
X 
X 
Refer to Table 4 for single 12-lead ECG collections. 
Contraception check 
X* 
X 
X 
On Day -1, on Day 12 (or any day that coincides with discharge) and if 
participants discontinues early, the investigator or their designee will discuss 
with the participant and their partner the need to use highly effective 
contraception consistently and correctly according to contraception 
guidelines. 
Urine drug testing 
X* 
Urine drug (mandatory) and alcohol breath and blood test (at discretion of 
investigator) will be performed at on Day -1. These tests may be performed at 
any other time at the discretion of the investigator. 
COVID-19 related 
measures 
X 
X 
X 
X 
X 
Performed according to CRU procedure. 
Itraconazole 
administration 
X 
X 
X 
Participants will receive itraconazole 200 mg (in a 20 mL solution) once 
daily while fasted with approximately 220 mL of water from Day 1 to 
Day 11. Itraconazole does not need to be administered under fasted 
conditions when taken with ARV-471 on Day 5. 


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Table 2. 
Period 2: ARV-471 in the Presence of Itraconazole 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 11. 
Period 2 
F/U 
Early 
Discontinuation 
Notes 
Days Relative to Day 1 
Day -1 
Day 1-4 
Day 5 
Day 6- 
11 
Day 12 
28-35 
Days 
• 
Day relative to start of study intervention (Period 2 Day 1). 
• 
Follow-up may occur via telephone contact and must occur 28 to 35 
days after administration of the final dose of study intervention. 
*: At PI discretion, participant are allowed to remain in CRU from D-1 
Period 1 until D12 of Period 2. In that case, admission assessment for Period 
2 describe below will not be performed. 
ARV-471 administration 
X 
On Period 2 Day 5, participants will be given a high fat, high calorie meal at 
approximately 30 minutes prior to ARV-471 dosing. The high fat, high 
calorie breakfast will be consumed within a 20-minute period, with the study 
drug administered within approximately 10 minutes after completion of the 
meal. Administration of 200 mg ARV-471 will occur with approximately 220 
mL of water followed by at least 4 hours fast post dosing. 
CRU discharge 
X 
Follow-up visit activities (if necessary) will be performed at the discretion of 
the principal investigator, if there is an unresolved AE(s) at discharge, or in 
the case of an early discontinuation. These activities may include physical 
examination, safety laboratory, contraception check, single 12-lead ECG and 
supine blood pressure and pulse rate. 
Serious and nonserious AE 
monitoring 
→ 
→ 
→ 
→ 
X 
X 
X 
See Section 8.4.3 for AE and SAE assessments. 


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Table 3. 
PK, ECG, BP, and PR Sampling Schema for Period 1 
 
Visit Identifier 
Screening 
Study C4891009 
Early 
Discontinuation 
Notes 
Study 
Day 
Day -28 
to 
Day -2 
1 
2 
3 
4 
5 
6 
*: At PI discretion, participant are allowed to remain in CRU from D-1 
Period 1 until D12 of Period 2. In that case, admission assessment for 
Period 2 describe below will not be performed. 
Hours Before/After 
Dose 
Pre- 
dose 
0 
1 
2 
4 
6 
8 12 
24 
48 
72 96 
120 
ARV-471/ARV-473 
PK blood samplinga 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a: Blood samples (3 mL) for PK analysis of ARV-471 will be taken 
after completion of ECGs, blood pressure and pulse rate at pre-dose 
(within 15 minutes prior to starting breakfast), 1 2, 4, 6, 8, 12, 24, 48, 
72, 96, and 120 hours post dosing. If ECG and blood pressure/pulse 
rate assessments are scheduled at the same time point, PK samples 
should be collected after completion of these assessments. 
12-Lead ECG 
X 
X 
(Tripl 
icate 
ECG) 
X 
X 
X 
X* 
X 
Singlet 12-lead ECG readings approximately 2 minutes apart will be 
taken at specified times. Triplicate ECG will be collected at pre-dose 
on Day 1. All ECG assessments will be made after at least a 5-minute 
rest in a supine position and prior to any blood draws or vital sign 
measurements. See Section 8.3.3 for details. 
Blood pressure and 
pulse rate 
X 
X 
X 
X 
Single supine blood pressure and pulse rate will be performed 
following at least a 5-minute rest in a supine position. BP and PR 
assessments will be performed after collection of ECGs and prior to 
collection of blood draws if scheduled at the same time. See 
Section 8.3.2 for details. 


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Table 4. 
PK, ECG, BP, and PR Sampling Schema for Period 2 
 
Visit Identifier 
Study C4891009 
Early 
Discontinuation 
Notes 
Study 
Day 
1-4 
5 
6 
7 
8 
9 
10 
11 
12 
Hours Before/After 
Dose 
Predose 
0 1 2 4 6 8 12 24 48 72 96 120 144 168 
ARV-471/ARV-473 PK 
blood samplinga 
X 
X X X X X X X X X X 
X 
X 
X 
X 
a: Blood samples (3 mL) for PK analysis of ARV-471 
will be taken after completion of ECGs, blood pressure 
and pulse rate at pre-dose (within 15 minutes prior to 
starting breakfast), 1 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 
144, 168 hours post dosing. If ECG and blood 
pressure/pulse rate assessments are scheduled at the same 
time point, PK samples should be collected after 
completion of these assessments. 
12-Lead ECG 
X 
(Triplicate 
ECG) 
X 
X X 
X 
X 
Single 12-lead ECG readings approximately 2 minutes 
apart will be taken at specified times. Triplicate ECG will 
be collected at pre-dose on Day 5. All ECG assessments 
will be made after at least a 5-minute rest in a supine 
position and prior to any blood draws or vital sign 
measurements. 
Blood pressure and pulse 
rate 
X 
X 
X 
Single supine blood pressure and pulse rate will be 
performed following at least a 5-minute rest in a supine 
position. BP and PR assessments will be performed after 
collection of ECGs and prior to collection of blood draws 
if scheduled at the same time. 


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2. INTRODUCTION 
ARV-471 (also known as PF-07850327) is a potent, selective, orally bioavailable 
PROteolysis TArgeting Chimeric (PROTAC®) small molecule that induces degradation of 
the ER. ARV-471 is a hetero-bifunctional PROTAC molecule that simultaneously binds the 
ER and the cereblon E3 ligase complex, enabling protein-protein interactions between ER 
and the ligase complex. As a result, the ER becomes poly-ubiquitinated on accessible lysine 
residues and subsequently undergoes targeted degradation by the proteasome to affect its 
elimination from cells. 
2.1. Study Rationale 
Itraconazole and its primary metabolite (hydroxy-itraconazole) are specific strong inhibitors 
of CYP3A. Since ARV-471 is a substrate for CYP3A, concomitant administration of 
multiple doses of itraconazole along with ARV-471 may lead to increased systemic exposure 
of ARV-471. The objective of this study is to estimate the effect of multiple doses of 
itraconazole on the PK of ARV-471. 
2.2. Background 
ARV-471 is a potent, selective, orally bioavailable, PROTAC® small molecule that induces 
the degradation of the ER. ARV-471 is being developed for the treatment of patients with 
ER+/HER2- breast cancer. 
2.2.1. Nonclinical Pharmacology 
In nonclinical studies, ARV-471 demonstrated in vitro CCI  (< 
CCInM) and CCI  (>CCI ER 
degradation even in the presence of clinically relevant, mutated (Y537S and D538G) forms 
of ER. Based on non-clinical studies, ARV-471 may have advantages over fulvestrant and 
other oral SERDs in clinical development such as RAD1901/elacestrant.1 While SERDs 
destabilize ER and indirectly lead to ER degradation, ARV-471 actively degrades ER, which 
may lead to less drug resistance. In vivo, ARV-471 inhibits tumor growth in multiple mouse 
xenograft models. Notably, ARV-471 demonstrates superior TGI compared to fulvestrant in 
a Y537S ESR1 mutant patient-derived xenograft model (ARV-471 IB). In the MCF7- 
xenograft mouse model, 3 to 30 mg/kg ARV-471, orally administered to mice once daily for 
28 days, displayed dose-dependent efficacy with doses of 3 and 10 mg/kg/day inhibiting 
tumor growth by 85% and 98%, respectively and 30 mg/kg/day leading to tumor shrinkage 
(124% TGI). At study termination, the tumor ER levels were reduced by ≥94%, suggesting 
that higher doses are required for maximal efficacy than for maximal ER degradation. 
These nonclinical data suggest that ARV-471 has the potential to offer improved ER 
degradation as compared to fulvestrant. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
The PK profile of ARV-471 in the nonclinical species (mouse, rat, dog, and monkey) was 
characterized by a CCI 
clearance (CCI 
of hepatic blood flow), 
CCI 
tissue distribution CCI   L/kg), CCI 
 half-life of elimination (t½) 


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CCI 
CCI 
 and CCI 
 oral bioavailability CCI 
 ARV-471 can 
interconvert to its epimer, ARV-473 (ARV-471 IB). 
A dose-dependent increase in ARV-471 exposure was observed when ARV-471 was 
administered as an oral solution in the mouse (10, 30, 100 mg/kg), rat (30, 100, 300 mg/kg), 
dog (15, 45, 90, 200, and 400 mg/kg), and monkey (1 and 3 mg/kg) (ARV-471 IB). 
A 3-fold increase in AUC and reduced inter-animal variability was observed in fed dogs; as 
such, the data indicated that the tablets should be administered with food in clinical trials. 
A CYP reaction phenotyping study was conducted using 2 orthogonal methods in human 
liver microsomes and recombinant CYP isoforms. This study indicated CYP3A4 as the 
principal isoform responsible for CYP metabolism of ARV-471 (accounting for 85%). 
(ARV-471 IB) 
2.2.3. Nonclinical Safety 
A high-level review of key nonclinical safety data is summarized below, additional 
information can be found in the investigator’s brochure (Version 4.0) and in Appendix 9. 
The potential for ARV-471 and ARV-473 to impact the cardiovascular system was assessed 
in vitro and in single- and repeat-dose in vivo studies. Neither compound directly CCI 
the 
CCI 
; however, CCI 
 in the CCI 
 were 
noted after  
C Cm
I  onths (but not 1-month) ARV-471 administration in dogs. Changes in the 
interval were only observed after 
days of continuous dosing. No indication of 
CCI 
 
 were observed in any study. There were no significant 
respiratory or CNS effects. ARV-471 and ARV-473 did not impact CCI 
 
CCI 
 was initially assessed at the nominal concentration of CCI 
concentrations, respectively. 
In a dedicated GLP cardiovascular assessment, a single dose of ARV-471 was administered 
via oral gavage to telemetered conscious male and female beagle dogs at doses of CCI 
 
and CCI mg/kg. No ARV-471-related effects were noted after oral administration of 
ARV-471 at 90 and 200 mg/kg. Following administration of ARV-471 atCCI mg/kg a 
CCI 
 7 ms CCI 
of the CCI 
 was noted from CCI 
 hours 
postdose. No other ARV-471 related effects were noted at CCI mg/kg. At CCImg/kg (the 
only dose studied in the TK phase), dogs (n=8, males and females combined) achieved a 
mean of CCI  ng/mL for Cmax,CCI hours for Tmax, and CCI  ng•h/mL for AUC0-24. 
Nonclinical toxicology studies were conducted with ARV-471 to evaluate the potential 
toxicity and toxicokinetic profile of ARV-471 and its epimer ARV-473 when administered 
QD orally (by gavage). The toxicity program includes up to 3-month GLP-compliant 
repeat-dose studies in rats and dogs, GLP-compliant in vitro bacterial reverse mutation 
(Ames) assays, an in vitro micronucleus assay, and a GLP-compliant in vitro 3T3 
phototoxicity study. 
CCI 


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of ARV-471 in rat and dog, it is concluded that the CCI 
have been noted in the dog toxicity studies up to 3-months in 
duration. Subsequently, in the 3-month study in rats there were CCI 
in the CCI 
of CCI 
 
(compared to controls) of 
were noted in rats in the 28-day study. No 
in the CCI 
CCI 
of ARV-471. The CCI 
CCI 
. The CCI 
in the CCI 
and considered to be due to the CCI 
were CCI 
CCI 
and included changes in the CCI 
to CCI mg/kg/day. ARV-471-related CCI 
were considered related to the 
in repeat dose rat studies up to 3-months in duration at doses up 
ARV-471 was CCI 
. Based on the collective nonclinical data evaluating CCI 
CCI 
CCI 
CCI 
CCI 
 
 
 
 
 
 
 
 
 
 
 
observed only in the 1-month rat study was a spurious finding and not relevant to patients. 
The NOAEL for 3 months of oral dosing was determined to be the highest dose tested of 
CCI mg/kg/day in male rats. A NOAEL was not identified in female rats as the effects on the 
CCI 
 were consider CCI . However, these findings are related to the primary 
pharmacology of ARV-471,CCI 
and CCI 
after CCI 
. At the 
mg/kg/day dose level, the Cmax was CCI 
  ng/mL in males and females, 
respectively, and the AUC0-24 was CCI 
 ng•h/mL in males and females, 
respectively. 
ARV-471 was CCI 
 in repeat dose dog studies up to 3-months in duration at doses 
up 
mg/kg/day. ARV-471 produced changes in female and male CCI 
, 
consistent with 
. The CCI mg/kg/day was identified as the 
NOAEL for daily dosing for 3 months in males. A NOAEL was not identified for females 
based upon microscopic findings in the CCI 
,CCI 
 at 
≥CCI mg/kg/day that were considered adverse, but it is acknowledged that these effects were 
consistent with the CCI 
 of ARV-471 and were also observed in the 7- and 
28-day studies in dogs. In males and females at CCI mg/kg/day, the Cmax was CCI and 
ng/mL and AUC0-24 was CCI 
 ng•h/mL on Day 91, respectively. 
2.2.4. Clinical Overview 
In the ongoing FIH Study [ARV-471-mBC-101], ARV-471 is being assessed as a 
monotherapy and in combination with palbociclib in participants with ER+/HER2- aBC who 
had previously received CDK4/6 inhibitors and/or endocrine therapy and/or chemotherapy in 
the locally advanced/metastatic setting. The FIH study has 3 parts: Part A is a monotherapy 
dose escalation, Part B is a monotherapy dose expansion (200 mg or 500 mg, oral daily 
dosing), and Part C is evaluating the combination of ARV-471 and palbociclib (escalation 
and expansion). As of 06 June 2022, 176 participants have been treated in the FIH study 
(Part A n=78; Part B n=71, Part C n=27) (ARV-471 IB). 
Based on the current safety data (data cutoff date of 06 June 2022), ARV-471 has been 
well-tolerated across total daily doses of 30 mg to 700 mg in patients with mBC, with no 
DLTs observed and most TRAE were Grade 1 or 2. In addition, evaluation of preliminary 
safety data from participants treated with palbociclib in combination with ARV-471 shows 
TEAEs consistent with TEAEs observed after treatment with either ARV-471 or palbociclib 
alone (ARV-471 IB). 
CCI 


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CCI 
CCI 
CCI 
Concentration-QTc modeling analysis of data from the ongoing ARV-471-mBC-101 study 
revealed a concentration-dependent increase in QTcF. Based on the model, a QTcF change 
from baseline is predicted to beCCI msec (90% CI: CCI ) at the geometric mean Cmax for 
the sum of ARV-471 and ARV-473 (CCI ng/mL) at steady-state after 200 mg QD dosing. 
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 >CCI msec (1 of 
each at 180 mg, 200 mg, and 500 mg daily dose) and 4 participants had CCI 
 
from baseline >CCI msec (1 at 200 mg, 2 at 500 mg and 1 at 700 mg daily dose). From the 
ongoing ARV-471-mBC-101 study, as of 06 June 2022, 13 participants reported TEAEs of 
CCI 
 
 (12 participants had TRAEs and in 1 participant the AE was 
considered as not related to ARV-471 per investigator). Most participants experienced grade 
1 or 2 CCI 
 events (11 out of 13), two patients reported Grade 3 events and no 
Grade 4/5 have been reported. An external CCI 
 consultant review concluded that of 
the 13 participants who reported 
events, only 2 participants had a true 
diagnosis of CCI 
, of which CCI  
 were 
confounding factors. 
 
There have been 
aths reported in the ARV-471-mBC-101 study:CCI in Part A and 
CCI in 
Part B. CCI of these CCI  were attributable to ARV-471. CCI 
 have been reported in 
Part C. 
There was evidence of preliminary clinical activity in the Part A monotherapy dose 
escalation of Study ARV-471-mBC-101, with several patients achieving clinical benefit as 
defined by CBR as of 06 June 2022. CBR (rate of confirmed CR, PR, or SD ≥24 weeks) was 
36.2% (95% CI: 25.0 - 48.7) in 25 of 69 evaluable participants. Clinical benefit (by CBR) 
was observed in CDK4/6 inhibitor-pretreated patients with ER+/HER2- BC in all Part A dose 
cohorts. Efficacy data collection is ongoing for Part B and Part C. 
Preliminary PK data following single and multiple dosing from Part A monotherapy dose 
escalation of Study ARV-471-mBC-101 are available in mBC participants receiving 
ARV-471 at total daily dose levels ranging from 30 mg to 700 mg (administered either as QD 
CCI 
or BID) under fed conditions. The median Tmax ranged from 
to hours across the dose 
levels. The mean effective t½ at steady state ranged from 
hours. Clinical exposure of 
ARV-471 on Day 15 at 60 mg QD (geometric mean AUCtau CCI ng.h/mL) has exceeded the 
nonclinical efficacious range associated with TGI (30 mg/kg single dose in mice). Following 
200 mg QD dosing (N=8), a geometric mean accumulation ratio for AUCtau of CCIwas 
observed between Day 1 and Day 15. ARV-471 can interconvert to its epimer, ARV-473. 
Following 200 mg QD dosing (N=8), the ratio, based on AUCtau, of ARV-473 / ARV-471 on 
Cycle 1 Day 15 isCCPIreclinical data showed ARV-471 has both CCI   and 
degradation activities against ER, whereas ARV-473 displays only CCI 
 activity 
(ARV-471 IB). 
Safety and PK data in healthy volunteers is based on the Phase 1 clinical pharmacology 
study, Study CCI 
, which is evaluating the effect of food or a PPI 
(esomeprazole) and the rBA of different tablet formulations on the single-dose PK and safety 
of ARV-471 in healthy postmenopausal female volunteers. As of data cut-off date of 16 June 
CCI 


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2022, a total of 47 healthy participants have been treated in Study CCI 
 (14 
participants in FE, 17 participants in PPI, and 16 participants in rBA portions). Each 
participant received 2 doses of 200 mg ARV-471, 1 in each of the 2 periods, and the 
ARV-471 treatments were separated by a washout period of at least 14 days. Preliminary 
analysis results showed the median Tmax ranged from 
hours across the cohorts. The 
geometric mean t½ following a single 200 mg dose was about CCI hours under fed condition. 
Food intake CCI 
 ARV-471 Cmax and AUCinf 
fold, respectively, as 
compared with fasted conditions. Thus, patients should be instructed to take ARV-471 with 
food. ARV-471 AUC values were similar when administered with PPI or without PPI, 
although PPI CCI 
 ARV-471 Cmax about CCI which is not considered clinical 
CCI 
 This indicates that there are CCI 
 of PPI on exposure of ARV-471 when 
administered with a CCI 
-fat meal. 
Analysis of 14 paired biopsies from patients treated in Part A (monotherapy dose escalation) 
at various doses of ARV-471 suggest CCI ER degradation (up to CCI decrease, with a 
median ER decrease of CCI [range: CCI 
 across all doses up to 500 mg QD, 
regardless of ESR1 mutation status with no apparent relationship between dose or exposure 
and ER degradation in patients with wild-type or mutant ER. 
The totality of data from these nonclinical pharmacology, PK and metabolism, and 
toxicology studies and available safety and efficacy clinical data support continued clinical 
development of ARV-471 in ER(+) / HER2(-) advanced breast cancer. 
2.3. Benefit/Risk Assessment 
ARV-471 alone or in combination with itraconazole is not expected to provide any clinical 
benefit to healthy participants. This study is designed primarily to generate safety, 
tolerability, and pharmacokinetic data for further clinical development. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ARV-471 may be found in the IB, which is the SRSD for this study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of itraconazole are provided in the EU SmPC, 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 
CCI 
 
CCI 
based on CCI 
 
to date as per Section 2.2.3. 
CCI 
 modeling analysis 
revealed a CCI  
 
 
Thirteen participants were reported 
with CCI 
CCI 
 in the ongoing FIH study 
CCI 
 
 ; for 12 
participants the event was considered 
related. An external CCI 
 
consultant review concluded that 2 
participants had a true diagnosis of 
CCI 
 of which CCI 
were confounding factors. 
Clinical safety not yet fully 
characterized. 
Participants receive a single dose during Periods 1 and 2 with a washout of at least 
10 days between administration of ARV-471 doses. 
Participants will be monitored for CCI 
 changes with CCI 
 at 
screening and during the study intervention period (Table 3 and Table 4). 
Participants at high risk of CCI 
 as per EC #9 are excluded from 
participation in the study (see Section 5.2). 
Use of prescription or nonprescription medications, including vitamins, herbal and 
dietary supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products are prohibited within 7 days prior to the 
first dose of study intervention, with the exception of moderate/potent CYP3A 
inducers which are prohibited within 14 days plust 5 half-lives prior to the first dose of 
study intervention. Limited use of nonprescription medications that are not believed to 
affect participant safety or the overall results of the study may be permitted on a case 
by case basis following approval by the sponsor. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Venous Embolism 
Potential risk based on metastatic 
cancer setting and known class effect 
with CCI 
 
One Grade 3 related CCI  
 case, 
with confounding factors of obesity, 
diabetes and immobility due to recent 
biopsy procedure, and a Grade 3 
serious CCI 
 case assessed as 
unlikely related to ARV-471 by the 
investigator, were reported in the FIH 
Study CCI 
 
 
Participants receive a single dose during Periods 1 and 2 with a washout of at least 
10 days between administration of ARV-471 doses. 
Participants with a history of clinically significant CCI 
 
events are excluded from participation in the study as per EC #1 (see Section 5.2). 
Study Intervention(s) Itraconazole 
Hepatotoxicity 
Itraconazole has been associated with 
rare cases of serious hepatotoxicity, 
including liver failure and death. 
AEs, vital signs, ECGs, and clinical laboratory test results will be monitored on an 
ongoing basis. Instructions for managing potential cases of drug induced liver injury, 
should they occur, are provided in Appendix 6. 
Participants will be monitored for QT interval changes with ECG monitoring at 
screening and during the study intervention period (Table 3 and Table 4). 
Participants at high risk of QT prolongation as per EC #9 are excluded from 
participation in the study (see Section 5.2). 
Cardiac Dysrhythmias 
Life-threatening cardiac dysrhythmias 
and/or sudden death have occurred in 
patients using drugs such as cisapride, 
pimozide, methadone, or quinidine 
concomitantly with itraconazole 
and/or other CYP3A inhibitors. 
Cardiac Disease 
Itraconazole has been associated with 
reports of congestive heart failure. In 
post-marketing experience, heart 
failure was more frequently reported 
in patients receiving a total daily dose 
of 400 mg although there were also 
cases reported among those receiving 
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2.3.2. Benefit Assessment 
Participants are not expected to receive any clinical benefit. Participants contribute to the 
process of developing a new therapy for the treatment of patients with ER+/HER2- breast 
cancer. 
2.3.3. Overall Benefit/Risk Conclusion 
Taking into account the measures 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 in the future to patients with ER+HER- metastatic breast cancer. 
3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary: 
• 
To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a single oral 
200 mg dose of ARV-471. 
Primary: 
• Plasma AUCinf and Cmax of ARV-471 and ARV-473, as 
data permits (AUClast if AUCinf cannot be estimated). 
Secondary: 
• 
To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a single oral 
200 mg dose of ARV-471. 
• Plasma AUClast, Tmax, t1/2, CL/F and Vz/F of ARV-471 
and ARV-473, as data permits. 
• 
To evaluate the safety and tolerability of a single 
oral 200 mg dose of ARV-471 administered to 
healthy participants in the absence and presence of 
multiple doses of itraconazole under fed conditions. 
• Safety laboratory tests, physical examination, vital signs, 
electrocardiograms, concomitant medication and adverse 
event monitoring. 
 
4. STUDY DESIGN 
4.1. Overall Design 
This is a Phase 1, open-label, 2-period fixed-sequence crossover study to estimate the effect 
of multiple doses of the strong CYP3A inhibitor, itraconazole, on ARV-471 and ARV-473 
pharmacokinetics in healthy males, and females of nonchildbearing potential. A total of 
approximately 12 participants will be enrolled in the study. The study will consist of 
2 periods; Period 1 = single dose of ARV-471 alone and Period 2 = multiple doses of 
itraconazole + single dose of ARV-471. Following Period 1, a washout period of at least 
10 days must occur between the 2 single doses of ARV-471. Following administration of 
ARV-471 in each period, participants will undergo serial PK sampling. Participants who 
withdraw may be replaced at the discretion of the sponsor. 
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment (ie, within 28 days prior to Day 1 of Period 1). Medical history and results of 
physical examination, physical measurements, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will determine eligibility. 
In Period 1 (ARV-471 alone), each participant will be admitted to the research unit on 
Day -1. Participants will be required to remain in the research unit for at least 4 days until 
completion of the 72-hour PK sampling on Day 4, after which participants may be eligible 


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for discharge. Two additional outpatient visits (Days 5 and 6) are required to complete the 
PK sampling for Period 1. Alternatively, participants may be kept in-house through Day 12 
of Period 2 at the discretion of the investigator. 
Participants will be required to return to the research unit to start Period 2 at least 1 day after 
collection of the last PK sample on Day 6 of Period 1 in order to have at least 10 days 
between the 2 successive doses of ARV-471, and 4 days of pre-treatment with itraconazole. 
Participants may be admitted to the research unit on or before Day -1 of Period 2 until 
completion of 168-hour PK sampling on Day 12 of Period 2, after which participants will be 
discharged. The total study duration for each participant will be at least 17 days. 
On Period 1 Day 1, participants will be provided the recommended high fat, high calorie 
breakfast 30 minutes prior to administration of ARV-471. No food will be allowed for at 
least 4 hours post-dose. Each participant will undergo serial blood samplings at pre-dose 
(before breakfast) and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after ARV-471 
administration to determine plasma concentrations of ARV-471. 
During Period 2 Day 1 through Day 11 (except Day 5 for ARV-471 administration), 
participants will receive an itraconazole oral solution dose of 200 mg once daily under fasted 
conditions. Itraconazole does not need to be administered under fasted conditions on Day 5. 
No food will be allowed for at least 1 hour post itraconazole dose. 
On Period 2 Day 5, participants will be provided a high fat, high calorie breakfast 30 minutes 
prior to the concomitant administration of itraconazole and ARV-471. Itraconazole 200 mg, 
as 20 mL Sporanox 10 mg/mL oral solution will be administered first, immediately followed 
by two 100 mg tablets of ARV-471. The study drugs (itraconazole and ARV-471) should be 
administered with approximately 220 mL of ambient temperature water. No food will be 
allowed for at least 4 hours following ARV-471 administration. PK sampling will be 
followed up to 168 hours on Day 12 (the planned time points include pre-dose, 1, 2, 4, 6, 8, 
12, 24, 48, 72, 96, 120, 144, and 168 hours). 
Physical examinations, 12-lead ECG, vital sign measurements, and clinical laboratory tests 
will be conducted and adverse events will be monitored throughout the study to assess safety. 
A safety follow-up visit may be conducted at the discretion of the investigator. 
ARV-471 will be supplied by Pfizer as 100 mg tablets. Itraconazole (Sporanox®) oral solution 
for this study will be sourced locally by the CRU. 
4.2. Scientific Rationale for Study Design 
Study Treatment and Dose Rationale for Itraconazole: Itraconazole and its primary 
metabolite (hydroxy-itraconazole) are specific strong inhibitors of CYP3A. For these 
characteristics, along with its safety profile, itraconazole has often been utilized as a 
perpetrator drug for CYP3A inhibition PK drug interaction studies.3, 4, 5, 6 Since ARV-471 is a 
substrate for CYP3A, concomitant administration of multiple doses of itraconazole along 
with ARV-471 may lead to increased systemic exposure of ARV-471. This may require 
ARV-471 dose adjustment when it is utilized with medications that are strong 


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CCI 
CYP3A inhibitors. The objective of this study is to estimate the effect of multiple doses of 
itraconazole on the PK of ARV-471. 
Itraconazole 200 mg is a typical clinical dose that achieves adequate strong CYP3A 
inhibition.7 PK data indicates that itraconazole 200 mg oral solution provides highest 
itraconazole and hydroxy-itraconazole (both of which inhibit CYP3A) plasma exposure with 
less PK variability, when compared to itraconazole 200 mg capsules given in either fed or 
fasted states.7, 8,9,10 Though exposure is maximized under fasted conditions with the solution 
formulation, oral exposures of itraconazole and hydroxy-itraconazole achieves adequate 
CYP3A inhibition under fed conditions.7 
Washout period: Following a single dose of 200 mg ARV-471 administered with a high-fat 
meal, ARV-471 geometric mean terminal half-life was approximately CCI hours. Thus, a CCI 
is considered adequate for the washout of the ARV-471 from plasma. During the study, 
plasma concentrations should typically have dropped to BLQ before administration of the 
next dose (ie, no residual concentrations from the prior period) to minimize the carryover 
from the previous treatment. 
Rationale for study population 
Healthy Adults 
Singles doses of ARV-471 200 mg was well tolerated in a Phase 1, multi-part, open-label 
study to evaluate the effect of food or a proton-pump inhibitor (esomeprazole) and to 
evaluate the relative bioavailability of different tablet formulations in healthy 
post-menopausal female participants. 
It is well acknowledged that protein degradation and resynthesis rates are equal in the steady 
state.11 ER protein levels are regulated by the ubiquitin-proteosome system12 and 
resynthesized to maintain proper ER levels. The t½ of ER is 1-3 hours in the presence of 
estradiol or dimethyl sulfoxide.13, 14 In vitro nonclinical pharmacology studies demonstrated 
that ARV-471-mediated ER degradation was CCI 
 of ER 
following compound removal. Therefore, it is anticipated that ER will be rapidly 
CCI 
 as systemic levels of ARV-471 decline in healthy participants after 
administration of single doses of ARV-471 in this study. Because washout of ARV-471 and 
CCI 
 is anticipated within 28 days, the risk of long-term adverse effects from a 
single dose of 200 mg ARV-471 is considered low. 
Females of Non-childbearing Potential 
ARV-471 is known to cause 
in the CCI 
rats and dogs and male dogs, which may be regarded as CCI 
, and which are considered related to the CCI  
of 
ARV-471. Therefore, there is a CCI 
of CCI 
. Studies to 
evaluate the CCI 
CCI 
CCI 
of ARV-471 in CCI 
ARV-471 may cause CCI 
therefore CCI 
. However, 
when administered to the 
. 


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CCI 
Males 
Nonclinical toxicology studies are reviewed in Sections 2.2.1-2.2.3 and the most recent IB is 
included for reference. 
The repeat dose CCI 
 studies in rats and dogs have consistently shown ARV-471 to be 
CCI 
 after once-daily dosing. The 3-month studies have shown CCI 
 of 
CCI  and CCI 
and CCI 
 of the animals following daily oral 
doses of ARV-471 up to CCI mg/kg/day in rats and CCI mg/kg/day in dogs. Across the studies, 
there were CCI 
 , or CCI 
 
 
In all studies, the pharmacologic effects of ARV-471 were on the CCI 
 
affected in the toxicology studies in both rat and dog 
are known to express both ERa and ERb. Findings in the CCI 
 
and, at 
low doses, CCI 
 are consistent with the 
CCI 
 of ARV-471 on the ER and have been observed for agents that target 
the ER (eg, fulvestrant). 
Findings in CCI 
 were only observed in the dog and CCI 
 were 
noted in the rat in studies up to 3-month in duration. In the 28-day toxicity study 
ARV-471-related CCI 
 effects included CCI 
 
in animals administered ≥CCI mg/kg/day. ARV-471-related CCI 
noted in recovery sacrifice males included CCI 
 
of the 
and 
, which correlated 
with CCI 
. These findings in CCI 
 
may have reflected the CCI 
after degradation 
of the ER, compared to the CCI 
 
. A contributing factor to the 
effects on the CCI 
 CCI 
) in the 28-day toxicity studies is likely 
the male dog sexually maturity at the initiation of dosing (7-9 months old). The male 
specific findings were considered non-adverse and NOAEL of CCI mg/kg/day was 
determined. In a follow-up 3-month (91-day) study the key findings in males consisted of 
CCI 
 in the CCI 
 of the CCI 
) and CCI 
 
at CCI mg/kg/day with 
in the 3-month toxicity study may be 
explained by the sexual maturity of the dogs at the initiation of dosing. The exposure margins 
for testicular toxicity in rat and dog toxicity studies are shown in Table 5. 
CCI 
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There was no evidence of effects on 
CCI 
Table 5. 
Exposure Margin Determination for CCI 
 in Rat and Dog 
Toxicity Studies 
 
Species 
Duration of 
ARV-471 
administration 
No effect or no 
adverse effect dose 
(mg/kg/day) 
Male Total 
AUC24 
(ng•h/mL) 
Total Predicted Margins 
with Itraconazolea 
Low 
Mediu 
m 
High 
Rat 
7 days 
300 (NOEL) CCI 
Rat 
28 days 
100 (NOEL) 
Rat 
91 days 
300 (NOEL) 
Dog 
7 days 
120 (NOAEL) 
Dog 
28 days 
90 (NOAEL) 
Dog 
91 days 
90 (NOAEL) 
a. 
Total predicted margins with itraconazole were based on the geometric mean AUCinf (CCI 
ng*h/mL) following 
a single 200 mg dose of ARV-471 administered with a high fat meal in Study CCI  
 3. Predicted 
AUCs were calculated from AUCinf multiplied by an AUCR of CCI 
based on ARV-471 fm,CYP3A 
values of CCI 
 for the low, medium, and high columns, respectively. AUCR values reflect the 
magnitude of the model-predicted effect of the strong CYP3A inhibitor, itraconazole. 
 
In vitro CCI 
 have been conducted with ARV-471 to CCI 
 of 
studies in healthy participants and results are CCI 
. 
While a single dose of ARV-471 may carry CCI 
 of producing CCI 
 
based on theCCI 
of ARV-471, the risk of 
 
the 
, confirming 
. Learnings from 
published literature support the position that male tissues would fully recover and there 
would not be a permanent effect on male fertility.15 The chronic administration of fulvestrant 
(selective estrogen receptor degrader) in dogs followed by a recovery period of 6 months 
demonstrated no long-term impact on fertility in male dogs (FDA website summary basis of 
approval) and full recovery of male tissues. These key data support the reversibility and 
resumed normal function in adult male animals when estrogen signaling is reengaged. 
Additionally, literature review of a total of 21 drugs administered at a single dose level and a 
single administration, to adult male mice, and groups of mice were euthanized and examined 
over the course of 56 days.16, 17 Given the germ cell kinetics in the mouse testis, measuring 
testicular spermatid heads 56 days after treatment reflects the activity of the stem cell 
spermatogonia, and presumably the long-term spermatogenic activity of the testis thereafter. 
Using doses at or near the LD50, most drugs gave modest or no detectable change at 56 days. 
Nineteen conventional chemotherapeutic drugs, given to mice as a single administration at or 
near the LD50, caused no permanent sterility.16, 17 Only 2 out of 21 drugs tested (thiotepa and 
ADR) produced a permanent reduction >50% in testicular spermatid heads. In addition, Lu et 
al pointed out that “the effects of ADR in humans appeared to be less drastic than in mice. 
Two of 4 patients who received ≥400 mg/m2 doses of ADR still possessed sperm counts of 


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over 2 million.”16 Meistrich et al also pointed out that these 2 drugs, thiotepa and adriamycin, 
are strong mutagens, 
.17 
In summary, given that the CCI 
 tested provided a CCI 
 
based on estimated low, medium, and high ARV-471 exposure, 
respectively, when given with a strong inhibitor of CYP3A4, itraconazole in the 3-month 
toxicity study, the CCI 
to spermatogenic activity in dogs shown in all 
studies to date, the CCI 
 in the rat and also the profile in mice for the 
nongenotoxic drugs at doses around the LD50 in the literature, the risk of any CCI 
is assessed to beCCI 
when ARV-471 is administered as a single oral 
dose. 
The current study will be conducted in healthy participants who will receive single oral doses 
of ARV-471 200 mg alone and concomitantly with itraconazole in the fed state with at least a 
10 day washout period between ARV-471 doses. As indicated above, for a single oral 
200 mg dose the CCI 
 provides a safety margin ofCCI fold 
based on estimated medium ARV-471 exposure with respect to theCCI 
 in the 3- 
month toxicity study recommended by ICH Guidance. Plasma exposure of ARV-471 is 
generally dose-proportional within the dose range of 30 to 500 mg QD in humans. Based on 
the expected increase in ARV-471 systemic exposure in the presence of itraconazole 
(estimated to be CCI-fold increase for AUC following concomitant administration of a single 
200 mg dose of ARV-471 with itraconazole compared to ARV-471 alone (Section 4.3), and 
assuming dose proportionality, then the extrapolated safety margin over the effect of male 
reproductive effects when a single 200 mg oral dose of ARV-471 is given with itraconazole 
is projected to be an acceptable fold safety margin. Exposure margins estimates are provided 
in Table 8 and Table 9 in Section 4.3 for rat and dog, respectively. 
4.2.1. Choice of Contraception/Barrier Requirements 
ARV-471 is known to CCI 
 
 
 in 
humans or suspected on the basis of the  
. Therefore, the use of a 
CCI 
 is required (see Appendix 4). 
4.2.1.1. Females 
Females of childbearing potential will not be allowed in this study. 
Female participants of non-childbearing potential must meet at least one of the criteria 
defined in Section 5.1 (all other female participants, including females with tubal 
ligations, will be considered to be of childbearing potential; Inclusion Criterion #1). 
4.2.1.2. Males 
All fertile male participants who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must agree to use a highly effective 
method of contraception consistently and correctly for the duration of the active 
treatment period and continue for at least 90 days after the last dose of investigational 
product (ARV-471). The investigator or his or her designee, in consultation with the 
participant, will confirm that the participant has selected an appropriate method of 
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contraception for the individual participant and his partner from the permitted list of 
contraception methods and instruct the participant in its consistent and 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). 
In addition, the investigator or his or her 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 the participant’s partner. 
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 
A single dose of 200 mg ARV-471 has been tested in a Phase 1, multi-part, open-label study 
to evaluate the effect of food or a proton-pump inhibitor (esomeprazole) and to evaluate the 
relative bioavailability of different tablet ARV-471 formulations in healthy post-menopausal 
female participants. In the food effect part of the study, geometric mean AUCinf and Cmax 
ARV-471 CCI 
, respectively, when ARV-471 was administered with 
a high-fat, high caloric meal compared to under fasted conditions. 
Multiple daily doses up to 700 mg ARV-471 have been shown to be safe and well tolerated 
in patients with mBC. Following multiple doses of 500 mg daily, geometric mean AUC tau on 
Cycle 1 Day 15 was 
 ng*h/mL in CCI 
 In the food effect portion of 
Study CCI 
, the geometric mean AUCinf following a single dose of 
ARV-471 200 mg administered with a high fat meal wasCCI 
 ng*h/mL (nCCI) (Table 
6). Using the in vitro-derived point estimate of ARV-471 fm,CYP3A of CCI, ARV-471 plasma 
exposure when administered under fed conditions with a high fat meal is estimated to be 
CCI  ng*h/mL, which is CCI than AUCtau observed for 500 mg daily dosing on Cycle 1 
Day 15 in CCI 
. 
 
Table 6. 
Summary of Plasma ARV-471 AUCinf (h*ng/mL) by Treatment 
(Fed/Fasted) in Study CCI 
 
 
AUCinf (h*ng/mL) 
ARV-471 200 mg Fasted 
(N=CCI ) 
ARV-471 200 mg Fed (N= CCI ) 
n 
CCI  
Mean 
SD 
CV% 
Median 
Minimum 
Maximum 
Geometric mean 
Geometric CV% 


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CCI 
CCI 
CCI 
CCI 
CCI 
 
Table 6. 
Summary of Plasma ARV-471 AUCinf (h*ng/mL) by Treatment 
(Fed/Fasted) in Study CCI 
 
 
Note: Geometric CV% = 100 × (exp[SD2]-1)0.5, where SD is the standard deviation of the logarithmic- 
transformed data. 
AUCinf = area under the plasma concentration-time curve from the time of dosing extrapolated to infinity 
 
An in vitro study was conducted to provide a preliminary estimate of the fraction of 
 
The preliminary estimate of ARV-471 fm,CYP3A is CCI(ie, CYP3A accounts for CCIof the 
metabolic clearance of ARV-471). 
The magnitude of the model-predicted effect of the strong CYP3A inhibitor itraconazole 
(200 mg QD; solution formulation, fasted state) on the PK of ARV-471, over a range of 
ARV-471 fm,CYP3A values of CCI  , is summarized in Table 7. 
 
Table 7. 
Mechanistic static DDI model predictions of the effect of steady-state 
itraconazole (200 mg QD) on the PK of ARV-471 
 
Prediction 
Object Drug 
fm,CYP3A 
AUCR of Object Drug 
Predicted 
Observed 
P/O 
Point Estimate 
ARV-471 CCI 
-- 
-- 
Sensitivity Analysis (Low) 
ARV-471 
-- 
-- 
Sensitivity Analysis (High) 
ARV-471 
-- 
-- 
Positive Control 
lorlatinib 
CCI 
 
Using the in vitro-derived point estimate of ARV-471 fm,CYP3A of 
predicted to increase ARV-471 exposure by CCI (AUCR = 
itraconazole is 
). A sensitivity analysis of 
ARV-471 fm,CYP3A 
) resulted in predicted increases in ARV-471 exposure 
ranging fromCCI  (AUCR = CCI 
 (AUCR = CCI), respectively. This prediction 
indicates that ARV-471 plasma exposures are not expected to be substantially increased (eg, 
CCI-fold) in the presence of a strong CYP3A inhibitor like itraconazole. 
Exposure margins estimates are provided in Table 8 and Table 9 below for rat and dog, 
respectively. 
In rats, 
mg/kg/day was identified as the CCI  for daily dosing for 3 months in males. 
A CCI 
 
 for females based upon CCI 
 in the female 
reproductive tract that were consideredCCI 
, however these findings were consistent with 
the CCI 
 
 
 of ARV-471 and are expected to be  
based on 
other toxicity studies with ARV-471. In dogs, CCI mg/kg/day was identified as the CCI  
ARV-471 metabolized by CYP3A (fm,CYP3A). As metabolic turnover of ARV-471 is CCI in 
human in vitro metabolic systems, a CCI 
approach was utilized. CCI 
were used as the preferred in CCIsystem, as they are 
considered a CCI 
. 


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CCI 
CCI 
for daily dosing for 3 months in males. CCI 
 for females 
based upon 
in the CCI 
again attributed to the 
CCI 
 of ARV-471. CCI 
 were identified, 
and all findings are expected to be CCI 
. 
The nonclinical toxicity assessments up to 3 months support the safety of ARV-471 and 
confirm the CCI 
key identified effects on CCI 
. The projected maximal AUC 
with the 
(CCI  ng*h/mL) that may be achieved in the current clinical study was exceeded in both 
rats and dogs in the 3-month toxicity studies and was CCI 
 with key findings associated 
with the pharmacological effects of ARV-471. The margins based on the fed state are CCI- 
CCI 
 
 in rats and CCI 
 
 in dogs 
based on estimated low, medium, and high ARV-471 exposure, respectively, when given 
with a strong inhibitor of CYP3A4, itraconazole. The nonclinical profile supports the 
administration of the proposed two dose regimen in study C4891009 and increased exposures 
in patients would be anticipated to be 
. 
 
Table 8. 
Repeat Dose Toxicity Study ARV-471 Exposure Margins in Male and 
Female Rats 
 
Study 
Male Rats 
Female Rats 
Dose, 
mg/kg/ 
day 
Total 
AUCa, 
ng*h/ 
mL 
Total Predicted Margins 
with Itraconazoleb 
Dose, 
mg/kg/ 
day 
Total 
AUCa, 
ng*h/ 
mL 
Total Predicted Margins 
with Itraconazole 
Low 
Mediu 
m 
High 
Low 
Mediu 
m 
High 
7 Day 
30 CCI 
30 CCI 
7 Day 
100 
100 
7 Day 
300 
300 
28- 
Day 
3 
3 
28- 
Day 
10 
10 
28- 
Day 
30 
30 
28- 
Day 
100c 
100c 
3- 
Month 
30 
30 
3- 
Month 
100 
100c 
3- 
Month 
300c 
300 
a. 
Day last 
b. 
Total predicted margins with itraconazole were based on the geometric mean AUCinf CCI 
 
ng*h/mL) following a single 200 mg dose of ARV-471 administered with a high fat meal in Study CCI 
 
. Predicted AUCs were calculated from AUCinf multiplied by an AUCR of CCI 
based on ARV-471 fm,CYP3A values of CCI 
, for the low, medium, and high columns, 
respectively. AUCR values reflect the magnitude of the model-predicted effect of the strong CYP3A 
inhibitor, itraconazole. 
c. 
NOAEL 


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CCI 
Table 9. 
Repeat Dose Toxicity Studies Exposure Margins in Male and Female 
Beagle Dogs 
 
Male Dogs 
Female Dogs 
Study 
Dose, 
mg/kg/ 
day 
Total 
AUCa, 
ng*h/ 
mL 
Total Predicted Margins 
with Itraconazoleb 
Dose, 
mg/kg/ 
day 
Total 
AUCa, 
ng*h/ 
mL 
Total Predicted Margins 
with Itraconazoleb 
Low 
Mediu 
m 
High 
Low 
Mediu 
m 
High 
7 Day 
30 CCI 
30 CCI 
7 Day 
60 
60 
7 Day 
120 
120 
28-Day 
15 
15 
28-Day 
45 
45 
28-Day 
90c 
90c 
3- 
Month 
10 
10 
3- 
Month 
30 
30 
3- 
Month 
90c 
90 
a. 
Day last 
b. 
Total predicted margins with itraconazole were based on the geometric mean AUCinf (CCI 
 
ng*h/mL) following a single 200 mg dose of ARV-471 administered with a high fat meal in Study CCI 
 
. Predicted AUCs were calculated from AUCinf multiplied by an AUCR of 
based on ARV-471 fm,CYP3A values of CCI 
 for the low, medium, and high columns, 
respectively. AUCR values reflect the magnitude of the model-predicted effect of the strong CYP3A 
inhibitor, itraconazole. 
c. 
NOAEL 
 
 
4.4. End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
for the last participant in the trial. 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last scheduled procedure shown in the SoA. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, and race, and ethnicity. 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. 


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5.1. Inclusion Criteria 
Participant eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before participants are included in the study. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Healthy male and/or female participants of non-childbearing potential who are overtly 
healthy as determined by medical evaluation and are between the ages of 18 and 
65 years, inclusive at the time of signing the ICD. Healthy is defined as no clinically 
relevant abnormalities identified by a detailed medical history, full physical 
examination, including blood pressure and pulse rate measurement, 12-lead ECG or 
clinical laboratory tests. Female participants of non-childbearing potential must meet 
at least one of the following criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum FSH level 
confirming the post-menopausal state; 
b. Have undergone a documented hysterectomy, bilateral salpingectomy, and/or 
bilateral oophorectomy; 
c. Have medically confirmed ovarian failure. 
All other female participants (including females with tubal ligations and females that 
do NOT have a documented hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy and/or ovarian failure) will be considered to be of childbearing 
potential. 
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) 
participants. 
Other Inclusion Criteria: 
2. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg. 
3. Evidence of a personally signed and dated informed consent document indicating that 
the participant has been informed of all pertinent aspects of the study. 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 


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Medical Conditions: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, cerebrovascular, hepatic, psychiatric, 
neurological, or allergic disease (including drug allergies, but excluding untreated, 
asymptomatic, seasonal allergies at the time of dosing). 
• Any condition possibly affecting drug absorption (eg, gastrectomy). 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 
2. Pregnant female participants, breastfeeding female participants, female participants of 
childbearing potential. Male participants with partners currently pregnant; fertile male 
participants who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for 90 days 
after the last dose of investigational product. 
3. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy: 
4. Use of prescription or non-prescription medications, including vitamins, herbal and 
dietary supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products within 7 days prior to the first dose of 
study intervention with the exception of: 
• Moderate/potent CYP3A inducers which are prohibited within 14 days plus 
5 half-lives prior to the first dose of study intervention 
• Moderate/potent CYP3A inhibitors which are prohibited within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. 
5. Current use of any prohibited concomitant medication(s) or participant 
unwilling/unable to use a permitted concomitant medication(s). 
Refer to Section 6.9 Prior and Concomitant Therapy. 
Prior/Concurrent Clinical Study Experience: 
6. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 


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Diagnostic Assessments: 
7. A positive urine drug test or alcohol breath test at discretion of investigator. 
8. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility. 
9. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, 
STT interval changes suggestive of myocardial ischemia, second- or third- degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice 
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant. 
10. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• AST or ALT level >1.0 × ULN; 
• Total bilirubin level >1.0 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
11. Renal impairment as defined by an eGFR<60 mL/min/1.73m2. Based upon 
participant age at screening, eGFR is calculated using the recommended CKD-EPI 
formulas in Table 14 to determine eligibility and to provide a baseline to quantify any 
subsequent kidney safety events. 
Other Exclusion Criteria: 
12. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 
13. History of use of tobacco or nicotine-containing products in excess of the equivalent 
of 5 cigarettes/day or 2 chews of tobacco/day. 


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14. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
15. Known hypersensitivity or previous adverse events associated with azole antifungals 
or any of the formulation components of ARV-471. 
16. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
17. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
18. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
5.3. Lifestyle Considerations 
The following guidelines are provided: 
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in 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 and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner. 
5.3.2. Meals and Dietary Restrictions 
• Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to ARV-471 dose 
administration and itraconazole dose administration days in both Periods 1 and 2. 
Participants must also abstain from all food and drink (except water) at least 4 hours 
post ARV-471 dose on Period 1 Day 1 and Period 2 Day 5. 


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• Water will be permitted until 1 hour prior to ARV-471 administration on Period 1 
Day 1 and Period 2 Day 5. Water may be consumed without restriction beginning 1 
hour after ARV-471 administration on Period 1 Day 1 and Period 2 Day 5. There will 
be no water restrictions for itraconazole dosing. 
• On Period 1 Day 1 and Period 2 Day 5, participants will be provided the 
recommended high fat (approximately 50% of total caloric content of the meal), high- 
calorie (approximately 800‑1000 calories with 150, 250, and 500-600 calories from 
protein, carbohydrate and fat, respectively) breakfast 30 minutes prior to 
administration of ARV-471. This meal will be consumed within a 20-minute period, 
with study drug (ARV-471) administered with approximately 240 mL of ambient 
temperature water within approximately 10 minutes after completion of the meal. 
• During Period 2 Day 1 through Day 11 (except Day 5 for ARV-471 dosing), 
participants should take itraconazole under fasted conditions at approximately the 
same time each day. Itraconazole does not need to be administered under fasted 
conditions on Day 5. No food will be allowed for at least 1 hour post itraconazole 
dose. 
• Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices—see 
below) may be consumed with meals and the evening snack. 
• Lunch will be provided at least 4 hours after dosing with ARV-471. 
• Dinner will be provided approximately 9 to 10 hours after dosing with ARV-471. 
• An evening snack may be permitted. 
• Participants will refrain from consuming red wine, grapefruit, or grapefruit--related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 
• While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal. 
5.3.3. Caffeine, Alcohol, and Tobacco 
• Participants will abstain from caffeine containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 
• Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample of each study 
period. Participants may undergo an alcohol breath test or blood alcohol test at 
screening and Day -1, at the discretion of the investigator. 


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• Participants will abstain from the use of tobacco or nicotine containing products for 
24 hours prior to dosing and during confinement in the CRU. 
5.3.4. Activity 
• Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted. 
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. Screen failure data are collected and remain as 
source and are not reported on the CRF. 
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 interventions are all prespecified investigational and non-investigational medicinal 
products, medical devices, and other interventions (eg, surgical and behavioral) intended to 
be administered to the study participants during the study conduct. For the purposes of this 
protocol, study interventions refers to investigational product ARV-471 and itraconazole. 
6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
ARV-471 (PF-07850327) 
Itraconazole 
Type 
Drug 
Drug 
Dose Formulation 
Tablet 
Oral Solution 
Unit Dose Strength(s) 
100 mg 
10 mg/mL 
Dosage Level(s) 
200 mg 
200 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Experimental treatment to assess an endpoint 
IMP or NIMP/AxMP 
IMP 
NIMP/AxMP 
Sourcing 
Provided centrally by the sponsor 
Sourced locally by the trial site 


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Study Intervention(s) 
Packaging and Labeling 
Study intervention will be provided in 
high-density polyethylene bottle with 
child resistant cap. Each bottle will be 
labeled as required per country 
requirement. 
Study intervention will be dispensed into oral 
syringes 
Current/Former Name(s) 
or Alias(es) 
ARV-471 
(PF-07850327) 
Itraconazole (Sporanox) 
ARV-471 will be supplied to the CRU as a bulk supply in high-density polyethylene bottles 
with child-resistant caps and labelled according to local regulatory requirements. The bulk 
supply will be provided to the site for dispensing by the pharmacy. Itraconazole (Sporanox®) 
will be supplied locally by the CRU. 
6.1.1. Administration 
Period 1 Day 1: Following an overnight fast of least 10 hours and after the collection of the 
pre-dose ARV-471 PK sample, participants will start the recommended high fat, high-calorie 
breakfast consumed prior to administration of ARV-471, as two 100 mg tablets. Participants 
will receive study medication at approximately 0800 hours (plus or minus 2 hours). 
Investigator site personnel will administer study medication with ambient temperature water 
to a total volume of 240 mL. Participants will swallow the study medication whole and will 
not manipulate or chew the medication prior to swallowing. No additional food will be 
allowed for at least 4 hours post dose. 
Period 2 Days 1-4 and 6-11: Following an overnight fast of at least 10 hours, participants 
will be administered 200 mg itraconazole (as 20 mL Sporanox 10 mg/mL oral solution) once 
daily under fasted conditions with approximately 220 mL of water. No food will be allowed 
for at least 1 hour post itraconazole dose. 
Period 2 Day 5: Following an overnight fast of at least 10 hours and after the collection of 
the pre-dose ARV-471 PK sample, participants will start the recommended high fat, 
high-calorie breakfast consumed prior to the concomitant administration of itraconazole and 
ARV-471. Participants will receive study medications at approximately 0800 hours (plus or 
minus 2 hours). Itraconazole 200 mg, as 20 mL Sporanox 10 mg/mL oral solution will be 
administered first, immediately followed by the two 100 mg tablets of ARV-471. The study 
drugs (itraconazole and ARV-471) should be administered with approximately 220 mL of 
ambient temperature water. Participants will swallow the ARV-471 tablets whole, and will 
not manipulate or chew the medication prior to swallowing. No additional food will be 
allowed for at least 4 hours post dose of both drugs. 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm that appropriate conditions 
(eg, temperature) have been maintained during transit for all study interventions 


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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, prepare, and/or administer study intervention. 
3. 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 upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
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 excursion definition and information to 
report for each excursion will be provided to the site. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
6. Study interventions should be stored in their original containers. 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff 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. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU site procedures. 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. 


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6.2.1. Preparation and Dispensing 
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider or 
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities. 
ARV-471 tablets will be prepared at the CRU in the individual dosing containers by 
2 operators, 1 of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets will be provided in unit dose containers and 
labeled in accordance with Pfizer regulations and the clinical site’s labeling requirements. 
Commercial itraconazole (Sporanox ®) oral solution will be dispensed at the CRU into oral 
syringes by 2 operators, 1 of whom is an appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance and 
labeled in accordance with Pfizer regulations and the investigator site’s labeling 
requirements. 
6.3. Assignment to Study Intervention 
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled. 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number. 
6.4. Blinding 
This is an open-label study. 
6.4.1. Blinding of Participants 
Participants will be unblinded to their assigned study intervention. 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. 
6.4.3. Blinding of the Sponsor 
Sponsor staff will be unblinded to participants’ assigned study intervention. 
6.5. Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 


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administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested. 
6.6. Dose Modification 
Dose modification is not permitted during the study. 
6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose 
For this study, any dose of ARV-471 greater than CCI mg or itraconazole greater than 
200 mg within aCCI  time period will be considered an overdose. 
There is no specific treatment for an overdose 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the study medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
5. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
6.9. Prior and Concomitant Therapy 
Use of prescription or non-prescription medications, including vitamins, herbal and dietary 
supplements, grapefruit/grapefruit containing products, and Seville orange/Seville orange 
containing products within 7 days prior to the first dose of study intervention with the 
exception of: 
• Moderate/potent CYP3A inducers which are prohibited within 14 days plus 
5 half-lives prior to the first dose of study intervention 


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• Moderate/potent CYP3A inhibitors which are prohibited within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. 
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. Acetaminophen/paracetamol may be used at doses of ≤1 g/day. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
6.9.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with ARV 471 or itraconazole; 
standard medical supportive care must be provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following. 
• AE requiring discontinuation at the discretion of investigator 
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention. 
7.1.1. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment may continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case temporary or permanent discontinuation may be required. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
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 include the following: 
• Unacceptable toxicity; 


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• Significant protocol violation; 
• Lost to follow-up; 
• Participant refused further treatment; 
• Study terminated by sponsor; 
• Death. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
If a participant withdraws from the study, they 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 will be performed and no 
additional data will 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 them 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 the participant 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: 
• 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; 


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• 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, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Administrative and Screening 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. 
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. 
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate. 
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 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 they have 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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If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter. 
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. 
The total blood sampling volume for individual participants in this study is approximately 
125 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol. 
8.1.1. Screening Procedures 
The following procedures will be completed: 
• Obtain written informed consent. 
• Review Inclusion and Exclusion criteria. 
• Confirm proper contraception is being used. 
• Demographics (race, age, gender and ethnicity). 
• Collect height and weight as part of physical examination to obtain BMI for 
eligibility criteria. 
• Obtain medical history, including but not limited to history of drug, alcohol and 
tobacco use as well as blood donation within 60 days prior. 
• Obtain complete medication history of all prescription or nonprescription drugs, 
including vitamins, and dietary and herbal supplements, grapefruit/grapefruit 
containing products, and Seville orange/Seville orange containing products taken 
within 28 days prior to the planned first dose. 
• Conduct full physical examination including height and weight. The Screening 
physical examination may be performed on Day -1, Period 1. 
• Collect single 12-lead ECG. 
• Obtain supine blood BP and PR following at least a 5 minute rest in a supine position. 
• Following at least a 4-hour fast, collect blood and urine specimens for the following: 
o Safety laboratory tests (urinalysis, hematology, and chemistry); 
o Urine drug test (alcohol breath and blood test at discretion of investigator); 
o Serum FSH concentration for any female who has been amenorrheic for at 
least 12 consecutive months without an alternative pathological or 
physiological reason; 
o Collect blood for HBsAb, HBsAg, HBcAb, HCVAb, and HIV testing. 
To prepare for study participation, participants will be instructed on the use of the 
Lifestyle Requirements and Concomitant Treatment(s) sections of the protocol. 


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8.2. Efficacy Assessments 
Efficacy is not evaluated in this study. 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
8.3.1. Physical Examinations 
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
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. 
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 (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3. 
8.3.2. Vital Signs 
8.3.2.1. Blood Pressure and Pulse Rate 
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. 
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 


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Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data. 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 
8.3.3. 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 interval, QT interval, QTcF, and QRS 
complex. 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. At pre-dose on Period 1 Day 1 
and Period 2 Day 5, triplicate 12 lead ECGs will be obtained approximately 2 to 4 minutes 
apart; the average of the triplicate ECG measurements collected at each nominal time point 
and will serve as each participant’s time controlled baseline QTcF value. Single ECGs will 
be collected for all other timepoints. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements for each period. Additional ECG monitoring will 
occur if a) a postdose QTcF interval is increased by ≥60 ms from the baseline and is 
>450 ms; or b) an absolute QT value is ≥500 ms for any scheduled ECG. If either of these 
conditions occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes 
apart to confirm the original measurement. If the QTcF values from these repeated ECGs 
remain above the threshold value, then a single ECG must be repeated at least hourly until 
QTc values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values 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 QTc 
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 Appendix 8. 


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8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 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 
Appendix 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 significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that 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 significant and 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 study 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 Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments 
Participants will undergo COVID-19 related measures per CRU procedures. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 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 


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event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant 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. 
8.4.1. 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 undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days after the last 
administration of the study intervention. 
 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 
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 the 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 they consider 
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. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 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 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available. 


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8.4.1.2. 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 8.4.1, 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. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
8.4.2. 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 Appendix 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. 
8.4.3. 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 provided in Appendix 3. 
8.4.4. 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. 


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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. 
8.4.5. 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 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.4.5.1. 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 
inseminates a female partner. 
• A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of 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 inseminates 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 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant or 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 at least 28 
days after the last dose of ARV-471. 
• 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 
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 should be reported 
as an SAE; 
• 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 


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the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.4.5.2. Exposure During Breastfeeding 
An EDB occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female nonparticipant 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, 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 accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB. 
8.4.5.3. 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. 
8.4.6. Cardiovascular and Death Events 
Not applicable. 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.4.8. Adverse Events of Special Interest 
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. Should an aggregate analysis indicate that 


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these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOP. 
AEs that are considered AESIs for ARV-471 include CCI 
. Based on 
current understanding of the safety profile, no expedited reporting by the investigator to 
sponsor is required for non-serious AESIs. Additional details and mitigation strategies are 
summarized in Section 8.4.1. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form. 
8.4.8.1. Lack of Efficacy 
This section is not applicable because efficacy is not expected in the study population. 
8.4.9. Medical Device Deficiencies 
Not Applicable. 
8.4.10. 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. 


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Medication errors are recorded and reported as follows: 
 
Recorded on the 
Medication Error Page 
of the CRF 
Recorded on the 
Adverse Event Page 
of the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
All (regardless of whether 
associated with an AE) 
Any AE or SAE associated 
with the medication error 
Only if associated with an 
SAE 
Medication errors include: 
• 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. 
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. 
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 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of ARV-471 and ARV-473 
Whole blood samples of approximately 3 mL, to provide a minimum of 1 mL plasma, will be 
collected for measurement of plasma concentrations of ARV-471 and ARV-473 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. The actual date and time (24-hour clock 
time) of each sample will be recorded. 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) 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. Collection of samples more than 10 hours after dose 
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 


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the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows. 
Samples will be used to evaluate the PK of ARV-471 and ARV-473. Each plasma sample 
will be divided into 2 aliquots for PK analyses (one aliquot to be shipped, the other aliquot to 
remain at the site as a backup sample). Samples collected for analyses of ARV-471 and 
ARV-473 plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
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. 
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 reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
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 informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.5.2. Derivation of Pharmacokinetic Parameters 
PK parameters, as appropriate, will be derived from the ARV-471 and ARV-473 
concentration-time profiles as described in Table 10. 
 
Table 10. Definitions of PK Parameters 
 
Parametera 
Definition 
Method of Determination 
AUClast 
Area under the plasma 
concentration time profile from 
time zero to the time of the last 
quantifiable concentration (Clast) 
Linear-log trapezoidal method. 
AUCinf 
Area under the plasma 
concentration-time profile from 
time zero extrapolated to 
infinite time 
AUClast + (Clast/kel). 
where Clast is the predicted plasma 
concentration at the last quantifiable 
time point and kel is the elimination 
rate constant estimated from the log- 
linear regression analysis. 
Cmax 
Maximum plasma concentration 
Observed directly from the data. 
Tmax 
Time for Cmax 
Observed directly from the data as 
time of first occurrence. 


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Table 10. Definitions of PK Parameters 
 
Parametera 
Definition 
Method of Determination 
t1/2 
Terminal plasma elimination 
half-life 
Loge(2)/kel 
Only those data points judged to 
describe the terminal log-linear 
decline will be used in the regression. 
CL/F 
Apparent clearance after oral 
dose 
Dose/AUCinf after oral dose. 
Vz/F 
Apparent volume of distribution 
after oral dose 
Dose/(AUCinf*kel) after oral dose. 
Clast 
Last measurable observed 
concentration 
Observed directly from the data 
Tlast 
The time for Clast 
Observed directly from the data 
a. 
As data permit. 
 
Actual PK sampling times will be used in the derivation of PK parameters whenever 
possible. In the case that actual PK sampling times are not available, nominal PK sampling 
time may be used in the derivation of PK parameters. 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
8.6.2. Retained Research Samples for Genetics 
A 4 -mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual. 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
8.7.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study. 
8.7.2. Specified Protein Research 
Specified protein research is not included in this study. 


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8.7.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
8.7.4. Retained Research Samples for Biomarkers 
Not applicable. 
8.8. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the 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 Hypothesis 
No statistical hypothesis will be tested in this study. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis datasets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“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 after screening. 
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, unless otherwise 
specified by the protocol. 
Safety Analysis Set 
All participants enrolled and who take at least 1 dose of study 
intervention. 
PK Concentration 
Analysis Set 
All participants who are in the Safety Analysis Set and have at 
least 1 measurable ARV-471 or ARV-473 concentration. 


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Participant Analysis 
Set 
Description 
PK Parameter Analysis 
Set 
All participants who are in the Safety Analysis Set and have at 
least 1 of the ARV-471 or ARV-473 PK parameters of primary 
interest. 
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. Pharmacokinetic Analyses 
ARV-471 and ARV-473 PK parameters following a single dose administration of ARV-471 
will be derived from the ARV-471 and ARV-473 plasma concentration versus time profiles 
using non-compartmental methods as data permit. The PK parameters to be assessed in this 
study, their definition, and method of determination are outlined in Table 10. ARV-471 and 
ARV-473 PK parameters (primary endpoints: AUCinf, and Cmax; Secondary 
endpoints:AUClast, Tmax, t1/2, CL/F, and Vz/F) will be summarized descriptively by treatment. 
Individual participant parameters for AUCinf, AUClast and Cmax will be plotted by treatment 
and overlaid with geometric mean. ARV-471 and ARV-473 concentrations will be listed and 
summarized descriptively by PK sampling time and treatment. Summary profiles (means and 
medians) of concentration time data will be plotted by treatment on linear and semi log scale. 
Individual participant concentration time profiles will also be presented. For summary 
statistics and summary plots by sampling time, the nominal PK sampling time will be used, 
for individual participant plots by time, the actual PK sampling time will be used. 
Natural log transformed ARV-471 and ARV-473 AUCinf (if data permit), AUClast and Cmax 
will be analyzed using a mixed effect model with treatment as a fixed effect and participant 
as a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Treatment A 
(ARV-471 given alone) is the Reference Treatment while Treatments B (ARV-471 given 
after multiple doses of itraconazole) is the Test Treatment. 
9.3.2. Safety Analyses 
All safety analyses will be performed on the safety population. 
AEs, ECGs, BP, pulse rate, continuous cardiac monitoring, 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. 


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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. 
9.3.2.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters HR, QTcF , PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Table 11.  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. If any of the 3 individual ECG tracings 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. However, values from individual tracings 
within triplicate measurements that are >500 ms will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 ms. Changes from 
baseline will be defined as the change between the postdose QTcF value and the average of 
the predose triplicate values on Day 1. 
9.3.3. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR. 
9.4. Interim Analyses 
No interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct reviews of the data during the course of the study for the purpose of 
safety assessment and/or supporting clinical development. 


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9.5. Sample Size Determination 
A sufficient number of participants will be screened to ensure that at least 12 participants are 
enrolled in the study. 
The sample size is empirically selected and is not based on statistical power calculation. 
A sample size of 12 PK evaluable participants who have at least 1 of the ARV-471/ARV-473 
PK parameters of primary interest (AUCinf or Cmax) is expected to provide 90% CIs for the 
difference between treatments of CCI 
 on the natural log scale for AUCinf 
and Cmax, respectively, with 80% coverage probability. Table 12 presents the width of 90% 
CI for different estimated effects. Sample size was based on ARV-471 only. 
 
Table 12. Confidence Interval Estimation of PK Endpoints for Bioavailability 
 
Parameter 
Estimated Effect 
(100*Test/Reference) 
90% CI 
CI Width 
AUCinf 
100% 
CCI 
110% 
120% 
130% 
150% 
Cmax 
100% 
110% 
120% 
130% 
150% 
These calculations are based on estimates of within-participant standard deviation of CCI  
ARV-471 for loge AUCinf and loge Cmax, respectively, based on the results from 
crossover study CCI 
. 


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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. 
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, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations. 
10.1.1.1. 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. 


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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 guidelines that the investigator 
becomes aware of. 
10.1.2. Financial Disclosure 
Not applicable. 
10.1.3. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant 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 will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center. 
The investigator must ensure that each participant 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 must be informed that their 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 . 
The participant must be informed that their 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 is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
theirpersonal 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 must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations. 
A copy of the ICD(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICD. 


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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 their 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. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study will not use an E-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/CTIS, and/or 
www.pfizer.com, and other public registries and websites 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. 


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www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) 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. 
EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
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 from these trials available 
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 anonymized. 
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. 


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Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
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. 
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 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. 
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the Pfizer CRU. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the Pfizer CRU. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The sponsor or designee will perform monitoring 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, 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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. 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 if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 


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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; 
• 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. 
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 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer 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-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication. 


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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
10.1.11. Sponsor’s Medically Qualified Individual 
 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, 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 identification number, (c) and site 
emergency phone number active 24 hours/day, 7 days per week. 
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. 
10.1.12. Transfer of Obligations Statement 
 
For the purposes of this protocol, sponsor refers to Pfizer. 
CCI 
CCI 


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10.2. Appendix 2: Clinical Laboratory Tests 
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 13. Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
If Hb/RBC abnormal: 
MCV, MCH, MCHC 
BUN 
Creatinine 
CystatinC and eGFR 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
Local dipstick 
pHa 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Laboratory: 
Microscopy and 
cultureb 
• 
COVID-19 testing (per 
CRU procedures) 
• 
Urine drug screeningc 
• 
Alcohol breath and blood 
test (at discretion of 
investigator) 
At screening: 
• 
FSHd 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV 
• 
Hepatitis B surface 
antibody 
• 
Hepatitis B core 
antibody 
a. 
May be performed using local dipstick or pH-meter device. 
b. 
Urinary culture only if deemed appropriate by the investigator (eg, Only if UTI is suspected and/or and 
urine dipstick is positive for nitrites or leukocyte esterase or both) 
c. 
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). 
d. 
For confirmation of postmenopausal status only. 
 
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. 
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study. 


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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 
 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, 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 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, 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 
abnormal 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 drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either 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 start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’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 
participant’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 occurrence 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 start of the study that do not worsen. 
10.3.2. Definition of an SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below: 
a. Results in death 
b.  Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant 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 participant has been admitted (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 are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 


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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, diarrhea, 
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 
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 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. 
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 
reporting SAEs on the CT SAE Report Form 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. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using the CT SAE Report 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 Report 
Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, 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 exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
• When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE or SAE information in the CRF. 
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 EDB 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)** 
Environmental or 
None. Exposure to a study 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported*** 
occupational exposure 
non-participant is not 
to the product under 
collected on the CRF 
study to a 
nonparticipant (not 
involving EDP or EDB) 


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• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant 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 information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL. 
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
• Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
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. 


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Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship. 
• A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
• 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 information, for 
marketed products, in their assessment. 
• For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report 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 their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting 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 
reporting 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 report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements. 


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Follow-Up of AEs and SAEs 
• The investigator is obligated to perform or arrange 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 laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers. 
• If a participant dies during participation in the study or during a recognized 
followup period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT. 
• If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available. 
• After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone. 


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SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames. 


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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 90 days after the last dose of study intervention 
(ARV-471), 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 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 WOCBP 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 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she (a) is not pregnant or breastfeeding; and 
(b) at least 1 of the following conditions applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
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 Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 


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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 a 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 old and not using hormonal 
contraception or HRT. 
• A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she 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. 


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The following contraceptive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner. 
• 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 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral + barrier* 
• Intravaginal + barrier* 
• Transdermal + barrier* 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral + barrier* 
• Injectable + barrier* 
8. 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. 
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following: 
• 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). 


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10.5. Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis. 
• The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation. 
• The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained as indicated: 
• Retained samples will be stored indefinitely or for another period as per local 
requirements. 
• Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses. 
• Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 


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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.” 
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below. 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available. 
• For participants with baseline AST OR ALT OR T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and T bili 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. 
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 T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. 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 
CCI 
 
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 
T bili 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: Kidney Safety: Monitoring Guidelines 
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after baseline, 
then reflex measurement of Scys is indicated to estimate the combined Scr-Scys eGFR 
calculation (for adults only). 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
Table 14. Adults (18 Years and Above)—2021 CKD-EPI 
Equations18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to CTCAE 
criteria. 
2021 CKD- 
EPI 
Scr 
Only 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age 
Female 
if > 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age 
Male 
if ≤ 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age 
Male 
if > 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age 
2021 CKD- 
EPI 
Scr- 
Scys 
Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤ 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age 
Female 
if > 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if > 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤ 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤ 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if > 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if > 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• 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 atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 ms. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset LBBB (QRS complex >120 ms). 
• New-onset right bundle branch block (QRS complex >120 ms). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants 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 participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 
• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR 
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 


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monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>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 arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory 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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10.9. Appendix 9: Overview of GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) 
Table 15. Overview of GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
Study title/code 
Date of 
completi 
on of the 
Final 
Report 
Test facility/test site in 
which the study was 
conducted (name and 
complete address) 
 
 
 
 
 
 
CCI 
Period in 
which the 
test 
facility/test 
site was 
used 
Was the test 
facility/test 
site in that 
period part of 
an EU or an 
OECD MAD 
accepted GLP 
monitoring 
programme? 
(Y/N) 


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Table 15. Overview of GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
 
 
Table 16. Facilities for GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
CCI 
Was the test 
facility/test 
site in that 
period part of 
an EU or an 
OECD MAD 
accepted GLP 
monitoring 
programme? 
(Y/N) 
Period in 
which the 
test 
facility/test 
site was 
used 
Test facility/test site in 
which the study was 
conducted (name and 
complete address) 
Date of 
completi 
on of the 
Final 
Report 
Study title/code 
Facility 
CCI 
Documents provided 
Inspection Date 


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Table 16. Facilities for GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
CCI 
Inspection Date 
Facility 
Documents provided 


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10.10. Appendix 10: Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below: 
 
Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
1.3. Schedule of 
Activities Table 
2. Period 2: 
ARV-471 in the 
Presence of 
Itraconazole 
Contraception check 
on Period 2 Day 4 was 
removed. 
Contraception check at 
Period 2 Day 4 is not 
required since participants 
will be confined 
throughout the duration of 
Period 2 (Day -1 through 
Day 12) and contraception 
checks will occur Day -1 
and Day 12. 
Nonsubstantial 
1.3. Schedule of 
Activities Table 
1. Period 1: 
ARV-471 Alone 
Table reformatted for 
contraception checks 
with a note added that 
“If participants are 
discharged on Day 4, 
the contraception 
check will be done at 
each outpatient visit.” 
Added for clarity since 
participants can be 
discharged on Period 1 
Day 4. 
Nonsubstantial 
5.1. Inclusion 
Criteria 
Added bilateral 
salpingectomy as a 
criteria that meets the 
definition for female 
participants of non- 
childbearing potential 
Text added to align with 
Appendix 4 Section 10.4.3 
Woman of Childbearing 
Potential 
Nonsubstantial 
Section 4.3. 
Justification for 
Dose 
Content and tables 
were added to include 
exposure margin 
estimates for rat and 
dog. 
Added content provide 
additional information on 
worst case scenario in 
terms of nonclinical 
safety. 
Nonsubstantial 
10.9. Appendix 
9: Overview of 
GLP Safety 
Pharmacology 
and Toxicology 
Testing Program 
for ARV-471 
(PF-07850327) 
Tables were added for 
an overview of ARV- 
471 GLP safety 
pharmacology and 
toxicology testing 
program. 
A summary table was 
provided specifying the 
details of the GLP studies 
and the facilities they 
were conducted at. 
Nonsubstantial 
1.3. Schedule of 
Activities Table 
1. Period 1: 
ARV-471 Alone 
Table reformatted to 
move 12-Lead ECG 
from Day 6 to Day 4 in 
Period 1. 
Change made to be 
consistent with discharge 
on Period 1 Day 4. 
Nonsubstantial 
1.3. Schedule of 
Activities 
Table 3. PK, 
ECG, BP, and 
PR Sampling 
Table reformatted to 
move 12-Lead ECG 
from Day 6 to Day 4 in 
Period 1. 
Change made to be 
consistent with discharge 
on Period 1 Day 4. 
Nonsubstantial 


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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Schema for 
Period 1 
4.2. Scientific 
Rationale for 
Study Design - 
Males 
Section was revised 
with new data. 
New data from the 3- 
month dog study provide 
further support for 
inclusion of male 
participants. 
Nonsubstantial 
1.1. Synopsis 
Objectives and 
Endpoints 
Added "(AUClast if 
AUCinf cannot be 
estimated)." 
Detail added to specify the 
action taken in the event 
that one of the primary PK 
endpoints cannot be 
estimated. 
Nonsubstantial 
3. OBJECTIVES 
AND 
ENDPOINTS 
Added "(AUClast if 
AUCinf cannot be 
estimated)." 
Detail added to specify the 
action taken in the event 
that one of the primary PK 
endpoints cannot be 
estimated. 
Nonsubstantial 
2.3. Benefit/Risk 
Assessment 
EU SmPC has been 
added as the SRSD for 
itraconazole 
SRSD for interacting drug 
was not stated in the 
original protocol. 
Nonsubstantial 
1.1. Synopsis 
Exclusion 
Criteria 
“male participants of 
childbearing potential” 
has been replaced with 
“fertile male 
participants” 
Changed to improve 
clarity and avoid 
confusion with the term 
"women of 
nonchildbearing 
potential". 
Nonsubstantial 
5.2. Exclusion 
Criteria 
“male participants of 
childbearing potential” 
has been replaced with 
“fertile male 
participants” 
Changed to improve 
clarity and avoid 
confusion with the term 
"women of 
nonchildbearing 
potential". 
Nonsubstantial 
2.2.1. 
Nonclinical 
Pharmacology 
Revised background 
information 
Revision made to align 
with updated IB. 
Nonsubstantial 
2.2.2. 
Nonclinical 
Pharmacokinetics 
and Metabolism 
Revised background 
information 
Revision made to align 
with updated IB. 
Nonsubstantial 
2.2.3. 
Nonclinical 
Safety 
Revised background 
information 
Revision made to align 
with updated IB and 
include new data. 
Nonsubstantial 
2.2.4. Clinical 
Overview 
Revised background 
information 
Revision made to align 
with updated IB. 
Nonsubstantial 
2.3.1. Risk 
Assessment 
Revised background 
information 
Revision made to align 
with updated IB. 
Nonsubstantial 
8.3.5. COVID-19 
Specific 
Assessments 
Section revised to 
“Participants will 
undergo COVID-19 
related measures per 
CRU procedures.” 
Language updated to 
allow for flexibility 
around COVID-19 
assessments as rules 
continually change at the 
CRU. 
Nonsubstantial 


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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
1.1. Synopsis 
Objectives and 
Endpoints 
Added "200 mg" to 
dose 
Added detail about dosing 
regimen. 
Nonsubstantial 
3. OBJECTIVES 
AND 
ENDPOINTS 
Added "200 mg" to 
dose 
Added detail about dosing 
regimen. 
Nonsubstantial 
4.2.1.2. Males 
Added “(ARV-471)” 
to distinguish from 
itraconazole when 
investigational product 
is referred to. 
Detail added for clarity 
Nonsubstantial 
10.4.1. Male 
Participant 
Reproductive 
Inclusion Criteria 
Added “(ARV-471)” 
to distinguish from 
itraconazole when 
investigational product 
is referred to. 
Detail added for clarity 
Nonsubstantial 
1.1. Synopsis 
Protocol Title 
"Ar" changed to 
"ARV" 
Drug name error. 
Nonsubstantial 
10.2. Appendix 
2: Clinical 
Laboratory Tests 
One bullet point was 
separated into two 
bullet points. 
Formatting error. 
Nonsubstantial 
Title Page 
EudraCT 
Number 
Number changed. 
New EU CT Number 
assigned following 
resubmission of 
application. 
Nonsubstantial 


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10.11. Appendix 11: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
aBC 
advanced Breast Cancer 
ADL 
activity/activities of daily living 
ADR 
adriamycin 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
aromatase inhibitor 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24 
area under the concentration-time curve from time zero to 24 hours 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero 
extrapolated to infinity 
AUClast 
area under the plasma concentration time profile from time zero to 
the time of the last quantifiable concentration 
AUCR 
ratio of the AUC of the object drug co-administered with itraconazole 
to the AUC of the object administered alone 
AUCtau 
rea under plasma concentration-time curve over dosing interval 
AV 
atrioventricular 
AxMP 
auxiliary medicinal product 
BBS 
Biospecimen Banking System 
BID 
twice a day 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CDK 
cyclin dependent kinase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CL/F 
apparent clearance after oral dose 
Clast 
last quantifiable plasma concentration 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CO2 
carbon dioxide (bicarbonate) 


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Abbreviation 
Term 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trial Information System 
CV 
cardiovascular 
CYP 
cytochrome P450 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram or electrocardiography 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
ER 
estrogen receptor 
eSAE 
electronic serious adverse event 
ESR 
erythrocyte sedimentation rate 
ET 
endocrine therapy 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
FDA 
Food and Drug Administration 
FE 
food effect 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
good laboratory practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HER2 
human epidermal growth factor receptor 2 


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Abbreviation 
Term 
hERG 
human ether-a-go-go related gene 
HHEP 
human hepatocytes 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ID 
identification 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IoR 
Importer of Record 
IPAL 
Investigational Product Accountability Log 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
K 
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function) 
LBBB 
left bundle branch block 
LD50 
lethal dose 50% 
LFT 
liver function test 
MAD 
mutal acceptance of data 
mBC 
metastatic breast cancer 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MQI 
medically qualified individual 
N/A 
not applicable 
NIMP 
noninvestigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
OECD 
Organization for Economic Co-operation and Development 
PCR 
polymerase chain reaction 
PCRU 
Pfizer Clinical Research Unit 
PE 
physical exam 
PK 
pharmacokinetic(s) 
P/O 
predicted / observed 
PPI 
proton pump inhibitors 
PR 
pulse rate 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
QD 
once a day 


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Abbreviation 
Term 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
qual 
qualitative 
rBA 
relative bioavailability 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SD 
stable disease 
SERD 
selective estrogen receptor degrader 
SERM 
selective estrogen receptor modulator 
SmPC 
Summary of Product Characteristics 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
Single Reference Safety Document 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
terminal elimination half-life 
T bili 
total bilirubin 
TEAE 
treatment emergent adverse event 
TGI 
tumor growth inhibition 
THC 
tetrahydrocannabinol 
TK 
toxicokinetic(s) 
Tlast 
the time for Clast 
Tmax 
the time for Cmax 
TOC 
table of contents 
TRAE 
treatment related adverse event 
ULN 
upper limit of normal 
US 
United States 
UTI 
urinary tract infection 
VE 
Venous Embolism 
Vz/F 
apparent volume of distribution after oral dose 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
1. 
Flanagan J, Qian Y, Gough S, et al. Abstract P4-04-04: Identification and development 
of oral estrogen receptor PROTAC degraders for breast cancer. Cancer Research. 
2018;78(4_Supplement):P4-04-04-P4-04-04. 
2. 
Hamilton E, Vahdat L, Han HS, et al. Abstract PD13-08: First-in-human safety and 
activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- 
locally advanced or metastatic breast cancer. Cancer Research. 
2022;82(4_Supplement):PD13-08-PD13-08. 
3. 
Backman JT, Kivisto KT, Olkkola KT, & Neuvonen PJ (1998) The area under the 
plasma concentration-time curve for oral midazolam is 400-fold larger during treatment 
with itraconazole than with rifampicin. European journal of clinical pharmacology 
54(1):53-58. 
4. 
Neuvonen PJ, Varhe A, & Olkkola KT (1996) The effect of ingestion time interval on 
the interaction between itraconazole and triazolam. Clinical Pharmacology & 
Therapeutics 60(3):326-331. 
5. 
Olkkola KT, Ahonen J, & Neuvonen PJ (1996) The Effect of the Systemic 
Antimycotics, Itraconazole and Fluconazole, on the Pharmacokinetics and 
Pharmacodynamics of Intravenous and Oral Midazolam. Anesthesia & Analgesia 82(3). 
6. 
Templeton I, Peng CC, Thummel KE et al. (2010) Accurate Prediction of Dose- 
Dependent CYP3A4 Inhibition by Itraconazole and Its Metabolites From In Vitro 
Inhibition Data. Clinical Pharmacology & Therapeutics 88(4):499-505. 
7. 
Liu L, Bello A, Dresser MJ, et al. Best practices for the use of itraconazole as a 
replacement for ketoconazole in drug-drug interaction studies. J Clin Pharmacol. 
2016;56(2):143-151. 
8. 
Barone JA, Moskovitz BL, Guarnieri J, et al. Food interaction and steady-state 
pharmacokinetics of itraconazole oral solution in healthy volunteers. Pharmacotherapy. 
1998; 18(2):295–301. 
9. 
SPORANOX – itraconzole solution label. Raritan, NJ: JANSSEN_Pharmaceuticals; 
2014. 
10. SPORANOX – itraconzole capsule label. Raritan, NJ: JANSSEN_Pharmaceuticals; 
2012. 
11. Chou CJ, Affolter M, Kussmann M. A nutrigenomics view of protein intake: 
macronutrient, bioactive peptides, and protein turnover. Progress in Molecular Biology 
and Translational Science. 2012 Jan 1;108:51-74. 


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12. Nawaz Z, Lonard DM, Dennis AP, et al. Proteasome-dependent degradation of the 
human estrogen receptor. Proceedings of the National Academy of Sciences. 1999 Mar 
2;96(5):1858-62. 
13. Dauvois S, Danielian PS, White R, et al. Antiestrogen ICI 164,384 reduces cellular 
estrogen receptor content by increasing its turnover. Proceedings of the National 
Academy of Sciences. 1992 May 1;89(9):4037-41. 
14. Weir HM, Bradbury RH, Lawson M, et al. AZD9496: an oral estrogen receptor 
inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in 
preclinical models. Cancer Research. 2016 Jun 1;76(11):3307-18. 
15. Steinbach, TJ, Patrick, DJ, Cosenza, ME (Eds.). (2019). Toxicologic pathology for non- 
pathologists. Springer New York. 
16. Lu, C.C. and M.L. Meistrich, Cytotoxic effects of chemotherapeutic drugs on mouse 
testis cells. Cancer Res, 1979. 39(9): p. 3575-82. 
17. Meistrich, M.L., Finch M, da Cunha MF et al., Damaging effects of fourteen 
chemotherapeutic drugs on mouse testis cells. Cancer Res, 1982. 42(1): p. 122-31. 
18. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C–based equations 
to estimate GFR without race. N Engl J Med. 2021;385:1737-49. 

SAP_001.pdf: 
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Protocol C4891009 
 
 
 
 
An Interventional, Phase 1, Open-Label, Fixed Sequence, 2-Period Study to Estimate the 
Effect of Multiple Doses of Itraconazole on the Pharmacokinetics Of Single Dose ARV- 
471 in the Fed Condition in Healthy Adult Males, and Females of Nonchildbearing 
Potential 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
 
Version: 
1 
Date: 
12 Sep 2022 


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................3 
APPENDICES ............................................................................................................................3 
1. VERSION HISTORY ............................................................................................................4 
2. INTRODUCTION ..................................................................................................................4 
2.1. Modifications to the Analysis Plan Described in the Protocol ..................................4 
2.2. Study Objectives, Endpoints, and Estimands ............................................................4 
2.3. Study Design ..............................................................................................................5 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ...................................................................................................................5 
3.1. Primary Endpoints .....................................................................................................5 
3.2. Secondary Endpoints .................................................................................................6 
3.3. Other Endpoint(s) ......................................................................................................6 
3.4. Baseline Variables .....................................................................................................6 
3.5. Safety Endpoints ........................................................................................................7 
3.5.1. Adverse Events .............................................................................................7 
3.5.2. Laboratory Data ............................................................................................7 
3.5.3. Vital Signs .....................................................................................................7 
3.5.4. Electrocardiograms ........................................................................................8 
3.5.5. Concomitant Medication ...............................................................................8 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ......................................................8 
5. GENERAL METHODOLOGY AND CONVENTIONS .......................................................9 
5.1. Hypotheses and Decision Rules .................................................................................9 
5.2. General Methods ........................................................................................................9 
5.2.1. Analyses for Binary/Categorical Endpoints ..................................................9 
5.2.2. Analyses for Continuous Endpoints ..............................................................9 
5.3. Methods to Manage Missing Data .............................................................................9 
5.3.1. Pharmacokinetic Data ...................................................................................9 
5.3.2. Safety Data ..................................................................................................10 
6. ANALYSES AND SUMMARIES .......................................................................................10 
6.1. Primary Endpoints ...................................................................................................10 
6.2. Secondary Endpoints ...............................................................................................11 


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6.2.1. Other PK parameters ................................................................................... 11 
6.2.2. Safety data ................................................................................................... 12 
6.3. Subset Analyses ....................................................................................................... 12 
6.4. Baseline and Other Summaries and Analyses .......................................................... 12 
6.4.1. Demographic Summaries ............................................................................ 12 
6.4.2. Study Conduct and Participant Disposition ................................................ 12 
6.4.3. Study Treatment Exposure .......................................................................... 13 
6.4.4. Concomitant Medications and Nondrug Treatments................................... 13 
6.5. Safety Summaries and Analyses .............................................................................. 13 
6.5.1. Adverse Events ........................................................................................... 13 
6.5.2. Laboratory Data .......................................................................................... 13 
6.5.3. Vital Signs ................................................................................................... 13 
6.5.4. Electrocardiograms ...................................................................................... 13 
7. INTERIM ANALYSES ....................................................................................................... 14 
7.1. Introduction .............................................................................................................. 14 
7.2. Interim Analyses and Summaries ............................................................................ 14 
APPENDICES .......................................................................................................................... 15 
 
 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................4 
Table 2. 
Definitions of PK Parameters .....................................................................6 
Table 3. 
PK Parameters to be Summarized Descriptively by Treatment ................11 
 
 
APPENDICES 
Appendix 1. Summary of Analyses .......................................................................................... 15 
Appendix 2. SAS Code for Analyses ....................................................................................... 15 
Appendix 3. List of Abbreviations ........................................................................................... 17 


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NOTE: Italicized text within this document has been taken verbatim from the Protocol. 
1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
12 Sep 2022 
Original 
20 Jul 2022 
N/A 
N/A 
 
2. INTRODUCTION 
ARV-471 (also known as PF-07850327) is a potent, selective, orally bioavailable 
PROteolysis TArgeting Chimeric (PROTAC®) small molecule that induces degradation of the 
ER. ARV-471 is a hetero-bifunctional PROTAC molecule that simultaneously binds the 
estrogen receptor (ER) and the cereblon E3 ligase complex, enabling protein-protein 
interactions between ER and the ligase complex. As a result, the ER becomes poly- 
ubiquitinated on accessible lysine residues and subsequently undergoes targeted degradation 
by the proteasome to affect its elimination from cells. 
Itraconazole and its primary metabolite (hydroxy-itraconazole) are specific strong inhibitors 
of CYP3A. Since ARV-471 is a substrate for CYP3A, concomitant administration of multiple 
doses of itraconazole along with ARV-471 may lead to increased systemic exposure of ARV- 
471. The objective of this study is to estimate the effect of multiple doses of itraconazole on 
the PK of ARV-471. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4891009. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 
2.2. Study Objectives, Endpoints, and Estimands 
The following are the objectives and endpoints in this study. Estimand framework will not 
be applied to this Phase 1 study in healthy participants. 


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Objectives 
Endpoints 
Primary: 
Primary: 
• To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a 
single oral dose of ARV-471. 
• Plasma AUCinf and Cmax of ARV-471 
and ARV-473, as data permits. 
Secondary: 
Secondary: 
• To estimate the effect of multiple doses of 
itraconazole on the pharmacokinetics of a 
single oral dose of ARV-471. 
• To evaluate the safety and tolerability of a 
single dose of ARV-471 administered to 
healthy participants in the absence and 
presence of multiple doses of itraconazole 
under fed conditions. 
• Plasma AUClast, Tmax, t1/2, CL/F and 
Vz/F of ARV-471 and ARV-473, as data 
permits, and as appropriate. 
• Safety laboratory tests, physical 
examination, vital signs, 
electrocardiograms (ECG), 
concomitant medication and adverse 
event monitoring. 
 
2.3. Study Design 
This is a Phase 1, open-label, 2-period fixed-sequence crossover study to estimate the effect 
of multiple doses of the strong CYP3A inhibitor, itraconazole, on ARV-471 and ARV-473 
pharmacokinetics in healthy males, and females of nonchildbearing potential. A total of 
approximately 12 participants will be enrolled in the study. The study will consist of 2 
periods; Period 1 = single dose of ARV-471 alone and Period 2 = multiple doses of 
itraconazole + single dose of ARV-471. Following Period 1, a washout period of at least 10 
days must occur between the 2 single doses of ARV-471. Following administration of ARV- 
471 in each period, participants will undergo serial PK sampling. Participants who 
withdraw may be replaced at the discretion of the sponsor. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
The primary endpoints of the study are plasma AUCinf (if data permit) and Cmax of ARV-471 
and ARV-473 following a single dose administration of ARV-471 (alone) and 
coadministered with multiple doses of itraconazole. Adjusted geometric mean ratios of 
AUCinf and Cmax will be derived. If data do not permit derivation of plasma AUCinf, plasma 
AUClast will be used in place of AUCinf. 
ARV-471 and ARV-473 PK parameters, as appropriate, following a single dose 
administration of ARV-471 will be derived from the ARV-471 and ARV-473 plasma 
concentration versus time profiles using non-compartmental methods as data permit. The PK 


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parameters to be assessed in this study, their definition, and method of determination are 
outlined in Table 2. Actual PK sampling times will be used in the derivation of PK 
parameters whenever possible. In the case that actual PK sampling times are not available, 
nominal PK sampling time may be used in the derivation of PK parameters. 
 
Table 2. 
Definitions of PK Parameters 
 
Parametera 
Definition 
Method of Determination 
AUCinf 
Area under the plasma concentration-time profile 
from time zero extrapolated to infinite time 
AUClast + (Clast/kel), 
where Clast is the predicted plasma 
concentration at the last quantifiable 
time point and kel is the elimination 
rate constant estimated from the log- 
linear regression analysis. 
Cmax 
Maximum plasma concentration 
Observed directly from the data. 
AUClast 
Area under the plasma concentration-time profile 
from time zero to the time of the last quantifiable 
concentration (Clast) 
Linear-log trapezoidal method. 
Tmax 
Time for Cmax 
Observed directly from the data as time 
of first occurrence. 
t½ 
Terminal plasma elimination half-life 
Loge(2)/kel, 
Only those data points judged to 
describe the terminal log-linear decline 
will be used in the regression. 
CL/F 
Apparent clearance after oral dose 
Dose/AUCinf after oral dose. 
Vz/F 
Apparent volume of distribution after oral dose 
Dose/(AUCinf * kel) after oral dose. 
Clast 
Last measurable observed concentration 
Observed directly from the data. 
Tlast 
The time for Clast 
Observed directly from the data. 
a. As data permit. 
 
 
3.2. Secondary Endpoints 
The secondary endpoints are additional plasma PK parameters (including AUClast, Tmax, t1/2, 
CL/F and Vz/F, defined in Table 2) of ARV-471 and ARV-473, as appropriate, (following a 
single dose administration of ARV-471 alone and with multiple doses of itraconazole). 
Other secondary endpoints of the study include the overall safety profile of a single dose of 
ARV-471 alone and with multiple doses of itraconazole, as characterized by laboratory tests, 
vital signs, ECG, concomitant medication and adverse events (discussed in Section 3.5). 
3.3. Other Endpoint(s) 
None. 
3.4. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 


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3.5. Safety Endpoints 
The following data will be considered in standard safety summaries (see protocol for 
collection days, baseline assessment, and list of parameters): 
• Adverse events (AE) 
• Laboratory data 
• Vital signs data 
• ECG results 
• Concomitant medication 
3.5.1. Adverse Events 
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 28 days after the last ARV-471 dose will be counted as treatment emergent and 
attributed to the last treatment taken. Events that occur during the washout period (up to 28 
days from the last treatment) between study periods will be counted as treatment emergent 
and attributed to the previous treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent. 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the haematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
sponsor reporting standards. The assessment will not take into account whether each 
participants’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter. 
For Period 1, the baseline measurement is the predose measurement on Day -1. For Period 2, 
the baseline measurement for itraconazole alone is the predose measurement on Day -1 and 
for ARV-471 with itraconazole the baseline measurement is the predose measurement on 
Day 4. Changes from baseline will be defined as the change between the postdose and 
baseline measurements. 
3.5.3. Vital Signs 
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA given in the protocol. 
For Period 1, the baseline measurement is the predose measurement on Day 1. For Period 2, 
the baseline measurement is the predose measurement on Day 5. Changes from baseline will 
be defined as the change between the postdose and baseline measurements. 


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3.5.4. Electrocardiograms 
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. If not supplied, QTcF will be derived using 
Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided) 
For Period 1, the baseline value is the average of the triplicate ECG measurements collected 
before dose administration on Day 1. For Period 2, the baseline value is the average of the 
triplicate ECG measurements collected before dose administration on Day 5. Changes from 
baseline will be defined as the change between the postdose ECG measurement and the 
derived baseline ECG. 
The maximum absolute value (postdose) and the maximum increase from baseline for QTcF, 
PR and QRS, over all measurements taken postdose, will be determined. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken. 
3.5.5. Concomitant Medication 
Concomitant medications are documented in the case report form (CRF) as treatments taken 
after the first dose of study intervention. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures. 
 
Participant Analysis Set Description 
Enrolled 
“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 after screening. 
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, unless otherwise 
specified by the protocol. 
Safety Analysis Set 
All participants enrolled and who take at least 1 dose of study 
intervention. 


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Participant Analysis Set Description 
PK Concentration 
Analysis Set 
All participants who received at least 1 dose of ARV-471 
and/or itraconazoleand have at least 1 measurable ARV-471 
or ARV-473 concentration. 
PK Parameter Analysis 
Set 
All participants who received at least 1 dose of ARV-471 
and/or itraconazole and have at least 1 of the ARV-471 or 
ARV-473 PK parameters of primary interest. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following last 
participant last visit. 
5.1. Hypotheses and Decision Rules 
No statistical hypothesis will be tested in this study. 
5.2. General Methods 
5.2.1. Analyses for Binary/Categorical Endpoints 
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS). 
5.2.2. Analyses for Continuous Endpoints 
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized. 
5.3. Methods to Manage Missing Data 
5.3.1. Pharmacokinetic Data 
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification: 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.). 
Deviations, Missing Concentrations and Anomalous Values: 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample). 


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2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst or pharmacokineticist. 
PK Parameters: 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues). In summary tables, statistics will be calculated by setting NC 
values to missing; and statistics will be presented for a particular treatment with ≥3 evaluable 
measurements. PK parameter analyses will not be performed for a particular parameter if 
more than 50% of the data are NC. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed 
from the gastrointestinal tract), this will be footnoted in summary tables and will not be 
included in the calculation of summary statistics or statistical analyses. 
5.3.2. Safety Data 
Missing values in standard summaries of AEs, concomitant medications, laboratory data, 
vital signs, and ECGs will be imputed according to CaPS. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
The primary endpoints AUCinf and Cmax will be summarized descriptively by treatment and 
will include the set of summary statistics as specified in Table 3. AUClast will also be 
included in case AUCinf cannot be derived. Individual participant parameters for AUCinf (if 
data permit, otherwise AUClast) and Cmax will be plotted by treatment and overlaid with 
geometric mean. Summary profiles (means and medians) of concentration time data will be 
plotted by treatment on linear and semi log scale. Individual participant concentration time 
profiles will also be presented. For summary statistics and summary plots by sampling time, 
the nominal PK sampling time will be used, for individual participant plots by time, the 
actual PK sampling time will be used. 
Natural log transformed ARV-471 and ARV-473 AUCinf (if data permit), AUClast and Cmax 
will be analyzed using a mixed effect model with treatment as a fixed effect and participant 


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as a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Treatment A (ARV- 
471 given alone) is the Reference Treatment while Treatments B (ARV-471 given after 
multiple doses of itraconazole) is the Test Treatment. 
 
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be provided in the clinical study report. 
6.2. Secondary Endpoints 
6.2.1. Other PK parameters 
AUClast,Tmax, t1/2, CL/F, Vz/F, Clast and Tlast will be summarized descriptively by treatment and 
will include the set of summary statistics as specified in Table 3. AUClast will be analyzed 
using the same mixed effect model used in the primary endpoints. 
PK parameter summaries: 
The ARV-471 and ARV-473 PK parameters, as appropriate, will be summarized 
descriptively by treatment in accordance with Pfizer data standards for the PK Parameter 
Analysis Set, as data permit. A listing of the individual participant ratios (Test-Reference) 
will be provided. Missing values will be handled as detailed in Section 5.3.1. Each ARV-471 
and ARV-473 PK parameter will be summarized by treatment and will include the set of 
summary statistics as specified in Table 3. 
 
Table 3. 
PK Parameters to be Summarized Descriptively by Treatment 
 
Parameter 
Summary Statistics 
AUCinf, AUClast, 
Cmax, CL/F, 
Vz/F, Clast 
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV 
Tmax, Tlast 
N, median, minimum, maximum 
t½ 
N, arithmetic mean, median, SD, %CV, minimum, maximum 
 
PK concentration summaries: 
The plasma concentrations of ARV-471 and ARV-473 will be listed and descriptively 
summarized by nominal PK sampling time and treatment for the PK Concentration Analysis 
Set. Individual participant and summary profiles (mean and median plots) of the plasma 
concentration-time data will be plotted by treatment using actual and nominal times, 


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respectively. Mean and median ARV-471 and ARV-473 plasma concentration profiles will 
be presented on both linear and semi-log scales. 
Presentations for ARV-471 and ARV-473 plasma concentrations will include: 
• A listing of all concentrations sorted by participant ID, treatment and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be provided in a separate listing. 
• A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ. 
• Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose). 
• Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose). 
• Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale). 
• Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant (containing 
all treatments) per scale]. 
6.2.2. Safety data 
Safety data will be analyzed in accordance with the CaPS (see Section 6.5). 
6.3. Subset Analyses 
There are no planned subset analyses. 
6.4. Baseline and Other Summaries and Analyses 
6.4.1. Demographic Summaries 
Demographic characteristics will be summarized for enrolled population in accordance with 
the CaPS. 
6.4.2. Study Conduct and Participant Disposition 
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment (ARV-471 alone, 
ARV-471 with itraconazole, and itraconazole alone). Data will be reported in accordance 
with the CaPS. 


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6.4.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
6.4.4. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings. 
6.5. Safety Summaries and Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
Safety data will be summarized for three (3) separately defined treatments: (a) ARV-471 
alone (from Period 1, Day 1 up to just before the first dose of itraconazole administered alone 
in Period 2, Day 1), (b) itraconazole alone (from first dose of itraconazole administered alone 
in Period 2, Day 1 up to just before coadministration of ARV-471 with itraconazole), and (c) 
itraconazole with ARV-471 (from coadministration of ARV-471 with itraconazole in Period 
2, Day 5 through the end of the study). 
A set of summary tables split by these 3 treatments will be produced to evaluate any potential 
risk associated with the safety and toleration of administering ARV-471 alone, itraconazole 
alone, and ARV-471 in the presence of itraconazole. 
6.5.1. Adverse Events 
Adverse events will be reported in accordance with the CaPS. 
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS. 
6.5.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the CaPS. 
6.5.3. Vital Signs 
Vital signs data will be listed and summarized by treatment in accordance with the CaPS. 
6.5.4. Electrocardiograms 
Changes from baseline for the ECG parameters HR, QTcF , PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 


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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 
 
In addition, PR and QRS maximum values and maximum increases from baseline will also 
be tabulated by treatment using the following categories: 
 
Safety PR and QRS Assessment 
 
PR (ms) 
Max. >300 
PR (ms) increase from baseline 
Baseline >200 and max. >25% increase; 
Baseline <200 and max. >50% increase 
QRS (ms) 
Max. >140 
QRS (ms) increase from baseline 
>50% increase 
 
7. INTERIM ANALYSES 
No formal 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 modeling, and/or supporting clinical 
development. 
7.1. Introduction 
Not applicable. 
7.2. Interim Analyses and Summaries 
Available safety and PK data may be reviewed. 


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APPENDICES 
Appendix 1. Summary of Analyses 
 
Endpoint 
Population 
Data Inclusion and Rules 
for Handling Intercurrent 
Events and Missing Data 
Analysis 
Method 
Ratio of ARV-471 
and ARV-473 
AUCinf, Cmax, AUClast 
PK Parameter 
Analysis Set 
Observed data 
Mixed effect 
ANOVA 
model 
ARV-471 and ARV- 
473 PK parameters 
PK Parameter 
Analysis Set 
Observed data 
Descriptive 
statistics 
ARV-471 and ARV- 
473 PK 
concentrations 
PK Concentration 
Analysis Set 
Observed and imputed 
(Section 5.3.1) data 
Descriptive 
statistics 
Safety data 
Safety Analysis 
Set 
Observed and imputed 
(Section 5.3.2) data 
Descriptive 
statistics 
 
Appendix 2. SAS Code for Analyses 
An example of the PROC MIXED code is provided below: 
For primary and secondary objectives: 
• 
Treatment B (Test) vs Treatment A (Reference) 
 
proc mixed data=tab.pk; 
class trt participant; 
model l&var=trt / ddfm=KR; 
random participant / subject=participant; 
lsmeans trt; 
estimate 'B vs A' trt -1 1 /cl alpha=0.1; 
 
 
 
 
 
run; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 


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/* Letter assignments for treatments (trt) within the estimate statement above are as follows 
A: single dose of ARV-471 alone 
B: multiple doses of itraconazole + single dose of ARV-471 
*/ 


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Appendix 3. List of Abbreviations 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
ANOVA 
analysis of variance 
AUCinf 
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time 
AUClast 
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CaPS 
Clinical Data Interchange Standards Consortium and Pfizer 
Standards 
CI 
confidence interval 
CL/F 
apparent clearance 
Clast 
predicted plasma concentration at the last quantifiable time point 
from the log-linear regression analysis 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CSR 
clinical study report 
CYP3A 
cytochrome P450, family 3, subfamily A 
ECG 
electrocardiogram 
ER 
estrogen receptor 
HR 
heart rate 
kel 
elimination rate constant estimated from the log-linear regression 
analysis 
LLQ 
lower limit of quantitation 
ms 
milliseconds 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
rBA 
relative bioavailability 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 


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Abbreviation 
Term 
t1/2 
terminal plasma elimination half-life 
TEAE 
treatment emergent adverse event 
Tmax 
time for Cmax 
Vz/F 
apparent volume of distribution after oral dose