Clinical trial NCT05767905
Conditions: Healthy
Keywords: PF-06821497 Relative Bioavailability Food Effect
Sponsor: Pfizer
Start date: 2023-03-17; Completion date: 2023-06-20
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to understand the effect of tablet formulation and presence of food on the study medicine PF-06821497 in healthy adult participants.

The study is seeking for male and female participants who:

* Are 18 years of age or more.
* Are confirmed to be healthy after performing some medical and physical tests.
* Weigh more than 50kgs of body weight and have a body mass index of 17 and a half kg per meter squared or more.

The study consists of two parts. In each part of the study, the selected participants will take part in 3 study periods to receive 3 different treatments which are randomly assigned. There will also be a 5-day gap between each study period. This is done so that the medicine is passed out of the body before the start of next study period.

Each treatment consists of a single dose of PF-06821497. The treatments differ by tablet formulation and/or whether the medicine is to be given with food or without food conditions.

How the medicine is processed in the body will be studied after giving the medicines to the participants. This will be done by collecting blood samples after each administration. The results will be used to see the effect of tablet formulation and presence of food on the amount of PF-06821497 available in the blood of the participants.

In each part, participants will be on the study up to 10 weeks, including the screening and follow-up periods.

Detailed description:

Arms: arm 1: Participants randomized to Sequence 1 will receive Treatments A, B, and C in Periods 1 through 3, respectively in the form of tablets by mouth.

Interventions:

* Drug: Single dose of PF-06821497 Treatment A
* Drug: Single dose of PF-06821497 Treatment B
* Drug: Single dose of PF-06821497 Treatment C arm 2: Participants randomized to Sequence 2 will receive Treatments B, A and C in Periods 1 through 3, respectively in the form of tablets by mouth.

Interventions:

* Drug: Single dose of PF-06821497 Treatment A
* Drug: Single dose of PF-06821497 Treatment B
* Drug: Single dose of PF-06821497 Treatment C arm 3: Participants randomized to Sequence 1 will receive Treatments D, E and F in Periods 1 through 3, respectively in the form of tablets by mouth.

Interventions:

* Drug: Single dose of PF-06821497 Treatment D
* Drug: Single dose of PF-06821497 Treatment E
* Drug: Single dose of PF-06821497 Treatment F
Interventions: intervention 1: PF-06821497 Treatment A intervention 2: PF-06821497 Treatment B intervention 3: PF-06821497 Treatment C intervention 4: PF-06821497 Treatment D intervention 5: PF-06821497 Treatment E intervention 6: PF-06821497 Treatment F
Intervention descriptions: intervention 1: A single dose of PF-06821497 administered under fasting conditions. intervention 2: A single dose of PF-06821497 administered under fasting conditions. intervention 3: A single dose of PF-06821497 administered under fasting conditions. intervention 4: A single dose of PF-06821497 administered under fasting conditions. intervention 5: A single dose of PF-06821497 administered after low fat meal intervention 6: A single dose of PF-06821497 administered after high fat meal.

Protocol documents:
Prot_000.pdf: 
PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
A PHASE 1, RANDOMIZED, OPEN-LABEL, 3-PERIOD, CROSSOVER, SINGLE- 
DOSE, 2-PART STUDY IN HEALTHY PARTICIPANTS TO INVESTIGATE THE 
EFFECT OF TABLET FORMULATION AND FOOD ON THE RELATIVE 
BIOAVAILABILITY OF PF-06821497 
 
 
 
Study Intervention Number: 
PF-06821497 
Study Intervention Name: 
NA 
US IND Number: 
CCI 
 
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C2321005 
Phase: 
Phase 1 
Brief Title: A Phase 1, Single-dose, Relative Bioavailability Study to Investigate the 
Effect of Tablet Formulation and Food on PF-06821497 Pharmacokinetics in Healthy 
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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Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
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Document History 
 
Document 
Version Date 
Original protocol 
02 Feb 2023 


PF-06821497 
Protocol C2321005 
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PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 8 
1. PROTOCOL SUMMARY ..................................................................................................... 9 
1.1. Synopsis ..................................................................................................................... 9 
1.2. Schema..................................................................................................................... 17 
1.3. Schedule of Activities .............................................................................................. 18 
2. INTRODUCTION ................................................................................................................ 23 
2.1. Study Rationale ........................................................................................................ 23 
2.2. Background .............................................................................................................. 23 
2.2.1. Nonclinical Pharmacology .......................................................................... 23 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 23 
2.2.3. Nonclinical Safety ....................................................................................... 24 
2.2.4. Clinical Overview ....................................................................................... 25 
2.2.5. 2.2.4.1 Safety Overview .............................................................................. 25 
2.2.6. 2.2.4.2. Summary of PF-06821497 Pharmacokinetics in Humans ............. 27 
2.3. Benefit/Risk Assessment ......................................................................................... 28 
2.3.1. Risk Assessment ......................................................................................... 29 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 31 
4. STUDY DESIGN ................................................................................................................. 31 
4.1. Overall Design ......................................................................................................... 31 
4.2. Scientific Rationale for Study Design ..................................................................... 34 
4.2.1. Assessment of Safety Data Before Administration of the High-fat 
Meal in Part 2 of the Study .............................................................................. 35 
4.2.2. Choice of Contraception/Barrier Requirements .......................................... 35 
4.2.3. Collection of Retained Research Samples ................................................... 35 
4.3. Justification for Dose ............................................................................................... 36 
4.4. End of Study Definition ........................................................................................... 37 
5. STUDY POPULATION ...................................................................................................... 37 
5.1. Inclusion Criteria ..................................................................................................... 37 
5.2. Exclusion Criteria .................................................................................................... 38 
5.3. Lifestyle Considerations .......................................................................................... 40 
5.3.1. Contraception .............................................................................................. 40 


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5.3.2. Meals and Dietary Restrictions .................................................................. 41 
5.3.3. Caffeine, Alcohol, and Tobacco ................................................................. 42 
5.3.4. Activity ...................................................................................................... 42 
5.4. Screen Failures ........................................................................................................ 42 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 42 
6.1. Study Intervention(s) Administered ........................................................................ 43 
6.1.1. Administration ............................................................................................ 43 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 45 
6.2.1. Preparation and Dispensing ........................................................................ 46 
6.3. Assignment to Study Intervention .......................................................................... 46 
6.4. Blinding .................................................................................................................. 46 
6.5. Study Intervention Compliance .............................................................................. 46 
6.6. Dose Modification .................................................................................................. 46 
6.7. Continued Access to Study Intervention After the End of the Study ..................... 47 
6.8. Treatment of Overdose ........................................................................................... 47 
6.9. Prior and Concomitant Therapy .............................................................................. 47 
6.9.1. Rescue Medicine ........................................................................................ 48 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 48 
7.1. Discontinuation of Study Intervention .................................................................... 48 
7.1.1. COVID-19 .................................................................................................. 49 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 49 
7.2.1. Withdrawal of Consent .............................................................................. 49 
7.3. Lost to Follow-up ................................................................................................... 50 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 50 
8.1. Administrative Procedures ...................................................................................... 50 
8.2. Efficacy Assessments ............................................................................................. 51 
8.3. Safety Assessments ................................................................................................. 51 
8.3.1. Physical Examinations ............................................................................... 52 
8.3.2. Vital Signs .................................................................................................. 52 
8.3.2.1. Blood Pressure and Pulse Rate ................................................. 52 
8.3.2.2. Respiratory Rate ....................................................................... 53 


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CCI 
8.3.2.3. Temperature ............................................................................... 53 
8.3.3. Electrocardiograms ...................................................................................... 53 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 54 
8.3.5. COVID-19 Specific Assessments ............................................................... 54 
8.3.6. Pregnancy Testing ....................................................................................... 54 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 55 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 55 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 56 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 56 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 56 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 56 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 57 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 57 
8.4.5.1. Exposure During Pregnancy ...................................................... 57 
8.4.5.2. Exposure During Breastfeeding ................................................. 59 
8.4.5.3. Occupational Exposure .............................................................. 59 
8.4.6. Cardiovascular and Death Events ................................................................ 60 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 60 
8.4.8. Adverse Events of Special Interest ............................................................. 60 
8.4.8.1. Lack of Efficacy ......................................................................... 60 
8.4.9. Medical Device Deficiencies ...................................................................... 60 
8.4.10. Medication Errors ...................................................................................... 60 
8.5. Pharmacokinetics ..................................................................................................... 61 
 
 
 
 
 
 
 
8.8. Immunogenicity Assessments ................................................................................ 63 


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8.9. Health Economics ................................................................................................... 63 
9. STATISTICAL CONSIDERATIONS ................................................................................ 63 
9.1. Statistical Hypotheses ............................................................................................. 63 
9.2. Analysis Sets ........................................................................................................... 63 
9.3. Statistical Analyses ................................................................................................. 64 
9.3.1. Pharmacokinetic Analysis .......................................................................... 64 
9.3.1.1. Derivation of Pharmacokinetic Parameters .............................. 64 
9.3.2. Statistical Methods for PK Data ................................................................. 65 
9.3.3. Other Safety Analyses ................................................................................ 65 
CCI 
 
9.4. Interim Analyses ..................................................................................................... 66 
9.5. Sample Size Determination .................................................................................... 66 
10. SUPPORTING  DOCUMENTATION  AND  OPERATIONAL 
CONSIDERATIONS .......................................................................................................... 68 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 68 
10.1.1. Regulatory and Ethical Considerations .................................................... 68 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 68 
10.1.2. Financial Disclosure ................................................................................. 69 
10.1.3. Informed Consent Process ....................................................................... 69 
10.1.4. Data Protection ......................................................................................... 70 
10.1.5. Committees Structure ............................................................................... 70 
10.1.5.1. Data Monitoring Committee ................................................... 70 
10.1.6. Dissemination of Clinical Study Data ...................................................... 70 
10.1.7. Data Quality Assurance ............................................................................ 71 
10.1.8. Source Documents ................................................................................... 73 
10.1.9. Study and Site Start and Closure .............................................................. 73 
10.1.10. Publication Policy .................................................................................. 74 
10.1.11. Sponsor’s Medically Qualified Individual ............................................. 75 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 76 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 78 
10.3.1. Definition of AE ....................................................................................... 78 


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PFIZER CONFIDENTIAL 
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10.3.2. Definition of an SAE ................................................................................ 79 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 80 
10.3.4. Reporting of SAEs ................................................................................... 84 
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................ 85 
10.4.1. Male Participant Reproductive Inclusion Criteria .................................... 85 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 85 
10.4.3. Woman of Childbearing Potential ............................................................ 86 
10.4.4. Contraception Methods ............................................................................ 87 
CCI 
 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 90 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................ 92 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ............................................................................. 92 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ............... 92 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .......................................................................................... 92 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 92 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ................................... 93 
10.9. Appendix 9: Abbreviations ................................................................................... 95 
11. REFERENCES ................................................................................................................ 100 


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LIST OF TABLES 
Table 1. 
Treatment Schedule.................................................................................. 33 
Table 2. 
Summary of PF-06821497 Formulations ................................................. 43 
Table 3. 
Plasma PF-06821497 PK Parameters Definitions .................................... 64 
Table 4. 
Expected Widths of the 90% CIs for Different Possible Estimated 
Effects and Parameters of Interest for Part 1 Study ................................. 66 
Table 5. 
Expected Widths of the 90% CIs for Different Possible Estimated 
Effects and Parameters of Interest for Part 2 Study ................................. 67 
Table 6. 
Protocol-Required Safety Laboratory Assessments ................................. 76 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Randomized, Open-label, 3-period, crossover, single-dose, 2-part 
study in healthy participants to investigate the effect of tablet formulation and food on the 
bioavailability of PF-06821497 
Brief Title: A Phase 1, Single-dose, Relative Bioavaialbility Study to Investigate the Effect 
of Tablet Formulation and Food on PF-06821497 Pharmacokinetics in Healthy Participants 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
CCI 
 
EudraCT Number: 
NA 
ClinicalTrials.gov ID: 
NA 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C2321005 
Phase: 
Phase 1 
 
Rationale: 
The purpose of the study is to investigate the relative bioavailability of tablet formulations of 
PF-06821497 and to characterize the effect of food on a PF-06821497 CCI  tablet formulation 
(Formulation 2). The data generated from this study will be used to support the pivotal study 
formulation, to inform dose administration instructions for PF-06821497 with regard to 
dosing with or without food, and to enable the establishment of the API particle size 
specifications for eventual commercialization. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To estimate the bioavailability of a single C  mg dose of PF- 
06821497 CC tablet formulation (Formulation 2) relative to a 
single C  mg dose of PF-06821497 CCI tablet formulation 
(Formulation 1) under fasted conditions in adult healthy 
participants 
• Plasma AUCinf and Cmax for PF-06821497. 
(AUClast will be used as the primary estimate if 
AUCinf cannot be reliably estimated). 
Secondary: 
Secondary: 
• 
To estimate the bioavailability of a single C  mg dose of PF- 
06821497 CC tablet (larger API particle size) formulation 
(Formulation 3) relative to a single C  mg dose of PF- 
06821497 CC tablet (Formulation 2) and a single C  mg dose 
of the PF-06821497 CCI tablet formulation (Formulation 1) 
under fasted conditions in adult healthy participants 
•  Plasma AUCinf and Cmax for PF-06821497 for 
CC tablet (larger API particle size) (Formulation 
3) relative to CC (Formulation 2) and CCI 
tablet (Formulation 1) formulations. (AUClast will 
be used as the primary estimate if AUCinf cannot 
be reliably estimated). 


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Protocol C2321005 
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PFIZER CONFIDENTIAL 
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C 
 
Objectives 
Endpoints 
• 
 To estimate the effect of a high-fat, high-calorie meal on the 
bioavailability of a single CCI mg dose of the PF-06821497 
CC tablet formulation (Formulation 2) relative to fasted 
conditions in adult healthy participants 
• 
 To estimate the effect of a low-fat, low-calorie meal on the 
bioavailability of a single CCI mg dose of the PF-06821497 
CC tablet formulation (Formulation 2) relative to fasted 
conditions in adult healthy participants 
• 
Plasma AUCinf and Cmax for PF-06821497 
under fed (high-fat, high-calorie meal) 
conditions relative to fasting conditions. 
(AUClast will be used as the primary estimate if 
AUCinf cannot be reliably estimated). 
• Plasma AUCinf and Cmax for PF-06821497 under 
fed (low-fat, low-calorie meal) conditions relative 
to fasting conditions. (AUClast will be used as the 
primary estimate if AUCinf cannot be reliably 
estimated). 
• To evaluate the safety and tolerability of PF-06821497 when 
administered as a tablet formulation to healthy participants 
• Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, physical examinations, 
and 12-lead ECGs. 
Overall Design: 
This is a Phase 1, randomized, open-label, 3-period, single-dose 2-part study in healthy adult 
participants to investigate the effect of tablet formulation and food on the bioavailability of 
PF-06821497. 
Intervention Groups and Duration: 
Part 1 (rBA): 
Sequence 
Period 1 
Washout: at 
least C days 
between PF- 
06821497 
doses 
Period 2 
Washout: at 
least C days 
between PF- 
06821497 doses 
Period 3 
1 (6 Participants) 
A 
B 
C 
2 (6 Participants) 
B 
A 
C 
Treatment A – CCI  formulation (Formulation 1) 
Treatment B – CC  formulation (Formulation 2) 
Treatment C – CC  formulation (Formulation 3) 
 
Part 2 (Food effect): 
C 
fasted; 
CC 
fasted; 
C 
; larger particle size) fasted ; 
C 
 
 
 
 
 
Treatment D – CC  formulation ((Formulation 2) 
C 
fasted; 
Treatment E – CC formulation (Formulation 2) 
Treatment F – CC formulation (Formulation 2) 
CC 
fed: Low-fat meal; 
C 
fed: High-fat meal 
C 
There will be a minimum of CCI 
 washout period between successive PF-06821497 doses. 
F 
Period 3 
Washout: at 
least C days 
between PF- 
06821497 doses 
Period 2 
E 
Washout: at 
least C days 
between PF- 
06821497 
doses 
D 
1 (6 Participants) 
Period 1 
Sequence 


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Blood samples for PF-06821497 PK analysis will be collected predose and at CCI 
 
post the PF-06821497 dose in each period. 
In each part, participants will be on the study up to 10 weeks, including the screening and 
follow-up periods. Participants will be screened within 28 days prior to the first dose of the 
IP and if all entry criteria are fulfilled, the participants will report to the PCRU on the day 
prior to Day 1 dosing (Day -1) of each period. For Treatments A, B, and C, following an 
overnight fast of at least 10 hours, and after the collection of the pre-dose PF-06821497 PK 
sample on Day 1 of each period, participants will be administered a CCI mg dose of PF- 
06821497. For Treatment D, following an overnight fast of at least 10 hours, and after the 
collection of the pre-dose PF-06821497 PK sample on Day 1 of each period, participants will 
be administered a CCI  mg dose of PF-06821497. For Treatment E, after an overnight fast of 
at least 10 hours and after the collection of pre-dose PF-06821497 PK sample on Day 1, 
participants will receive a low-fat, low-calorie breakfast 30 minutes prior to dosing. For 
Treatment F, after an overnight fast of at least 10 hours and after the collection of pre-dose 
PF-06821497 PK sample on Day 1, participants will receive a high-fat, high-calorie breakfast 
30 minutes prior to dosing. Participants are strongly encouraged to consume the breakfast in 
its entirety. PF-06821497 will be administered as intact tablets with approximately 240 mL 
of ambient temperature water. Tablets will be swallowed and not chewed. 
In Part 2 of the study, before the Period 3 doses are administered to participants that have 
eaten a high-fat meal, the safety data for Period 2, including at least 3 participants 
administered a low-fat meal in Period 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 Period 2 were well-tolerated. 
Following administration of PF-06821497, participants will be confined in the PCRU for a 
minimum of C days until completion of the CCI 
 PK sample collection and discharge 
assessments on Day C  in each period, or at the discretion of the investigator participants 
could remain admitteCd to the PCRU throughout study conduct and discharged on Day C of 
Period 3 in each part. Participants will be discharged at the discretion of the investigator. A 
follow-up phone call will be made at least 28 calendar days and up to 35 calendar days after 
the last administration of study intervention to capture any potential AEs and confirm 
appropriate contraceptive usage. 
Number of Participants: 
Approximately 18 participants will be enrolled to the study intervention. If there are 
participants who withdraw or discontinue treatment and are considered to be non-evaluable 
with respect to the primary PK objective(s), additional participants can be enrolled at the 
discretion of the investigator upon consultation with the sponsor. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
assignment to study intervention. A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study activity. Potential participants 


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PFIZER CONFIDENTIAL 
Page 12 
 
 
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 years of age, inclusive, at screening. 
2. Male and female participants 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 kg/m2; and a total body weight >50 kg (110 lb) 
4. Evidence of a personally signed and dated ICD indicating that the participant has 
been informed of all pertinent aspects of the study. 
5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing) or prior allergic reaction to any component of 
PF-06821497. 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy, prior bariatric surgery, ileal resection, inflammatory 
gastrointestinal disease, chronic diarrhea, known diverticular disease). 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAB or HCVAb. Hepatitis B vaccination is allowed. 
• Chronic liver diseases including alcoholic liver disease, viral hepatitis, 
primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune 


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hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, 
human immunodeficiency virus, or other chronic liver disease. 
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 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. 
• Current use or anticipated need for food or drugs that are known strong 
inducers or inhibitors of CYP3A4/5, including their administration within 10 
days or 5 half-lives of the strong inducer or inhibitor of CYP3A4/5, whichever 
is longer prior to first dose of investigational product 
o Strong CYP3A4/5 inhibitors: eg, grapefruit juice or 
grapefruit/grapefruit related citrus fruits (eg, Seville oranges, 
pomelos), ketoconazole, miconazole, itraconazole, voriconazole, 
posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, 
ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, 
troleandomycin, mibefradil, and conivaptan. 
 
o Strong CYP3A4/5 inducers: eg, phenobarbital, rifampin, phenytoin, 
carbamazepine, rifabutin, rifapentin, clevidipine, St. John’s Wort. 
 
• Time dependent inhibitors of CYP3A4/5 for atleast 21 days prior to the 
treatment 
o Time dependent inhibitors of CYP3A4/5: azamulin, troleandomycin, 
verapamil, boceprevir, nelfinavir, and telapravir 
4. 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). 
5. A positive urine drug test. 
6. 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. 
7. Standard 12 lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results. 


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8.  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 > ULN; 
• Total bilirubin level >1 × ULN; 
• PT, international normalized ratio (INR) and aPTT outside of normal limits at 
baseline 
• eGFR <60 mL/min/1.73 m2 based on the CKD-EPI equation; 
• Absolute neutrophil count <0.8 × LLN. 
9. History of alcohol abuse or binge drinking [more than 4 drinks on any day or 14 
drinks per week where 1 drink is defined as the alcoholic beverage containing 
approximately (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 
ounces (90 mL) of wine)] in the last 6 months prior to study screening. 
10. Use of tobacco or nicotine containing products within 3 months of screening or a 
positive urine cotinine test (ie, active smokers and those who currently use nicotine 
containing products are excluded from participation in this study). 
11. Pregnant female participants; breastfeeding female participants; fertile male 
participants and female participants of childbearing potential who are unwilling or 
unable to use 2 highly effective methods of contraception as outlined in this protocol 
for the duration of the study and for at least 3 months after the last dose of 
investigational product. 
12. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
13. History of sensitivity to heparin or heparin induced thrombocytopenia. 
14. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
15. 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. 
Study Arms and Duration: 
Each participant will be screened within 28 days prior to the first dose of the IP and if all 
entry criteria are fulfilled, the participants will report to the PCRU on the day prior to Day 1 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 15 
 
 
dosing (Day -1) of each period. A safety follow-up call will be made to participants 28 to 35 
days from administration of the final dose of study intervention. 
In each part of the study, each enrolled participant will participate in 3 study periods to 
receive 3 different treatments according to the sequence determined by randomization with C- 
day washouts between PF-06821497 administration: 
Part 1: 
• Treatment A – CCI  formulation (Formulation 1) CCI 
 fasted; 
• Treatment B – CCI  formulation (Formulation 2) CCI 
 fasted; 
• Treatment C – CCI  formulation (Formulation 3) CCI 
; larger API 
particle size) fasted; 
Part 2: 
• Treatment D – CCI  formulation (Formulation 2) CCI 
 fasted; 
• Treatment E – CCI  formulation (Formulation 2) CCI 
 fed: Low-fat 
meal; 
• Treatment F – CCI  formulation (Formulation 2) CCI 
 fed: High-fat 
meal; 
Statistical Methods: 
Part 1: 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects 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% confidence intervals will be obtained from the model. 
The adjusted mean differences and 90% confidence intervals for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% confidence intervals for the ratios. Treatment A (CCI  formulation (Formulation 1) 
CCI 
 fasted) will be the Reference treatment and Treatment B (CCI  
formulation (Formulation 2) CCI 
 fasted) will be the Test treatment. 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects model with sequence and treatment as fixed effects and participant within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment A (CCI  formulation (Formulation 1) CCI 
 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 16 
 
 
CCI 
 fasted) will be the Reference treatment and Treatment C (CCI  formulation 
(Formulation 3) CCI 
; larger API particle size) fasted) will be the Test 
treatment. For the second comparison, Treatment B (CCI  formulation (Formulation 2) CCI 
will be the Reference treatment and Treatment C (CCI formulation 
(Formulation 3) CCI 
; larger API particle size) fasted) will be the Test 
treatment. 
Part 2: 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects model with treatment as a fixed effect and participant as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
confidence intervals will be obtained from the model. The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios. Treatment D (CCI  formulation (Formulation 2) CCI 
 fasted) will be 
the Reference treatment and Treatments E and F (CCI  formulation (Formulation 2) 1250 mg 
CCI 
 fed: low-fat meal and CCI  formulation (Formulation 2)CCI 
 
 
fed: high-fat meal) will be the Test treatments. 
 
Pharmacokinetics Analysis 
The PK concentration population is defined as all participants randomized and treated who 
have at least 1 PF-06821497 concentration in at least 1 treatment period. 
The PK parameter analysis population is defined as all participants randomized and treated 
who have at least 1 of the PF-06821497 PK parameters of primary interest in at least 1 
treatment period. 
PK parameters for PF-06821497 will be analyzed using standard noncompartmental methods 
of analysis. Actual PK sampling times will be used in the derivation of PF-06821497 PK 
parameters when available, otherwise nominal times will be used. The PF-06821497 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 using actual and nominal times, respectively. 
Safety Analysis 
AEs, ECGs, BP, PR, RR, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants. Any clinical laboratory, 
ECG, BP, RR, and PR abnormalities of potential clinical concern will be described. Safety 
data will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate. 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
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Page 17 
 
 
Ethical Considerations: 
PF-06821497 will not provide any clinical benefit to healthy participants in this study. This 
study is designed primarily to further the understanding of human PK, metabolism, and 
elimination of PF-06821497. Participants will be expected to commit time and may 
experience some discomfort while undergoing study assessments. 
1.2. Schema 
Not applicable. 


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Protocol C2321005 
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Page 18 
 
 
 
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 9. 
Days Relative to 
Day 1 
 
 
 
 
 
Hours After Dose 
 
Informed consent 
 
 
CRU confinement 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
Medical/medicatio 
n history 
Screening 
 
 
 
 
Day -28 
to 
Day -2 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
Day 
-1 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 0 
Period 1 to Period 3 
 
 
 
 
Day 1 
 
 
 
 
 
 
CCI 
 
 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
C 
F/U 
 
 
 
 
28- 
35 
Day 
s 
Early 
Termination/ 
Discontinuation 
Notes 
 
 
 
 
• Screening will be performed within 28 days prior to the 
first dose of PF-06821497. 
• Day -1 is applicable for each check-in to the PCRU, 
unless particularly specified. 
• Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention 
 
 
• Informed consent should be obtained prior to 
undergoing any study-specific procedures 
• See Section 10.1.3 for additional information. 
• Participants will be admitted to the PCRU on Day -1 of 
each period. Participants may be discharged on Day Cof 
each period at the discretion of the investigator 
following the completion of all Day Cassessments, or at 
the discretion of the investigator participants could 
remain admitted to the PCRU throughout study conduct 
and discharged on Day Cof Period 3. 
• Inclusion/exclusion criteria will be reviewed at 
Screening and at the Day -1 check-in for Period 1. 
• Medical history will include a history of prior illegal 
drug, alcohol, and tobacco use and will be recorded at 
Screening and updated on Period 1 Day -1. 


PF-06821497 
Protocol C2321005 
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PFIZER CONFIDENTIAL 
Page 19 
 
 
 
Visit Identifier 
Abbreviations used 
in this table may be 
found in 
Appendix 9. 
Screening 
Period 1 to Period 3 
F/U 
Early 
Termination/ 
Discontinuation 
Notes 
Days Relative to 
Day 1 
Day -28 
to 
Day -2 
Day 
-1 
Day 1 
Day 
2 
Day 
3 
28- 
35 
Day 
s 
• Screening will be performed within 28 days prior to the 
first dose of PF-06821497. 
• Day -1 is applicable for each check-in to the PCRU, 
unless particularly specified. 
• Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention 
Hours After Dose 
Pre-dose 0 C I 
 
Physical exam 
X 
X 
X 
• A completed physical examination will be performed by 
trained medical personnel at the PCRU at Screening or 
Period 1 Day -1 only (height and weight must be 
obtained at Screening to obtain BMI for eligibility 
criteria). Additional physical examination may be 
performed at other designated time points at the 
discretion of the investigator. 
PT, PTT, INR 
X 
X 
X 
X 
Safety laboratory 
X 
X 
X 
X 
• Safety laboratory assessments will be performed at 
Screening, prior to dosing in each treatment period (can 
be Day -1 or pre-dose on Day 1 at discretion of 
investigator), and prior to each discharge from the 
PCRU (could be Day Cin each period or only at Day C 
of Period 3 at discretion of investigator), and prior to 
early termination/discontinuation if applicable. 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 (see Appendix 2) 
Demography 
X 
• Demographics will include participant race, ethnicity, 
age, sex, height, and weight during the Screening visit. 
Pregnancy test 
(WOCBP only) 
X 
X 
X 
X 
• For Day Cit is only applicable for Period 3 (See 
Section 8.3.6). 
Contraception 
check 
X 
X 
X 
X 
• Contraception check will be performed according to the 
conditions described in Section 5.3.1 
FSH 
X 
• For postmenopausal (amenorrheic for at least 12 
consecutive months) female participants only 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 20 
 
 
 
Visit Identifier 
Abbreviations used 
in this table may be 
found in 
Appendix 9. 
Screening 
Period 1 to Period 3 
F/U 
Early 
Termination/ 
Discontinuation 
Notes 
Days Relative to 
Day 1 
Day -28 
to 
Day -2 
Day 
-1 
Day 1 
CCI 
28- 
35 
Day 
s 
• Screening will be performed within 28 days prior to the 
first dose of PF-06821497. 
• Day -1 is applicable for each check-in to the 
PCRU, unless particularly specified. 
• Follow-up contact may occur via telephone contact 
and must occur 28 to 35 days from administration of 
the final dose of study intervention 
Hours After Dose 
Pre-dose 0 C I 
Urine drug 
screening/Urine 
cotinine/Alcohol 
breath test 
X 
X 
C 
C 
• Urine drug and urine cotinine (mandatory) and alcohol 
breath test (at discretion of investigator) will be 
performed at Screening, on Period 1 Day -1, and upon 
PCRU check-in on Day -1 of each subsequent period. 
These tests may be performed at any other time at the 
discretion of the investigator. 
12-Lead ECG 
X 
X 
X 
• Single 12-lead ECG readings will be taken at 
approximately the specified time point. 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. Additional ECGs may be taken at 
any time at the discretion of the investigator. 
• Single 12-lead ECG monitoring will be done pre-dose of 
Day 1 of each treatment period. 
• Chour post-dose ECG readings are applicable only for 
Periods 2 and 3 in Part 2. Day Cmeasurements are for 
Period 3 only. 
Vital signs 
(BP/PR/RR and 
temperature) 
X 
X 
X 
• Single supine BP, RR and PR will be performed 
following at least a 5 minute rest in a supine position, at 
specified time point. BP, RR and PR assessments will be 
performed after collection of ECGs and prior to 
collection of blood draws if scheduled at the same time. 
• Vital sign measurements will be done pre-dose of Day 1 
of each treatment period. 
• Chour post-dose vital sign measurements are applicable 
only for Periods 2 and 3 in Part 2. Day Cmeasurements 
are for Period 3 only. 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 21 
 
 
 
Visit Identifier 
Abbreviations used 
in this table may be 
found in 
Appendix 9. 
Days Relative to 
Day 1 
 
 
 
 
 
Hours After Dose 
Screening 
 
 
 
 
Day -28 
to 
Day -2 
 
 
 
 
 
Day 
-1 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dose 0 
Period 1 to Period 3 
 
 
 
 
Day 1 
 
 
 
 
 
 
CCI 
 
 
 
 
CCI 
F/U 
 
 
 
 
28- 
35 
Day 
s 
Early 
Termination/ 
Discontinuation 
Notes 
 
 
 
 
• Screening will be performed within 28 days prior to the 
first dose of PF-06821497. 
• Day -1 is applicable for each check-in to the PCRU, 
unless particularly specified. 
• Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention 
 
HIV, HBsAg, 
X 
HBcAb, HCVAb 
COVID-19 related 
X 
measures 
COVID-19 testing 
X 
 
PF-06821497 
dosing 
 
 
 
Pharmacokinetic 
blood sampling for 
PF-06821497 
 
X 
X 
 
X 
 
 
 
X 
CCI 
 
 
• The measures will be according to PCRU procedures. 
 
• The testing for COVID-19 will be performed per PCRU 
procedures or by the Principal Investigator. 
• PF-06821497 will be administered orally on Day 1 after 
overnight fasting until the start of study procedures for 
each treatment period. PF-06821497 will be 
administered orally and in fasted or fed state according 
to the conditions described in Protocol Section 5.3.2. 
X 
• Blood samples (~2 mL) for PK analysis of PF-06821497 
will be taken at predose (within approximately 1 hour 
prior to PF-06821497 dosing), and at the specified 
timepoints post dose. If ECG and BP/PR assessments 
are scheduled at the same nominal time point as a PK 
sample, PK samples should be collected after 
completion of these assessments. A 10% time window is 
allowable for samples collected upto CCI 
. ≤ 1hour is 
allowed for samples collected at more than CCI 
 
 
CCI 


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Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 22 
 
 
 
 
CCI 
C 
C 
•
See Section 8.4.3 for follow-up AE and SAE 
assessments. 
X 
→ 
→ 
X 
Serious and 
nonserious AE 
monitoring 
•
CRU discharge will be applicable for discharge day 
from the PCRU (could be DayC in each period or only 
at DayC of Period 3 at discretion of investigator, and 
prior to early termination/discontinuation if applicable). 
CRU discharge 
0 
Pre-dose 
Hours After Dose 
•
Screening will be performed within 28 days prior to the 
first dose of PF-06821497. 
•
Day -1 is applicable for each check-in to the PCRU, 
unless particularly specified. 
•
Follow-up contact may occur via telephone contact and 
must occur 28 to 35 days from administration of the 
final dose of study intervention 
28- 
35 
Day 
s 
CCI 
Day 1 
Day 
-1 
Day -28 
to 
Day -2 
Days Relative to 
Day 1 
Notes 
Early 
Termination/ 
Discontinuation 
F/U 
Period 1 to Period 3 
Screening 
Visit Identifier 
Abbreviations used 
in this table may be 
found in 
Appendix 9. 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 23 
 
 
PF-06821497 has relatively CCI 
Based on the solubility and permeability 
data collected in the pre-clinical phase, PF-06821497 is considered to be a CCI 
drug. For this class of compound, food is CCI 
to show aCCI 
Following single-dose oral administration as a 
suspension in dogs, oral bioavailability was higher in a fed state than in a fasted state. CCI 
2. INTRODUCTION 
PF-06821497 is a potent and selective inhibitor of EZH2 as evidenced by its biochemical 
inhibition of both WT and EZH2 Y641N mutant enzymes. PF-06821497 is currently being 
proposed for investigation in patients with SCLC, CRPC, DLBCL, and FL. 
2.1. Study Rationale 
The purpose of the study is to investigate the relative bioavailability of tablet formulations of 
PF-06821497 and to characterize the effect of food on a PF-06821497 CCI  tablet formulation 
(Formulation 2). The data generated from this study will be used to support the pivotal study 
formulation, to inform dose administration instructions for PF-06821497 with regard to 
dosing with or without food, and to enable the establishment of the API particle size 
specifications for eventual commercialization. 
2.2. Background 
The histone methyltransferase EZH2 is the catalytic subunit of the PRC2 which methylates 
lysine 27 on histone H3 leading to repression of gene transcription. PF-06821497 is a potent 
and selective small molecule inhibitor of EZH2 as evidenced by its biochemical inhibition of 
both WT and EZH2 Y641N mutant enzymes. PF-06821497 is currently being proposed for 
investigation in patients with SCLC, CRPC, and FL. To date, clinical drug supplies of PF- 
06821497 have used the CCI  tablet formulation, CCI 
. 
As the clinical development program of PF-06821497 is preparing to move to later stages of 
development, activities are underway to further develop and optimize the manufactured PF- 
06821497 drug product. 
 
2.2.1. Nonclinical Pharmacology 
Details of the nonclinical pharmacology of PF-06821497 can be found in the current IB. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
PF-06821497 exhibited CCI 
 CLp and a moderate Vss in rats and dogs. Renal 
excretion was low in rats and dogs, and biliary excretion was CCI  in rats. Following oral 
administration, PF-06821497 was rapidly absorbed with CCI oral bioavailability in rats and 
CCI 
 
 oral bioavailability in dogs. Following single-dose oral administration as a 
suspension in dogs, oral bioavailability was CCI 
 in a fed state than in a fasted state, 
suggesting a potential food effect in the clinic. In oral repeat dose toxicity studies in mice and 
dogs, the systemic exposure of PF-06821497 generally CCI 
 in a CCI 
   
CCI 
 up to CCI kg/kg/day (CCI mg/kg/dose BID) with no consistent sex-related differences 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 24 
 
 
CCI 
CCI 
of CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
observed. CCI 
accumulation 
was observed over the dosing period. PF-06821497 is 
a 
 of the 
 ; however, nonclinical in vivo PK results suggested a 
impact of 
on intestinal absorption. 
PF-06821497 showed CCI  
 plasma protein binding with fu in plasma of CCI 
 across 
species tested and partitioning of PF-06821497 into blood cells was modest with blood to 
plasma ratios of CCI 
. Brain penetration of PF-06821497 was CCI 
 in mice, with 
unbound brain to plasma AUC ratios of 
. PF-06821497 distributed into human 
hepatocytes by CCI 
 
 
 
 and showed the CCI 
 for biliary 
excretion in sandwich cultured human hepatocytes. 
Preliminary in vitro metabolism evaluation of PF-06821497 showed similar metabolite 
profiles across species with no evidence of human specific metabolites. PF-06821497 was 
primarily metabolized by CCI 
 and CCI 
 pathways via CYP and non-CYP mediated 
metabolism. CYP-mediated metabolism accounted for CCI  of the hepatic metabolism with 
and 
the predominant CYP isoforms, whereas 
n 
-mediated metabolism (CCI 
 was due, in part, to CCI 
 
 
PF-06821497 showed minimal reversible 
PF-06821497 exhibited weak potential for 
time dependent inhibition of 
, and weakly 
in human 
hepatocytes. PF-06821497 showed minimal inhibition of 
 
, and 
Additionally, PF-06821497 weakly 
in vitro. 
Based on in vitro data, PF-06821497 showed minimal inhibition of 
 
, 
, but may have the potential to inhibit 
in humans at a 
predicted PAD of CCI mg PO BID PF-06821497. 
Additional information of the nonclinical PK and metabolism of PF-06821497 is available in 
the current IB. 
2.2.3. Nonclinical Safety 
The nonclinical safety profile of PF-06821497 was adequately characterized through the 
conduct of oral, acute or repeat-dose mouse and dog oral toxicity studies up to 1 month in 
duration, as well as genetic toxicity studies. In the pivotal 1-month toxicity studies, the 
primary effects of PF-06821497 were observed in the dog, while no findings were detected in 
the mouse. The key toxicities identified in nonclinical safety studies were observed in the 
gastrointestinal tract (mucosal atrophy, congestion and erosion), hemato-lymphopoietic 
system (decreased cellularity in the bone marrow, myeloid and erythroid toxicity, decreased 
lymphocyte cellularity in the lymphoid organs), and male reproductive organs (seminiferous 
tubule degeneration and reduced sperm in epididymis). Partial to complete reversibility of 
target organ toxicities was established following a 1-month non-dosing period. 
PF-06821497 was assessed in a series of exploratory genetic toxicity studies consisting of the 
bacterial mutagenicity, in vitro cytogenetic (micronucleus in human lymphoblastoid TK6 
cells), a GLP bacterial mutagenicity assay, and a GLP in vivo mouse micronucleus assays. 
CCI 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 25 
 
 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
All in vitro tests were conducted with and without exogenous metabolic activation using 
concentrations up to the limits recommended in the regulatory guidelines for the test system. 
PF-06821497 was not genotoxic in either in vitro or in vivo assays micronucleus study. 
Reproductive and developmental toxicity studies with PF-06821497 have not been 
conducted. Effects on male and female reproductive system have been assessed as part of the 
repeat-dose toxicity studies in mice and dogs. EZH2 has been shown to be abundantly 
expressed during embryonic development and EZH2 knockout caused embryonic lethality2 
therefore, PF-06821497 is expected to have the potential to cause embryo-fetal toxicity. 
PF-06821497 may have phototoxicity potential based on its molar extinction coefficients. In 
an investigative study of liver fibrosis in male mice, PF-06821497 did not increase or 
mitigate CCl4-induced liver toxicity. 
Additional information of the nonclinical safety of PF-06821497 is available in the current 
IB. 
2.2.4. Clinical Overview 
PF-06821497 is currently being evaluated in an ongoing FIP open-label, multi-center, dose 
escalation and expanded cohort Phase 1 study (C2321001) to investigate the safety, 
tolerability, PK, PD, and preliminary efficacy of PF-06821497 as a single agent and in 
combination with SOC (Carboplatin or Cisplatin with etoposide for SCLC and enzalutamide 
for mCRPC) to patients with SCLC, mCRPC, and FL. The study is comprised of 2 parts: 
Part 1 testing PF-06821497 monotherapy in 3 arms (Part 1A, 1B, 1C) and Part 2 testing 
combination therapy in 3 parts (Part 2A, 2B, 2C). For Part 2, PF-06821497 in combination 
with SOC will be evaluated in dose escalation (Part 2A) in patients with SCLC and mCRPC 
and then the combination regimen will be evaluated in a randomized dose expansion in 
patients with mCRPC (Part 2B). Alternative doses of PF-06821497 in combination with SOC 
may be evaluated in patients with mCRPC (Part 2C). 
2.2.5. 2.2.4.1 Safety Overview 
Preliminary data from the ongoing study, C2321001, indicate that PF-06821497 as 
monotherapy and in combination with SOC has been well tolerated in doses from 75 mg to 
1250 mg BID. As of 19 November 2021, PF-06821497 has been administered to 87 
participants with advanced cancer in Study C2321001. Among the 87 participants with 
advanced cancer treated in Study C2321001 who received 75, 150, 250, 375, 500, 625, 750, 
875, or 1250 mg BID of PF-06821497 either as single agent or in combination with SOC, 86 
patients reported at least 1 TEAE. Among the 87 patients treated at the same dose levels 
either as single agent or in combination with SOC, 65 patients reported at least 1 TEAE 
considered to be treatment-related. 
The most frequently reported (≥15%) all causality TEAEs across all the tumor types and dose 
groups in single agent or in combination with SOC regimens were anemia 
, nausea 
, thrombocytopenia 
, diarrhea 
, neutropenia 
, fatigue 
, decreased appetite 
, leukopenia 
, asthenia and alopecia CCI 
 
each), dysgeusia CCI 
, vomiting CCI 
, and arthralgia CCI 
. Note that 29 out of the 


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Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 26 
 
 
31 patients with SCLC treated in the study received PF-06821497 in combination with 
marrow toxic SOC backbones, which may have contributed to AEs of cytopenias. 
The most frequently reported (≥10%) PF-06821497 treatment related TEAEs across all the 
tumor types and dose groups were thrombocytopenia and nausea CCI 
 each), anemia 
CCI 
, neutropenia and diarrhea (CCI 
 each), fatigue and decreased appetite CCI 
each), dysgeusia CCI 
, leukopenia CCI 
, and alopecia and vomiting (CCI 
 each). 
Across the study the majority of the TEAEs reported were Grade 2 or lower. Of the 87 
patients, 23 (26.4%) patients reported Grade 3 TEAEs, 24 (27.6%) patients reported Grade 4 
TEAEs and 4 (4.6%) patients reported Grade 5 TEAEs. Of these TEAEs, 14 patients 
experienced Grade 3 TEAEs (16.1%) and 9 patients experienced Grade 4 TEAEs (10.3%) 
that were deemed related to study drug (PF-06821497). 
Across the study there were 52 SAEs (all-causality) reported in 33 participants. Of these 13 
SAEs reported in 7 patients were considered to be treatment related. SAEs reported were 
hepatic failure and sepsis (in one patient), thrombocytopenia and hemorrhagic disorder (in 
one patient), acute coronary syndrome (in one patient), febrile neutropenia and pancytopenia 
(in one patient), thrombocytopenia and haemorrhage (in one patient), anemia (in one patient) 
and electrocardiogram QT prolongation and presyncope (in one patient). 
Across the study there were 12 deaths reported with eleven (11) deaths considered unrelated 
to study treatment. One (1) event of hepatic failure was considered to be treatment-related. 
The event of hepatic failure was reported during the trial and was considered to be treatment- 
related. Hepatic failure with a fatal outcome occurred in a PPD 
 subject with 
CRPC enrolled in Cohort 2 (150 mg BID, single agent treatment of PF-06821497) who also 
developed significant increases in ALT, AST, bilirubin, and alkaline phosphatase associated 
with hepatic failure and sepsis. The etiology of hepatic failure is unclear. Liver 
transaminases, bilirubin, and alkaline phosphatase were initially normal at baseline, and 
began to significantly increase approximately 3 months after starting oral administration of 
PF-06821497 and remained elevated, along with subsequent development of increased PT 
and PTT, at time of death 2 months later. Shortly prior to the time of death, subject also 
developed pneumonia and sepsis. Much of the diagnostic work up including imaging and 
ERCP was inconclusive. The liver biopsy showed minimal hepatocellular injury or loss, and 
no evidence of extensive hepatic necrosis suggesting cholestasis as a cause of jaundice rather 
 
06821497 based on the mechanism of action and the toxicology observations in the non- 
clinical studies. PF-06821497 exposures in this patient after first and multiple doses in Cycle 
than hepatocellular in origin. CCI 
. Hepatic toxicity was not anticipated as a result PF- 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 27 
 
 
CCI 
CCI 
1 did not appear to differ markedly from the other patients in this 150 mg BID dose cohort. 
Considering the plausible drug-event temporal association and the provided clinical course of 
this event, including results of extensive lab tests, imaging, ERCP, liver biopsy, lacking at 
present alternative explanations, the reported liver failure is assessed as possibly related to 
PF-06821497. In conclusion, subject PPD 
 developed cholestatic jaundice during the 
terminal course while receiving PF-06821497. Since the study drug is temporally associated, 
the possibility of a cholestatic reaction cannot be entirely excluded, but the presence of 
multiple other factors makes it impossible to attribute a definite cause in this case. This 
patient, along with the 86 other patients dosed (by the IB version 6 data cut off of 19 Nov 
2021) in the FIH study received PF-06821497 BID in continuous 21-day cycles. No other 
cases of confirmed or suspected treatment-related hepatic failure have been reported for PF- 
06821497. As of the CTSUR/DSUR data cut off of 19 Dec 2022, no new safety signals have 
been identified. Further details on the clinical safety information with PF-06821497 are 
provided in the current IB. 
2.2.6. 2.2.4.2. Summary of PF-06821497 Pharmacokinetics in Humans 
PK of PF-06821497 following the first dose (C1D1), and Day 15 morning dose (C1D15) are 
being evaluated in the ongoing study (C2321001). Preliminary NCA was conducted with 
draft concentration-time data (QC’d, non-QA’d) available as of 09 Nov 2021, using nominal 
times of sample collection and Phoenix WinNonlin version 8.2. Draft data of C1D1 and 
C1D15 from patients at 6 dose levels (75 to 625 mg BID) from Part 1A and 1B, 4 dose levels 
(150 to 500 mg BID) from Part 2A SCLC, and 8 dose levels (150 to 250 mg BID) Part 2A 
CRPC of the study. PF-06821497 was administered orally on an empty stomach conditions. 
In Part 1A and Part 1B of C2321001, PF-06821497 was given as monotherapy in patients 
with SCLC, CRPC, and FL. After oral administration, PF-06821497 was CCI 
 absorbed 
following doses ranging from 75 to 625 mg BID in monotherapy, with a median Tmax ranging 
from CCI 
 after single dose and CCI 
hours after multiple dosing. After achieving 
Cmax, PF-06821497 appeared to have 
decline with a CCI  mean t1/2 ranging 
from CCI 
 hours at single dose and CCI 
 
 after multiple dosing. Both single 
dose AUCinf and steady state AUCtau exhibit 
 
 
. The interpatient 
variability across dose levels (geometric %CV) for steady-state AUCtau ranges from CCI 
 
 
In Part 2A of C2321001, PF-06821497 was given in combination with chemotherapy (either 
carboplatin or cisplatin) to patients with SCLC. After oral administration, PF-06821497 was 
CCI 
 absorbed following doses ranging from 150 to 500 mg BID in combination with 
chemotherapy, with a median Tmax ranging from CCI 
 hours after single dose and CCI  
hours after multiple dosing. After achieving Cmax, PF-06821497 appeared to have multi- 
phasic decline with a short mean t1/2 ranging from CCI 
 hours at single dose and CCI  
after multiple dosing. When PF-06821497 was given in combination with 
chemotherapy, the PK parameters were CCI 
 to the PK parameters for PF-06821497 in 
monotherapy, for each respective dose level. 
In Part 2A of C2321001, PF-06821497 was given in combination with enzalutamide 160 mg 
QD to patients with CRPC. After oral administration, PF-06821497 was CCI 
 absorbed 


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CCI 
following doses ranging from 150 to 1250 mg BID in combination with enzalutamide 160 
mg QD, with a median Tmax ranging from CCI 
 hours after single dose and CCI 
hours 
after multiple dosing. After achieving Cmax, PF-06821497 appeared to have 
c 
decline with a CCI  mean t1/2 ranging from CCI 
 hours at single dose and CCI 
 
 
after multiple dosing. 
Enzalutamide 160 mg QD is a strong inducer of CYP3A (as well as other enzymes and 
transporters) and CCI 
 PF-06821497 CCI 
 exposure at steady state after 
multiple dosing as compared to single dose. There is an approximate CCI 
 in 
PF-06821497 exposure (geometric mean steady state AUCtau) when given as monotherapy as 
compared to when given in combination with enzalutamide at the same respective dose levels 
(150 mg BID to 500 mg BID). 
Further details on the clinical PK of PF-06821497 are provided in the current IB. 
2.3. Benefit/Risk Assessment 
PF-06821497 will not provide any clinical benefit to healthy participants in this study. This 
study is designed primarily to further the understanding of human PK, metabolism, and 
elimination of PF-06821497. Participants will be expected to commit time and may 
experience some discomfort while undergoing study assessments. 
 
Study C2321005 is the first time that PF-06821497 will be administered to healthy adult 
participants. Prior to this study, PF-06821497 has been administered as monotherapy or in 
combination with other anti-cancer agents to advanced cancer patients at doses ranging from 
75 mg to 1250 mg BID continuously. Based on the results of the nonclinical toxicity studies 
(Section 2.2.3), the potential risk of PF-06821497 administration to healthy participants can 
be managed adequately, and be mitigated with preventive measures in place that includes 
routine monitoring of adverse events and changes in clinical laboratory test parameters for 
clinical management, including study drug discontinuation as appropriate to ensure the safety 
of the study participant. Based on the available data from Study C2321001, the clinical safety 
profile favors further development of PF-06821497. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06821497 may be found in the IB, which is the SRSD for this study. 


PF-06821497 
Protocol C2321005 
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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-06821497 
Potential of PF-06821497 to cause embryo-fetal 
and reproductive organ toxicity 
Reproductive and developmental toxicity studies 
with PF-06821497 have not been conducted. 
Effects on male and female reproductive system 
have been assessed as part of the repeat-dose 
toxicity studies in mice and dogs. Male 
reproductive organ toxicities were observed in 
repeat dose studies, namely seminiferous tubule 
degeneration and reduced sperm in epididymis. 
EZH2 has been shown to be abundantly expressed 
during embryonic development and EZH2 
knockout caused embryonic lethality, therefore, 
PF-06821497 is expected to have the potential to 
cause embryo-fetal toxicity. 
Eligibility criteria and contraceptive lifestyle 
requirements for this protocol have been crafted to 
mitigate these identified potential risks (see 
Section 5). 
Potential phototoxicity effects of PF-06821497 
PF-06821497 absorbs in the UVA-UVB/visible 
range from 290 to 700 nm with a calculated MEC 
of >1000 L/(mol cm) and, as a result, could have 
photosafety risks. 
The lifestyle guidelines for this protocol include 
participant instructions to limit exposure to 
sunlight/high intensity ultraviolet light and use 
sunscreen products with high sun protection 
factor. 
Potential risks associated with PF-06821497 
include the following: GI toxicities (nausea, 
diarrhea), hematological (thrombocytopenia, 
nausea, anemia, neutropenia,), hepatotoxicity, and 
fatigue, decreased appetite, dysgeusia 
The potential risks are based on emerging clinical 
data from the ongoing study C2321001 following 
continuous administration of PF-06821497 to 
advanced cancer patients at doses ranging from 75 
to 1250 mg BID. 
The present study will test single doses of 
PF-06821497 and implement a washout period 
between doses across treatment periods to 
minimize exposure of PF-06821497 in the healthy 
participants. 
AEs and clinical laboratory results will be 
monitored on an ongoing basis. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Procedures 
Blood draws for assessment of PK, safety labs, 
and retained samples. 
A blood draw may cause participant discomfort 
including faintness, inflammation of the vein, pain, 
bruising, or bleeding at the site of puncture. There 
is also a slight chance of infection. 
Blood draws will be performed by experienced 
and trained site staff within the confines of the 
PCRU. 
Other 
The COVID-19 pandemic may pose risks to study 
participation. 
Participants may have increased risk of SARS- 
CoV-2 infection by undergoing a study procedure 
at a study facility. 
Inclusion of COVID-19 specific assessments 
according to the SoA. 


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3. OBJECTIVES AND ENDPOINTS 
Objectives 
Primary: 
 
 
 
 
Primary: 
 
 
Endpoints 
•  To estimate the bioavailability of a single C  mg dose 
of PF-06821497 CC tablet formulation (Formulation 
2) relative to a single C  mg dose of PF-06821497 
CCI tablet formulation (Formulation 1) under fasted 
conditions in adult healthy participants 
Secondary: 
• 
 To estimate the bioavailability of a single C  mg 
dose of PF-06821497 CC tablet (larger API particle 
size) formulation (Formulation 3) relative to a single 
C  mg dose of PF-06821497 CC tablet 
(Formulation 2) and a single C mg dose of the PF- 
06821497 CCI tablet formulation (Formulation 1) 
under fasted conditions in adult healthy participants 
 
• 
To estimate the effect of a high-fat, high-calorie meal 
on the bioavailability of a single CCI mg dose of the 
PF-06821497 CC tablet formulation (Formulation 2) 
relative to fasted conditions in adult healthy 
participants 
 
• 
To estimate the effect of a low-fat, low-calorie meal 
on the bioavailability of a single CCI mg dose of the 
PF-06821497 CC tablet formulation (Formulation 2) 
relative to fasted conditions in adult healthy 
participants 
• 
To evaluate the safety and tolerability of PF- 
06821497 when administered as a tablet formulation 
to healthy participants 
CCI 
 
• Plasma AUCinf and Cmax for PF-06821497. (AUClast will 
be used as the primary estimate if AUCinf cannot be 
reliably estimated). 
 
 
Secondary: 
• Plasma AUCinf and Cmax for PF-06821497 for CC tablet 
(larger API particle size) (Formulation 3) relative to CC 
(Formulation 2) and CCI tablet (Formulation 1) 
formulations. (AUClast will be used as the primary 
estimate if AUCinf cannot be reliably estimated). 
 
 
 
• 
Plasma AUCinf and Cmax for PF-06821497 under fed 
(high-fat, high-calorie meal) conditions relative to 
fasting conditions. (AUClast will be used as the primary 
estimate if AUCinf cannot be reliably estimated). 
 
 
• Plasma AUCinf and Cmax for PF-06821497 under fed 
(low-fat, low-calorie meal) conditions relative to fasting 
conditions. (AUClast will be used as the primary estimate 
if AUCinf cannot be reliably estimated). 
 
• 
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, physical examinations, and 
12-lead ECGs. 
 
 
 
 
4. STUDY DESIGN 
4.1. Overall Design 
This is a Phase 1, randomized, open-label, 3-period, crossover, single-dose 2-part study in 
healthyparticipants to investigate the effect of tablet formulation and food on the 
bioavailability of PF-06821497. 


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In each part of the study, 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-06821497 administration: 
Part 1 (rBA): 
• Treatment A – Single CCI mg dose CCI 
 tablet formulation 
(Formulation 1), under fasting conditions (following an overnight fast of at least 10 
hours) 
• Treatment B – Single CCI mg dose CCI 
 tablet formulation 
(Formulation 2), under fasting conditions (following an overnight fast of at least 10 
hours) 
• Treatment C – Single CCI mg dose CCI 
 tablet formulation (larger 
API particle size) (Formulation 3), under fasting conditions (following an overnight 
fast of at least 10 hours) 
Part 2 (Food Effect): 
• Treatment D – Single CCI  mg dose CCI 
 tablet formulation 
(Formulation 2), under fasting conditions (following an overnight fast of at least 10 
hours) 
• Treatment E – Single CCI  mg dose CCI 
 tablet formulation 
(Formulation 2), given with a low-fat/low-calorie meal 
• Treatment F – Single CCI  mg dose CCI 
 tablet formulation 
(Formulation 2), given with a high-fat/high-calorie meal 
Approximately 18 participants will be enrolled to the study intervention. If there are 
participants who withdraw or discontinue treatment and are considered to be non-evaluable 
with respect to the primary PK objective(s), additional participants can be enrolled at the 
discretion of the investigator upon consulation with the sponsor. 
In each part of the study, each enrolled participant will receive 1 of the 3 treatments in each 
period according to treatment schedule shown in Table 1Table 1. A minimum of C day 
washout period between successive single doses of PF-06821497 is included to minimize any 
residual PF-06821497 concentrations prior to start of the next treatment period. For 
Treatments A, B, and C, following an overnight fast of at least 10 hours, and after the 
collection of the pre-dose PF-06821497 PK sample on Day 1 of each period, participants will 
be administered a CCI mg dose of PF-06821497. For Treatment D, following an overnight 
fast of at least 10 hours, and after the collection of the pre-dose PF-06821497 PK sample on 
Day 1, participants will be administered a CCI  mg dose of PF-06821497. For Treatment E, 
after an overnight fast of at least 10 hours and after the collection of pre-dose PF-06821497 
PK sample on Day 1, participants will receive a low-fat, low-calorie breakfast 30 minutes 
prior to dosing. For Treatment F, after an overnight fast of at least 10 hours and after the 


PF-06821497 
Protocol C2321005 
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C 
C 
C 
Treatment A – CCI  formulation (Formulation 1) 
Treatment B – CC  formulation (Formulation 2) 
Treatment C – CC  formulation (Formulation 3) 
C 
C 
C 
C 
fasted; 
fasted; 
; larger API particle size) fasted ; 
 
 
 
 
C 
C 
C 
C
E 
Washout: at 
least C days 
between PF- 
06821497 doses 
Period 2 
Washout: at 
least C days 
between PF- 
06821497 
doses 
Period 1 
Sequence 
D 
1 (6 
Participants) 
F 
Period 3 
collection of pre-dose PF-06821497 PK sample on Day 1, participants will receive a high-fat, 
high-calorie breakfast 30 minutes prior to dosing. Participants are strongly encouraged to 
consume the breakfast in its entirety. PF-06821497 will be administered as intact tablets with 
approximately 240 mL of ambient temperature water. Tablets will be swallowed and not 
chewed. In each period, participants will undergo blood sampling for determination of PF- 
06821497 PK at timepoints shown in SoA. Participants who withdraw may be replaced at the 
joint discretion of the investigator and the sponsor. 
 
Table 1. 
Treatment Schedule 
Part 1 (rBA): 
 
Sequence 
Period 1 
Washout: at 
least C days 
Period 2 
Washout: at 
least C days 
Period 3 
1 (6 
Participants) 
A 
between 
PF-06821497 
doses 
B 
between 
PF-06821497 
doses 
C 
2 (6 
B 
A 
C 
Participants) 
 
 
 
 
Part 2 (Food effect): 
 
Treatment D – CC  formulation (Formulation 2) 
fasted; 
Treatment E – CC 
Treatment F – CC 
formulation (Formulation 2) 
fed: Low-fat meal; 
formulation (Formulation 2) 
fed: High-fat meal 
 
In each part, participants will be on the study up to 10 weeks, including the screening and 
follow-up periods. Participants will be screened within 28 days prior to the first dose of the 
investigational product in Period 1. Participants will be admitted to the PCRU Day -1 and 
will be required to remain the PCRU for a minimum of C days until completion of 48 hours 
PK sampling on Day 3. The investigator could choose to confine participants in the PCRU 
beyond Day C and discharge them following completion of Day C assessments in Period 3 in 
each part of the study. Alternatively, participants will be eligible for discharge from the 
PCRU at C  hours post dose in each period following review of the discharge safety 
assessmenCtIs, provided that the participants are able to return to the PCRU on Day -1 for each 
of the remaining study periods. 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 


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CCI 
asked to remain in the PCRU until such abnormalities are deemed not clinically significant, 
or it is safe for outpatient follow-up. A follow-up contact will be completed at least 28 
calendar days and up to 35 calendar days after the last administration of PF-06821497 to 
capture any potential AEs and to confirm appropriate contraception usage. Contact with the 
participant may be done via a phone call. 
4.2. Scientific Rationale for Study Design 
The purpose of the study is to investigate the relative bioavailability of tablet formulations of 
PF-06821497 and to characterize the effect of food on a PF-06821497 CCI  tablet 
formulation. The data generated from this study will be used to support the pivotal study 
formulation, to inform dose administration instructions for PF-06821497 with regard to 
dosing with or without food, and to enable the establishment of the API particle size 
specifications for eventual commercialization. 
Relative Bioavailability Assessment: In the ongoing clinical Phase 1 study (C2321001) for 
evaluating the safety and efficacy of PF-06821497, an CCI  tablet formulation of PF- 
06821497 has been utilized. The current CCI  tablet formulation (Formulation 1) has a CCI 
drug loading with respect to the required pivotal dose and is considered undesirable for 
further clinical development. A new formulation of PF-06821497 manufactured using a CCI  
process (Formulation 2) is planned to be used in the pivotal Phase 2/3 trials. Therefore, the 
primary objective of the rBA study is to compare the relative bioavailability of the CCI  tablet 
formulation (Formulation 2) to that of CCI  tablet formulation (Formulation 1) and confirm 
that they are comparable. 
The relative bioavailability of the CCI tablet formulation containing an API with larger 
particle size (Formulation 3) CCI 
 relative to the WG tablet formulation 
(Formulation 2) and CCI 
tablet formulation (Formulation 1), containing API with a standard 
particle size CCI 
 will be evaluated as a secondary objective of this study. This 
comparison will enable the establishment of the API particle size specification for the 
commercial API manufacturing process. 
Food effect assessment: Based on the solubility and permeability data collected in the pre- 
clinical phase, PF-06821497 is considered to be a BCS CCI 
 drug. For this class of 
compound, food is most likely to show a CCI 
 food effect, due to CCI 
 
in fed state. Therefore, PK of the 
tablet formulation (Formulation 2) following 
administration of a standard low-fat/low-calorie or high-fat/high-calorie meal will be 
evaluated as secondary objectives of this study to investigate the effect of food on the 
bioavailability of PF-06821497. The data from food effect assessment will inform dose 
administration instructions for PF-06821497 with regard to dosing with or without food and 
can potentially make future trials easier to conduct given the BID regimen. Given the BID 
regimen of PF-06821497, evaluating both low and high-fat meal will provide data to guide 
upcoming studies in terms of flexibility or restriction in administration of IP with different 
types of meals during the day that may have varying degree of fat content (eg, Breakfast 
versus dinner). 


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CCI 
For the food effect assessment of the study, single doses of CCI  mg will be administered 
with sufficient washout between the doses. The effect of food on PF-06821497 exposures 
based on its properties (BCS CCI   compound, CCI   is expected to be less than CCI   
2. Therefore, there is a potential for this study to generate    exposures that may be 
CCI   than what was observed in the FIP study. However, the single dose administration at 
mg is not expected to have significant safety concerns even if there is a CCI 
 
in exposure, as PF-06821497 at CCI  mg/day CCI 
 has been tolerated following 
repeated administration with enzalutamide. Further, safety data from at least 3 participants 
from Part 2 Period 2 (where subjects will receive low-fat meal) will be reviewed before 
proceeding to Period 3 (high-fat meal condition) to provide an additional safeguard. In 
addition to the usual participant selection and safety monitoring measures implemented in 
such healthy volunteer studies, this study restricts the population to participants without a 
history of liver disease and with normal baseline liver tests, in accordance with FDA 
guidance provided during the course of the FIH study, in response to one patient developing 
fatal heptoxicity that has been classified as an important potential but not identified risk for 
PF-06821497. In addition, post treatment ECG monitoring has been added as additional 
measure, as one case of G3 QTcF prolongation, potentially related to PF-06821497 has been 
observed while QTcF prolongation has not been identified as a risk for PF-06821497. 
The study is being designed as a crossover study to minimize the potential for intrinsic 
factors that may impact inter-individual variability in the PK of PF-06821497 from 
confounding the comparisons of PK parameters across the treatment periods and better 
estimate the true differences between the study treatments. Between each administered single 
dose, a C-day washout is proposed to minimize any residual PF-06821497 concentrations 
prior to start of next period, which is sufficient based on the observed half-life of CCI 
 
hours. 
4.2.1. Assessment of Safety Data Before Administration of the High-fat Meal in Part 2 
of the Study 
The high-fat meal is expected to potentially CCI 
 exposures by CCI  approximately 
CCI 
 .2 In Part 2 of the study, before the Period 3 doses are administered to participants that 
have eaten a high-fat meal, the safety data for Period 2, including at least 3 participants 
administered a low-fat meal in Period 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 Period 2 were well-tolerated. 
4.2.2. Choice of Contraception/Barrier Requirements 
Studies to evaluate the developmental toxicity of PF-06821497 have not been conducted. 
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. 
CCI 


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CCI 
CCI 
CCI 
4.3. Justification for Dose 
Part 1: A single CCI mg dose of PF-06821497 is planned for each period in Part 1 (rBA) of 
this study. A tablet strength of CCI mg is being planned for the pivotal study and hence the 
rBA assessment in Part 1 of this study is conducted at CCI mg dose which is the single unit 
CCI 
 dose strength for the tablets being evaluated. 
Part 2: A single CCI  mg dose of PF-06821497 is planned for each period in Part 2 (food 
effect) of this study. Based on preliminary data from the ongoing Phase 1 study (C2321001) 
in advanced cancer patients, PF-06821497 has been well tolerated as monotherapy and in 
combination with SOC in doses from 75 mg to 1250 mg BID given continuously in 21-day 
cycles. The highest doses tested in monotherapy and in combination with enzalutamide are 
625 mg BID and 1250 mg BID, respectively. No MTD was determined for both the 
monotherapy and combination arms. Given that PF-06821497 is intended for use in oncology 
patients, the highest dose or exposure tested in the nonclinical studies does not limit the dose- 
escalation or highest dose investigated in a clinical trial in cancer patients, which is primarily 
guided safety findings. As such, the FIP study had evaluated doses beyond the HNSTD dose 
tested in preclinical toxicology studies, andno major safety concerns have been identified at 
any of the dose levels. Safety data from ongoing C2321001 study indicate that single doses 
of PF-06821497 up to CCI  mg BID CCI 
 were not associated with any major acute 
safety concerns. 
The effect of food on PF-06821497 exposures based on its properties (BCS CCI 
 
compound, CCI 
 is expected to be 
  .2 Therefore, there is a potential 
for this study to generate peak exposures that may be CCI   than what was observed in the 
FIP study. However, the single dose administration at 
  mg is not expected to have 
significant safety concerns even if there is a CCI 
 in exposure, as PF-06821497 at 
CCI  mg/day CCI  
 has been tolerated following repeated administration with 
enzalutamide. Preliminary analyses of data from C2321001 indicate that there is 
. In addition, based on 
preliminary PK data from C2321001 at CCI  mg BID dose, the day 1 geometric mean and 
range of observed unbound Cmax of PF-06821497 is CCI  ng/mL, and CCI 
 ng/mL, 
respectively. If there is a CCI 
 in peak exposures by food, it would likely result in 
an unbound Cmax of approximately CCI ng/mL, which would still be CCI 
 the 
highest observed Cmax at CCI  mg dose in study C2321001. Considering the healthier 
population in this study and PCRU confinement where more intense safety monitoring will 
be conducted, potential risks to study participants can be managed adequately and be 
mitigated with preventive measures in place that include routine monitoring of adverse 
events and changes in clinical laboratory test parameters for clinical management, including 
study drug discontinuation as appropriate to ensure the safety of the study participants. 
Further, safety data from at least 3 participants from Part 2 Period 2 (where subjects will 
receive low-fat meal) will be reviewed before proceeding to Period 3 (high-fat meal 
condition), where maximum food effect is expected, to provide an additional safeguard. 


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Protocol C2321005 
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Page 37 
 
 
Based on safety data of PF-06821497 as described above, a single CCI mg dose in Part 1 and 
single CCI  mg dose in Part 2 with a washout for 3 periods in this study is expected to pose 
little risk to healthy adult participants and the potential risks can be managed effectively. 
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. 
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 years of age, inclusive, at screening. 
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
2. Male and female participants 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 kg/m2; and a total body weight >50 kg (110 lb). 
4. Evidence of a personally signed and dated ICD indicating that the participant has 
been informed of all pertinent aspects of the study. 


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5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing) or prior allergic reaction to any component of 
PF-06821497. 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy, prior bariatric surgery, ileal resection, inflammatory 
gastrointestinal disease, chronic diarrhea, known diverticular disease). 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAB or HCVAb. Hepatitis B vaccination is allowed. 
• Chronic liver diseases including alcoholic liver disease, viral hepatitis, 
primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune 
hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, 
human immunodeficiency virus, or other chronic liver disease. 
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 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). 
• Current use or anticipated need for food or drugs that are known strong 
inducers or inhibitors of CYP3A4/5, including their administration within 10 
days or 5 half-lives of the strong inducer or inhibitor of CYP3A4/5, whichever 
is longer prior to first dose of investigational product. Refer to Section 6.9. 
• Time dependent inhibitors of CYP3A4/5 for atleast 21 days prior to the 
treatment 


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Prior/Concurrent Clinical Study Experience: 
4. 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: 
5. A positive urine drug test. 
6. 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. 
7. 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 
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. 
8. 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 > ULN; 
• Total bilirubin level >1 × ULN; 
• PT, INR and aPTT outside of normal limits at baseline 
• eGFR <60 mL/min/1.73 m2 based on the CKD-EPI equation; 
• Absolute neutrophil count <0.8 x LLN. 
Other Exclusion Criteria: 
9. 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, 


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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). 
10. Use of tobacco or nicotine containing products within 3 months of screening or a 
positive urine cotinine test (ie, active smokers and those who currently use nicotine 
containing products are excluded from participation in this study). 
11. Pregnant female participants; breastfeeding female participants; fertile male 
participants and female participants of childbearing potential who are unwilling or 
unable to use 2 highly effective methods of contraception as outlined in this protocol 
for the duration of the study and for at least 3 months after the last dose of 
investigational product. 
12. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
13. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
14. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
15. 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 2 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. 


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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 on Day 1 of each Period. 
• Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack. 
• There will be no predose water restriction for the fed treatment periods in Part 2 of 
the study (Treatment E and Treatment F) on Day 1. For Treatment E, following an 
overnight fast of at least 10 hours, participants will start the recommended low-fat 
(approximately 25% of total caloric content of the meal), low-calorie (approximately 
400 to 500 calories) breakfast 30 minutes prior to administration of PF-06821497. 
Breakfast will be consumed within an approximate 20 minute period with 
PF-06821497 administered approximately 10 minutes after completion of the meal. 
Participants are strongly encouraged to consume the low-fat/low-calorie breakfast in 
its entirety. 
• For Treatment F, following an overnight fast of at least 10 hours, participants will 
start the recommended high-fat (approximately 50% of total caloric content of the 
meal), high-calorie (approximately 800 to 1000 calories) breakfast 30 minutes prior to 
administration of PF-06821497. Breakfast will be consumed within an approximate 
20 minute period with PF-06821497 administered approximately 10 minutes after 
completion of the meal. Participants are strongly encouraged to consume the high- 
fat/high-calorie breakfast in its entirety. 
• Lunch will be provided approximately 4 hours after PF-06821497 dosing. 
• Dinner will be provided approximately 9 to 10 hours after PF-06821497 dosing. 
• An evening snack may be permitted. 
• Participants will refrain from consuming red wine from 7 days prior to the first dose 
of study intervention until collection of the final PK blood sample. 
• While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein with the exception for 
dosing days where a high fat/high calorie or low fat/low calorie meal will be given 
prior to study intervention. The daily caloric intake per participant should not exceed 
approximately 3200 kcal. 


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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 or as specified above for red 
wine 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. 
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 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 high intensity UVB light 
sources such as tanning beds, tanning booths and sunlamps. Participants should be 
encouraged to apply sunscreen/sunblock daily. 
• Participants will be confined to the procedure room for the first C hours after dosing 
on Day 1 of Period 2 and 3 in Part 2 of the study, except to use the bathroom. After 
this, participants may be ambulatory but should not engage in strenuous activities. 
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 at the joint discretion of the investigator and medical monitor. 
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-06821497 tablets. 


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CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
6.1. Study Intervention(s) Administered 
For this study, the study interventions are the tablet formulations of PF-06821497 
administered as single dose (CCI mg in Part 1, CCI  mg in Part 2) under fasted or fed 
conditions; Treatment A [CCI 
 mg of 
 
tablet formulation (Formulation 1), under 
fasting conditions], Treatment B [ 
mg of CCI  tablet formulation (Formulation 2), 
under fasting conditions], Treatment C [  
 
of CCI  tablet formulation (larger API 
particle size) (Formulation 3), under fasting conditions], Treatment D [ 
mg of CCI 
tablet formulation (Formulation 2), under fasting conditions], Treatment E 
 
mg of 
tablet formulation (Formulation 2), given with a low-fat/low-calorie meal], Treatment F 
[ 
mg of 
tablet formulation (Formulation 2), given with a high-fat/high-calorie 
meal]. The PF-06821497 tablet formulations will be supplied by Pfizer. 
PF-06821497 CCI mg strength tablets for the 3 tablet formulations will be supplied to the 
PCRU in bulk along with individual dosing containers for unit dosing. A brief description of 
the PF-06821497 tablet formulations supplied in this study is provided in Table 2. 
 
Table 2. 
Summary of PF-06821497 Formulations 
 
Description 
Material ID (DMID)/ Lot 
Number 
Included in 
Treatment(s) 
Route of 
Administration 
PF-06821497 CCI 
DP-001550/22-DP-00973 
Treatment A 
Oral 
tablets (Formulation 1) 
PF-06821497 CCI 
DP-005872/23-DP-01411 
Treatment B, D, E and 
F 
Oral 
tablets (Formulation 2) 
PF-06821497 CCI 
DP-005872/23-DP-01412 
Treatment C 
Oral 
tablets (larger API particle 
size) (Formulation 3) 
 
6.1.1. Administration 
All Treatment 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 the study intervention whole, and will not manipulate or chew the study intervention 
prior to swallowing. 
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. 
Treatment A 
 tablets (Formulation 1) , fasting conditions]: 
Following an overnight fast of at least 10 hours and after the collection of the predose PK 
sample on Day 1, participants will take a single 
mg dose CCI 
mg tablets) of the 


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CCI  tablet formulation (Formulation 1) of PF-06821497 at approximately 0800 hours (plus 
or minus 2 hours). 
Treatment B [CCI 
  tablets (Formulation 2), fasting conditions]: 
Following an overnight fast of at least 10 hours and after the collection of the predose PK 
sample on Day 1, participants will take a single CCI mg dose (CCI 
 mg tablets) of the CCI  
tablet formulation (Formulation 2) of PF-06821497 at approximately 0800 hours (plus or 
minus 2 hours). 
Treatment C CCI 
  tablets (larger API particle size) (Formulation 3), fasting 
conditions]: 
Following an overnight fast of at least 10 hours and after the collection of the predose PK 
sample on Day 1, participants will take a single CCI mg dose (CCI 
 mg tablets) of the CCI  
tablet formulation (larger API particle size) (Formulation 3) of PF-06821497 at 
approximately 0800 hours (plus or minus 2 hours). 
Treatment D [CCI 
  tablets (Formulation 2) , fasting conditions]: 
Following an overnight fast of at least 10 hours and after the collection of the predose PK 
sample on Day 1, participants will take a single CCI  mg dose CCI 
 mg tablets) of the 
CCI  tablet formulation (Formulation 2) of PF-06821497 at approximately 0800 hours (plus 
or minus 2 hours). 
Treatment E [CCI 
  tablets (Formulation 2), fed conditions: low-fat meal]: 
Following an overnight fast of at least 10 hours, participants will start the recommended low- 
fat (approximately 25% of total caloric content of the meal), low-calorie (approximately 400 
to 500 calories) breakfast 30 minutes prior to administration of the CCI  tablet formulation 
(Formulation 2) of PF-06821497. Breakfast will be consumed within an approximate 20 
minute period with PF-06821497 administered approximately 10 minutes after completion of 
the meal. Participants are strongly encouraged to consume the low-fat/low-calorie breakfast 
in its entirety. Percentage of the meal consumed will be documented in the CRF. PF- 
06821497 should be administered at approximately 0800 hours (plus or minus 2 hours). 
Treatment F [CCI 
  tablets (Formulation 2), fed conditions: high-fat meal]: 
Following an overnight fast of at least 10 hours, participants will start the recommended 
high-fat (approximately 50% of total caloric content of the meal), high-calorie 
(approximately 800 to 1000 calories) breakfast 30 minutes prior to administration of the CCI  
tablet formulation (Formulation 2) of PF-06821497. Breakfast will be consumed within an 
approximate 20 minute period with PF-06821497 administered approximately 10 minutes 
after completion of the meal. Participants are strongly encouraged to consume the high- 
fat/high-calorie breakfast in its entirety. Percentage of the meal consumed will be 


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documented in the CRF. PF-06821497 should be administered at approximately 0800 hours 
(plus or minus 2 hours). 
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 interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the PCRU local/site 
procedures. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
6. Study interventions should be stored in their original containers. 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s local/site procedures. All destruction must 
be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer. 


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Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery. 
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, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities. 
PF-06821497 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. 
6.3. Assignment to Study Intervention 
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled. 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number. 
6.4. Blinding 
This is an open-label study. 
6.5. 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. 
6.6. Dose Modification 
No dose modification is anticipated. 


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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-06821497 greater than CCI mg in Part 1 and CCI  mg in Part 2 
within a 24-hour time period ±6 hours will be considered an overdose. 
There is no specific treatment for a PF-06821497 overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the study medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
5. Obtain a blood sample for PK analysis within C days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
6.9. Prior and Concomitant Therapy 
Use of prescription or 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. 
As PF-06821497 is primarily metabolized by CYP3A4/5, as determined in in vitro studies, 
concomitant use of any medications or substances that are strong inducers or inhibitors of 
CYP3A4/5 are prohibited within 10 days or 5 half-lives, whichever is longer, prior to dosing 
of study intervention and within 2 days after the last dose of PF-06821497. 
Strong CYP3A4/5 inhibitors may include grapefruit juice or grapefruit/grapefruit related 
citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, 
and conivaptan. 
Strong CYP3A4/5 inducers may include phenobarbital, rifampin, phenytoin, carbamazepine, 
rifabutin, rifapentin, clevidipine, and St. John’s Wort. 


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Time dependent inhibitors of CYP3A4/5 are prohibited for at least 21 days prior to the 
treatment. Time dependent inhibitors of CYP3A4/5 may include azamulin, troleandomycin, 
verapamil, boceprevir, nelfinavir, and telaprevir. 
It is preferred that moderate CYP3A4/5 inhibitors and/or inducers be replaced prior to the 
first dose of study treatment and during study conduct. Moderate CYP3A4/5 inhibitors may 
include erythromycin, ciprofloxacin, verapamil, diltiazem, atazanavir, fluconazole, darunavir, 
delavirdine, amprenavir, fosamprenavir, aprepitant, imatinib, tofisopam, and cimetidine. 
Moderate CYP3A4/5 inducers may include bosentan, efavirenz, etravirine, modafinil, and 
nafcillin. If the replacement is not possible, then caution should be exercised with 
coadministration of PF-06821497 with moderate CYP3A4/5 inhibitors and/or inducers. 
Additionally, concomitant use of PF-06821497 and a substrate of the CCI 
 renal 
transporter may increase the exposure of the CCI 
substrate. Therefore, caution is 
warranted if coadministration of PF-06821497 with CCI 
 substrates. 
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4). 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
6.9.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with PF-06821497; 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 
the study intervention. 


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7.1.1. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Temporary discontinuation of 
the study intervention may be medically appropriate until the participant has recovered from 
COVID-19. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study 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 


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with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law. 
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to 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. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
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 
230 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, 
the respiratory and cardiovascular systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3. 
8.3.2. Vital Signs 
8.3.2.1. Blood Pressure and Pulse Rate 
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. 
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data. 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 


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8.3.2.2. Respiratory Rate 
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. When BP is to be taken at the same time, respiration measurement will be done during 
the 5 minutes of rest and before BP measurement. 
8.3.2.3. Temperature 
Temperature will be measured orally. No eating or drinking is allowed for 15 minutes prior 
to the measurement. 
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. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements (from within the current Treatment Period). 
Additional ECG monitoring will occur if a) a postdose QTcF interval is increased by ≥60 ms 
from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any scheduled 
ECG. If either of these conditions occurs, then 2 additional ECGs will be collected 
approximately 2 to 4 minutes apart to confirm the original measurement. If the QTcF values 
from these repeated ECGs remain above the threshold value, then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine -read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 8. 


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8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 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. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments 
COVID-19 specific assessments will be performed as per PCRU procedures or by the PI. 
8.3.6. Pregnancy Testing 
A serum pregnancy test is required at screening. Following screening, pregnancy tests may 
be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. Pregnancy tests 
will be performed in WOCBP at the times listed in the SoA. Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the PF-06821497. Pregnancy tests will also be done whenever 1 menstrual cycle is missed 
during the active treatment period (or when potential pregnancy is otherwise suspected) and 
at the end of the study. Pregnancy tests may also be repeated if requested by IRBs/ECs or if 
required by local regulations. If a urine test cannot be confirmed as negative (eg, an 


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ambiguous result), a serum pregnancy test is required. In such cases, the participant must be 
excluded if the serum pregnancy result is positive. 
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. 
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. 


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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 theyconsider 
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. 
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). 


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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. 
8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 


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• 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 or participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 72 hours 
after 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 
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 


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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, inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB. 
8.4.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form regardless of whether 


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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 
Section 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form. 
8.4.8.1. Lack of Efficacy 
This section is not applicable because efficacy is not expected in the study population. 
8.4.9. Medical Device Deficiencies 
Not applicable. 
8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
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 


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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 
Blood samples of approximately 2 mL, to provide approximately 0.5 mL plasma, will be 
collected for measurement of plasma concentrations of PF-06821497 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 C  hours after dose administration that are obtained within 
10% of the nominal time relaCtiIve 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 C  hours after dose 
administration that are obtained ≤1 hour away from the nominal timeCIrelative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. 
Samples will be used to evaluate the PK of PF-06821497. Samples collected for analyses of 
PF-06821497 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. 
 


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Samples collected for measurement of plasma concentrations of PF-06821497 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. 
 
 
 
 
 
 
 
 
 
 


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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 
There are no statistical hypotheses for this study. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
PK Concentration 
Population 
The PK concentration population is defined as all participants 
randomized and treated who have at least 1 PF-06821497 
concentration in at least 1 treatment period. 
PK Parameter Population 
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of the 
PF-06821497 PK parameters of primary interest in at least 
1 treatment period. 
Safety analysis set 
All participants randomly 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. 


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9.3. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
9.3.1. Pharmacokinetic Analysis 
9.3.1.1. Derivation of Pharmacokinetic Parameters 
Plasma PK parameters of PF-06821497 will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods as outlined in Table 3. 
The PF-06821497 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 using actual and nominal times, 
respectively. 
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters. 
 
Table 3.  Plasma PF-06821497 PK Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
AUCinf* 
area under the concentration-time curve from time 
0 to infinity 
AUClast + (Clast*/kel), 
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear 
regression analysis and kel is the 
terminal phase rate constant calculated 
by a linear regression of the loglinear 
concentration-time curve 
AUClast 
area under the concentration-time curve from 0 to 
time of last measurable concentration 
Linear/Log trapezoidal method. 
Cmax 
maximum observed concentration 
Observed directly from data 
CCI 
 
 
 


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9.3.2. Statistical Methods for PK Data 
Part 1: 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects 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% confidence intervals will be obtained from the model. 
The adjusted mean differences and 90% confidence intervals for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% confidence intervals for the ratios. Treatment A (CCI  formulation (Formulation 1) 
CCI mg (CCI 
) fasted) will be the Reference treatment and Treatment B (CCI  
formulation (Formulation 2) CCI mg CCI 
 mg) fasted) will be the Test treatment. 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects model with sequence and treatment as fixed effects and participant within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment A (CCI  formulation (Formulation 1) CCI mg 
CCI 
 mg) fasted) will be the Reference treatment and Treatment C (CCI  formulation 
(Formulation 3) CCI mg CCI 
  mg; larger API particle size) fasted) will be the Test 
treatment. For the second comparison, Treatment B (CCI  formulation (Formulation 2) CCI 
mg CCI  
 mg) fasted) will be the Reference treatment and Treatment C (CCI  formulation 
(Formulation 3) CCI mg CCI 
 mg; larger API particle size) fasted) will be the Test 
treatment. 
Part 2: 
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effects model with treatment as a fixed effect and participant as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
confidence intervals will be obtained from the model. The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios. Treatment D (CCI  formulation (Formulation 2) CCI  mg (CCI 
 mg) fasted) will be 
the Reference treatment and Treatments E and F (CCI  formulation (Formulation 2) CCI  mg 
CCI 
 mg) fed: low-fat meal and CCI  formulation (Formulation 2) CCI  mg 
mg) 
fed: high-fat meal) will be the Test treatments. 
9.3.3. Other Safety Analyses 
All safety analyses will be performed on the safety population. 
AEs, ECGs, BP, PR, RR, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants. Any clinical laboratory, 
ECG, BP, RR and PR abnormalities of potential clinical concern will be described. Safety 


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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. 
CCI 
 
 
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 
Part 1: Sample size of 12 participants will provide adequate precision of 90% CIs. The width 
of 90% confidence interval for different estimated effects is presented in Table 4. 
 
Table 4. 
Expected Widths of the 90% CIs for Different Possible Estimated 
Effects and Parameters of Interest for Part 1 Study 
 
Parameter 
Estimated Effect 
(100*Test/Reference) 
90%CI 
CI Width 
AUC 
85% 
74.74% to 96.67% 
21.94% 
90% 
79.13% to 102.36% 
23.23% 
95% 
83.53% to 108.05% 
24.52% 
100% 
87.93% to 113.73% 
25.81% 
105% 
92.32% to 119.42% 
27.10% 
110% 
96.72% to 125.11% 
28.39% 
115% 
101.11% to 130.79% 
29.68% 
Cmax 
85% 
68.01% to 106.24% 
38.23% 
90% 
72.01% to 112.49% 
40.48% 
95% 
76.01% to 118.74% 
42.73% 
100% 
80.01% to 124.99% 
44.98% 
105% 
84.01% to 131.24% 
47.23% 
110% 
88.01% to 137.49% 
49.48% 
115% 
92.01% to 143.74% 
51.73% 


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These calculations are based on the estimates of within-subject standard deviations of CCI  
for loge AUCinf and loge Cmax, respectively, as obtained from study C2321001. 
Part 2: Sample size of 6 participants will provide adequate precision of 90% CIs. The 
following table presents the width of 90% confidence interval for different estimated effects: 
 
Table 5. 
Expected Widths of the 90% CIs for Different Possible Estimated 
Effects and Parameters of Interest for Part 2 Study 
 
Parameter 
Estimated Effect 
(100*Test/Reference) 
90%CI 
CI Width 
AUC 
CCI 
CCI 
Cmax 
These calculations are based on the estimates of within-subject standard deviations of CCI  
for loge AUCinf and loge Cmax,, respectively, as obtained from study C2321001. 
Participants who withdraw from the study may be replaced at the discretion of the 
investigator upon consultation with the sponsor. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations. 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of. 
10.1.2. Financial Disclosure 
Not applicable. 
10.1.3. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center. 
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
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. 


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A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 10 days from the previous ICD signature date. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC. 
10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
Data sharing 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
10.1.7. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 


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responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
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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10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU). 
Description of the use of the computerized system is documented in 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 mornitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study intervention or Pfizer- 
related information necessary for the appropriate scientific presentation or understanding of 
the study results. For joint publications, should there be disagreement regarding 
interpretation and/or presentation of specific analysis results, resolution of, and responsibility 
for, such disagreements will be the collective responsibility of all authors of the publication. 


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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
10.1.11. Sponsor’s Medically Qualified Individual 
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, (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 6. 
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) 
Urea and creatinine 
CystatinC and eGFR 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
Local dipstick: 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Laboratory: 
Microscopy and 
culturea 
• Urine cotinine 
• Pregnancy test (β-hCG)d 
• PT, PTT, INR 
At screening: 
• FSHb 
• Urine drug screeningc 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• Hepatitis B core antibody 
• HIV 
For suspected DILIe: 
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/DIKIf: 
Creatinine (Scr) 
CystatinC (Scys) 
eGFR (Scr only and 
combined Scr+Scys) 
Spot (dipstick) UACR 


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Table 6. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
a. 
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both. 
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). 
d. Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine -hCG for female participants of childbearing potential. 
e. 
See Appendix 6 for suggested actions and follow-up assessments in the event of potential DILI 
f. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and reporting 
laboratory test abnormalities. 
 
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 
 
These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study. 


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


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d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during pregnancy 
or breastfeeding, and occupational exposure. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include details 
of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
• When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE or SAE information in the CRF. 
• 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. 
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*** 


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• 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. 
• 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. 


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• 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 theiropinion 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. 
• 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. 


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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 3 months after the last dose of PF-06821497, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak, when having sexual intercourse with a WOCBP who is not 
currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
• 
A female participant is eligible to participate if she (a) is not pregnant or 
breastfeeding; (b) agrees to not donate eggs (ova, oocytes) for the purpose of reproduction 3 
months; and (c) at least 1 of the following conditions applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
• 
OR 
• Is a WOCBP who agrees to use a highly effective contraceptive method (failure rate 
of <1% per year) with low user dependency during the intervention period and for at 
least 3 months after the last dose of study intervention, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention(s). The 


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investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
OR 
• Is a WOCBP and agrees to use a highly effective (failure rate of <1% per year) user- 
dependent method of contraception during the intervention period and for at least 3 
months after the last dose of study intervention, which corresponds to the time needed 
to eliminate any reproductive safety risk of the study intervention(s). In addition to 
her use of the highly effective method above, she agrees to concurrently use an 
effective barrier method. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for reviewing the woman’s medical history, menstrual history, 
and recent sexual activity in order to decrease the risk of enrolling a woman with an early, 
undetected pregnancy. 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 


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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 progestogenonly hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner. 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral + barrier* 
• Intravaginal + barrier* 


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• Transdermal + barrier* 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral + barrier* 
• Injectable + barrier* 
8. Sexual Abstinence 
9. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following: 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods). 


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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;385:1737-49.3 
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 
• 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 
• QTcF prolongation >500 ms or > 60 ms from baseline 
• 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: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
Abs 
absolute 
ADL 
activity/activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
API 
Active Pharmaceutical Ingredients 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUClast 
area under the concentration-time curve from 0 to time of last 
measurable concentration 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUCtau 
area under the concentration-time curve at steady state over the 
dosing interval t 
AV 
atrioventricular 
BBS 
Biospecimen Banking System 
BCRP 
breast cancer resistance protein 
BCS 
Biopharmaceutics Classification System 
b-hCG 
b-human chorionic gonadotropin 
BID 
twice a day 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
C1D1 
Cycle 1 Day 1 
C1D15 
Cycle 1 Day 15 
CCl4 
carbon tetrachloride 
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 
Clast 
last quantifiable concentration 
CCI 
CLp 
plasma clearance 
Cmax 
maximum observed concentration 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 


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Abbreviation 
Term 
CRO 
contract research organization 
CRPC 
castration resistant prostate cancer 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CTIS 
Clinical Trial Information System 
CTSUR 
Clinical Trial Service Unit Report 
CV 
cardiovascular 
CYP 
cytochrome P450 
DCT 
data collection tool 
DICI 
drug-induced creatinine increase 
DIKI 
drug-induced kidney injury 
DILI 
drug-induced liver injury 
DLBCL 
diffuse large B-cell lymphoma 
DMID 
dosage material identification 
DSUR 
Development Safety Update Report 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram or electrocardiography 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
ERCP 
Endoscopic retrograde·cholangiao-pancreatography 
eSAE 
electrionic serious adverse event 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clincal Trials 
(European Clinical Trials Database) 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FIP 
first-in-patient 
FL 
follicular lymphoma 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
fu 
unbound fractions 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GGT 
gamma-glutamyl transferase 


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Abbreviation 
Term 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HNSTD 
Highest non-severly toxic dose 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ID 
identification 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
Investigational Product 
IPAL 
Investigational Product Accountability Log 
IPM 
investigational product manual 
IQMP 
Integrated quality management plan 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
kel 
terminal phase rate constant 
LBBB 
left bundle branch block 
LFT 
liver function test 
LLN 
lower limit of normal 
Loge 
natural logarithm 
MATE 
multidrug and toxin extrusion 
MATE2K 
multidrug and toxin extrusion protein 2 
MEC 
Minimum effective concentration 
MQI 
medically qualified individual 
CCI 
MTD 
Maximum therapeutic dose 
NA 
not applicable 
NCA 
non-compartmental analysis 
OAT 
organic anion transporter 
OCT 
organic cation transporter 
PAD 
pharmacologic active dose 
PCRU 
Pfizer Clinical Research Unit 
PD 
pharmacodynamic(s) 
P-gp 
p-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PO 
Oral 
PR 
pulse rate 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
PFIZER CONFIDENTIAL 
Page 98 
 
 
 
Abbreviation 
Term 
PRC2 
polycomb repressive complex 2 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
PTT 
Partial thromboplastin time 
PVC 
premature ventricular contraction/complex 
QA 
Quality assess 
QC 
Quality control 
QD 
Once a day 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
qual 
qualitative 
rBA 
relative Bioavailability 
RBC 
red blood cell 
CCI 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCLC 
small cell lung cancer 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SoA 
schedule of activities 
SOC 
Standard of care 
SOP 
standard operating procedure 
SRSD 
Single Reference Safety Document 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
C 
CT bili 
total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
Tmax 
time to reach Cmax 
UACR 
urine albumin/creatinine ratio 
UGT 
Uridine diphosphate glycosyltransferase 
ULN 
upper limit of normal 
US 
United States 
UTI 
urinary tract infection 
UVA 
ultraviolet A 
UVB 
ultraviolet B 
Vss 
volume of distribution at steady-state 
CCI 
WBC 
white blood cell 
CCI 


PF-06821497 
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Page 99 
 
 
 
Abbreviation 
Term 
WOCBP 
woman/women of childbearing potential 
WT 
Wild type 


PF-06821497 
Protocol C2321005 
Final Protocol, 02 Feb 2023 
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Page 100 
 
 
11. REFERENCES 
1. 
O’Carroll D, Erhardt S, Pagani M, et al. The polycomb-group gene Ezh2 is required for 
early mouse development. Mol Cel Biol. 2001;21(13):4330-6. 
2. 
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. 2022;24(16). DOI: 
10.1208/s12248-021-00667-w. 
3. 
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49. 

SAP_001.pdf: 
Protocol C2321005 (PF-06821497) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 of 20 
 
 
 
 
 
 
 
 
 
 
Protocol C2321005 
 
 
 
 
A Phase 1, Randomized, Open-label, 3-period, crossover, single-dose, 2-part study in 
healthy participants to investigate the effect of tablet formulation and food on the relative 
bioavailability of PF-06821497 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
 
Version: 
1 
Date: 
30 Mar 2023 


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Page 2 of 20 
 
 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 4 
APPENDICES ........................................................................................................................... 4 
1. VERSION HISTORY ........................................................................................................... 5 
2. INTRODUCTION ................................................................................................................. 5 
2.1. Modifications to the Analysis Plan Described in the Protocol ................................. 5 
2.2. Study Objectives and Endpoints ............................................................................... 5 
2.3. Study Design ............................................................................................................. 6 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................................. 8 
3.1. Primary Endpoints .................................................................................................... 8 
3.2. Secondary Endpoints ................................................................................................ 8 
3.3. Baseline Variables .................................................................................................... 8 
3.4. Other Endpoints ........................................................................................................ 8 
3.5. Safety Endpoints ....................................................................................................... 9 
3.5.1. Adverse Events ............................................................................................ 9 
3.5.2. Laboratory Data ......................................................................................... 10 
3.5.3. Vital Signs .................................................................................................. 10 
3.5.4. Electrocardiograms ..................................................................................... 10 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)................................................... 10 
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................... 11 
5.1. Hypotheses and Decision Rules ............................................................................. 11 
5.2. General Methods ..................................................................................................... 11 
5.2.1. Analyses for Binary/Categorical Endpoints ............................................... 11 
5.2.2. Analyses for Continuous Endpoints ........................................................... 11 
5.3. Methods to Manage Missing Data .......................................................................... 11 
5.3.1. Pharmacokinetic Data ................................................................................ 11 
5.3.2. Safety Data ................................................................................................. 12 
6. ANALYSES AND SUMMARIES ...................................................................................... 13 
6.1. Primary Endpoints .................................................................................................. 13 
6.2. Secondary Endpoints .............................................................................................. 13 
6.3. Other Endpoints ...................................................................................................... 14 


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6.4. Subset Analyses ....................................................................................................... 15 
6.5. Baseline and Other Summaries and Analyses .......................................................... 15 
6.5.1. Demographic Summaries ............................................................................ 15 
6.5.2. Study Conduct and Participant Disposition ................................................ 16 
6.5.3. Study Treatment Exposure .......................................................................... 16 
6.5.4. Concomitant Medications and Nondrug Treatments .................................. 16 
6.6. Safety Summaries and Analyses .............................................................................. 16 
6.6.1. Adverse Events ........................................................................................... 16 
6.6.2. Laboratory Data .......................................................................................... 16 
6.6.3. Vital Signs ................................................................................................... 16 
6.6.4. Electrocardiograms ...................................................................................... 16 
7. INTERIM ANALYSES ....................................................................................................... 16 
APPENDICES .......................................................................................................................... 17 


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LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................. 5 
Table 2. 
Treatment Schedule.................................................................................... 7 
Table 3. 
Plasma PF-06821497 PK Parameters Definitions ...................................... 9 
Table 4. 
PK Parameters to be Summarized Descriptively by Treatment ............... 14 
 
 
APPENDICES 
Appendix 1. SAS Code for Analyses ...................................................................................... 17 
Appendix 2. List of Abbreviations .......................................................................................... 19 


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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 / 
30 Mar 2023 
Original 
02 Feb 2023 
N/A 
N/A 
2. INTRODUCTION 
PF-06821497 is a potent and selective inhibitor of EZH2 as evidenced by its biochemical 
inhibition of both WT and EZH2 Y641N mutant enzymes. PF-06821497 is currently being 
proposed for investigation in patients with SCLC, CRPC, DLBCL, and FL. 
The purpose of the study is to investigate the relative bioavailability of tablet formulations of 
PF-06821497 and to characterize the effect of food on a PF-06821497 CCI tablet 
formulation (Formulation 2). The data generated from this study will be used to support the 
pivotal study formulation, to inform dose administration instructions for PF-06821497 with 
regard to dosing with or without food, and to enable the establishment of the API particle 
size specifications for eventual commercialization. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C2321005. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 
2.2. Study Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• To estimate the bioavailability of a single CC mg 
dose of PF-06821497 CC tablet formulation 
(Formulation 2) relative to a single CC mg dose 
of PF-06821497 CCI tablet formulation 
(Formulation 1) under fasted conditions in adult 
healthy participants 
• Plasma AUCinf and Cmax for PF-06821497. 
(AUClast will be used as the primary estimate if 
AUCinf cannot be reliably estimated). 
Secondary: 
Secondary: 
• 
To estimate the bioavailability of a single CC 
mg dose of PF-06821497 CC tablet (larger API 
particle size) formulation (Formulation 3) 
relative to a single CC mg dose of PF- 
06821497 CC tablet (Formulation 2) and a 
single 250 mg dose of the PF-06821497 CCI 
tablet formulation (Formulation 1) under fasted 
conditions in adult healthy participants 
• Plasma AUCinf and Cmax for PF-06821497 for CC 
tablet (larger API particle size) (Formulation 3) 
relative to CC (Formulation 2) and CCI tablet 
(Formulation 1) formulations. (AUClast will be used 
as the primary estimate if AUCinf cannot be 
reliably estimated). 


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Plasma AUCinf and Cmax for PF-06821497 under 
fed (high-fat, high-calorie meal) conditions 
relative to fasting conditions. (AUClast will be 
used as the primary estimate if AUCinf cannot be 
reliably estimated). 
 
Plasma AUCinf and Cmax for PF-06821497 under 
fed (low-fat, low-calorie meal) conditions relative 
to fasting conditions. (AUClast will be used as the 
primary estimate if AUCinf cannot be reliably 
estimated). 
•
To estimate the effect of a high-fat, high-calorie 
meal on the bioavailability of a single CCI  mg 
dose of the PF-06821497 CC tablet 
formulation (Formulation 2) relative to fasted 
conditions in adult healthy participants 
•
To estimate the effect of a low-fat, low-calorie 
meal on the bioavailability of a single CCI  mg 
dose of the PF-06821497 CC tablet 
formulation (Formulation 2) relative to fasted 
conditions in adult healthy participants 
Endpoints 
Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To evaluate the safety and tolerability of PF- 
06821497 when administered as a tablet 
formulation to healthy participants 
CCI 
 
• 
Assessment of TEAEs, clinical laboratory 
abnormalities, vital signs, physical examinations, 
and 12-lead ECGs. 
 
 
 
 
2.3. Study Design 
This is a Phase 1, randomized, open-label, 3-period, crossover, single-dose 2-part study in 
healthy participants to investigate the effect of tablet formulation and food on the 
bioavailability of PF-06821497. 
In each part of the study, 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-06821497 administration: 
Part 1 (rBA): 
• 
Treatment A – Single CCI mg dose CCI 
 tablet formulation 
(Formulation 1), under fasting conditions (following an overnight fast of at least 10 
hours) 
• 
Treatment B – Single CCI mg dose CCI 
 of WG tablet formulation 
(Formulation 2), under fasting conditions (following an overnight fast of at least 10 
hours) 
• 
Treatment C – Single CCI mg dose CCI 
 tablet formulation (larger 
API particle size) (Formulation 3), under fasting conditions (following an overnight 
fast of at least 10 hours) 


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C
C
C
Part 2 (Food Effect): 
• 
Treatment D – Single CCI 
 tablet formulation 
(Formulation 2), under fasting conditions (following an overnight fast of at least 10 
hours) 
• 
Treatment E – Single CCI 
 tablet formulation 
(Formulation 2), given with a low-fat/low-calorie meal 
• 
Treatment F – Single CCI 
 tablet formulation 
(Formulation 2), given with a high-fat/high-calorie meal 
Approximately 18 participants will be enrolled to the study intervention. If there are 
participants who withdraw or discontinue treatment and are considered to be non-evaluable 
with respect to the primary PK objective(s), additional participants can be enrolled at the 
discretion of the investigator upon consulation with the sponsor. 
In each part of the study, each enrolled participant will receive 1 of the 3 treatments in each 
period according to treatment schedule shown in Table 2. 
 
Table 2. 
Treatment Schedule 
 
Part 1 (rBA): 
Sequence 
Period 1 
Washout: at 
Period 2 
Washout: at 
Period 3 
least C days 
least C days 
1 (6 
A 
 
between 
B 
 
between 
C 
Participants) 
 
PF-06821497 
 
PF-06821497 
doses 
doses 
2 (6 
B 
A 
C 
Participants) 
Treatment A – CCI formulation (Formulation 1) 
 C 
 fasted; 
Treatment B – CC formulation (Formulation 2) 
CC 
) fasted; 
Treatment C – CC formulation (Formulation 3) 
C 
larger API particle size) fasted ; 
C 
Part 2 (Food effect): 
Sequence 
Period 1 
Washout: at 
least C days 
between PF- 
06821497 
doses 
Period 2 
Washout: at 
least C days 
between PF- 
06821497 doses 
Period 3 
1 (6 
Participants) 
D 
E 
F 
Treatment D – CC formulation (Formulation 2) 
Treatment E – CC formulation (Formulation 2) 
Treatment F – CC formulation (Formulation 2) 
C
) fasted; 
fed: Low-fat meal; 
fed: High-fat meal 
C 
C 
C 


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CCI 
CCI 
CCI 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
The primary endpoints are the plasma AUCinf (if data permit, otherwise AUClast) and Cmax for 
PF-06821497. The test/reference ratios for AUCinf (if data permit), AUClast and Cmax will be 
derived with Treatment B (CCI  formulation (Formulation 2) 
fasted) as 
the Test treatment and Treatment A (CCI  formulation (Formulation 1) CCI 
 
 
fasted) as the Reference treatment. 
3.2. Secondary Endpoints 
The test/reference ratios for AUCinf (if data permit), AUClast and Cmax will be derived with 
Treatment C (CCI  formulation (Formulation 3) CCI 
; larger API particle 
size) fasted) as the Test treatment and Treatment B (CCI formulation (Formulation 2) 
(CCI 
) fasted) and Treatment A (CCI  formulation (Formulation 1) CCI 
 
mg) fasted) as the Reference treatments. 
The test/reference ratios for AUCinf (if data permit), AUClast and Cmax will be derived with 
Treatments E and F (CCI  formulation (Formulation 2) CCI 
) fed: low-fat 
meal and CCI  formulation (Formulation 2) CCI 
) fed: high-fat meal) as the 
Test treatments and Treatment D (CCI  formulation (Formulation 2) CCI 
) 
fasted) as the Reference treatment. 
Included as secondary endpoints are the safety and tolerability data, discussed in Section 3.5. 
3.3. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
3.4. Other Endpoints 
 
Plasma PK parameters of PF-06821497 will be derived (as data permits) from the 
concentration-time data using standard noncompartmental methods as outlined in Table 3. 
The PF-06821497 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 using actual and nominal times, 
respectively. 
Actual PK sampling times will be used in the derivation of PK parameters. 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 3. 
Plasma PF-06821497 PK Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
AUCinf* 
area under the concentration-time curve from time 
0 to infinity 
AUClast + (Clast*/kel), 
where Clast* is the predicted plasma 
concentration at the last 
quantifiable time point from the log- 
linear regression analysis and kel is 
the terminal phase rate constant 
calculated by a linear regression of 
the loglinear concentration-time 
curve 
AUClast 
area under the concentration-time curve from 0 to 
time of last measurable concentration 
Linear/Log trapezoidal method. 
Cmax 
maximum observed concentration 
Observed directly from data 
CC  
I 
 
 
 
 
*If data permits. 
 
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) 
• laboratory data 
• vital signs data 
• electrocardiogram (ECG) results 
3.5.1. Adverse Events 
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 35 days after the last dose of study intervention will be counted as treatment emergent 
and attributed to the last treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent. 


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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), respiratory rate and temperature will be 
measured at times specified in the SoA given in the protocol. 
For each period, the baseline measurement is the predose measurement on Day 1. 
3.5.4. Electrocardiograms 
QT interval, QTcF, PR interval, QRS and heart rate (HR) will be recorded at each assessment 
time indicated in the SoA given in the protocol. 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 measurement is the predose measurement 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, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 


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Participant Analysis Set 
Description 
PK Concentration 
Population 
The PK concentration population is defined as all participants 
randomized and treated who have at least 1 PF-06821497 
concentration in at least 1 treatment period. 
PK Parameter 
Population 
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of the 
PF-06821497 PK parameters of primary interest in at least 
1 treatment period. 
Safety analysis set 
All participants randomly 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. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following last 
participant last visit. 
5.1. Hypotheses and Decision Rules 
No statistical hypothesis will be tested in this study. 
5.2. General Methods 
5.2.1. Analyses for Binary/Categorical Endpoints 
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS). 
5.2.2. Analyses for Continuous Endpoints 
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized. 
5.3. Methods to Manage Missing Data 
5.3.1. Pharmacokinetic Data 
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification: 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings, BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification. 


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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. 
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 not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to a dosing error or 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. CC 
I 
 
 
 
 
 
 
5.3.2. Safety Data 
Missing values in standard summaries of AEs and laboratory data will be imputed according 
to CaPS. 


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6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
AUCinf (if data permit), AUClast and Cmax will be summarized by treatment group and will 
include the set of summary statistics as specified in Table 4. 
For the evaluation of relative bioavailability, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effects 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% confidence intervals 
will be obtained from the model. The adjusted mean differences and 90% confidence 
intervals for the differences will be exponentiated to provide estimates of the ratio of adjusted 
geometric means (Test/Reference) and 90% confidence intervals for the ratios. Treatment A 
(CCI  formulation (Formulation 1) CCI 
 fasted) will be the Reference 
treatment and Treatment B (CCI formulation (Formulation 2) CCI 
 ) fasted) 
will be the Test treatment. 
For AUCinf, AUClast and Cmax, a listing of the individual participant ratios (Test/Reference) 
will be provided. Box and whisker plots for AUCinf, AUClast and Cmax, will be plotted by 
treatment and overlaid with geometric means. 
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 Endpoints 
For the evaluation of relative bioavailability, natural log transformed AUCinf (if data permit), 
AUClast and Cmax will be analyzed using a mixed effects model with sequence and treatment 
as fixed effects and participant within sequence as a random effect. Estimates of the adjusted 
mean differences (Test-Reference) and corresponding 90% confidence intervals will be 
obtained from the model. The adjusted mean differences and 90% confidence intervals for 
the differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% confidence intervals for the ratios. Treatment A (CCI  
formulation (Formulation 1) CCI 
 mg) fasted) will be the Reference treatment 
and Treatment C (CCI formulation (Formulation 3) CCI 
 mg; larger API 
particle size) fasted) will be the Test treatment. For the second comparison, Treatment B 
(CCI formulation (Formulation 2) CCI 
 mg) fasted) will be the Reference 
treatment and Treatment C (CCI formulation (Formulation 3) CCI 
 mg; larger 
API particle size) fasted) will be the Test treatment. 
For the evaluation of food effect, natural log transformed AUCinf (if data permit), AUClast 
and Cmax will be analyzed using a mixed effects model with treatment as a fixed effect and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 


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and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment D (CCI formulation (Formulation 2) CCI 
 
mg) fasted) will be the Reference treatment and Treatments E and F (CCI 
formulation (Formulation 2) CCI 
 mg) fed: low-fat meal and CCI formulation 
(Formulation 2) CCI 
) fed: high-fat meal) will be the Test treatments. 
For AUCinf, AUClast and Cmax, a listing of the individual participant ratios (Test/Reference) 
will be provided. Box and whisker plots for AUCinf, AUClast and Cmax, will be plotted by 
treatment and overlaid with geometric means. 
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. 
Analyses and summaries of safety data are described in Section 6.6. 
6.3. Other Endpoints 
PK Parameters: 
The PK parameters will be listed and summarized descriptively by treatment group in 
accordance with Pfizer data standards on the PK Parameter Analysis Set, as data permit. 
Missing values will be handled as 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 4. 
 
Table 4. 
PK Parameters to be Summarized Descriptively by Treatment 
 
Parameter 
Summary Statistics 
AUCinf, AUClast, Cmax, 
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV 
CCI 
CCI 
 
Supporting data from the estimation of t½ and AUCinf will be listed by analyte and group: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel. This data may be included in the clinical study 
report. 


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PK Concentrations: 
The plasma concentrations will be listed and descriptively summarized by nominal PK 
sampling time and treatment. Individual participant, as well as mean and median profiles of 
the plasma concentration time data will be plotted by treatment using actual (for individual) 
and nominal (for mean and median) times respectively. Mean and median profiles will be 
presented on both linear and semi-log scales. 
Presentations of 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]. 
6.4. Subset Analyses 
There are no planned subset analyses. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Demographic Summaries 
Demographic characteristics will be summarized for enrolled population in accordance with 
the CaPS. 


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6.5.2. 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. 
6.5.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
6.5.4. Concomitant Medications and Nondrug Treatments 
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported in 
the listings. 
6.6. Safety Summaries and Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
6.6.1. 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. 
6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the CaPS. 
6.6.3. Vital Signs 
Vital sign data will be databased and available upon request. 
6.6.4. Electrocardiograms 
ECG data will be databased and available upon request. 
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/PD modeling, and/or supporting clinical 
development. 
Final analysis will follow the official database release. As this will be an open-label study, 
there is no formal unblinding of the randomization code. 


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APPENDICES 
Appendix 1. SAS Code for Analyses 
An example of the PROC MIXED code is provided below: 
For the primary objective – relative BA: 
proc mixed data=tab.pk; 
class seq period trt participant; 
model l&var=seq period trt/ ddfm=KR; 
random participant(seq) /subject=participant(seq); 
lsmeans trt; 
estimate 'B vs A' trt -1 1 0 /cl alpha=0.1; 
 
 
 
 
 
run; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
 
For the secondary objective – relative BA: 
proc mixed data=tab.pk; 
class seq trt participant; 
model l&var=seq trt/ ddfm=KR; 
random participant(seq) /subject=participant(seq); 
lsmeans trt; 
estimate 'C vs A' trt -1 0 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; 
 
proc mixed data=tab.pk; 
class seq trt participant; 
model l&var=seq trt/ ddfm=KR; 
random participant(seq) /subject=participant(seq); 
lsmeans trt; 
estimate 'C vs B' trt 0 -1 1 /cl alpha=0.1; 
 
 
 
 
 
run; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 


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CCI 
CCI 
CCI 
For the secondary objective – food effect: 
proc mixed data=tab.pk; 
class trt participant; 
model l&var= trt/ ddfm=KR; 
random participant /subject=participant; 
lsmeans trt; 
estimate 'E vs D' trt -1 1 0 /cl alpha=0.1; 
 
 
 
 
 
run; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
 
proc mixed data=tab.pk; 
class trt participant; 
model l&var= trt/ ddfm=KR; 
random participant /subject=participant; 
lsmeans trt; 
estimate 'F vs D' trt -1 0 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 
Treatment A – 
 formulation (Formulation 1) CCI 
Treatment B – 
formulation (Formulation 2) CCI 
Treatment C – 
 formulation (Formulation 3) CCI 
size) fasted; 
Treatment D – WG formulation (Formulation 2) CCI 
Treatment E – WG formulation (Formulation 2) CCI 
Treatment F – WG formulation (Formulation 2) CCI 
fasted; 
fasted; 
; larger API particle 
 
fasted; 
fed: Low-fat meal; 
fed: High-fat meal */ 


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Appendix 2. List of Abbreviations 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
API 
Active Pharmaceutical Ingredients 
AUCextrap% 
the percent of AUCinf based on extrapolation 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUClast 
area under the concentration-time curve from 0 to time of last measurable 
concentration 
BA 
bioavailability 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CaPS 
Clinical Data Interchange Standards Consortium and Pfizer Standards 
CI 
confidence interval 
Clast 
last quantifiable concentration 
CCI 
Cmax 
maximum observed concentration 
CRPC 
castration resistant prostate cancer 
CSR 
clinical study report 
DLBCL 
diffuse large B-cell lymphoma 
ECG 
electrocardiogram 
FL 
follicular lymphoma 
HR 
heart rate 
kel 
terminal phase rate constant 
LLQ 
lower limit of quantitation 
mg 
milligram 
CCI 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
PR interval 
time from the beginning of the P wave to the beginning of the QRS 
complex 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram representing 
ventricular depolarization 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
r2 
goodness of fit statistic from the log-linear regression 
rBA 
relative bioequivalence 


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Abbreviation 
Term 
RR 
the time between the start of one QRS complex and the start of the next 
QRS complex 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SD 
single dose; standard deviation 
SoA 
schedule of activities 
C 
CTEAE 
treatment emergent adverse event 
CCI 
WT 
wild type