Clinical trial NCT05349864
Conditions: Healthy Participants
Keywords: Food effect study
Sponsor: Pfizer
Start date: 2022-06-17; Completion date: 2022-09-16
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the study is to evaluate the effect of a low-fat and high-fat meal on the medicine called PF-07284890 following three single doses PF-07284890. The study will include male participants and female participants of non-childbearing potential who are healthy. Participants will be required to stay in the clinical research unit for 15 days and 14 nights.

Detailed description:

Arms: arm 1: PF-07284890 tablet will be taken by mouth in a single dose for Treatment A while fasting.

Five days later PF-07284890 tablet will be taken by mouth for Treatment B after a low fat meal.

Five days later PF-07284890 tablet will be taken by mouth for Treatment C after a high fat meal. arm 2: PF-07284890 tablet will be taken by mouth for Treatment B after a low fat meal.

Five days later PF-07284890 tablet will be taken by mouth in a single dose for Treatment A while fasting.

Five days later PF-07284890 tablet will be taken by mouth for Treatment C after a high fat meal.
Interventions: intervention 1: PF-07284890 Treatment A intervention 2: PF-07284890 Treatment B intervention 3: PF-07284890 Treatment C
Intervention descriptions: intervention 1: PF-07284890 tablet by mouth while fasting intervention 2: PF-07284890 tablet after low fat meal intervention 3: PF-07284890 tablet after high fat meal

Protocol documents:
Prot_000.pdf: 
PF-07284890
Protocol C4471002
Final Protocol, 06 April 2022
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, 2-SEQUENCE, 
3-PERIOD CROSSOVER STUDY TO EVALUATE THE EFFECT OF A LOW-FAT 
AND HIGH-FAT MEAL ON THE RELATIVE BIOAVAILABILITY OF PF-07284890
IN HEALTHY ADULT PARTICIPANTS
Study Intervention Number:
PF-07284890
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID: 
N/A
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4471002
Phase:
1
Brief Title: A Phase 1 Study to Evaluate the Effect of a Low-Fat and High-Fat Meal on 
the Relative Bioavailability of PF-07284890 in Healthy Adult Participants
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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Document History
Document
Version Date
Original protocol
06 April 2022


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................19
2.1. Study Rationale .......................................................................................................19
2.2. Background .............................................................................................................19
2.2.1. Nonclinical Pharmacology..........................................................................20
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................20
2.2.3. Nonclinical Safety ......................................................................................20
2.2.4. Clinical Overview.......................................................................................22
2.2.4.1. First-in-Human Study (C4471001) ...........................................22
2.2.4.2. Summary of PF-07284890 Pharmacokinetics in Human..........25
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
2.3.2. Benefit Assessment.....................................................................................28
2.3.3. Overall Benefit/Risk Conclusion................................................................28
3. OBJECTIVES AND ENDPOINTS.....................................................................................28
4. STUDY DESIGN.................................................................................................................28
4.1. Overall Design.........................................................................................................28
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Assessment of Safety Data Before Administration of the High-fat 
Meal .................................................................................................................30
4.2.2. Choice of Contraception/Barrier Requirements .........................................31
4.2.3. Collection of Retained Research Samples..................................................31
4.3. Justification for Dose ..............................................................................................31
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
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5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................33
5.3. Lifestyle Considerations..........................................................................................36
5.3.1. Contraception..............................................................................................36
5.3.2. Meals and Dietary Restrictions...................................................................36
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................37
5.3.4. Activity .......................................................................................................38
5.3.5. Photosensitivity...........................................................................................38
5.4. Screen Failures ........................................................................................................38
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................38
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................39
6.2. Preparation, Handling, Storage, and Accountability...............................................40
6.2.1. Preparation and Dispensing........................................................................41
6.3. Assignment to Study Intervention...........................................................................41
6.4. Blinding...................................................................................................................41
6.5. Study Intervention Compliance...............................................................................41
6.6. Dose Modification...................................................................................................42
6.7. Continued Access to Study Intervention After the End of the Study......................42
6.8. Treatment of Overdose............................................................................................42
6.9. Prior and Concomitant Therapy..............................................................................42
6.9.1. Rescue Medicine.........................................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................44
7.1. Discontinuation of Study Intervention ....................................................................44
7.1.1. ECG Changes..............................................................................................45
7.1.2. Potential Cases of Acute Kidney Injury .....................................................45
7.1.3. COVID-19 ..................................................................................................45
7.2. Participant Discontinuation/Withdrawal From the Study.......................................46
7.2.1. Withdrawal of Consent...............................................................................46
7.3. Lost to Follow-up....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47


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8.1. Administrative Procedures ......................................................................................47
8.2. Efficacy Assessments..............................................................................................48
8.3. Safety Assessments .................................................................................................48
8.3.1. Physical Examinations................................................................................49
8.3.2. Vital Signs ..................................................................................................49
8.3.2.1. Blood Pressure and Pulse Rate..................................................49
8.3.2.2. Respiratory Rate........................................................................50
8.3.2.3. Temperature ..............................................................................50
8.3.3. Electrocardiograms.....................................................................................50
8.3.4. Ophthalmic Examinations ..........................................................................51
8.3.5. Clinical Safety Laboratory Assessments ....................................................51
8.3.6. COVID-19 Specific Assessments...............................................................52
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................52
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......52
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................53
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................53
8.4.2. Method of Detecting AEs and SAEs ..........................................................53
8.4.3. Follow-Up of AEs and SAEs......................................................................54
8.4.4. Regulatory Reporting Requirements for SAEs...........................................54
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................54
8.4.5.1. Exposure During Pregnancy......................................................55
8.4.5.2. Exposure During Breastfeeding ................................................56
8.4.5.3. Occupational Exposure .............................................................57
8.4.6. Cardiovascular and Death Events...............................................................57
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................57
8.4.8. Adverse Events of Special Interest.............................................................57
8.4.8.1. Lack of Efficacy........................................................................57
8.4.9. Medical Device Deficiencies......................................................................57
8.4.10. Medication Errors.....................................................................................57
8.5. Pharmacokinetics ....................................................................................................58
8.5.1. Plasma for Analysis of PF-07284890.........................................................58


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8.6. Genetics...................................................................................................................59
8.6.1. Specified Genetics ......................................................................................59
8.7. Biomarkers ..............................................................................................................60
8.7.1. Specified Gene Expression (RNA) Research .............................................60
8.7.2. Specified Protein Research.........................................................................60
8.7.3. Specified Metabolomic Research ...............................................................60
8.8. Immunogenicity Assessments.................................................................................60
8.9. Health Economics ...................................................................................................60
9. STATISTICAL CONSIDERATIONS ................................................................................60
9.1. Statistical Hypotheses .............................................................................................60
9.2. Analysis Sets ...........................................................................................................61
9.3. Statistical Analyses .................................................................................................61
9.3.1. Primary Endpoint(s) Analysis.....................................................................61
9.3.1.1. Definition of Endpoint(s) ..........................................................61
9.3.1.2. Statistical Methods for Pharmacokinetic Data..........................62
9.3.2. Other Safety Analyses ................................................................................63
9.3.2.1. Electrocardiogram Analyses......................................................63
9.4. Interim Analyses .....................................................................................................64
9.5. Sample Size Determination.....................................................................................64
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................66
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............66
10.1.1. Regulatory and Ethical Considerations ....................................................66
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................66
10.1.2. Informed Consent Process ........................................................................67
10.1.3. Data Protection .........................................................................................68
10.1.4. Committees Structure ...............................................................................68
10.1.5. Dissemination of Clinical Study Data ......................................................68
10.1.6. Data Quality Assurance ............................................................................69
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10.1.7. Source Documents....................................................................................71
10.1.8. Study and Site Start and Closure ..............................................................71
10.1.9. Publication Policy.....................................................................................72
10.1.10. Sponsor’s Medically Qualified Individual..............................................73
10.2. Appendix 2: Clinical Laboratory Tests .................................................................74
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................76
10.3.1. Definition of AE .......................................................................................76
10.3.2. Definition of an SAE ................................................................................77
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................78
10.3.4. Reporting of SAEs....................................................................................82
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................83
10.4.1. Male Participant Reproductive Inclusion Criteria....................................83
10.4.2. Female Participant Reproductive Inclusion Criteria.................................83
10.4.3. Woman of Childbearing Potential ............................................................83
10.4.4. Contraception Methods.............................................................................84
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......87
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................89
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................89
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............89
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................89
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................89
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................90
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI.......92
10.10. Appendix 10: Abbreviations ...............................................................................94
11. REFERENCES ..................................................................................................................99
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LIST OF TABLES
Table 1.
MOEs for Nonclinical Species Compared to Humans at Dose 
Levels of Interesta .....................................................................................21
Table 2.
PF-07284890 Monotherapy Dose Level Review and Status....................24
Table 3.
PF-07284890 Combination with Binimetinib (45 mg BID) Dose 
Level Review and Status ..........................................................................25
Table 4.
PF-07284890 Plasma PK Parameters Observed During 
Monotherapy Dose Escalation in C4471001a...........................................25
Table 5.
PF-07284890 Plasma PK Parameters Observed During 
Combination Dose Escalation in C4471001a............................................26
Table 6.
Plasma PF-07284890 PK Parameters Definitions....................................62
Table 7.
Confidence Interval Estimation of PK Endpoints ....................................64
Table 8.
Protocol-Required Safety Laboratory Assessments .................................74
Table 9.
Protocol-Required Follow-Up Safety Laboratory Assessments (In 
Case of Abnormality) ...............................................................................75
Table 10.
Prohibited Concomitant Medications that May Result in DDI ................92
LIST OF FIGURES
Figure 1.
C4471001 Study Schema..........................................................................15


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-Label, Randomized, Single Dose, 2 Sequence, 3 Period 
Crossover Study to Evaluate the Effect of a Low-fat and High-fat Meal on the Relative 
Bioavailability of PF-07284890 in Healthy Adult Participants 
Brief Title: A Phase 1 Study to Evaluate the Effect of a Low-Fat and High-Fat Meal on the 
Relative Bioavailability of PF-07284890 in Healthy Adult Participants
Regulatory Agency Identification Number(s):
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID: 
N/A
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4471002
Phase:
1
Rationale:
The purpose of the study is to evaluate the effect of a low-fat and high-fat meal on the 
relative bioavailability of PF-07284890 following single dose oral administration of 
PF-07284890 using 2 of the 100 mg PF-07284890 tablets currently used in the first-in-patient 
study C4471001 (200 mg per single dose).
Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary: 
To evaluate the effect of a low-fat meal on the 
exposures of PF-07284890 following a single oral 
200-mg dose
To evaluate the effect of a high-fat meal on the 
exposures of PF-07284890 following a single oral 
200-mg dose
Comparison of low-fat meal with fasted PK: The ratio of 
AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890
Comparison of high-fat meal with fasted PK: The ratio 
of AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890
Secondary: 
Secondary: 
To characterize the pharmacokinetic parameters of 
PF-07284890 following a single oral 200-mg dose
Tmax, t½, CL/F and Vz/F (if data permit).
To evaluate the safety and tolerability of PF-07284890 
in healthy participants
Assessment of TEAEs, clinical laboratory abnormalities, 
vital signs, and 12-lead ECGs.
Overall Design:
This is a Phase 1, open-label, randomized, single dose, 3-treatment, 2-sequence, 3-period 
crossover study to evaluate the effect of a low-fat and high-fat meal on the relative 
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bioavailability of PF-07284890 following a single oral dose of PF-07284890 using two 
100-mg tablets of PF-07284890 in healthy adult participants, males and females of 
non-childbearing potential. The study will consist of 3 treatments: a single oral dose of 
200 mg PF-07284890 (2 × 100 mg tablets) under fasted conditions (Treatment A, Reference), 
a single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under low-fat meal fed 
conditions (Treatment B, Test 1), and a single oral dose of 200 mg PF-07284890 (2 × 100 mg 
tablets) under high-fat meal fed conditions (Treatment C, Test 2). 
Approximately 12 healthy participants will be randomly assigned to study intervention such 
that approximately 6 participants will be enrolled to each sequence. Participants who 
discontinue from the study for non-safety reasons may be replaced at the sponsor’s discretion 
in collaboration with the investigator.
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of physical examination, physical measurements, vital 
signs, 12-lead ECGs, and clinical laboratory evaluations will determine eligibility. 
Participants will report to the CRU on Day -1, and will be required to stay in the CRU for 
15 days and 14 nights.
Eligible participants will be admitted to the CRU at least 12 hours prior to the dosing of 
PF-07284890 on Day 1 of Period 1. On the morning of Day 1 of each period, participants 
will receive a single dose of PF-07284890 200 mg as per randomization schedule. Study 
intervention will be administered with approximately 240 mL of ambient temperature water. 
In fed periods (Sequence 2 Period 1 and Sequence 1 Period 2 for the low-fat meal and 
Period 3 for the high-fat meal as shown in Section 1.2), following an overnight fast of at least 
10 hours, participants should begin breakfast approximately 30 minutes prior to 
PF-07284890 administration. For Sequence 2 Period 1 and Sequence 1 Period 2, a low-fat 
(approximately 25% of total caloric content of the meal), low-calorie (approximately 400 to 
500 calories) breakfast will be consumed over approximately a 20-minute interval with 
PF-07284890 administered within approximately 10 minutes of completion of the meal. For 
Period 3, a high-fat (approximately 50% of total caloric content of the meal), high-calorie 
(approximately 800 to 1000 calories) breakfast will be consumed over approximately a 
20-minute interval with PF-07284890 administered within approximately 10 minutes of 
completion of the meal. Serial PK samples will be collected up to 72 hours post dose. 
Period 2 will begin on Period 1 Study Day 5 (referred to as Period 2, Day -1). Period 3 will 
begin on Period 2 Study Day 5 (referred to as Period 3, Day -1). Participants will be 
discharged from the CRU at the end of Period 3, Study Day 4, following completion of all 
assessments.
Before the Period 3 doses are administered to participants that have eaten a high-fat meal, the 
safety data for Periods 1 and 2, including at least 8 participants administered a low-fat meal 
in Period 1 or 2, will be reviewed by the study team and the investigator and assessed based 
on safety and tolerability. Period 3 will initiate as planned if the doses administered in 
Periods 1 and 2 were well-tolerated.


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If a participant has any clinically significant, study related abnormalities at the conclusion of 
a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the CRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up.
A safety follow-up call will be made to participants 28 to 35 days from administration of the 
final dose of study intervention.
Number of Participants:
Approximately 12 participants will be randomly assigned to study intervention.
Note: "Enrolled" means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and assignment to study intervention. A 
participant will be considered enrolled if the informed consent is not withdrawn prior to 
participating in any study activity. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
Study Population: 
Inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study:
1. Participants ≥18 and 65 years of age, inclusive, at the time of signing the ICD. 
2. Male participants and female participants of non-childbearing potential who are 
overtly healthy as determined by medical evaluation including medical history, 
physical examination, laboratory tests, vital signs and 12-lead ECGs.
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
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Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Evidence or history of clinically significant uveitis, 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).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb or HCVAb. Hepatitis B vaccination is allowed.

Use of PPIs is not allowed within 7 days of study start (C1D1) and during study 
treatment.
2. 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 (eg, contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.
4. Current use or anticipated need for drugs that are known strong UGT2B7 inhibitors,
including the administration within 10 days or 5 half-lives, whichever is longer, or
strong UGT2B7 inducers, including the administration within 5 half-lives plus 10 
days, prior to first dose of PF-07284890. 
5. Participant who has received a COVID-19 vaccine within 7 days before screening or 
admission, or who are to be vaccinated with a COVID-19 vaccine at any time during 
the study confinement period.
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).
7. Positive test result (RT-PCR) for SARS-CoV-2 infection at the time of screening or 
Day -1.
8. A positive urine drug test at screening or admission.


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9. A positive urine cotinine test at screening or admission.
10. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. 
11. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results.
12. 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 ≥1.25 × ULN;

Total bilirubin level ≥1.5 × 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.

eGFR <75 mL/min/1.73 m2 with 10% variation based on the CKD-EPI equation.

Hemoglobin < 11 g/dL

ANC < 1.5 10e9/L

Platelets < 100,000/mm3
13. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.
14. Current smokers or history of the use of tobacco- or nicotine-containing products 
within 6 months of screening.
15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
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 
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Study Arms and Duration:
Each participant will be screened to determine eligibility within 28 days prior to study 
treatment. Eligible participants will report to the CRU on Day -1, Period 1 and will be 
required to stay in the CRU for 15 days and 14 nights. A safety follow-up call will be made 
to participants 28 to 35 days from administration of the final dose of study intervention. 
Each enrolled participant will participate in 3 study periods to receive 3 different treatments
according to the sequence determined by randomization with 5-day washouts between
PF-07284890 administration: 

Treatment A: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fasted 
conditions (Reference).

Treatment B: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fed 
conditions, low-fat meal (Test 1).

Treatment C: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fed 
conditions, high-fat meal (Test 2).
Participants will be randomly assigned to 1 of 2 sequences as shown in Section 1.2.
Statistical Methods:
Pharmacokinetics Analysis
The PK concentration population is defined as all participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention and in whom at least 
1 concentration value can be reported.
The PK parameter analysis population is defined as all participants randomly assigned to 
study intervention and who take at least 1 dose of study intervention and in whom at least 
1 of the PK parameters of interest can be reported.
PK parameters for PF-07284890 will be analyzed using standard noncompartmental method 
of analysis. Actual PK sampling times will be used in the derivation of PF-07284890 PK 
parameters when available, otherwise nominal times will be used. The PF-07284890 plasma 
PK parameters will be summarized descriptively by treatment. Plasma concentrations will be 
listed and summarized descriptively by treatment, and nominal PK sampling time. 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, respectively. 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effect model with sequence, period and treatment as fixed effects and participant 
within sequence 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 


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ratio of adjusted geometric means (Test/Reference) and 90% CI for the ratios. Treatment A 
(PF-07284890 administered under fasted condition) is the Reference treatment, Treatment B 
(PF-07284890 administered under fed condition, low-fat meal) is the first Test treatment, 
Test 1, and Treatment C (PF-07284890 administered under fed condition, high-fat meal) is 
the second Test treatment, Test 2. 
Safety Analysis
All safety analyses will be performed on the safety analysis set, which is defined as all 
participants randomly assigned to study intervention and who take at least 1 dose of study 
intervention. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Ethical Considerations:
PF-07284890 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate PK, safety and tolerability data for PF-07284890 
administered in the fasted and fed state for further clinical development.

Participants will be expected to commit time and may experience some discomfort 
while undergoing study assessments. 

Male participants must agree to use appropriate contraception methods.
1.2. Schema
A diagram of the study design is displayed in Figure 1.
Figure 1.
C4471002 Study Schema


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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.
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10
Screeninga
Periods 1-3b
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 2 Day 
3
Day 
4
28-35 dayst
Hours After Dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
16
24 36
48
72
Informed consent
X
CRU confinementc
X















X
Inclusion/exclusion criteria
X
X
Medical/medication history 
(update)d
X
X
Demographye
X
Physical examinationf
X
Xf
Safety laboratory (including 
aPTT, PT-INR and eGFR)g
X
Xv
X
X
FSHh
X
Urine drug and cotinine 
testingi
X
X
HIV, HBsAg, HBcAb,
HCVAb
X
Contraception checkj
X
X
X
X
Single supine 12-lead ECGk
X
X
X
X
X
X
Triplicate 12-lead ECGk
Xs
Vital signs 
(BP/PR/temperature)l
X
Xs
X
X
Full ophthalmic examm
If clinically indicated 
COVID-19 questionnairen
X
X


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Protocol C4471002
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10
Screeninga
Periods 1-3b
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 2 Day 
3
Day 
4
28-35 dayst
Hours After Dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
16
24 36
48
72
COVID-19 testingn
X
X


PF-07284890o
X
PK blood sampling for 
PF-07284890p
Xs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Retained Research Sample 
for Genetics (Prep D1)q
X
Serious and nonserious AE 
monitoring
X

















X
X
Concomitant treatments

X












X
X
CRU discharger
X
a.
Screening will be performed within 28 days prior to the first dose of PF-07284890. 
b.
Period 2 will begin on Study Period 1, Day 5 (referred to as Period 2, Day -1). Period 3 will begin on Study Period 2, Day 5 (referred to as Period 3, Day -1). Day -1 activities 
will be performed only for Day -1 of Period 1 unless otherwise indicated.
c.
Participants will be admitted to the CRU at least 12 hours prior to PF-07284890 dose on Day 1 of Period 1. Participants will be discharged on Day 4 of Study Period 3
following completion of all assessments.
d.
Medical history will include a history of prior illegal 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. 
e.
Demographics will include participant race, ethnicity, age, and gender during the screening visit. 
f.
Physical examination 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 brief PE will be performed on Day -1 of Periods 2 and 3, and may be performed at other designated time points at the 
discretion of the investigator. 
g.
Safety laboratory assessments including urinalysis, hematology, chemistry and coagulation will be performed at the indicated time-points, including Day -1 and Day 2 at 
24 hours post-dose of all 3 Periods. All the safety laboratory samples must be collected following at least a 4-hour fast. Additional safety laboratory assessments may be 
performed at any time at the discretion of the investigator. 
h.
For postmenopausal (amenorrheic for at least 12 consecutive months) female participants only.
i.
Urine drug and cotinine (mandatory) and alcohol breath test (at discretion of the investigator) will be performed at screening from Days -28 to -2 and again on Day -1 of 
Period 1. These tests may be performed at any other time at the discretion of the investigator.
j.
The investigator or his/her designee will discuss with the participant the need to use highly effective contraception consistently and correctly according to contraception 
guidelines.
k.
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. Day 4 ECGs are for Period 3 
only. Single ECGs are needed for screening, times after the study intervention has been administered, Day 4 of Period 3, and upon early termination/discontinuation, while 
triplicate ECGs are needed for baseline.
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10
Screeninga
Periods 1-3b
Follow-Up
Early 
Termination/
Discontinuation
Days Relative to Day 1
Days
-28 to -2
Day 
-1
Day 1
Day 2 Day 
3
Day 
4
28-35 dayst
Hours After Dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
16
24 36
48
72
l.
Single supine BP and PR 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. Day 4 measurements are for Period 3 only. Temperature will be measured as per CRU standard practice. RR will be 
collected if the PR is outside of normal range.
m.
Full ophthalmic exam will be conducted if treatment emergent ocular AEs are observed.
n.
See Section 8.3.6 for details.
o.
PF-07284890 will be administered orally on Day 1 after overnight fasting until the start of study procedures for each treatment period. PF-07284890 will be administered orally 
and in fasted or fed state according to the conditions described in Protocol Section 5.3.2 Meals and Dietary Restrictions.
p.
One (approximately 3 mL) blood sample for PK analysis of PF-07284890 will be taken at the designated time points post dose in each treatment period.
q.
Retained Research Samples Prep D1 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. These samples will be collected during Period 1 only.
r.
Participants will be discharged on Day 4 of of Period 3 after completion of all assessment.
s.
Collect at pre-dose for all 3 periods. For fed periods (Sequence 2 Period 1 and Sequence 1 Period 2 for the low-fat meal and Period 3 for the high-fat meal), the ECGs should 
be done before the pre-dose PK sample, and both should be done before the meals.
t.
Contact may occur via telephone and must occur 28 to 35 days from administration of the final dose of study intervention.
v.
Safety laboratories will be done on Day -1 of all 3 periods.
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2. INTRODUCTION
PF-07284890 (also known as ARRY-461) is a potent, selective, highly brain-penetrant 
small-molecule inhibitor of BRAF V600 mutations that is currently being developed for the 
treatment of BRAF V600-mutant solid tumors with or without brain involvement.
2.1. Study Rationale 
The purpose of the study is to evaluate the effect of a low-fat and high-fat meal on the 
relative bioavailability of PF-07284890 following single dose oral administration of 
PF-07284890 using 2 of the 100 mg PF-07284890 tablets currently used in the first-in-patient 
study C4471001 (200 mg per single dose). Results from the study will be used to inform food 
instructions for patients in PF-07284890 first-in-patient study C4471001, Phase 1b.
2.2. Background 
BRAF V600 mutations occur in approximately 50% of melanoma and PTC, 45% of ATC, 
15% of CRC, 2% of NSCLC and less commonly in several other tumor types (based on data 
from SEER database, seer.cancer.gov). BRAF mutations drive constitutive MAPK pathway 
activation and in turn proliferation with enhanced cellular survival. Small molecule BRAF 
inhibitors block mutant BRAF, MAPK signaling, proliferation and survival in some BRAF 
V600-mutant tumor cells, effects that are enhanced by combination with MEK inhibitors. To 
date, there are 3 BRAF inhibitor/MEK inhibitor combinations approved for select BRAF 
V600-mutant cancers: dabrafenib/trametinib (melanoma, NSCLC and ATC), 
vemurafenib/cobimetinib (melanoma) and encorafenib/binimetinib (melanoma). 
Metastatic spread to the CNS is a particularly poor prognostic factor for many solid cancers, 
with average survival typically <6 months.1 Among solid tumors, metastatic melanoma and 
NSCLC have the highest risks of spread to the CNS, with lifetime prevalences of 40-60% 
and 20-40%, respectively.2,3,4
Due to poor brain penetration and limited intracranial activity in early clinical trials, 
randomized studies of approved BRAF/MEK inhibitors in patients with melanoma and 
NSCLC (the frequency of brain metastases in CRC and ATC is low) excluded patients with 
untreated (ie, with local brain therapy), symptomatic (including a requirement for steroids 
and anti-epileptic therapy to control symptoms) and/or progressing brain metastases.5,6,7
Recent studies of BRAF/MEK inhibitor combination therapy in patients with solid tumor 
malignancies with brain metastases therapies have yielded intracranial response rates of 
between 41-75% in asymptomatic patients and 44-59% in symptomatic patients, with 
duration of response ranging from a median 12 months in patients with treated brain 
metastases to 4.5 months in patients with symptomatic brain metastases. 5,6,8,9 The addition of 
immunotherapy to these combinations yielded response rates of 54 and 59% (including 29% 
intracranial CR), with median intracranial and overall DoR not reached (12 month landmark 
global PFS was 56.6%).10 Patients with BRAF V600-mutant melanoma and NSCLC with 
metastases to the brain, therefore, usually receive local brain therapy (eg, SRS, surgical 
resection, WBRT) at some point during their disease course. SRS and surgery are generally 
limited to 3 or fewer lesions (SRS) or a single large (>3 cm) or posterior fossa lesion 
(surgery) and do not control disease at untreated sites. WBRT causes accelerated cognitive 


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Final Protocol, 06 April 2022
PFIZER CONFIDENTIAL
Page 20
decline and was no better than supportive care in NSCLC patients.11 There is therefore an 
unmet need to identify new treatment approaches that target BRAF V600-mutant cancers 
both systemically and in the brain.
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of PF-07284890 can be found in the current IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
After oral administration, plasma exposures of PF-07284890 (AUC and Cmax) increased with 
dose in all species and the absolute oral bioavailability was moderate to complete. GLP TK 
studies in the rat (doses of 10, 30 and 60 mg/kg) and monkey (doses of 10, 30 and 100 
mg/kg) showed less than dose-proportional exposures, as might be expected based on 
relatively low aqueous solubility (ie, in simulated gastric fluid at 37oC at a pH of 1.2, 131.6 
μg/mL, and in fasted state simulated intestinal fluid at a pH of 6.5, 7.6 μg/mL).
In vitro and in vivo metabolite identification suggested that PF-07284890 was metabolized 
through multiple oxidative and/or glucuronosyltransferase enzymes. Comparisons of across 
species suggested that direct N-glucuronidation is predicted to be the predominant metabolic 
route in humans. PF-07284890 glucuronidation is the primary route of metabolism in human 
hepatocytes with minor contribution from CYP3A4 and aldehyde oxidase. An in vitro study 
conducted to characterize the involvement of 11 selected human UGTs isoforms in the 
metabolism of PF-07284890 indicated that UGT2B7 was the principal human isoform likely 
responsible for primary glucuronide conjugates. Renal clearance was a minor elimination 
route of unchanged PF-07284890 in rats (<1% of an IV dose) and is predicted to be a minor 
route across all species, including humans.
Additional information of the nonclinical PK and metabolism of PF-07321332 is available in 
the current IB.
2.2.3. Nonclinical Safety
Safety pharmacology studies were conducted in rats and monkeys to assess the effects of 
PF-07284890 on key organ systems (cardiovascular, respiratory, neurobehavioral and 
gastrointestinal function). Rats and monkeys received single oral doses of up to 100 mg/kg 
PF-07284890. There were no significant in vivo safety pharmacology findings seen in either 
species. Additionally, PF-07284890 was evaluated at concentrations up to 100 µM in the in 
vitro GLP hERG channel assay and showed an IC50 of 70.15 M.
The toxicological evaluation of PF-07284890 included: 28-day repeat-dose studies in 
Sprague Dawley rats and cynomolgus monkeys, a genotoxicity assay (Ames), a local 
tolerance study (GI irritation in the rat) and an in vitro phototoxicity study. All of these 
studies were conducted in accordance with international regulatory guidelines for nonclinical 
toxicity studies and in adherence to current GLP guidelines. 
Following 28 days of once-daily oral administration of PF-07284890 (10, 30 or 60 mg/kg) to 
Sprague Dawley rats, the toxicological response was characterized primarily by the clinical 


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Page 21
observations of hindlimb swelling, requiring euthanasia of 6 (out of 150) rats, and mild 
clinical pathology changes (decreased ALP, decreased red cell parameters, increased 
reticulocytes, increased white cell parameters, increased aPTT and increased urine volumes); 
all of which resolved in the recovery animals. It is important to note that many of the 
PF-07284890 -treated animals were observed to have blistering, swelling and scab/crust 
formation on the hindlimbs, however, in all but the 6 animals that were euthanized the 
findings resolved or were of reduced severity and incidence with continued dosing. 
Target organs in the study were testes, epididymides, heart, and skin. Organ weight decreases 
in epididymides at 60 mg/kg, increases in heart at 30 and/or 60 mg/kg dose in females, and 
increases in liver, ovaries, and spleen in males and/or females were noted at all dose levels. 
Myxomatous degeneration of the heart valves at 30 and 60 mg/kg and degeneration of 
seminiferous tubules in the testes and debris in the lumen and decreased cellularity of sperm 
in the epididymides at 30 and 60 mg/kg were considered adverse histopathology changes 
from terminal necropsy. All PF-07284890 -related changes from terminal necropsy exhibited 
significant recovery, except for those in the testes and epididymides at 30 and 60 mg/kg. 
Based on the requirement for euthanasia, due to the impairment of mobility and pain (due to 
paw/hind limb swelling) at the lower dose level, the NOAEL could not be determined. 
However, these skin effects were not seen in rats until Study Day 10 and a single female 
required euthanasia due to this effect. The STD10 of 60 mg/kg was determined from test 
article-related lethality or irreversible and life-threatening findings. The lowest dose of 10 
mg/kg corresponded to plasma AUC24hr on Study Day 1 of 192 and 517 µg•hr/mL in male 
and female rats respectively, 12-32 multiple over the planned clinical dose (Table 1) based 
on comparison to the geometric mean AUC24hr for a 200-mg single dose (ie, based on C1D1)
as shown in Table 4.
Table 1.
MOEs for Nonclinical Species Compared to Humans at Dose Levels of 
Interesta
Subject area
Key Findings
Margin for HV 
C1D1 (AUC)
Margin for HV 
C1D1 (Cmax)
General Tox Rat 28-
Day Study QD oral 
10, 30, 60 m/k/d 
(473.05)
Beginning on Study Day 10 skin effects with 
rash and/or paw and hindlimb swelling all doses 
(10 mg/kg margin shown)
Male = 12x
Female = 32x
Male = 13x
Female = 21x
Myxomatous degeneration of heart valves, 
degeneration of seminiferous tubules of testes 
with decreased sperm in the epididymis at >30 
mg/kg
30 mg/kg M = 
39x
30 mg/kg F = 
74x
30 mg/kg M = 35x
30 mg/kg F = 55x
NOAEL not achieved due to impairment of 
mobility from hind limb swelling and pain 
requiring euthanasia at 10 mg/kg (a single 
female rat) (10 mg/kg MOE shown)
Male = 12x
Female = 32x
Male = 13x
Female = 21x


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Final Protocol, 06 April 2022
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Page 22
Table 1.
MOEs for Nonclinical Species Compared to Humans at Dose Levels of 
Interesta
Subject area
Key Findings
Margin for HV 
C1D1 (AUC)
Margin for HV 
C1D1 (Cmax)
STD10 60 mg/kg based on 4/32 early terminated 
animals
Male = 59x
Female = 110x
Male = 41x
Female = 67x
General Tox NHP 
28-Day Study QD 
oral 10, 30, 100 
m/k/d (473.04)
Well tolerated for 28 days
Minimal stomach ulceration 100 mg/kg
5x
8x
NOAEL and HNSTD 100 mg/kg
5x
8x
a.
Exposures from nonclinical TK data were divided by human monotherapy geometric mean AUC24hr and 
Cmax values as appropriate at the 200 mg dose level (data shown in Table 4).
Following 28 days of once-daily oral administration of PF-07284890 (10, 30 or 100 mg/kg) 
in cynomolgus monkeys, no adverse toxicological findings were observed, and the only 
histopathologic finding was minimal stomach ulceration at the high dose corresponding to a 
plasma AUC24 of 84.4 µg•hr/mL. Given the lack of adverse findings at any dose level, the 
NOAEL and HNSTD for daily oral dosing of PF-07284890 in male and female cynomolgus 
monkeys for 28 days was 100 mg/kg. 
In addition to the nonclinical investigations summarized above, there was no evidence of 
genotoxicity from the bacterial reverse mutation assay and no adverse effects on GI mucosa 
in the rat GI irritation assay.
PF-07284890 was determined to have phototoxic potential in the in vitro neutral red uptake 
assay.
2.2.4. Clinical Overview
PF-07284890 is being evaluated as a single-agent and in combination with binimetinib in 
Study C4471001.
2.2.4.1. First-in-Human Study (C4471001)
Study C4471001 is an ongoing Phase 1a/b, open-label, multicenter study of the safety, PK 
and preliminary clinical activity of PF-07284890 in adult participants with selected BRAF 
V600-mutant advanced or metastatic solid tumor malignancies and primary brain tumors. 
The study is being conducted in 2 parts, Phase 1a (Dose Escalation) and Phase 1b (Dose 
Expansion and a DDI sub-study). The Phase 1a dose escalation will evaluate the safety and 
PK of monotherapy (PF-07284890 alone) and combination therapy (PF-07284890 plus 
binimetinib) repeat-dosing. Phase 1b dose expansion will evaluate efficacy, safety, and PK at 
the MTD/RDE of the combination therapy (PF-07284890 plus binimetinib) in 5 cohorts of 
patients and a DDI Sub-Study.
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2.2.4.1.1. Study Design
Phase 1a – Dose Escalation
The study plans to enroll approximately 35 adult participants with selected BRAF V600-
mutant advanced or metastatic solid tumor malignancies and primary brain tumors to 
determine the MTD and/or recommended dose for further study of PF-07284890 alone and in
combination with binimetinib 45 mg BID. As of 10 January 2022, 4 dose levels (50 mg QD, 
100 mg QD, 200 mg QD, 200 mg BID) of PF-07284890 monotherapy had been evaluated 
and 3 dose levels of PF-07284890 had been evaluated (100 mg QD, 100 mg BID, and 150 
mg BID) in combination with binimetinib 45 mg BID. Patients included in the dose 
escalation are required to have evidence of disease progression despite prior treatment. 
Patients enrolled into the dose escalation are not required to have brain involvement, but the 
trial initially restricted enrollment to patients with brain lesions ≤ 4 cm and whose brain 
involvement was asymptomatic for at least 14 days prior to the start of study treatment. Once 
concentrations of PF-07284890 at steady state met or exceeded 0.168 µg/mL in at least two-
thirds of participants at the same dose level, a level at which antitumor activity in the brain 
and systemically was expected, patients whose brain involvement was symptomatic or whose 
brain lesions exceeded 4 cm were allowed to enroll. Additionally, once doses considered 
therapeutic were to be tested, patients with BRAF V600mutant melanoma, NSCLC, CRC or 
ATC who had not received prior BRAFi were allowed to enroll. Patients are required to have 
ECOG PS 0 or 1, adequate hematologic, renal, and liver function, must have resolution to 
prior adverse effects from prior treatments, and must not require immediate local intervention 
for the treatment of brain metastases/primary brain tumor. 
Phase 1b – Dose Expansion
After identification of the combination MTD/recommended dose for further study, 
approximately 40 participants will be enrolled to each of Cohorts 1-4 and 20 participants to 
Cohort 5 of Phase 1b dose expansion based on tumor type, symptomatic versus 
asymptomatic brain involvement, and prior treatment history.
2.2.4.1.2. Clinical Safety of PF-07284890
As of 10 January 2022, the study has dosed 22 patients in the Phase 1a Dose Escalation. 
Monotherapy:
At the 4 monotherapy dose levels assessed (50 mg QD, 100 mg QD, 200 mg QD, and 200 
mg BID), 12 patients have been treated, 9 patients were DLT evaluable, and no patients 
experienced DLTs (Table 2). Based on the safety of the prior dose and the available PK data 
for PF-07284890 suggesting that twice daily dosing would be needed to achieve trough 
concentrations at the fu-adj IC90, the recommendation to alter the schedule to twice daily 
dosing was supported by the BLRM and adopted with the next dose level studied being 
200 mg BID.
Preliminary safety results of the 200 mg QD dose of PF-07284890 in patients resulted in 
treatment emergent adverse events of Grade 2 worsening gout related to underlying condition 


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Page 24
(not related to PF-07284890) and sinus infection/sinusitis (not related to PF-07284890) as 
well as Grade 1 anorexia, arthritis, back pain, nausea and pain, all in 1 patient each. With 
repeat dosing of the 200 mg BID dose schedule, one patient experienced Grade 3 pneumonia, 
considered not related to study drug. Grade 2 events, occurring in 1 patient each, were 
ejection fracture decreased considered related to the patient’s underlying disease, fatigue, and 
oxygen saturation decreased preceding diagnosis of pneumonia, as well as maculo-papular 
rash. Dizziness, dry skin, and benign skin lesion were reported in 1 patient each as Grade 1. 
At lower doses, the only severe events reported were fatal disease progression of cancer, 
suprapubic pain related to the patient’s underlying disease, and 2 patients with Grade 3 
anemia, considered unrelated to study treatment in 1 case, and in another patient with 
Grade 1 anemia at baseline in the setting of renal dysfunction and iron deficiency. Data from 
repeat-dosing in patients suggests that the 200 mg dose is well tolerated.
Table 2.
PF-07284890 Monotherapy Dose Level Review and Status
PF-07284890 
Dose
DLRM Summary and Decision
50 mg QD
Number of participants reviewed: 2
Number of DLTs observed: 0
Escalate to 100 mg QD
100 mg QD
Number of participants reviewed: 4, 2 DLT evaluable 
Number of DLTs observed: 0
Escalate to 200 mg QD
200 mg QD
Number of participants reviewed: 3 
Number of DLTs observed: 0
Escalate to 200 mg BID
200 mg BID 
Number of participants reviewed: 3, 2 DLT evaluable
Number of DLTs observed: 0
Escalate to 300 mg BID
DLT evaluable: In the absence of a dose-limiting toxicity (DLT) a participant must receive ≥ 75% of their 
planned dose during the DLT observation period, which is the first cycle of treatment, a 21-day cycle.
Combination:
Within the combination therapy dose escalation, 3 dose levels of PF-07284890 have been 
studied in combination with binimetinib 45 mg BID, 10 patients have been treated and 9
were DLT evaluable. At the first dose level (PF-07284890 100 mg QD + binimetinib 45 mg 
BID), one patient of 4 evaluable experienced DLTs of Grade 3 creatine phosphokinase 
increased and Grade 3 hypertension, considered related to binimetinib. Based on the safety of 
the prior dose and the available PK data for PF-07284890 suggesting that twice daily dosing 
would be needed to achieve trough concentrations at the fu-adj IC90, the recommendation to 
alter the schedule to twice daily dosing was supported by the BLRM and adopted with the 
next dose level studied being 100 mg BID. No DLTs were observed at the 100 mg BID or 
150 mg BID levels (Table 3). 


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2.2.4.2. Summary of PF-07284890 Pharmacokinetics in Human
Single and repeat dose PK data from study C4471001 for monotherapy (Table 4) and for 
combination therapy when coadministered with binimetinib (Table 5) have been obtained
under fasted conditions. PF-07284890 plasma exposure increased in a less than dose 
proportional manner. For monotherapy, the geometric mean dose-normalized AUC24hr for the 
200 mg QD dose was approximately 1.83- and 1.43-fold higher than for the 50-mg dose on 
C1D1 and C1D15, respectively, when a 4-fold increase would be expected for linear PK. The 
Tmax ranged from 1.5 to 6.0 hours across dose groups. The median t½ across dose groups 
ranged from 5.7 to 10 hours. PF-07284890 exposures were somewhat higher for combination 
therapy than for monotherapy, with the difference attributable to PK variability.
The accumulation ratio based on AUC values, RAUC, for patients administered PF-07284890 
QD ranged from 0.709 to 1.31, suggesting limited accumulation for QD administration. For 
BID administration, the limited available data indicate more accumulation occurs, with an 
RAUC value of 1.69 for the 100 mg BID combination therapy cohort.
Table 4.
PF-07284890 Plasma PK Parameters Observed During Monotherapy 
Dose Escalation in C4471001a
PF-07284890 
Dose and 
Regimen
Cycle and 
Day (N)
Cmax, 
ng/mL
Tmax, hr
AUC, 
ng hr/mL
Ctrough, 
ng/mLb
t½, hr
RCmax
RAUC
50 mg QD
C1D1 (2)
795
1.5
8850

6.17c


C1D15 (2)
1440
1.5
11500
166
10.0
1.79
1.31
100 mg QD
C1D1 (4)
1610 (40.3)
5.0
14400 (40.5)

5.83


C1D15 (3) 1090 (16.2)
4.0
10400 (8.34) 115 (71.7)
9.11
0.703 
(37.1)
0.709 
(45.2)
Table 3.
PF-07284890 Combination with Binimetinib (45 mg BID) Dose Level 
Review and Status
PF-07284890 Dose
DLRM Summary and Decision
100 mg QD
Number of participants reviewed: 4
Number of DLTs observed: 1
Escalate to 100 mg BID
100 mg BID
Number of participants reviewed: 4, 3 DLT evaluable 
Number of DLTs observed: 0
Escalate to 150 mg BID
150 mg BID
Number of participants reviewed: 2 
Number of DLTs observed: 0
Escalate to 225 mg BID
DLT evaluable: In the absence of a dose-limiting toxicity (DLT) a participant must receive ≥ 75% of their 
planned dose during the DLT observation period, which is the first cycle of treatment, a 21-day cycle.


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Table 4.
PF-07284890 Plasma PK Parameters Observed During Monotherapy 
Dose Escalation in C4471001a
PF-07284890 
Dose and 
Regimen
Cycle and 
Day (N)
Cmax, 
ng/mL
Tmax, hr
AUC, 
ng hr/mL
Ctrough, 
ng/mLb
t½, hr
RCmax
RAUC
200 mg QD
C1D1 (3)
1580 (20.3)
6.0
16200 (22.5)

5.68


C1D15 (3) 1820 (15.5)
2.0
16500 (8.12) 116 (329)
9.64
1.15 
(36.6)
1.02
(14.3)
200 mg BID 
C1D1 (3)
1890 (39.2)
6.0
17000d




C1D15
ND
ND
ND
ND
ND
ND
ND
a.
Analysis includes bioanalytical data available through 21DEC2021, and results are preliminary data that 
did not use the actual sample times. Values are Geometric mean (geometric %CV) except for when N 
<3, for which median values are presented, and for Tmax and t½, where median is presented. ND = no 
data.
b.
Ctrough is the Cp value pre-dose on C1D15.
c.
Only could be determined for 1 subject.
d.
Only could be determined for 2 subjects.
Table 5.
PF-07284890 Plasma PK Parameters Observed During Combination Dose 
Escalation in C4471001a
PF-07284890 
Dose and 
Regimen (N)
Cycle and 
Day (N)
Cmax, 
ng/mL
Tmax, hr
AUC, 
ng hr/mL
Ctrough, 
ng/mLb
t½, hr
RCmax
RAUC
100 mg QD
C1D1 (4)
1700 (59.0)
3.5
18000 (94.7)

10.3c


C1D15 (3)
1710 (77.2)
4.0
14700 
(38.6)c
166 (53.8)
7.09
1.16 (119)
1.09 
(73.9)
100 mg BID
C1D1 (4)
1810 (62.7)
4.0
11100 
(72.8) c




C1D15 (4)
2170 (34.4)
2.0
16400 (42.0) 761 (67.2)

1.20 
(55.1)
1.69 
(31.0)c
150 mg BID 
C1D1 (2)
2790
4.0
18900




C1D15 (0)
ND
ND
ND
ND
ND
ND
ND
a.
Analysis includes bioanalytical data available through 21DEC2021, and results are preliminary data that 
did not use the actual sample times. Values are Geometric mean (geometric %CV) except for when N 
<3, for which median values are presented, and for Tmax and t½, where median is presented. ND = no 
data.
b.
Ctrough is the Cp value pre-dose on C1D15.
c.
Only could be determined for 3 subjects.
2.3. Benefit/Risk Assessment
PF-07284890 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, and PK data for PF-07284890 
administered in the fasted and fed state for further clinical development.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-07284890 may be found in the IB, which is the SRSD for this study.


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-07284890
Potential risks associated with PF-
07284890 include the following: GI 
irritation, skin toxicity, phototoxicity, 
heart valve ultrastructural changes, 
hyperplasia of several tissues including 
the GI tract, increased urine volume, 
decreased testicular size and 
oligospermia, mild decrease in red blood 
cell count, mild increase in white blood 
cell count, increased heart rate and 
vascular inflammation.
Potential risks associated with other 
approved BRAF inhibitors include the 
following: feeling tired, eye effects
(including pain, redness, light sensitivity 
and/or vision loss), rash, nausea that 
could lead to vomiting, painful joints, 
new or growing cancers on the skin and 
in the body, birth deformities or fetal 
death from effects on a developing fetus 
(only observed in animals to date), 
changes in how electrical impulses are 
conducted in the heart which may 
increase the risk of an irregular heartbeat, 
bleeding including in the gastrointestinal 
tract, skin reaction which could be 
severe, liver toxicity, cardiomyopathy. 
The potential risks are based on nonclinical toxicology 
studies in the rat and monkey. GI irritation (minimal stomach 
ulcerations) occurred in the 28-day monkey study and it was 
reversible. Structural changes in the heart valves (resulting in 
thickening of the valve leaflets) was seen in the 28-day rat 
study with near complete resolution after a non-dosing 
recovery period. Skin toxicity (swelling, blisters, scabs) was 
seen in rat hind paws and was reversible. Adverse effects on 
male rat reproductive organs (testicular atrophy/degeneration 
and hypospermia) of up to marked severity were seen and 
these were not completely reversible after a 28-day non-
dosing recovery period. Also, in the rat only: minimal to 
mild decreases in RBC, Hgb and Hct; minimal increases in 
WBC, neutrophils and eosinophils and mild increases in 
aPTT were observed and were reversible.
Preliminary safety data from the ongoing clinical trial show 
a majority of adverse events observed with monotherapy 
administration are low grade and consistent with the adverse 
event profile of BRAF inhibitors in a BRAF mutant 
advanced cancer population. Preliminary safety results of the 
200 mg QD continuous dosing of PF-07284890 in patients 
resulted in treatment emergent adverse events of Grade 2 
worsening gout related to underlying condition and sinus 
infection/sinusitis as well as Grade 1 anorexia, arthritis, back 
pain, nausea and pain, all in 1 patient each. AEs observed 
were similar to common AEs observed in an advanced 
cancer population.
Eligibility criteria have been selected to ensure 
that only appropriate participants are included in 
the study (see Section 5).
AEs and clinical laboratory results will be 
monitored on an ongoing basis.
A complete blood count will be performed to 
monitor for any changes in hematology 
parameters (eg, RBC, Hgb, Hct, WBC, 
neutrophils, eosinophils). 
Coagulation testing will be performed to 
monitor for any changes in aPTT.
Physical exams will be performed to assess 
overall status including skin checks to monitor 
for AEs of the skin.
Ophthalmic exam if ocular AEs are observed.
ECGs will be performed to monitor for changes 
in cardiac rhythms.
Maintaining sufficient margins of exposure 
between the rat and human (ie, 35-fold, see 
Table 1) is thought to mitigate risk associated 
with the heart and testicular findings.


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2.3.2. Benefit Assessment
PF-07284890 will not provide any clinical benefit to healthy participants in this study. Any 
anticipated benefit to participants would be in terms of contribution to the process of 
developing a new therapy in an area of unmet medical need.
2.3.3. Overall Benefit/Risk Conclusion
PF-07284890 is not expected to provide any clinical benefit to healthy participants in this 
study. Taking into account the measures taken to minimize risk to study participants, the 
potential risks identified in association with PF-07284890 are justified by the anticipated 
benefits, in terms of contribution to the process of developing a new therapy in an area of 
unmet medical need.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
To evaluate the effect of a low-fat meal on the 
exposures of PF-07284890 following a single oral 
200-mg dose
To evaluate the effect of a high-fat meal on the 
exposures of PF-07284890 following a single oral 
200-mg dose
Comparison of low-fat meal with fasted PK: The ratio of 
AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890
Comparison of high-fat meal with fasted PK: The ratio 
of AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890
Secondary:
Secondary: 
To characterize the pharmacokinetic parameters of 
PF-07284890 following a single oral 200-mg dose
Tmax, t½, CL/F and Vz/F (if data permit).
To evaluate the safety and tolerability of PF-07284890 
in healthy participants
Assessment of TEAEs, clinical laboratory abnormalities, 
vital signs, and 12-lead ECGs.
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, randomized, single dose, 3-treatment, 2-sequence, 3-period 
crossover study to evaluate the effect of a low-fat and high-fat meal on the relative 
bioavailability of PF-07284890 following a single oral dose of PF-07284890 using two 
100-mg tablets of PF-07284890 in healthy adult participants, males and females of 
non-childbearing potential. The study will consist of 3 treatments: a single oral dose of 200 
mg PF-07284890 (2 × 100 mg tablets) under fasted conditions (Treatment A, Reference), a 
single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under low-fat meal fed 
conditions (Treatment B, Test 1), and a single oral dose of 200 mg PF-07284890 (2 × 100 mg 
tablets) under high-fat meal fed conditions (Treatment C, Test 2). There will be a total of 2 
treatment sequences shown in Section 1.2 with the assigned Treatments A, B or C in each 
treatment period.
CCI


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Approximately 12 healthy participants will be randomly assigned to study intervention such 
that approximately 6 participants will be enrolled to each sequence. Participants who 
discontinue from the study for non-safety reasons may be replaced at the sponsor’s discretion 
in collaboration with the investigator.
Healthy participants will be screened to determine eligibility within 28 days prior to study 
treatment. Medical history and results of physical examination, physical measurements, vital 
signs, 12-lead ECGs, and clinical laboratory evaluations will determine eligibility.
Each enrolled participant will participate in 3 study periods to receive 3 different treatments 
according to the sequence determined by randomization with 5-day washouts between 
PF-07284890 administration: 

Treatment A: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fasted 
conditions (Reference).

Treatment B: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fed 
conditions, low-fat meal (Test 1).

Treatment C: Single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under fed 
conditions, high-fat meal (Test 2).
Participants will be randomly assigned to 1 of 2 sequences as shown in Section 1.2. Serial PK 
samples will be collected at timepoints shown in the SoA.
The total planned duration of participation, from the screening visit to the last Follow-up 
phone call, is up to approximately 11 weeks. Participants will be screened within 28 days 
prior to the first dose of investigational products and if all eligibility criteria are fulfilled, the 
participants will report to the CRU on Day -1 of Period 1 and will be required to stay in the 
CRU for 15 days and 14 nights. 
Eligible participants will be admitted to the CRU at least 12 hours prior to the dosing of 
PF-07284890 on Day 1. On the morning of Day 1 of each period, participants will receive a 
single dose of 200 mg PF-07284890 as per randomization schedule. Study intervention will 
be administered with approximately 240 mL of ambient temperature water. In the fasted 
period (Sequence 1 Period 1 and Sequence 2 Period 2), participants will get their first dose 
after an overnight fast of at least 10 hours. In fed periods (Sequence 2 Period 1 and Sequence 
1 Period 2 for the low-fat meal and Period 3 for the high-fat meal as shown in Section 1.2), 
following an overnight fast of at least 10 hours, participants should begin breakfast 
approximately 30 minutes prior to PF-07284890 administration. For Sequence 2 Period 1 and 
Sequence 1 Period 2, a low-fat (approximately 25% of total caloric content of the meal), low-
calorie (approximately 400 to 500 calories) breakfast will be consumed over approximately a 
20-minute interval with PF-07284890 administered within approximately 10 minutes of 
completion of the meal. For Period 3, a high-fat (approximately 50% of total caloric content 
of the meal), high-calorie (approximately 800 to 1000 calories) breakfast will be consumed 
over approximately a 20-minute interval with PF-07284890 administered within 


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approximately 10 minutes of completion of the meal. Serial PK samples will be collected up 
to 72 hours post dose for all periods. Period 2 will begin on Study Period 1, Day 5 (referred 
to as Period 2, Day -1). Period 3 will begin on Study Period 2, Day 5 (referred to as Period 3, 
Day -1). Participants will be discharged from the CRU at the end of Period 3, Study Day 4, 
following completion of all assessments.
After participants have been confined in the CRU, they will be discharged at the discretion of 
the investigator. If a participant has any clinically significant, study related abnormalities at 
the conclusion of a scheduled inpatient portion of the study, the Pfizer medical monitor (or 
designated representative) should be notified and the participant may be asked to remain in 
the CRU until such abnormalities are deemed not clinically significant, or it is safe for 
outpatient follow up. A safety follow-up call will be made to participants 28 to 35 days from 
administration of the final dose of study intervention.
4.2. Scientific Rationale for Study Design
The objective of the study is to evaluate the effect of a low-fat or high-fat meal on the 
relative bioavailability of PF-07284890 following single 200-mg dose oral administration 
using a 100 mg tablet formulation of PF-07284890 in healthy adult participants. A crossover 
design is used to control variability between participants and account for any period 
effects.Between each administered single dose, a 5-day washout is proposed to minimize any 
residual PF-07284890 concentrations prior to start of the next period, which is sufficient 
based on the observed half-life of approximately 5.7 to 10 hours (Table 4).
4.2.1. Assessment of Safety Data Before Administration of the High-fat Meal
The high-fat meal is expected to potentially increase exposures by up to approximately 
2-fold.12 Before the Period 3 doses are administered to participants that have eaten a high-fat 
meal, the safety data for Periods 1 and 2, including at least 8 participants (given that 
participants may not all be dosed at the same time) administered a low-fat meal in Period 1 or 
2 and at least data from Day 1 through Day 3 of Period 2, will be reviewed by the study team 
and the investigator and assessed based on safety and tolerability. Period 3 will take place 
after a discussion between the study team and the investigator. Period 3 will initiate as 
planned if the doses administered in Periods 1 and 2 were well-tolerated. 
Severe nonserious AEs considered as related to study intervention in 2 participants in a 
period would require a dose reduction. Any SAE considered related to study intervention 
would require a dose reduction. Dosing will be paused for any SAE that occurs in a 
participant receiving active treatment until causality is fully assessed by the PI and sponsor. 
Dosing may resume if the SAE is determined to be not drug related by the PI and sponsor. If 
the SAE is determined to be either drug related or unknown and is ≥ severe or CTCAE 
Grade 3, dosing of participants will be stopped. If the SAE is determined to be either drug 
related or unknown and is <severe or CTCAE Grade 3, the SAE will be evaluated by the 
sponsor’s protocol review committee (or similar review group), which is independent of the 
study team and investigators. If the protocol review committee determines that dosing may 
resume, a plan that mitigates risks to participants with the resumption of dosing will be 


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implemented. Such a plan could include reducing the dose or adding appropriate safety 
monitoring.
4.2.2. Choice of Contraception/Barrier Requirements
Nonclinical studies suggest risk for severe manifestations of developmental toxicity at 
relevant clinical exposures for PF-07284890. Therefore, the use of a highly effective method 
of contraception is required (see Appendix 4).
4.2.3. 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 200 mg dose of PF-07284890 is planned for each period of this study. 
Following 28 days of once-daily oral administration of PF-07284890 (10, 30 or 60 mg/kg) to 
Sprague Dawley rats (the sensitive species) in a GLP toxicology study, the STD10 was 60 
mg/kg. For the lowest dose of 10 mg/kg, exposures in male and female rats, respectively, are 
estimated to be 12-32 multiple over those of the planned clinical dose (ie, see details in 
Section 2.2.3). The effect of food on PF-07284890 exposures based on its properties
(Biopharmaceutics Classification System Class II compound, weak base) is expected to be 
less than a 2-fold increase;12 a 2-fold increase in human exposures would reduce these 
margins to be ~6-16 multiple over those of the planned clinical dose. The clinical data from 
C4471001 are also important for justifying the 200 mg dose.
Clinical experience with PF-07284890 is based on the FIH study, C4471001, in which 
dose-finding is being conducted based on the safety and PK of repeat doses of PF-07284890. 
As of 10 January 2022, the study has dosed 22 patients in the Phase 1a Dose Escalation. At 
the 4 monotherapy dose levels assessed (50 mg QD, 100 mg QD, 200 mg QD, and 200 mg 
BID), 12 patients have been treated, 9 patients were DLT evaluable, and no patients 
experienced DLTs (Table 2). 
Preliminary safety results of the 200 mg QD dose of PF-07284890 in patients resulted in 
treatment emergent adverse events of Grade 2 worsening gout related to underlying condition 
and sinus infection/sinusitis as well as Grade 1 anorexia, arthritis, back pain, nausea and pain, 
all in 1 patient each. With repeat dosing of the 200 mg BID dose schedule, one patient 
experienced Grade 3 pneumonia, considered not related to study drug. Grade 2 events, 
occurring in 1 patient each, were ejection fracture decreased considered related to the 
patient’s underlying disease, fatigue, and oxygen saturation decreased preceding diagnosis of 
CCI


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pneumonia, as well as maculo-papular rash. Dizziness, dry skin, and benign skin lesion were 
reported in 1 patient each as Grade 1. At lower doses, the only severe events reported were 
fatal disease progression of cancer, suprapubic pain related to the patient’s underlying 
disease, and 2 patients with Grade 3 anemia, considered unrelated to study treatment in 
1 case, and in another patient with Grade 1 anemia at baseline in the setting of renal 
dysfunction and iron deficiency. Data from repeat-dosing in patients suggests that the 200 mg 
dose is well tolerated. 
Based on clinical PK data, the AUC24hr from the highest tolerated dose of 200 mg BID is 
estimated to be approximately 3.4-fold higher than the AUC24hr for a single dose of 200 mg
(ie, based on the accumulation ratio of 1.69 observed for 100 mg BID administration, 
Table 5, compared to a single dose, BID administration can be expected to have 
approximately 2 x 1.69-fold higher AUC24hr). Food may increase the AUC24hr, but this 3.4-
fold margin based on fasted-state PK increases confidence in the safety of the single daily 
dose given one time every 5 days for 3 doses. The 5-day interval between doses is expected 
to avoid any accumulation.
A single dose of 200 mg PF-07284890 given once every 5 days for 3 doses is considered safe 
to be used in healthy volunteers.
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
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants ≥18 and 65 years of age, inclusive, at the time of signing the ICD.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Male participants and female participants of non-childbearing potential 
(Section 10.4.2) who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, vital signs and 
12-lead ECGs.
Other Inclusion Criteria: 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant uveitis, 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).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy).

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb or HCVAb. Hepatitis B vaccination is allowed.

Use of PPIs is not allowed within 7 days of study start (C1D1) and during study 
treatment.


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2. 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 (eg, contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details).
4. Current use or anticipated need for drugs that are known strong UGT2B7 inhibitors,
including the administration within 10 days or 5 half-lives, whichever is longer, or
strong UGT2B7 inducers, including the administration within 5 half-lives plus 10 
days, prior to first dose of PF-07284890. Refer to Section 6.9 Prior and Concomitant 
Therapy and Appendix 9.
5. Participant who have received a COVID-19 vaccine within 7 days before screening or 
admission, or who are to be vaccinated with a COVID-19 vaccine at any time during 
the study confinement period.
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). 
Diagnostic Assessments:
7. Positive test result (RT-PCR) for SARS-CoV-2 infection at the time of screening or 
Day -1.
8. A positive urine drug test at screening or admission.
9. A positive urine cotinine test at screening or admission.
10. 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.
11. 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, ST-T 


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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.
12. 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 ≥1.25 × ULN;

Total bilirubin level ≥1.5 × 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.

eGFR <75 mL/min/1.73 m2 based on the CKD-EPI equation.

Hemoglobin <11 g/dL

ANC <1.5 × 109/L

Platelets <100,000/mm3
Other Exclusion Criteria:
13. 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).
14. Current smokers or history of the use of tobacco- or nicotine-containing products
within 6 months of screening.
15. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
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.


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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 the collection of the predose 
PK sample. All 3 periods will have a 10-hour fast, followed by pre-dose ECGs and 
PK sampling (which will be followed by food in the fed periods, Sequence 2 Period 1
and Sequence 1 Period 2 for the low-fat meal and Period 3 for the high-fat meal, prior 
to dosing).

For the fasted period (Sequence 1 Period 1 and Sequence 2 Period 2), water is 
permitted until 1 hour prior to study intervention administration. Water may be 
consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
may be consumed with meals and the evening snack.

For the first fed period, low-fat meal (Sequence 2 Period 1 and Sequence 1 Period 2 
for the low-fat meal) only, a low-fat (approximately 25% of total caloric content of 
the meal), low-calorie (approximately 400 to 500 calories) meal will be used for the 
evaluation of a food effect in this study. The provided meal will be similar in 
composition to the meal referenced in the FDA guidance on food-effect 
bioavailability and fed bioequivalence studies.15 On Day 1 of the first fed period, 


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following an overnight fast of at least 10 hours, participants should begin breakfast 
approximately 30 minutes prior to PF-07284890 administration. The breakfast will be 
consumed over approximately a 20-minute interval with PF-07284890 administered 
within approximately 10 minutes of completion of the meal. Participants will be 
encouraged to complete the entire breakfast. There are no water restrictions prior to 
and after dosing.

For the second fed period, high-fat meal (Period 3) only, a high-fat (approximately 
50% of total caloric content of the meal), high-calorie (approximately 800 to 1000 
calories) meal will be used for the evaluation of a food effect in this study. The 
provided meal will be similar in composition to the meal referenced in the FDA 
guidance on food-effect bioavailability and fed bioequivalence studies.15 On Day 1 of 
the fed Period 3, following an overnight fast of at least 10 hours, participants should 
begin breakfast approximately 30 minutes prior to PF-07284890 administration. The 
breakfast will be consumed over approximately a 20-minute interval with 
PF-07284890 administered within approximately 10 minutes of completion of the 
meal. Participants will be encouraged to complete the entire breakfast. There are no 
water restrictions prior to and after dosing.

Lunch will be provided approximately 4 to 5 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

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 the 
discretion of the investigator.

Participants will not have used tobacco- or nicotine-containing products for 6 months
prior to screening and will not use such products during the screening period or after 
confinement in the CRU.


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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;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing;

Participants will be confined to the procedure room for the first 4 hours after dosing 
on Day 1, except to use the bathroom. After this, participants may be ambulatory but 
should not engage in strenuous activities.
5.3.5. Photosensitivity
Given the potential for phototoxicity from nonclinical toxicology studies with PF-07284890, 
participants will be advised to report any reaction to sun exposed skin. In addition, special 
precautions will be taken to limit any potential photo irritation effect, by minimizing the 
participants’ exposure to light including sunlight, and high intensity UVB light sources such 
as tanning beds, tanning booths and sunlamps. Participants should be encouraged to apply 
sunscreen/sunblock daily and to wear clothing that covers areas of exposed skin when 
outdoors during daylight hours until discharge from the CRU, which is more than 5 half-lives 
from the last dose of PF-07284890.
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 noninvestigational 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 intervention refers to PF-07284890.
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
PF-07284890
Type
Drug
Dose Formulation
Tablet


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Study Intervention(s)
Unit Dose Strength(s)
100 mg
Dosage Level(s)
3 single 200-mg doses
Route of Administration
Oral
Use
Experimental
IMP or NIMP/AxMP
IMP
Sourcing
Provided centrally by the sponsor 
Packaging and Labeling
Open-label study intervention will be provided in bulk (high-density polyethylene 
bottle) labeled as required per country requirement.
Current/Former Name(s) 
or Alias(es)
PF-07284890
ARRY-461
AR00504461
PF-07284890 will be provided by Pfizer as 100 mg tablets for oral administration at the 
CRU.
Tablets will be supplied to the CRU in bulk along with individual dosing containers for unit 
dosing.
6.1.1. Administration
Investigational product will be administered orally and according to the conditions described 
in the SoA section and Protocol Section 5.3.2 Meals and Dietary Restrictions.
For fasted period (Sequence 1 Period 1 and Sequence 2 Period 2):

On Day 1, following an overnight fast of at least 10 hours, the participants will receive 
200 mg PF-07284890 (as 2 × 100 mg tablets) administered orally at approximately 
08:00 hours (plus or minus 2 hours) without breakfast/standard meal on Day 1. 
For fed periods (Sequence 2 Period 1 and Sequence 1 Period 2 for the low-fat meal and 
Period 3 for the high-fat meal): 

On Day 1, following an overnight fast of at least 10 hours, participants will receive
breakfast approximately 30 minutes prior to dosing which is to be completed within
approximately 20 minutes as outlined in Section 5.3.2 Meals and Dietary Restrictions. 
The participants will then receive 200 mg PF-07284890 (as 2 × 100 mg tablets) 
administered orally at approximately 08:00 hours (plus or minus 2 hours). 
For all periods:

Investigator site personnel will administer study intervention during each period with 
ambient temperature water to a total volume of approximately 240 mL. Participants will 
swallow all tablet formulations whole, and will not manipulate or chew the study 
intervention prior to swallowing. 


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
In order to standardize the conditions on PK sampling days, all participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours 
after dosing.
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 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 intervention 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 in the IPM or PCRU site 
procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study intervention should be stored in its original container.
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 
intervention will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
intervention are provided in the IPM and PCRU’s 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 


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compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
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.
PF-07284890 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. 
See the IPM and/or CRU’s site procedures for instructions on how to prepare the study 
intervention for administration.
6.3. Assignment to Study Intervention
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. 
6.5. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
Participants will be dosed at the site and receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
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.


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6.6. Dose Modification
No dose modification is anticipated. A 200-mg dose is the maximum dose that will be 
administered. In case a dose reduction is necessary, the study intervention dose will be 
reduced or the study will be stopped early.
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.
6.8. Treatment of Overdose
For this study, any dose of PF-07284890 greater than the prescribed regimen within a 
24-hour time period ±6 hours will be considered an overdose.
Sponsor does not recommend 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 for at least 5 half-lives or 28 calendar days (whichever is 
longer) after the overdose of PF-07284890.
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 7 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).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Participants will abstain from all concomitant treatments, except for the treatment of adverse
events. Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 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.


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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.
The following sections contain information on the DDI properties of PF-07284890 and 
concomitant medications that are prohibited or must be used with caution. These DDI 
properties are needed for when concomitant medicines must be used to treat AEs. A list of 
example prohibited medications (eg, strong CYP3A inhibitors and inducers) is provided in
Section 10.9, Appendix 9: Prohibited Concomitant Medications That May Result in DDI.
CYP3A4/5:
Concomitant use of PF-07284890 and a CYP3A4/5 substrate may increase or decrease the
exposure of the CYP3A4/5 substrate. Coadministration of PF-07284890 with CYP3A4/5
substrates with narrow therapeutic indices, such as astemizole, terfenadine, cisapride,
pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil and fentanyl (excluding
transdermal patch), or ergot alkaloids (ergotamine, dihydroergotamine)16,17 is not permitted.
Coadministration with other CYP3A4/5 substrates is permitted but caution is warranted.
CYP2B6:
Concomitant use of PF-07284890 and a CYP2B6 substrate may decrease the exposure of the
CYP2B6 substrate. PF-07284890 coadministration with CYP2B6 substrates (eg, a sensitive
substrate like bupropion and narrow therapeutic index substrates like efavirenz, also a
sensitive substrate, and cyclophosphamide) 16,17 is permitted but caution is warranted.
CYP2C9:
Concomitant use of PF-07284890 and a CYP2C9 substrate may increase the exposure of the
CYP2C9 substrate. CYP2C9 substrates of a narrow therapeutic index, may include warfarin,
CCI


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phenytoin, glimepiride, glipizide, glyburide, ibuprofen, diclofenac, indomethacin, naproxen,
rosiglitazone, sulfamethoxazole, tolbutamide, candesartan, irbesartan, losartan and
valsartan.16,18 PF-07284890 coadministration with these and other CYP2C9 substrates is
permitted but caution is warranted.
BCRP:
Concomitant use of PF-07284890 and a BCRP inhibitor or inducer may alter the rate and/or
extent of PF-07284890 absorption, which could potentially increase (inhibitor) or decrease
(inducer) PF-07284890 exposures. PF-07284890 coadministration with BCRP inhibitors or
inducers is permitted but caution is warranted.
P-glycoprotein:
Concomitant use of PF-07284890 and a P-glycoprotein substrate may increase the exposure
of the P-glycoprotein substrate. PF-07284890 coadministration with P-glycoprotein
substrates is permitted but caution is warranted.
Acid Reducing Agents:
Concomitant use of PF-07284890 and an acid reducing agent (eg, PPIs) may cause reduced
exposures to PF-07284890. PPIs are not allowed within 7 days of study start (C1D1) and
during study treatment, but other acid reducing agents (eg, H2 blockers, antacids) may be
used, but only between 2 and 3 hours after administration of each dose of PF-07284890.
6.9.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-07284890; 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 in investigator’s view;

Positive COVID-19 test.
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.


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7.1.1. ECG Changes
A participant who meets either bulleted criterion based on ECG readings will be withdrawn 
from the study intervention. 

QTcF >500 ms.

Change from baseline: QTcF >60 ms and QTcF >450 ms.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.2. Potential Cases of Acute Kidney Injury
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period are noted to have 2 consecutive
SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken.
7.1.3. 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. Temporary discontinuation of 


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the study intervention may be medically appropriate until the participant has recovered from 
COVID-19. It is recommended that the investigator discuss temporary or permanent 
discontinuation of study intervention with the study medical monitor. 
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:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;

Investigator’s decision;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
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. 


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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 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;

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 Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 


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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.
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.
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 
210 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.
8.2. Efficacy Assessments
Not applicable.
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.


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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, 
skin, 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 and PR 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. BP and PR assessments will be performed after 
collection of ECGs and prior to collection of blood draws if scheduled at the same time.
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.
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. If the pulse rate is 
outside of the normal limits, respiratory rate will also be collected.
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.


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8.3.2.2. Respiratory Rate
RR will be collected if the PR is outside of normal range. Respiratory rate will be measured 
after approximately 5 minutes of rest in a supine position by observing and counting the 
respirations of the participant for 30 seconds and multiplying by 2. 
8.3.2.3. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement. Temperature will be measured as per CRU standard 
practice.
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. 
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected before dose administration on Day 1 of each 
period and before the meal for Sequence 1 Period 2, Sequence 2 Period 1, and Period 3 will 
serve as each participant’s baseline QTcF value.
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the mean 
value from the triplicate measurements for any 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 a single ECG measurement must be 
repeated at least hourly until QTcF 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.


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ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Ophthalmic Examinations
Full ophthalmic examination will be performed by an ophthalmologist if treatment emergent 
ocular AEs are observed (SoA) including best corrected visual acuity, slit lamp examination, 
and intraocular pressure.
For participants with clinical suspicion of retinal abnormalities occurring during study 
conduct (ie, photopsia, metamorphopsia, impairment of visual acuity) or RVO, additional 
assessments of OCT, dilated fundoscopy, optical coherence tomography (for RPED), and 
fluorescein angiography of the central 30 degrees (for RVO) should be conducted if deemed 
clinically necessary.
8.3.5. 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 48 hours 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.
Urine drug and cotinine (mandatory) and alcohol breath test (at discretion of investigator) 
will be performed at screening from Days -28 to -2 and again on Day -1. These tests may be 
performed at any other time at the discretion of the investigator.


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8.3.6. COVID-19 Specific Assessments
Participants will be checked for exposure to positive participant, residence or travel in area of 
high incidence and COVID-19 related signs and symptoms. Participants will be tested for 
COVID-19 infection by PCR prior to being admitted to the clinic for confinement and a 
subsequent COVID-19 test will be performed after 4 days (ie, upon completion of 4 × 24 
hours in house), or if they develop COVID-19-like symptoms. Additional testing may be 
required by local regulations and guidance or by the PI.
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 
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, except as indicated 
below, 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.


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If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study 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.
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.


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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.
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.


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8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

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 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant’s partner, the investigator must report this information 
to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental Form, 
regardless of whether an SAE has occurred. Details of the pregnancy will be collected 
after the start of study intervention and until 50 hours after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
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 


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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 
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 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.


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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 
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.
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 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 PF-07284890
Blood samples of approximately 3 mL, to provide a minimum of 1.2 mL plasma, will be 
collected for measurement of plasma concentrations of PF-07284890 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 PF-07284890. Samples collected for analyses of 
plasma PF-07284890 concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of PF-07284890 will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods.
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.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
 
 
 
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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.
8.7.3. Specified Metabolomic Research
Specified metabolomic research is not included in this study.
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 Hypotheses
No statistical hypothesis will be tested in this study. 
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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
“Enrolled” means a participant’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 assigned to study intervention and who take at 
least 1 dose of study intervention. Participants will be analyzed 
according to the product they actually received.
PK Concentration 
Population
All participants randomly assigned to study intervention and
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value can be reported.
PK Parameter Analysis 
Population
All participants randomly assigned to study intervention and
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest can be reported.
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. Primary Endpoint(s) Analysis
9.3.1.1. Definition of Endpoint(s)
Plasma PK parameters of PF-07284890 will be derived (as data permit) from the 
concentration-time data using standard noncompartmental methods of analysis as outlined in 
Table 6. Actual PK sampling times will be used in the derivation of PF-07284890 PK 
parameters when available. In the case that actual PK sampling times are not available, 
nominal PK sampling time will be used in the derivation of PK parameters. 


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Table 6.
Plasma PF-07284890 PK Parameters Definitions 
Parameter
Definition
Method of Determination
AUCinf*
Area under the plasma concentration-time curve 
from time zero extrapolated to infinity
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear 
regression analysis
AUClast
Area under the plasma concentration-time profile 
from time zero to the time of the last quantifiable 
concentration (Clast).
Linear/Log trapezoidal method.
Cmax
Maximum observed plasma concentration
Observed directly from data
Tmax
Time to reach Cmax
Observed directly from data as time of 
first occurrence
t½*
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the loglinear 
concentration-time curve. Only those 
data points judged to describe the 
terminal loglinear decline will be used 
in the regression.
CL/F*
Apparent clearance
Dose/AUCinf
Vz/F*
Apparent volume of distribution for extravascular 
dosing
Dose/(AUCinf • kel)
*If data permit.
9.3.1.2. Statistical Methods for Pharmacokinetic Data
Using data from Periods 1 and 2, natural log transformed AUCinf (if data permit), AUClast and 
Cmax will be analyzed using a mixed effect model with sequence, period and treatment as 
fixed effects and participant within sequence 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% CI 
for the ratios. Treatment A (PF-07284890 under fasted condition) is the Reference treatment 
and Treatment B (PF-07284890 administered under fed condition, low-fat meal) is the Test 
treatment.
Using data from Treatments A and C, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effect model with treatment and sequence as 
a fixed effect and participant within sequence 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% CI 
for the ratios. Treatment A (PF-07284890 under fasted condition) is the Reference treatment 
and Treatment C (PF-07284890 administered under fed condition, high-fat meal) is the Test 
treatment.


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The plasma concentrations of PF-07284890 will be listed and descriptively summarized by 
nominal PK sampling time and treatment. 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, respectively. Mean and median profiles will be presented on both 
linear and semi-log scales. 
The PK parameters listed in Table 6 will be summarized descriptively by treatment.
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.3.2. Other Safety 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 presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
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: 
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


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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 predose
single ECG value on Day 1.
 
 
9.4. 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/PD modeling, and/or supporting clinical 
development. 
9.5. Sample Size Determination
A sample size of 12 evaluable participants will provide 90% confidence intervals (CIs) for 
the difference between treatments of ±0.2995 and ±0.3337 on the natural log scale for AUCinf
and Cmax, respectively, with 80% coverage probability. Table 7 presents the width of 90% CI 
for different estimated effects.
Table 7.
Confidence Interval Estimation of PK Endpoints
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
150%
1.1118, 2.0237
0.9119
170%
1.2600, 2.2936
1.0335
180%
1.3342, 2.4285
1.0943
190%
1.4083, 2.5634
1.1551
200%
1.4824, 2.6983
1.2159
210%
1.5565, 2.8332
1.2767
220%
1.6306, 2.9682
1.3375
230%
1.7048, 3.1031
1.3983
250%
1.8530, 3.3729
1.5199
Cmax
150%
1.0744, 2.0942
1.0198
170%
1.2176, 2.3734
1.1558
180%
1.2893, 2.5131
1.2238
190%
1.3609, 2.6527
1.2918
CCI


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Table 7.
Confidence Interval Estimation of PK Endpoints
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
200%
1.4325, 2.7923
1.3598
210%
1.5041, 2.9319
1.4278
220%
1.5758, 3.0715
1.4957
230%
1.6474, 3.2111
1.5637
250%
1.7906, 3.4904
1.6997
These calculations are based on estimates of within-participant standard deviation of 0.3491 
and 0.3890 for loge AUCtau and loge Cmax respectively, based on the results from 
Study C4471001.


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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. 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 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants 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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10.1.3. 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.
10.1.4. Committees Structure
This study will not use an E-DMC.
10.1.5. 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.
10.1.6. 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/or 
IQMP 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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10.1.7. 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 sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Source Document 
Locator, which is maintained by the sponsor’s designee (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.
10.1.8. 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 IRB/ECs, 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.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 


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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the CTMS. 
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 and (c) 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. 


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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 8.
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)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
culturea
aPTT, PT-INR, eGFR 
(CKD-EPI)
Urine drug screeningc
Urine cotinine test
At screening only:

FSHb

Hepatitis B surface 
antigen

Hepatitis C antibody

Hepatitis B core antibody

HIV
a.
Only if UTI is suspected and urine dipstick is positive (1+) for blood, protein, nitrites or leukocyte 
esterase.
b.
For confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
The table below is a list of reflex safety laboratory tests, which are required for certain 
circumstances only. This is not an exhaustive list; other special reflex tests may be added as 
needed.


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Table 9.
Protocol-Required Follow-Up Safety Laboratory Assessments (In Case of 
Abnormality)
Hematology
Chemistry
Urinalysis on Site
Other
If Hb/RBC abnormal: 
MCV, MCH, MCHC 
Neutrophils (%) 
Eosinophils (%) 
Basophils (%) 
Lymphocytes (%) 
Monocytes (%) 
RBC morphology 
RBC distribution width
Required:
For suspected DILI:
AST/ALT 
T bili, direct and indirect 
bili 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol 
or 
protein adduct levels 
Hepatitis serology (even if 
screening negative) 
For suspected DICI/DIKI: 
Creatinine (Scr) 
CystatinC (Scys) 
eGFR (Scr only and 
combined Scr+Scys) 
Spot (dipstick) UACR
Local Laboratory
Microscopy and culture 
for positive local 
dipstick testsa

Hepatitis B DNA 

Hepatitis C RNA
a.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both. Any 
positive results are to be reported as an AE.
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.
CCI
CCI


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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 
sequelae.


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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.
d. Results in persistent or significant disability/incapacity


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
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.
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 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
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.


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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.
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.


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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product 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.
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 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.


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
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. 
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 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse 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.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 2 (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 is not a WOCBP (see definition in 
Section 10.4.3) and is not breastfeeding.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;


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
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.
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.


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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;

Intravaginal;

Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
Sexual Abstinence
8. 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.
Other Effective Methods
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.
10. Male or female condom, with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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CCI


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug Induced- Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede 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).
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.


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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and 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 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
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
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
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
Inker LA et al. N Engl J Med. 2021;385:1737-49.
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.


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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: Prohibited Concomitant Medications That May Result in DDI
The prohibited concomitant medications listed below should not be taken with PF-07284890
throughout the conduct of the study, and some have required washout period as listed in the 
table.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from sponsor, to include or exclude specific 
drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs).
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Investigators should consult the product label for any other medication used during the study 
for information regarding medication that is prohibited for concomitant use. 
Table 10.
Prohibited Concomitant Medications that May Result in DDI
Drug Category
Drugs
Guidance 
Required Washout 
Period Prior to the First 
Dose of PF-07284890
Proton pump 
inhibitors
dexlansoprazole
esomeprazole
ilaprazole a
lansoprazole
omeprazole
pantoprazole
rabeprazole
Prohibited
7 days
PF-07799933 as Perpetrator of DDI
CYP3A substrates 
that have a 
narrow
therapeutic index 
(NTI) 
alfentanil
amiodarone
argatroban
astemizole a
carbamazepine
cisapride a
cyclosporine
dihydroergotamine 
Prohibited
N/A
CCI


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Table 10.
Prohibited Concomitant Medications that May Result in DDI
Drug Category
Drugs
Guidance 
Required Washout 
Period Prior to the First 
Dose of PF-07284890
ergotamine
fentanyl (excluding 
transdermal patch)
pimozide
quinidine
sirolimus 
tacrolimus
terfenadine
a.
Not approved in the US as of October 2020, but may be available in other countries including Korea, 
China and Mexico.


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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CV
percent coefficient of variation
Abs
absolute
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
AKI
acute kidney injury
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATC
aanaplastic thyroid cancer
AUC
area under the plasma concentration-time curve
AUC24hr
area under the plasma concentration-time curve from time zero to 
24 hours
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 (Clast).
AUCtau
area under the plasma concentration-time curve from time zero to 
tau (ie, over the dosing interval)
AV
atrioventricular
AxMP
auxiliary medicinal product
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BID
twice daily
BLRM
Bayesian Logistic Regression Model
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BRAF
B-type Raf proto-oncogene
BRAFi
B-type Raf proto-oncogene inhibitor
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
C1D15
Cycle 1 Day 15
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


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Abbreviation
Term
CL/F
apparent clearance
Clast
the last quantifiable concentration
Cmax
maximum observed concentration
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
Cp
plasma concentration
CR
complete response
CRC
colorectal cancer
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
CTMS
Clinical Trial Management System
Ctrough
pre-dose plasma concentration
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DME
drug metabolizing enzyme
DNA
deoxyribonucleic acid
DoR
duration of response
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
ECOG
Eastern Cooperative Oncology Group
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
eSAE
electrionic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clincal Trials 
(European Clinical Trials Database)
FIH
first in human


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Abbreviation
Term
FSH
follicle-stimulating hormone
HR
heart rate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAg 
hepatitis B surface antigen
Hct
hematocrit
HCVAb
hepatitis C antibody
hERG 
human ether-à-go-go-related gene
Hgb
hemoglobin
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HR
heart rate
HRT
hormone replacement therapy
HV
healthy volunteer
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
IC90
90% of the maximum inhibition 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
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IQMP
Integrated Quality Management Plan
IRB
Institutional Review Board
IV
intravenous(ly)
K2-EDTA
dipotassium ethylenediaminetetraacetic acid
Kel
terminal phase rate constant
LBBB
left bundle branch block
LFT
liver function test
MAPK
mitogen-activated protein kinase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MEK
mitogen/extracellular signal regulated kinase
NHP
nonhuman primate 
MOE
margin of exposure


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Abbreviation
Term
MQI
medically qualified individual
MTD
maximum tolerated dose
N/A
not applicable
ND
no data
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
NTI
narrow therapeutic index
OCT
optical coherence tomography
PCR
polymerase chain reaction
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PE
physical examination
PFS
progression-free survival
PI
principal investigator
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PR
pulse rate
PS
performance status
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PTC
papillary thyroid cancer
PVC
premature ventricular contraction/complex
QD
once daily
QRS
time from ECG Q wave to the end of the S wave corresponding to 
ventricle depolarization
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RAUC
accumulation ratio based on AUC
RBC
red blood cell
RCmax
accumulation ratio based on Cmax
RDE
recommended dose for expansion
RNA
ribonucleic acid
RPED
retinal pigment epithelial detachment
RR
respiratory rate
RT-PCR
reverse transcriptase-polymerase chain reaction
RVO
retinal vein occlusion
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
Scys
serum cystatin C


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Page 98
Abbreviation
Term
SEER
Surveillance, Epidemiology, and End Results
SoA
schedule of activities
SOP
standard operating procedure
SRS
stereotactic radiosurgery
SRSD
Single Reference Safety Document
STD10
severely toxic dose in 10% of the animals
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal elimination half-life
T bili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TK
toxicokinetics
Tmax
time to reach Cmax
UACR
urine albumin/creatinine ratio
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
UVB
ultraviolet B
Vz/F
apparent volume of distribution for extravascular dosing
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WBRT
whole-brain radiotherapy
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11. REFERENCES
1.
Stelzer KJ. Epidemiology and prognosis of brain metastases. Surg Neurol Int 
2013;4(Suppl 4):S192-202.
2.
Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain 
metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer 
Surveillance System. J Clin Oncol 2004;22(14):2865-72.
3.
Cohen JV, Tawbi H, Margolin KA, et al. Melanoma central nervous system metastases: 
current approaches, challenges, and opportunities. Pigment Cell Melanoma Res 
2016;29(6):627-42.
4.
Mujoomdar A, Austin JH, Malhotra R, et al. Clinical predictors of metastatic disease to 
the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph 
node metastases. Radiology 2007;242(3):882-8.
5.
Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with 
BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, 
multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18(7):863-73.
6.
Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in 
advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a 
randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17(9):1248-60.
7.
Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-
mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or 
encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. 
Lancet Oncol 2018;19(10):1315-27.
8.
McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients 
with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 
2017;28(3):634-41.
9.
Holbrook K, Lutzky J, Davies MA, et al. Intracranial antitumor activity with 
encorafenib plus binimetinib in patients with melanoma brain metastases: a case series. 
Cancer 2020;126(3):523-30.
10.
Menter T, Tzankov A. Genetic alterations of 9p24 in lymphomas and their impact for 
cancer (immuno-)therapy. Virchows Arch 2019;474(4):497-509.
11.
Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or 
without whole brain radiotherapy in treating patients with non-small cell lung cancer 
with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): 
results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388(10055):2004-
14.


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Page 100
12.
Owens K, Argon S, Yu J, et al. Exploring the relationship of drug BCS classification, 
food effect, and gastric pH-dependent drug interactions. AAPS J. 2021;24(1):16. 
15.
FDA Draft Guidance, Guidance for Industry: Assessing the Effects of Food on Drugs in 
INDs and NDAs — Clinical Pharmacology Considerations. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-
effects-food-drugs-inds-and-ndas-clinical-pharmacology-considerations. Published: Mar 
2019. Accessed: Mar 2022.
16.
“Metabolism and Transport, Drug Interaction Database”, Department of Pharmaceutics, 
University of Washington. www.druginteractionsolutions.org. Accessed: May 2009.
17.
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. Available from 
http://courses.washington.edu/medch527/PDFs/Literature/527_fdatable.pdf. Accessed:
Mar 2022:
18.
Daly AK, Rettie AE, Fowler DM, et al. Pharmacogenomics of CYP2C9: functional and 
clinical considerations. J Pers Med 2017;8(1):1-31.
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SAP_001.pdf: 
Protocol C4471002 (PF-07284890) Statistical Analysis Plan 
 
 
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Page 1 of 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C4471002 
 
 
 
 
A Phase 1, Open-Label, Randomized, Single Dose, 2 Sequence, 3 Period Crossover Study 
to Evaluate the Effect of a Low-fat and High-fat Meal on the Relative Bioavailability of 
PF-07284890 in Healthy Adult Participants 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
 
 
 
Version: 
1 
 
Date:  
17 May 2022 


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................3 
LIST OF FIGURES ...................................................................................................................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 ..................................................................................................................6 
3.1. Primary Endpoints .....................................................................................................6 
3.2. Secondary Endpoints .................................................................................................6 
 
3.4. Baseline Variables .....................................................................................................7 
3.5. Safety Endpoints .......................................................................................................7 
3.5.1. Adverse Events .............................................................................................8 
3.5.2. Laboratory Data ............................................................................................8 
3.5.3. Vital Signs ....................................................................................................8 
3.5.4. Electrocardiograms .......................................................................................8 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .....................................................9 
5. GENERAL METHODOLOGY AND CONVENTIONS ......................................................9 
5.1. Hypotheses and Decision Rules ..............................................................................10 
5.2. General Methods .....................................................................................................10 
5.2.1. Analyses for Binary/Categorical Endpoints ...............................................10 
5.2.2. Analyses for Continuous Endpoints ...........................................................10 
5.3. Methods to Manage Missing Data ..........................................................................10 
5.3.1. Pharmacokinetic Data .................................................................................10 
5.3.2. Safety Data ..................................................................................................11 
6. ANALYSES AND SUMMARIES ......................................................................................11 
6.1. Primary Endpoints ...................................................................................................11 
6.2. Secondary Endpoint(s) ............................................................................................12 
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6.4. Baseline and Other Summaries and Analyses .........................................................13 
6.4.1. Demographic Summaries............................................................................13 
6.4.2. Study Conduct and Participant Disposition ................................................13 
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 ...........................................................................................14 
6.5.2. Laboratory Data ..........................................................................................14 
6.5.3. Vital Signs ..................................................................................................14 
6.5.4. Electrocardiograms .....................................................................................14 
7. INTERIM ANALYSES .......................................................................................................15 
7.1. Introduction .............................................................................................................15 
7.2. Interim Analyses and Summaries ............................................................................15 
APPENDICES .........................................................................................................................16 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................4 
Table 2. 
Plasma PF-07284890 PK Parameters Definitions ......................................7 
Table 3. 
PK Parameters to be Summarized Descriptively by Treatment ...............13 
 
LIST OF FIGURES 
Figure 1. 
C4471002 Study Schema ............................................................................6 
 
APPENDICES 
Appendix 1. Summary of Analyses .........................................................................................16 
Appendix 2. SAS Code for Analyses .......................................................................................17 
Appendix 3. List of Abbreviations...........................................................................................18 
 
 
 
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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 
17 May 2022 
Original 
06 Apr 2022 
N/A 
N/A 
 
2. INTRODUCTION 
PF-07284890 (also known as ARRY-461) is a potent, selective, highly brain-penetrant 
small-molecule inhibitor of BRAF V600 mutations that is currently being developed for the 
treatment of BRAF V600-mutant solid tumors with or without brain involvement. 
The purpose of the study is to evaluate the effect of a low-fat and high-fat meal on the 
relative bioavailability of PF-07284890 following single dose oral administration of 
PF-07284890 using 2 of the 100 mg PF-07284890 tablets currently used in the first-in-
patient study C4471001 (200 mg per single dose). Results from the study will be used to 
inform food instructions for patients in PF-07284890 first-in-patient study C4471001, Phase 
1b. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4471002.   
2.1. Modifications to the Analysis Plan Described in the Protocol 
Not applicable. 
 
2.2. Study Objectives, Endpoints, and Estimands 
The following are the objectives and endpoints in this study. Estimand framework is not 
applied to this phase 1 study. 
 


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Objectives 
Endpoints 
Primary:  
Primary:  
• To evaluate the effect of a low-fat meal 
on the exposures of PF-07284890 
following a single oral 200-mg dose 
• To evaluate the effect of a high-fat meal 
on the exposures of PF-07284890 
following a single oral 200-mg dose 
• Comparison of low-fat meal with fasted 
PK: The ratio of AUClast, AUCinf (if data 
permit) and Cmax of PF-07284890 
• Comparison of high-fat meal with fasted 
PK: The ratio of AUClast, AUCinf (if data 
permit) and Cmax of PF-07284890 
Secondary:  
Secondary:  
• To characterize the pharmacokinetic 
parameters of PF-07284890 following a 
single oral 200-mg dose 
• Tmax, t½, CL/F and Vz/F (if data permit). 
 
• To evaluate the safety and tolerability of 
PF-07284890 in healthy participants 
• Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, and 12-lead 
ECGs. 
 
  
 
 
 
 
 
 
 
 
 
2.3. Study Design 
This is a Phase 1, open-label, randomized, single dose, 3-treatment, 2-sequence, 3-period 
crossover study to evaluate the effect of a low-fat and high-fat meal on the relative 
bioavailability of PF-07284890 following a single oral dose of PF-07284890 using two 
100-mg tablets of PF-07284890 in healthy adult participants, males and females of 
non-childbearing potential. The study will consist of 3 treatments: a single oral dose of 
200 mg PF-07284890 (2 × 100 mg tablets) under fasted conditions (Treatment A, 
Reference), a single oral dose of 200 mg PF-07284890 (2 × 100 mg tablets) under low-fat 
meal fed conditions (Treatment B, Test 1), and a single oral dose of 200 mg PF-07284890 (2 
× 100 mg tablets) under high-fat meal fed conditions (Treatment C, Test 2).  
Approximately 12 healthy participants will be randomly assigned to study intervention such 
that approximately 6 participants will be enrolled to each sequence. Participants who 
discontinue from the study for non-safety reasons may be replaced at the sponsor’s 
discretion in collaboration with the investigator. 
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Figure 1. C4471002 Study Schema 
 
 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
The primary endpoints are the ratios of AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890 under the fed conditions (low-fat meal or high-fat meal), relative to the PK 
parameters under the fasted conditions. 
3.2. Secondary Endpoints 
The secondary endpoints are the plasma PK parameters of PF-07284890, which will be 
derived (as data permit) from the concentration-time data using standard noncompartmental 
methods of analysis as outlined in Table 2. Actual PK sampling times will be used in the 
derivation of PF-07284890 PK parameters when available. In the case that actual PK 
sampling times are not available, nominal PK sampling time will be used in the derivation of 
PK parameters. 


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Table 2. 
Plasma PF-07284890 PK Parameters Definitions  
Parameter Definition 
Method of Determination 
AUCinf* 
Area under the plasma concentration-
time curve from time zero extrapolated to 
infinity 
AUClast + (Clast*/kel), 
where Clast* is the predicted 
plasma concentration at the last 
quantifiable time point from the 
log-linear regression analysis 
AUClast 
Area under the plasma concentration-
time profile from time zero to the time of 
the last quantifiable concentration (Clast). 
Linear/Log trapezoidal method. 
Cmax 
Maximum observed plasma concentration 
Observed directly from data 
Tmax 
Time to reach Cmax 
Observed directly from data as 
time of first occurrence 
t½* 
Terminal elimination half-life 
Loge(2)/kel, 
where kel is the terminal phase 
rate constant calculated by a 
linear regression of the loglinear 
concentration-time curve. Only 
those data points judged to 
describe the terminal loglinear 
decline will be used in the 
regression. 
CL/F* 
Apparent clearance 
Dose/AUCinf 
Vz/F* 
Apparent volume of distribution for 
extravascular dosing 
Dose/(AUCinf • kel) 
*If data permit. 
 
Safety data are also considered as secondary endpoints and are discussed in Section 3.5. 
 
  
3.4. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol.  
3.5. Safety Endpoints 
The following data are considered in standard safety summaries (see protocol for collection 
days, baseline assessment, and list of parameters):  
• adverse events (AE) 
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• laboratory data 
• vital signs data 
• electrocardiogram (ECG) results 
3.5.1. Adverse Events 
Any events occurring following start of treatment will be considered as treatment emergent 
adverse event (TEAE). Events that occur in a non-treatment period (ie washout or follow-up 
period) within the lag time of 28 days will be counted as treatment emergent and attributed to 
the previous treatment taken. Similarly, 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 each period, the baseline measurement is the predose measurement on Day -1. 
3.5.3. Vital Signs 
Supine blood pressure (BP), pulse rate (PR) and temperature will be measured at times 
specified in the SoA given in the protocol. Respiratory rate (RR) will be measured if the PR 
is outside of normal range. 
For each period, the baseline measurement is the predose measurement on Day 1. 
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 each period, the baseline value is the average of the triplicate ECG measurements 
collected before dose administration on Day 1. 
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 


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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. 
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 clinical study report (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 ECG 
measurement and the predose baseline ECG value on Day 1. 
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 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 assigned to study intervention and who take 
at least 1 dose of study intervention. Participants will be 
analyzed according to the product they actually received. 
PK Concentration 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value can be reported. 
PK Parameter Analysis 
Population 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest can be reported. 
   
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following last 
participant last visit. 


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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 1 of the following cases is true: 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample). 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged 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. 
 


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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 dose with ≥3 evaluable 
measurements. 
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, laboratory data, vital signs, and ECGs will be 
imputed according to CaPS. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
The primary endpoints are the ratios of AUClast, AUCinf (if data permit) and Cmax of 
PF-07284890 under the fed conditions (low-fat meal or high-fat meal), relative to the PK 
parameters under the fasted condition.  
Using data from Treatments A and B, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effect model with sequence, period and 
treatment as fixed effects and participant within sequence 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% CI for the ratios. Treatment A (PF-07284890 under fasted condition) is the 
Reference treatment and Treatment B (PF-07284890 administered under fed condition, low-
fat meal) is the Test treatment. 
Using data from Treatments A and C, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effect model with treatment and sequence as 
a fixed effect and participant within sequence 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% CI 
for the ratios. Treatment A (PF-07284890 under fasted condition) is the Reference treatment 
and Treatment C (PF-07284890 administered under fed condition, high-fat meal) is the Test 
treatment. 


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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 given in the report of the study. 
6.2. Secondary Endpoint(s) 
PK data: 
The plasma concentrations of PF-07284890 will be listed and descriptively summarized by 
nominal PK sampling time and treatment on the PK Concentration Population. 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, respectively. Mean and 
median profiles will be presented on both linear and semi-log scales.  
Presentations for PF-07284890 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 given 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]. 
The PK parameters will be summarized descriptively by treatment group in accordance with 
Pfizer data standards on the PK Parameter Analysis Population, as data permit. A listing of 
the individual participant ratios (Test-Reference) and a scatterplot of the ratio of fed and 
fasted AUCinf versus fasted AUCinf will be provided. Missing values will be handled as 


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detailed in Section 5.3.1. Each PK parameter will be summarized by treatment group 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 
N, arithmetic mean, median, SD, %CV, minimum, maximum, geometric 
mean and geometric %CV 
Tmax 
N, median, minimum, maximum 
t½ 
N, arithmetic mean, median, SD, %CV, minimum, 
maximum 
 
Safety data: 
See Section 6.5. 
 
 
 
6.4. Baseline and Other Summaries and Analyses 
6.4.1. Demographic Summaries 
Demographic characteristics (age, gender, ethnicity, race, weight, height and body mass 
index) 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. Data will be reported 
in accordance with the CaPS. 
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. 
CCI


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Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
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 postdose. 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:  
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 
 
 


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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 AUClast, 
AUCinf, Cmax 
PK Parameter 
Analysis 
Population 
Observed data 
Mixed effect 
ANOVA model 
PK parameters 
PK Parameter 
Analysis 
Population 
Observed data 
Descriptive 
statistics 
PK concentrations 
PK 
Concentration 
Population 
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 
 
 
 
 


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Appendix 2. SAS Code for Analyses 
An example of the PROC MIXED code is provided below: 
For comparison of fasted versus low-fat meal:  
proc mixed data=tab.pk; 
where trt in (“A” “B”); 
 
class seq period trt participant; 
 
model l&var=seq period trt / ddfm=KR; 
 
random participant(seq) / subject=participant(seq); 
 
lsmeans trt; 
 
estimate 'Test vs Reference' trt -1  1  /cl alpha=0.1; 
 
ods 'Estimates' out=est&var; 
 
ods 'lsmeans' out=ls&var; 
 
ods 'covparms' out=cov&var; 
 
ods 'tests3' out=tst&var; 
run; 
 
For comparison of fasted versus high-fat meal: 
proc mixed data=tab.pk; 
where trt in (“A” “C”); 
 
class seq trt participant; 
 
model l&var=seq trt / ddfm=KR; 
 
random participant(seq) / subject=participant(seq); 
 
lsmeans trt; 
 
estimate 'Test vs Reference' trt -1  1 / cl alpha=0.1; 
 
ods 'Estimates' out=est&var; 
 
ods 'lsmeans' out=ls&var; 
 
ods 'covparms' out=cov&var; 
 
ods 'tests3' out=tst&var; 
run; 
 
 
/* Letter assignments for treatments (trt) within the estimate statement above are as follows; 
 
For comparison of fasted versus low-fat meal: 
A = 200 mg PF-07284890 (2 × 100 mg tablets) under fasted conditions (Reference); 
B = 200 mg PF-07284890 (2 × 100 mg tablets) under low-fat meal fed conditions (Test)  
 
For comparison of fasted versus high-fat meal: 
A = 200 mg PF-07284890 (2 × 100 mg tablets) under fasted conditions (Reference); 
C = 200 mg PF-07284890 (2 × 100 mg tablets) under high-fat meal fed conditions (Test) */; 
 


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Appendix 3. List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ANOVA 
analysis of variance 
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 
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 observed plasma concentration 
CSR 
clinical study report 
%CV 
coefficient of variation 
ECG 
electrocardiogram 
HR 
Heart rate 
kel 
the terminal phase rate constant calculated by a linear regression of the 
loglinear concentration-time curve 
LLQ 
lower limit of quantitation 
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) 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
t1/2 
terminal elimination half-life 
Tmax 
time to reach Cmax 
TEAE 
treatment emergent adverse event 
Vz/F 
apparent volume of distribution for extravascular dosing 
 
CCI