Clinical trial NCT03865446
Conditions: Severe Hepatic Impairment
Keywords: Pharmacokinetics Dacomitinib Hepatic Impairment
Sponsor: Pfizer
Start date: 2019-04-05; Completion date: 2019-10-24
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a post approval requirement to study the effect of severe hepatic impairment on the pharmacokinetics of dacomitinib.

Detailed description:
This is a Phase 1, open label, parallel group study to investigate the effect of severe hepatic impairment on the plasma PK, safety and tolerability after a single oral 30 mg dose of dacomitinib under fasted conditions.

Approximately 18 participants will be enrolled into the study to ensure at least 6 PK evaluable (having data for estimating primary PK parameters for dacomitinib) participants in each cohort.

Arms: arm 1: severe hepatic impairment group arm 2: normal hepatic function
Interventions: intervention 1: Dacomitinib
Intervention descriptions: intervention 1: anti-cancer agent

Protocol documents:
Prot_000.pdf: 
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A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL-GROUP STUDY TO 
EVALUATE THE PLASMA PHARMACOKINETICS AND SAFETY OF 
DACOMITINIB IN PARTICIPANTS WITH SEVERELY IMPAIRED HEPATIC 
FUNCTION RELATIVE TO PARTICIPANTS WITH NORMAL HEPATIC 
FUNCTION
Investigational Product Number:
PF-00299804
Investigational Product Name:
Dacomitinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
A7471058
Phase:
1
Short Title: Hepatic Impairment Study
CCI


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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original Protocol
14 November 2018
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ......................................................................................................................8
1.3. Schedule of Activities (SoA).....................................................................................9
2. INTRODUCTION ...............................................................................................................12
2.1. Study Rationale .......................................................................................................12
2.2. Background .............................................................................................................13
2.2.1. Nonclinical Pharmacology..........................................................................13
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................14
2.2.3. Nonclinical Safety ......................................................................................14
2.2.4. Clinical Overview.......................................................................................15
2.3. Benefit/Risk Assessment.........................................................................................16
3. OBJECTIVES AND ENDPOINTS.....................................................................................17
4. STUDY DESIGN.................................................................................................................17
4.1. Overall Design.........................................................................................................17
4.2. Scientific Rationale for Study Design.....................................................................19
4.3. Justification for Dose ..............................................................................................20
4.4. End of Study Definition ..........................................................................................20
5. STUDY POPULATION......................................................................................................21
5.1. Inclusion Criteria.....................................................................................................21
5.1.1. All Participants ...........................................................................................21
5.1.2. Additional Inclusion Criteria for Participants with Normal Hepatic 
Function (Cohort 2)..........................................................................................21
5.1.3. Additional Inclusion Criteria for Participants with Severely Impaired 
Hepatic Function (Cohort 1)............................................................................22
5.2. Exclusion Criteria....................................................................................................23
5.2.1. All Participants ...........................................................................................23
5.2.2. Additional Exclusion Criteria for Participants with Normal Hepatic 
Function (Cohort 2)..........................................................................................24


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5.2.3. Additional Exclusion Criteria for Participants with Severely 
Impaired Hepatic Function (Cohort 1).............................................................24
5.3. Lifestyle Considerations..........................................................................................26
5.3.1. Meals and Dietary Restrictions...................................................................26
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................26
5.3.3. Activity .......................................................................................................27
5.3.4. Contraception..............................................................................................27
5.4. Screen Failures ........................................................................................................27
6. STUDY INTERVENTION..................................................................................................28
6.1. Study Intervention Administered ............................................................................28
6.1.1. Administration............................................................................................28
6.2. Preparation/Handling/Storage/Accountability ........................................................28
6.2.1. Preparation and Dispensing........................................................................29
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................30
6.3.1. Allocation to Investigational Product .........................................................30
6.4. Study Intervention Compliance...............................................................................30
6.5. Concomitant Therapy..............................................................................................30
6.6. Dose Modification...................................................................................................30
6.7. Intervention After the End of the Study..................................................................31
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................31
7.1. Discontinuation of Study Intervention ....................................................................31
7.2. Participant Discontinuation/Withdrawal From the Study.......................................31
7.3. Lost to Follow up ....................................................................................................32
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................32
8.1. Efficacy Assessments..............................................................................................33
8.2. Safety Assessments .................................................................................................33
8.2.1. Physical Examinations................................................................................34
8.2.2. Vital Signs ..................................................................................................34
8.2.3. Electrocardiograms.....................................................................................34
8.2.4. Clinical Safety Laboratory Assessments ....................................................35
8.3. Adverse Events and Serious Adverse Events..........................................................36


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......36
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................37
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................37
8.3.2. Method of Detecting AEs and SAEs ..........................................................37
8.3.3. Follow-up of AEs and SAEs.......................................................................37
8.3.4. Regulatory Reporting Requirements for SAEs...........................................38
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................38
8.3.5.1. Exposure During Pregnancy......................................................38
8.3.5.2. Exposure During Breastfeeding ................................................38
8.3.5.3. Occupational Exposure .............................................................39
8.3.6. Medication Errors .......................................................................................39
8.4. Treatment of Overdose............................................................................................40
8.5. Pharmacokinetics ....................................................................................................40
8.5.1. Pharmacokinetic Assessment of Dacomitinib and PF-05199265...............40
8.5.2. Protein Binding Assessment.......................................................................41
8.6. Pharmacodynamics..................................................................................................41
8.7. Genetics...................................................................................................................42
8.7.1. CYP2D6 Genotyping Analysis...................................................................42
8.7.2. Banked Biospecimens for Genetics............................................................42
8.8. Biomarkers ..............................................................................................................42
8.9. Health Economics ...................................................................................................42
9. STATISTICAL CONSIDERATIONS ................................................................................43
9.1. Statistical Hypotheses .............................................................................................43
9.2. Sample Size Determination.....................................................................................43
9.3. Populations for Analysis .........................................................................................43
9.4. Statistical Analyses .................................................................................................43
9.4.1. Efficacy Analyses .......................................................................................43
9.4.2. Safety Analyses ..........................................................................................43
9.4.2.1. Electrocardiogram Analyses......................................................44
9.4.3. Other Analyses............................................................................................44
9.4.3.1. Pharmacokinetic Analyses ........................................................44


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9.4.3.2. Pharmacodynamic Analyses .....................................................45
9.5. Interim Analyses .....................................................................................................45
9.5.1. Data Monitoring Committee.......................................................................45
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................46
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............46
10.1.1. Regulatory and Ethical Considerations ....................................................46
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................46
10.1.2. Financial Disclosure .................................................................................47
10.1.3. Informed Consent Process ........................................................................47
10.1.4. Data Protection .........................................................................................48
10.1.5. Dissemination of Clinical Study Data ......................................................49
10.1.6. Data Quality Assurance ............................................................................50
10.1.7. Source Documents....................................................................................51
10.1.8. Study and Site Closure..............................................................................51
10.1.9. Publication Policy.....................................................................................52
10.1.10. Sponsor’s Qualified Medical Personnel .................................................53
10.2. Appendix 2: Clinical Laboratory Tests .................................................................54
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................55
10.3.1. Definition of AE .......................................................................................55
10.3.2. Definition of SAE.....................................................................................56
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................57
10.3.4. Reporting of SAEs....................................................................................60
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................62
10.4.1. Male Participant Reproductive Inclusion Criteria....................................62
10.4.2. Female Participant Reproductive Inclusion Criteria.................................62
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................62
10.4.4. Contraception Methods.............................................................................63
10.5. Appendix 5: Genetics............................................................................................67
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........68


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................70
10.8. Appendix 8: Modified Child-Pugh Classification (CPC) of Liver 
Dysfunction ...............................................................................................................72
10.9. Appendix 9: Abbreviations ...................................................................................73
11. REFERENCES ..................................................................................................................76
LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child-Pugh Classification ......................18
Table 2.
Protocol-Required Safety Laboratory Assessments .............................................54


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1. PROTOCOL SUMMARY
1.1. Synopsis
Not applicable.
1.2. Schema
Not applicable.


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1.3. Schedule of Activities (SoA)
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 Identifiera
Screeningb
Study Period
Follow Ups
or Early 
Terminationt
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
12
Hours After Dose
0
2
4
6
8
12
24
48
72
96
120
144
168
192
216
264
Informed consent
X
CRU confinementc
X






X
Review inclusion/exclusion 
criteria
X
X
Demographyd
X
Medical/medication history 
(update)e
X
X
Physical examination, 
height, and body weightf
X
X
X
Xt
Safety laboratory testsg
X
X
X
X
Xt
Contraception checkh
X
X
Xs,t
Alcohol/tobacco use & 
Breath alcohol testi
X
X
FSH (only females 
amenorrheic for at least 
12 months)
X
Urine drug testing
X
X
Supine 12-Lead ECGj
X
X
X
X
Xt
Blood pressure and pulse 
ratek
X
X
X
X
Xt
Child-Pugh assessmentl
X


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Visit Identifiera
Screeningb
Study Period
Follow Ups
or Early 
Terminationt
Days Relative to Day 1
Day -28 to 
Day -2
Day -1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
12
Hours After Dose
0
2
4
6
8
12
24
48
72
96
120
144
168
192
216
264
Hepatitis B (HepBsAg, 
HepBcAb),
Hepatitis C (HCVAb), and 
HIV tests
X
Study treatment 
administrationm
X
PK blood samplingn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protein binding blood 
samplingo
X
X
X
Pharmacogenomics blood 
sampling (CYP2D6)p
X
Pfizer Prep D1 banked 
sample(s)q
X
Prior/concomitant treatments
X
X











Xs,t
CRU discharger
X
Serious and nonserious 
adverse event monitoring
X
X











Xs,t
Abbreviations: = ongoing/continuous event; AE = adverse event; BMI = body mass index; CRU = clinical research unit; CYP = cytochrome P450; 
ECG = electrocardiogram; FSH = follicle-stimulating hormone; HCVAb = hepatitis C antibody; HepBcAb = hepatitis B core antibody; HepBsAg = hepatitis B 
surface antigen; HIV = human immunodeficiency virus; PK = pharmacokinetic.
a.
Day relative to start of study treatment (Day 1).
b.
Screening will be performed within 28 days prior to the dosing of investigational product (dacomitinib) (Section 4.1).
c.
All participants will be admitted to the CRU on Day -1. All participants will be required to stay in-house at least until the collection of the 144 hour PK 
sample following dacomitinib dosing.
d.
Demographics will include participant height, weight, race, age and gender data collected during Screening.
e.
Medical/medication history will include a history of illegal drug, alcohol, and tobacco use, as well as blood donation within 60 days prior to first dose.  
Medical/medication history will be recorded at Screening and updated when the participant is admitted to the CRU on Day -1.
f.
A complete physical examination may be conducted by a physician, trained physician's assistant, or nurse practitioner as acceptable according to local 
regulation at the investigator site either during Screening or Day -1 only (height and body weight must be obtained at Screening to obtain BMI for eligibility 
criteria).  If complete physical examination is performed during the screening visit, then only a brief physical examination is needed on Day -1.  A brief
physical examination may be conducted at the discretion of the investigator on Day 7 prior to discharge for new or ongoing AEs and during early 
termination.


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g.
Safety laboratory assessments including urinalysis, hematology (including prothrombin time/partial thromboplastin time), and chemistry will be performed 
at Screening, on Day -1, on Day 2, Day 7 prior to discharge and during early termination.  All assessments must be collected following at least a 4-hour fast.  
For participants with severe hepatic impairment (Cohort 1), the Day -1 safety labs including liver function assessments and evaluation of renal function must 
be completed prior to dacomitinib dosing on Day 1, for review of inclusion/exclusion criteria.  Additional assessments may be performed at the discretion of 
the investigator. 
h.
On Day -1, on Day 7 (or any subsequent day that coincides with discharge) and during follow-up or early termination, the investigator or his/her designee 
will discuss with the participant the need to use highly effective contraception consistently and correctly according to protocol contraception guidelines in
Section 5.3.4.
i.
Alcohol/tobacco use and alcohol breath test will be performed during Screening or on Day -1.  These tests may also be performed at any other time at the 
discretion of the investigator.
j.
A single 12-lead ECG will be obtained at Screening, 6 hours post-dose on Day 1, prior to discharge on Day 7 and during early termination.  A triplicate ECG 
will be obtained approximately 2 to 4 minutes apart at pre-dose on Day 1. All ECG assessments will be made following at least a 10-minute rest in a supine 
position and should be collected before PK sample collection, if scheduled at the same time point.
k.
Supine blood pressure will be determined following approximately 5-minute rest in a supine position. 
l.
The modified Child-Pugh assessment as outlined in Appendix 8 should be followed. 
m. On Day 1, administration of dacomitinib will occur with approximately 8 oz (240 mL) of ambient temperature water after at least a 10 hour fast. Following 
dacomitinib administration, no food will be allowed for at least another 4 hours post dose except that a light snack or juice may be provided to a diabetic 
participant.
n.
Blood samples (3 mL each) for PK will be taken upon completion of ECGs, blood pressure and pulse measurements.  Serial blood samples for the 
measurements of dacomitinib and its metabolite, PF-05199265, will be collected prior to dosing and at 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 
and 264 hours following dosing.
o.
Blood samples (10 mL each) will be collected prior to dacomitinib dosing and at 6 and 8 hours following dosing.
p.
One (1) blood sample (3 mL) only will be collected on Day -1 for CYP2D6 genotyping.
q.
One (1) 4 mL blood sample should be drawn on Day -1.  If not collected on the designated collection day, collect at the next available time point when 
biospecimens are being collected in conjunction with a participant visit.
r.
Participants will be eligible for discharge from the CRU following completion of the following: 144-hour PK sample collection, a single supine 12-lead 
ECG, supine blood pressure and pulse rate, discussion of the need for highly effective contraception, safety laboratory test, evaluation of participant-reported 
adverse events, review of prior and concomitant medications, brief physical examination, and body weight. Day 7 safety laboratory tests can be collected 
early (ie. On Day 6) so results are available in time for intended participant discharge on that day.
s.
All participants will be followed up by phone call at least 28 days and up to 35 days after the administration of the dacomitinib dose for potential AEs, 
concomitant treatment use and to confirm appropriate contraception usage.
t.
Participant withdrawal/early termination activities will include a brief physical examination (if there is a new or ongoing AE or a previous clinically 
significant abnormal physical finding), safety laboratory tests, a contraception check, a single supine 12-lead ECG, supine blood pressure and pulse rate, 
concomitant treatment and AE assessment.


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2. INTRODUCTION
Dacomitinib (PF-00299804) is a selective, adenosine triphosphate (ATP) competitive, 
irreversible, small-molecule inhibitor of the HER (ERBB) family of receptor tyrosine kinases 
(RTKs), including the epidermal growth factor receptor (EGFR, HER1), the HER2 receptor 
(ERBB2), the HER4 receptor (ERBB4), and their oncogenic variants (eg, EGFR with del 
exon 19 or L858R mutations).  It is currently approved for the first-line treatment of patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) with 
EGFR-activating mutations.
2.1. Study Rationale
The primary metabolic pathways for dacomitinib in human liver microsomes and human 
hepatocytes in vitro are comprised of oxidation and glutathione conjugation.  In vitro studies 
with human liver microsomes and recombinant cytochrome P450 (CYP) (rCYP) enzymes 
indicated that the formation of PF-05199265 (O-desmethyl dacomitinib) was mediated 
primarily by CYP2D6, while CYP3A was involved in the formation of other minor oxidative 
metabolites observed in humans following oral administration of a single dose of 
[14C]dacomitinib.
In the absorption, distribution, metabolism, and excretion (ADME) study in humans 
(Study A7471020), following oral administration of a single [14C]dacomitinib dose (45 mg, 
100 Ci) to 6 male healthy participants, approximately 79% of the administered radioactive 
dose was recovered in feces (approximately 20% unchanged dacomitinib) and 3% in urine
(<1% unchanged dacomitinib). Dacomitinib is orally bioavailable with mean absolute 
bioavailability of 80%.  These data indicated significant hepatic component in the 
elimination of dacomitinib and minimal renal excretion of dacomintib.
A dedicated hepatic impairment clinical study of dacomitinib (Study A7471018) in 
participants with mild or moderate hepatic impairment has been completed.
Study A7471018 was a multi-center, Phase 1, open-label, non-randomized, single-dose, 
parallel group study conducted to evaluate the impact of mild hepatic impairment 
(Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B) on the 
pharmacokinetics (PK) of dacomitinib.  In that study, a total of 25 men who had normal 
hepatic function (n = 8), mild hepatic impairment (n = 8), or moderate hepatic impairment 
(n = 9) but were otherwise healthy were enrolled and received a single 30 mg dose of 
dacomitinib following an overnight fasting for at least 8 hours.  Results demonstrated that 
plasma dacomitinib area under the concentration time curve from time 0 to infinity (AUCinf)
and maximum observed plasma concentration (Cmax) were similar in participants with mild 
hepatic impairment and were reduced marginally (by 15% and 20% for AUCinf and Cmax, 
respectively) for participants with moderate hepatic impairment relative to participants with 
normal hepatic function. 


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The effect of hepatic impairment on dacomitinib was further evaluated using the National 
Cancer Institute (NCI) hepatic impairment classification in a pooled population PK analysis 
of 1381 participants, which included 158 participants with mild hepatic impairment (total 
bilirubin upper limit of normal [ULN] and aspartate transaminase [AST] > ULN, or total 
bilirubin >1 to 1.5 × ULN with any AST), 5 participants with moderate hepatic impairment 
(total bilirubin >1.5 to 3 × ULN and any AST) and 1 participant with severe hepatic 
impairment (total bilirubin > 3 × ULN and any AST). Limited data (n=1) were available for 
severe hepatic impairment. Participants with mild hepatic impairment had similar 
dacomitinib clearance (CL) compared to participants with normal hepatic function.  
Dacomitinib CL was higher in participants with moderate hepatic impairment with mean CL
of 31.4 L/h (n=5) compared to 20.5 L/h (n=1202) in participants with normal hepatic 
function. Hepatic function was not a significant covariate on dacomitinib CL. 
Based on the results from both the formal hepatic impairment Study A7471018 and the 
pooled population PK analysis, mild or moderate hepatic impairment is considered to not
have a clinically relevant effect on dacomitinib PK. Therefore, no dose adjustment of 
dacomitinib is recommended in patients with mild or moderate hepatic impairment. 
Insufficient data are however available regarding the use of dacomitinib in patients with 
severe hepatic impairment to provide dosing recommendations in this patient population.
The purpose of this study is to evaluate the effect of severe hepatic impairment on the single 
dose PK of dacominitinib.
2.2. Background 
2.2.1. Nonclinical Pharmacology
Dacomitinib is a highly selective irreversible small molecule inhibitor of the HER (human 
epidermal growth factor receptor) family of tyrosine kinases.  The IC50 values against the 
human catalytic domains of HER-1, HER-2, and HER-4 (HER-3 does not possess tyrosine 
kinase activity) are 2.8 ng/mL (6.0 nM), 21.5 ng/mL (45.7 nM) and 34.7 ng/mL (74 nM), 
respectively.  Dacomitinib is >500 selective relative to the concentrations required to 
inhibit the janus kinase 3 (JAK3), protein kinase b (Akt), insulin-like growth factor 
1 receptor (IGF1R), and the platelet-derived growth factor receptor (PDGFR) in kinase 
assays.  The IC50 values are 1676, >18,800, >18,800, and 6298 ng/mL (3566, >40,000, 
>40,000, and 13,400 nM), respectively.  Dacomitinib inhibits the tyrosine kinase activity of 
the HER family through binding at the ATP binding site, which results in covalent 
modification of a cysteine in the ATP binding pocket.  Dacomitinib exhibited anti-tumor
effects in 4 different human xenograft models that express and/or overexpress HER family 
members.  In these xenograft models, the therapeutic activity ranged from complete 
regression to delayed progression.  The inhibitory effects on tumor growth generally lasted 
throughout compound administration.  An active metabolite, PF-05199265, has been 
identified which has similar inhibitory and selectivity profiles compared to dacomitinib. 


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2.2.2. Nonclinical Pharmacokinetics and Metabolism
In nonclinical species (rats, dogs, and monkeys), dacomitinib exhibited moderate to high 
total plasma clearance in relation to hepatic blood flow, high volume of distribution, and 
moderate to high oral bioavailability ranging from 56% to 109%. Ratios of the AUC from 
time 0 to 24 hours postdose (AUC24) for PF-05199265, a circulating active metabolite in 
humans, to parent were 0.18 in rats and 1.9 in dogs after oral administration of dacomitinib 
for 3 days.  In toxicokinetic studies with rats, rabbits, and dogs, systemic exposure of 
dacomitinib generally increased with increasing of dose within the dose ranges examined.
After oral administration, [14C]dacomitinib undergoes oxidation and glutathione conjugation 
as the primary metabolic pathways in rats, dogs, and humans.  Formation of PF-05199265 is 
mediated primarily by CYP2D6 and to a lesser extent, by CYP2C9.  CYP3A4 contributes to 
the metabolism of dacomitinib in the formation of other minor oxidative metabolites. The 
route of excretion of radioactivity in rats, dogs, and humans was primarily via feces. 
Dacomitinib and PF-05199265 demonstrated little or no inhibition of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, or CYP3A activities in human liver microsomes.  However, 
dacomitinib and PF-05199265 inhibited CYP2D6 activity, and may have the potential for 
clinically relevant drug-drug interaction (DDI) with concomitantly administered CYP2D6 
substrates.  No significant induction of CYP3A, CYP1A2 or CYP2B6 in cryopreserved 
human hepatocytes was observed.  Based on in vitro data, dacomitinib may have the potential 
to inhibit uridine-diphosphate glucuronosyltransferase (UGT)1A1 activity.
Dacomitinib has a low potential to cause DDI by inhibiting the efflux transporters 
P-glycoprotein (P-gp) systemically, organic anion transporting polypeptides (OATP)1B1, 
OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, and 
human bile salt export pump (BSEP). However, dacomitinib may have the potential to 
inhibit breast cancer resistance protein (BCRP), P-gp in the gastrointestinal (GI) tract, and 
OCT1.
2.2.3. Nonclinical Safety
Dacomitinib was assessed in a series of nonclinical studies that included repeated-dose 
toxicity studies in rats and dogs up to 6 or 9 months in duration, respectively, and safety 
pharmacology, genotoxicity, and reproductive embryo-fetal development studies.  Based on 
the nonclinical studies conducted, the kidney, digestive system, epithelial cells, and liver 
have been identified as the primary target tissues/organs of toxicity.  Based on the results of 
the genotoxicity assays conducted, dacomitinib would not be expected to pose a genetic risk 
for acute or chronic dosing in humans.  Embryo-fetal development studies were performed in 
rats and rabbits where the effects were limited to reductions in maternal and fetal body 
weight, and lower maternal food consumption.  There was no teratogenicity, mortality, or 
moribundity detected at any dose level tested.


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2.2.4. Clinical Overview
As of 29 July 2016, 3182 patients have been treated in 17 clinical studies and 143 healthy 
participants and 15 patients with solid tumors have been treated in 9 clinical pharmacology 
studies.  Dacomitinib was administered to 2148 of the patients in these trials, in 1975 patients 
as a single agent or in combination with figitumumab (CP-751,871, a monoclonal antibody 
targeting the IGF1R), crizotinib (an anaplastic lymphoma kinase [ALK],
mesenchymal-epithelial transition [MET] and c-ROS oncogene 1 [ROS1] tyrosine kinase 
inhibitor), or gedatolisib (PF-05212384, a phosphoinositide 3-kinase [PI3K]/mTOR 
inhibitor), and in 173 patients in Phase 1 combination therapy studies.  Most patients treated 
in clinical studies had locally advanced or metastatic NSCLC.  There were 1473 patients with 
NSCLC who received single-agent dacomitinib 45 mg once daily (QD), the maximum 
tolerated dose as determined by Studies A7471001, A7471003, and A7471005.  Of these 
patients, 394 patients had NSCLC with EGFR-activating mutations; 255 of these patients 
received dacomitinib as first-line treatment.
The most frequently reported adverse events (AEs) in 10% of patients included GI-related, 
skin-and-nail-related, respiratory, and constitutional events.  
Results from Study A7471015 indicated that dacomitinib can be administered with or 
without food.  Following a single oral administration of dacomitinib at 45 mg in patients with 
advanced malignant solid tumors, the median time to reach the maximum observed plasma 
concentration (Tmax) of dacomitinib occurred approximately at 5 to 6 hours after dosing.  
Dacomitinib underwent extensive extravascular distribution with a geometric mean apparent 
volume of distribution (Vz/F) ranging from 2424 to 2537 L/h and had a mean apparent 
terminal plasma half-life (t½) ranging from 54 to 80 hours.  Following administration of 
multiple daily doses of dacomitinib at 45 mg to patients with advanced malignant solid 
tumors, steady-state was reached within 14 days, accumulation of dacomitinib in patients 
ranged from 5.0 to 6.4-fold for AUC, reflecting the observed long t½. The geometric AUC
over dosing interval (AUCtau) and Cmax of dacomitinib at steady-state ranged from 1621 to 
2213 ng•h/mL and 79.5 to 108.0 ng/mL, respectively. Plasma exposure of dacomitinib 
increased proportionally with dose in the dose range of 2 mg to 60 mg, indicating linear PK.
Dacomitinib undergoes oxidative metabolism and glutathione conjugation.  Oxidative 
metabolism of dacomitinib involves CYP2D6 for the formation of O-desmethyl dacomitinib 
(PF-05199265) and CYP3A for the formation of other minor oxidative metabolites. The 
O-desmethyl metabolite, PF-05199265, is also a potent inhibitor of the HER kinase family in 
vitro.  However, the steady-state exposure of PF-05199265 in human plasma is <20% when 
compared with the exposure observed for dacomitinib.  Furthermore, PF-05199265 is also 
highly bound to plasma proteins (>99%), which indicates that the unbound fraction for 
PF-05199265 in plasma is <1% of the reported total plasma exposure.
A dedicated hepatic impairment study (Study A7471018) was conducted to evaluate the 
effect of hepatic impairment on dacomitinib exposure after a single 30 mg dose.  This was a 
Phase 1 open-label, non-randomized, single-dose, parallel-group study in 25 participants with 
mild hepatic impairment (Child-Pugh Class A, score 5-6, n = 8), moderate hepatic 


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impairment (Child-Pugh Class B, score 7-9, n = 9), and a control group of healthy 
participants with normal hepatic function (n = 8).  The results showed that the mean fraction 
of dacomitinib unbound in plasma (fu) was identical across the 3 groups (fu = 0.02).  The 
mean (percent coefficient of variation [%CV]) fu of PF-05199265 was 0.00011 (28%), 
0.00016 (69%), and 0.00025 (62%) for participants with normal hepatic function, mild 
hepatic impairment, and moderate hepatic impairment, respectively.  Results also showed 
that mild hepatic impairment status did not alter dacomitinib plasma exposures and that 
moderate hepatic impairment status reduced dacomitinib plasma exposures (AUCinf and Cmax
by 15% and 20%, respectively) as compared to normal hepatic function. These changes are 
not considered clinically significant and no starting-dose adjustment is currently 
recommended for patients with mild or moderate hepatic impairment. In addition, a single 
oral 30 mg dose of dacomitinib was well tolerated in participants with mild or moderate 
impaired hepatic function.  No participants in the normal hepatic function group or the mild 
hepatic impairment group experienced an AE.  One (1) participant in the moderate hepatic 
impairment group died due to a road traffic accident. This death was classified as a serious 
adverse event (SAE) and was considered to be severe but was not treatment-related.  There 
were no laboratory safety tests, vital signs results, or electrocardiogram (ECG) results of 
clinical concern.
2.3. Benefit/Risk Assessment
Dacomitinib is not expected to provide any clinical benefit to the participants of this study.  
This study is designed to evaluate safety, tolerability, and PK in participants with severe 
hepatic impairment and matched controls to assist the further clinical development of 
dacomitinib.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dacomitinib may be found in the investigator’s brochure (IB), which is the 
single reference safety document (SRSD) for this study. 


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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To evaluate the effect of severe hepatic 
impairment on the single dose plasma
PK of dacomitinib.

Plasma Cmax and AUCinf of dacomitinib. 
If AUCinf cannot be reliably estimated,
then AUC from time 0 to the time of last 
quantifiable concentration (AUClast) will 
be used as the primary endpoint.
Secondary:
Secondary: 

To assess the safety and tolerability of a 
single oral dose of dacomitinib in 
participants with normal hepatic 
function and participants with severe 
hepatic impairment.

Overall safety profile as characterized by 
laboratory test abnormalities, physical 
examination, vital signs, ECGs, and AE
monitoring.
Tertiary/Exploratory: 
Tertiary/Exploratory: 

To characterize the effect of severe 
hepatic impairment on other plasma PK
parameters of dacomitinib and its 
metabolite PF-05199265.

Plasma AUClast, apparent oral clearance 
(CL/F), Vz/F, t½, Tmax, fu, unbound 
AUCinf (AUCinf,u), unbound AUClast
(AUClast,u), unbound Cmax (Cmax,u), 
unbound CL/F (CLu/F) and unbound Vz/F 
(Vz,u/F) for dacomitinib; Cmax, AUCinf, 
AUClast, t½, Tmax, fu, AUCinf,u, AUClast,u, 
Cmax,u for PF-05199265, as data permit.

To analyze CYP2D6 genotype in 
pharmacogenetic samples. 

CYP2D6 phenotype.

To enable exploratory research through 
collection of banked biospecimens, 
unless prohibited by local regulations or 
ethics committee decision.

Potential results from exploratory 
analysis of banked biospecimens (these 
results may or may not be generated in 
the context of the present study).
4. STUDY DESIGN
4.1. Overall Design
This will be a Phase 1, open-label, parallel-group study to investigate the effect of severe 
hepatic impairment on the plasma PK, safety and tolerability after a single oral 30 mg dose of 
dacomitinib under fasted conditions. 


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At Screening, the modified Child-Pugh classification score as outlined in Appendix 8 will be 
utilized to assess entry criteria and to assign participants into the appropriate hepatic 
impairment group (Table 1). The modified Child-Pugh classification criteria will permit 
enrollment of participants with a history of Stage 3 or Stage 4 encephalopathy who are 
receiving medication(s) to prevent recurrent encephalopathy; participants with clinically 
active Stage 3 or 4 encephalopathy will be excluded from participation in the study. The 
criteria will also allow enrollment of participants with history of severe ascites who are on 
medication(s) to control their ascites. Details of the modified Child-Pugh assessment can be 
found in Appendix 8.
Table 1.
Hepatic Function Categories Based on Child-Pugh Classification
Cohort
Description
Child-Pugh Score
Number of 
Participants
1
Severe hepatic impairment
Class C (10 to 15 points)
8
2
Normal hepatic function
Not applicable
8a
a.
Participants in Cohort 2 may be dosed to a maximum of 10 participants to ensure that the age of each 
participant in Cohort 2 is within 10 years and the body weight is within 15 kg to the median age and 
median body weight of participants in Cohort 1, respectively.
Approximately 18 participants will be enrolled into the study to ensure at least 6 PK 
evaluable (having data for estimating primary PK parameters for dacomitinib) participants in 
each cohort.  Participants who withdraw may be replaced upon agreement with the Sponsor.
The participants from the severely impaired hepatic function cohort will be recruited first, 
and a median value for age and weight will be determined for all evaluable participants 
across study sites in this cohort. Then the control participants from the normal hepatic 
function cohort will be recruited later such that the age of each participant in Cohort 2 is 
within 10 years and the body weight is within 15 kg of the median of the participants in 
the severe hepatic impairment cohort (Cohort 1).  An attempt will be made to maintain a 
similar male/female ratio and racial make-up between Cohorts 1 and 2. Approval from the 
Sponsor must be obtained before proceeding with dosing participants in Cohort 2. 
In this study, participants will be screened for participation within 28 days prior to the dosing 
of dacomitinib.  Each participant will be admitted to the clinical research unit (CRU) on 
Day -1.  Results from the Day -1 safety assessments will be reviewed along with the 
screening assessments and the participant’s recent medical history to ensure that each 
participant meets the inclusion and exclusion criteria for this study as defined in Sections 5.1
and 5.2 of this protocol, respectively.  Additional assessment may be done at the discretion of 
the investigator. Participants who meet the inclusion and exclusion criteria for the study on 
Day -1 will be assigned a randomization number on Day 1 (see Section 6.3 for details), and 
will be enrolled into the study.


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Following an overnight fast of at least 10 hours, participants will be administered a single 
oral 30 mg dose of dacomitinib with approximately 240 mL (8 ounces) of ambient 
temperature water on the morning of Day 1.  No food will be allowed for at least 4 hours 
post-dose except that a light snack or juice may be provided to diabetic participants.  Each 
participant will undergo serial blood sampling to determine plasma concentrations of 
dacomitinib and PF-05199265 until 264 hours (Day 12) post-dose.  At pre-dose and at 6 and 
8 hours post-dose, separate aliquots of blood (10 mL) will be collected for measurement of
protein binding.  Participants will be confined to the unit until Day 7.
After the PK data from all participants with severe hepatic impairment (Cohort 1) have been 
reviewed, the Sponsor will notify the site if additional participants for Cohort 1 are required.  
If no additional participants are required, recruitment for participants with normal hepatic 
function (Cohort 2) will begin.  If the PK variability is greater than expected, additional 
participants may be enrolled in Cohort 1 and the sample size for Cohort 2 will also be 
increased accordingly. 
Physical examinations, single or triplicate supine 12-lead ECG, vital sign measurements, and 
clinical laboratory tests will be conducted and AEs will be monitored throughout the study to 
assess safety.  All participants will be followed up by a phone call at least 28 days and up to 
35 days after dacomitinib dosing. 
4.2. Scientific Rationale for Study Design
A parallel group design will be utilized to compare the dacomitinib PK between participants 
with normal hepatic function and participants with severely impaired hepatic function but are 
otherwise healthy. The participants from the severely impaired hepatic function cohort will 
be recruited first, then the participants from the normal hepatic function cohort will be 
recruited later to match the median demographics from severe hepatic impairment group. 
The modified Child-Pugh classification system will be the method used in this study to 
identify participants with severe hepatic impairment. Additionally, total bilirubin and AST 
will be assessed in this study as per the recommendations of the National Cancer Institute 
Organ Dysfunction Working Group Criteria for assessment of hepatic impairment.2
This study is designed using a single dose of dacomitinib considering that single dose plasma 
PK of dacomitinib has been documented to be generally predictive of exposure at steady
state. All participants enrolled in this study will receive 1 single oral 30 mg dose of 
dacomitinib administered as tablet(s).  The PK samples will be collected serially up to 
264 hours postdose, which has been shown to be adequate for participants with normal, mild 
or moderate hepatic function.  This sampling duration is also expected to be adequate for 
characterizing the elimination phase of the plasma dacomitinib concentration-time profile for 
participants with severe hepatic impairment, for whom the elimination half-life of 
dacomitinib may be prolonged.


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Dacomitinib undergoes both oxidative metabolism and glutathione conjugation.  Oxidative 
metabolism of dacomitinib involves CYP2D6 for the formation of major circulating 
metabolite, PF-05199265, which has similar in vitro pharmacological activities as 
dacomitinib. Therefore the plasma PK for both dacomitinib and PF-05199265 will be 
evaluated in this study.
Since CYP2D6 metabolism is a component of dacomitinib elimination, genetic 
polymorphisms of CYP2D6 may have the potential to alter dacomitinib PK.  A 3-mL blood 
sample will be collected on Day -1 from each participant for genotyping CYP2D6 
polymorphism. Only participants identified as an CYP2D6 extensive metabolizer (EM) or
CYP2D6 intermediate metabolizer (IM) will be included in the primary statistical analysis to 
evaluate the impact of severe hepatic impairment on dacomitinib plasma PK.
Banked biospecimens will be collected for exploratory pharmacogenomics (PGx)/genomic 
analyses and retained in the Biospecimen Banking System (BBS), which makes it possible to 
better understand the investigational product’s (IP’s) mechanism of action and to seek 
explanations for differences in, for example, exposure, tolerability, safety, and/or efficacy not 
anticipated prior to the beginning of the study.
4.3. Justification for Dose
In the current study, a single 30 mg oral dose of dacomitinib will be administered to 
participants with normal hepatic function or participants with severe hepatic impairment.  
The single oral dose of dacomitinib 30 mg is the same dose that was tested in the previously 
conducted hepatic impairment study of dacomitinib (Study A7471018), where this dose was 
well-tolerated in participants with mild or moderate hepatic impairment.  There were no 
clinically significant findings in vital signs, clinical laboratory test parameters, or ECGs.
Hence previous investigations have indicated that mild and moderate hepatic impairment had 
no clinically relevant effects on dacomitinib PK, and no adjustment of starting dose is 
currently recommended for patients with mild or moderate hepatic impairment. In addition, 
there were 1473 patients with advanced NSCLC who received dacomitinib 45 mg QD, the 
recommended starting dose. Following multiple oral administration of 45 mg QD doses, 
accumulation of dacomitinib in patients ranged from 5.0- to 6.4-fold for AUCtau. The AUC 
in participants receiving a single 30 mg dose is expected to be 7.5 to 9.6 fold lower than the 
exposure in patients receiving 45 mg QD at steady state. 
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the study.


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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
5.1.1. All Participants
Age and Sex:
1. Male and/or female participants of non-childbearing potential must be 18 to 75 years 
of age, inclusive, at the time of signing the informed consent document (ICD).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.1.2. Additional Inclusion Criteria for Participants with Normal Hepatic Function 
(Cohort 2)
1. No known or suspected hepatic impairment based on liver function tests (eg, alanine 
aminotransferase [ALT], AST, alkaline phosphatase [ALP], and bilirubin), albumin 
and prothrombin time defined as the following, with a single repeat permitted to 
assess eligibility, if needed:
a.
ALT and AST upper limit of normal (ULN);


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b. Total bilirubin ULN. Note that participants with a history of Gilbert syndrome 
(and hence elevated total bilirubin) are eligible provided direct bilirubin level is 
ULN plus ALT and AST are ULN plus alkaline phosphatase, hemoglobin, and
reticulocyte count are all ULN;
c.
ALP ULN;
d. Albumin within the normal range (local laboratory ranges);
e.
Prothrombin time ULN.
2. Healthy is defined as no clinically relevant abnormalities identified by a detailed 
medical history, complete physical examination, including blood pressure (BP) and 
pulse rate measurement, 12-lead ECG or clinical laboratory tests.
3. Participants must fit the demographic-matching criteria, including:

Body weight 15 kg of the median of the severe hepatic impairment cohort 
(Cohort 1), as provided by the Sponsor.

Age 10 years of the median of the severe hepatic impairment cohort (Cohort 1), 
as provided by the Sponsor.
5.1.3. Additional Inclusion Criteria for Participants with Severely Impaired Hepatic 
Function (Cohort 1)
1. Satisfy the criteria for Class C (severe hepatic impairment) of the modified 
Child-Pugh classification. 
2. A diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary 
to any acute ongoing hepatocellular process) documented by medical history, 
physical examination, liver biopsy, hepatic ultrasound, computerized tomography 
scan, or magnetic resonance imaging (MRI).
3. Stable hepatic impairment, defined as no clinically significant known change in 
disease status within the last 30 days, as documented by the participant’s recent 
medical history (eg, no worsening clinical signs of hepatic impairment, or no 
worsening of total bilirubin or prothrombin time by more than 50%). 
4. Stable drug regimen is defined as not starting a new drug or changing dosage within 
7 days or 5 half-lives (whichever is longer) prior to the dosing of dacomitinib. 
5. History of alcohol abuse is permissible providing that the results of alcohol test are 
negative at Screening or on Day -1, and the participant is willing and able to abide by 
the lifestyle guidelines described in Section 5.3.2 of this protocol.


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
5.2.1. All Participants
Medical Conditions:
1. Any condition possibly affecting drug absorption (eg, gastrectomy).
2. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
3. History of or current positive results for human immunodeficiency virus (HIV).
Prior/Concomitant Therapy:
Not applicable.
Prior/Concurrent Clinical Study Experience:
4. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of IP used in this 
study (whichever is longer). 
5. Hypersensitivity to dacomitinib or its excipients.
Diagnostic Assessments:
6. A positive urine drug test. Participants with severe hepatic impairment (Cohort 1) 
will be eligible to participate if their urine drug test is positive with a drug for a 
prescribed condition that is not expected to interfere with the PK of dacomitinib.
Other Exclusions:
7. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
8. History of sensitivity to heparin or heparin-induced thrombocytopenia.
9. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
10. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.


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5.2.2. Additional Exclusion Criteria for Participants with Normal Hepatic Function 
(Cohort 2)
In addition, participants in the normal hepatic function cohort (Cohort 2) presenting with any 
of the following will not be included in the study:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including drug allergies deemed relevant for participation in this 
study, but excluding untreated, asymptomatic, seasonal allergies at the time of 
dosing).
2. History of regular alcohol consumption exceeding 7 drinks/week for females or
14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces 
(360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
3. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If initial supine 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. 
4. Screening 12-lead ECG demonstrating corrected QT (Fridericia method) 
(QTcF) >450 msec and/or a QRS complex >120 msec.  If initial QTcF exceeds 
450 msec, or QRS complex exceeds 120 msec, the ECG should be repeated 2 more 
times and the average of the three QTcF and/or QRS complex values should be used 
to determine the participant’s eligibility.
5. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to the first dose of study medication.  As an 
exception, acetaminophen/paracetamol may be used at doses of 1 g/day.  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.  Herbal supplements and hormone replacement therapy 
must have been discontinued at least 28 days prior to the dose of dacomitinib.
6. Participants with a history of or current positive results for hepatitis B or hepatitis C, 
including hepatitis B surface antigen (HepBsAg), hepatitis B core antibody 
(HepBcAb), or hepatitis C antibody (HCVAb).
5.2.3. Additional Exclusion Criteria for Participants with Severely Impaired Hepatic 
Function (Cohort 1)
1. Other clinically significant disease that contraindicates study drug or that may affect 
the PK of dacomitinib (stable, chronic, controlled disorders such as hypertension and 
diabetes may be acceptable upon Sponsor agreement). 
2. Hepatic carcinoma and hepatorenal syndrome.


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3. Undergone porta-caval shunt surgery. 
NOTE: Participants with a transjugular intrahepatic portosystemic shunt (TIPS) are 
permitted provided that they meet the Child-Pugh classification criteria.
4. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 1 month prior to study entry.
5. Any clinically significant laboratory abnormality except for those parameters 
influenced by hepatic impairment. 
6. Participants with an estimated glomerular filtration rate (eGFR) of 
60 mL/min/1.73 m2 based on the Modification of Diet in Renal Disease (MDRD) 
equation, with a single repeat permitted to assess eligibility, if needed; 
7. Presence of clinically active Stage 3 or 4 encephalopathy.
8. Severe uncontrolled ascites and/or pleural effusion.
9. Screening supine blood pressure 160 mm Hg (systolic) or 90 mm Hg (diastolic), on 
a single measurement following at least 5 minutes of rest.  If initial supine BP is 
160 mm Hg (systolic) or 90 mm Hg (diastolic), the BP should be repeated two 
more times and the average of the three BP values should be used to determine the 
participant’s eligibility.
10. Screening supine 12-lead ECG demonstrating QTcF >470 msec.  If initial QTcF 
exceeds 470 msec, the ECG should be repeated two more times and the average of the 
three QTcF values should be used to determine the participant’s eligibility.
11. Use of food, drugs, or dietary supplements that may affect the PK of dacomitinib
within 7 days or 5 half-lives (whichever is longer) prior to the dose of dacomitinib.  
Use of medications that are not believed to affect participants’ safety and are 
medically necessary for the treatment and maintenance of hepatic disease and other 
pre-existing and/or concurrent stable comorbid conditions are permitted with
approval by the Sponsor.  Limited use of nonprescription medications that are not 
believed to affect participants’ safety or the overall results of the study may be 
permitted on a case by case basis with approval by the Sponsor.  Herbal supplements 
and hormone replacement therapy must have been discontinued at least 28 days prior 
to the dose of dacomitinib.
12. Use of CYP2D6 substrates with a narrow therapeutic index.
13. Use of food or drugs that are CYP2D6 inhibitors within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of dacomitinib until the completion of the 
last PK sample collection.  All concomitant medication must be approved by the 
Sponsor.


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14. Use of proton-pump inhibitors (PPIs) within 7 days prior to the first dose of 
dacomitinib until the completion of the last PK sample collection. 
15. Participants will abstain from taking lactulose or other medications which could result 
in diarrhea or have excessive (>2) bowel movements per day within 24 hours prior to 
dacomitinib dosing and 24 hours post dosing.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. 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.

Water is permitted until 1 hour prior to dacomitinib administration on Day 1.  Water 
may be consumed without restriction beginning 1 hour after dosing.  No food will be 
allowed for at least 4 hours postdose except that a light snack or juice may be provide 
to a diabetic particpant.

Lunch will be provided approximately 4 hours after dacomitinib dosing on Day 1.

Dinner will be provided approximately 9 to 10 hours after dacomitinib dosing on 
Day 1.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of IP until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample.  Participants 
will undergo an alcohol breath test as indicated in SoA.

Consumption of caffeinated drinks and nicotine containing products (5 cigarettes per 
day or equivalent) is permitted during participation in the study; however, participants 
will abstain from nicotine or caffeine containing products for at least 2 hours prior to 
any scheduled ECG or BP determinations. 


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5.3.3. 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 dacomitinib dosing.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
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 the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to IP/entered in the study.  Screen failure data are 
collected and remain as source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
Additionally during Screening: 

For inclusion and Child-Pugh classification, clinical laboratories that are deemed 
inconsistent, by the investigator, with the usual stage of hepatic impairment may be 
repeated;

For eligibility purposes, vital signs, laboratory tests, or ECG results may be repeated 
if an abnormal result is observed at the initial reading;

In the event that the participation of a participant in the study is delayed and any 
required screening procedures will be outside of the allowed screening window 
(28 days), these screening procedures can be repeated;


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
Participants who are not qualified based on a reversible medical condition or 
mild/acute/intercurrent illness may be re-evaluated after further testing/examination 
or re-screened after the condition has resolved.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term IP may be used synonymously with study 
intervention.
6.1. Study Intervention Administered
For this study, the IP is dacomitinib.
Tablets will be supplied to the CRU in bulk along with individual dosing containers for unit 
dosing.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive a single 30 mg 
dacomitinib tablet at approximately 0800 hours (2 hours).  Investigator site personnel will 
administer dacomitinib tablet with approximately 240 mL of ambient temperature water.  
Participants will swallow the tablet whole, and should not manipulate or chew the tablet prior 
to swallowing.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.


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3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions will be accounted for using an IP accountability form/record.
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion.  Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation. Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the IP manual. 
8. The Sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  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, and all destruction must be adequately 
documented.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the IP ready for administration or dispensing to the participant by qualified staff.  Dispensing 
is defined as the provision of IP, 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.
Tablets will be dispensed at the CRU in the individual dosing containers by 2 operators, one
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. 


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Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
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. Study Intervention Compliance
IP will be administered under the supervision of investigator site personnel.  The oral cavity 
of each participant will be examined following dosing to ensure the IP was taken.
6.5. Concomitant Therapy
For participants with normal hepatic function (Cohort 2), 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 IP.  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.
For participants with severe hepatic impairment (Cohort 1), stable concomitant medications 
may be given if they are considered necessary for the welfare of the participants(eg, standard 
therapy for the underlying diseases), considering these medications are not contraindicated 
with dacomitinib and are unlikely to interfere with the PK of dacomitinib.
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 IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
6.6. Dose Modification
Participants in this study will receive a single oral dose of 30 mg dacomitinib. No dose 
modification is allowed.


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6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Not applicable since this is a single dose study.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
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 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 at 
that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) for 
disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 


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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 IP or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page.  In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
Participants will be screened within 28 days prior to administration of the IP to confirm that 
they meet the study population criteria for the study.  The investigator (or an appropriate 
delegate at the investigator site) must obtain a signed and dated ICD before performing any 
study-specific procedures.  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.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.


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Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness.
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.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
If an intravenous (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 
140 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 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Efficacy assessments are not applicable in this study.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.


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8.2.1. 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 body weight will also be measured and recorded as per the SoA.  For measuring 
body 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 body weight. 
8.2.2. Vital Signs
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.
8.2.3. Electrocardiograms
Single or triplicate 12-Lead ECG should be collected at times specified in the SoA section of 
this protocol using an ECG machine that automatically calculates the heart rate and measures 
PR, QT, and corrected QT (QTc) intervals and QRS complex. All scheduled ECGs should 
be performed after the participant has rested quietly for at least 10 minutes in a supine 
position. 
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected on Day 1 at predose will serve as each 
participant’s time-controlled baseline QTc value.


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To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Additional ECG monitoring will occur if a) a 
postdose QTc interval is increased by 30 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is 500 msec 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 QTc 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 postdose QTc interval remains 30 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is 500 msec for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator), or QTc intervals get progressively longer, the participant
should undergo continuous ECG monitoring.  A cardiologist should be consulted if QTc 
intervals do not return to less than the criterion 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 QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. 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.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those which are not associated 
with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after dacomitinib dosing should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the Sponsor notified.


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All protocol-required laboratory test assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
If laboratory test values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
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 IP. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative).
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 it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving IP), through and including a minimum of 
28 calendar days, except as indicated below, after the last administration of the IP.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF, not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.


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Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the Sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately 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 it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to IP must be 
reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in 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.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.


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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards 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, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female partners of male participants will be collected after the 
start of study intervention and until 3 weeks after the last dose.
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.


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8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information 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 is maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the IP by the wrong 
participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the IP under study may occur in clinical trial settings, such as medication 
errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report Form to 
Pfizer Safety Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the IP;

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.
In the event of a medication dosing error, the Sponsor should be notified immediately.
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 an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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8.4. Treatment of Overdose
For this study, any dose of dacomitinib greater than 30 mg will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
dacomitinib can no longer be detected systemically (at least 17 days, 5 × dacomitinib 
half-life).
3. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Pharmacokinetic Assessment of Dacomitinib and PF-05199265
Blood samples of approximately 3 mL, to provide a minimum of 1 mL of plasma, will be 
collected into appropriately labeled tubes containing dipotassium ethylenediamine tetraacetic 
acid (K2EDTA) at each specified time point for measurement of plasma concentrations of 
dacomitinib and its metabolite PF-05199265 as specified in the SoA.  Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual or by 
the Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time (eg, within 6 minutes of a 60-minute sample) relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and data collection tool (eg, CRF).  Collection of samples more than 
10 hours after dose administration that are obtained 1 hour away from the nominal time 
relative to dosing will not be captured as a protocol deviation, as long as the exact time of the 
collection is noted on the source document and data collection tool (eg, CRF). 


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Samples will be used to evaluate the PK of dacomitinib and PF-05199265. Samples 
collected for analyses of dacomitinib and PF-05199265 plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study, for metabolite identification and/or evaluation of the bioanalytical method, or for other 
internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of dacomitinib and 
PF-05199265 will be analyzed using a validated analytical method in compliance with 
applicable standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the Sponsor.  
On a case-by-case basis, the Sponsor may make a determination as to whether sample 
integrity has been compromised.
8.5.2. Protein Binding Assessment
Blood samples (10 mL of blood to obtain 4 ml of plasma) for protein binding analysis will be 
collected into appropriately labeled tubes containing K2EDTA at times specified in the SoA.  
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the protein binding samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
SOPs.
The blood samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the 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.
8.6. Pharmacodynamics
Pharmacodynamic (PD) parameters are not evaluated in this study.


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8.7. Genetics
8.7.1. CYP2D6 Genotyping Analysis
A 3-mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected.  DNA 
samples will be analyzed for the purpose of determining the genotype of CYP2D6.
Genes for other drug-metabolizing enzymes or transporters suspected to be involved in the 
metabolism and/or excretion of dacomitinib may also be evaluated.  No other genes will be 
analyzed.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant.
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the laboratory manual or by the 
Sponsor.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected as local 
regulations and IRBs/ECs allow.
Banked biospecimens may be used for research related to drug response.  Genes and other 
analytes (eg, proteins, ribonucleic acid (RNA), nondrug metabolites) may be studied using 
the banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other 
diseases and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked biospecimens.  
The optional additional research does not require the collection of any further samples.
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in laboratory manual or by the 
Sponsor.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.


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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (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
Not applicable.
9.2. Sample Size Determination
Approximately 18 participants will be enrolled into the study to ensure 6 PK evaluable 
participants in each of the 2 cohorts.  This sample size is consistent with recommendations 
from the Food and Drug Administration (FDA) Guidance for Industry: Pharmacokinetics in 
Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on 
Dosing and Labeling3 (issued by Center for Drug Evaluation and Research [CDER]/ Center 
for Biologics Evaluation and Research [CBER], May 2003). 
9.3. Populations for Analysis
Population
Description
Safety
All participants assigned to dacomitinib and who take 1 dose of 
dacomitinib.
PK Concentration
All participants who take 1 dose of dacomitinib and have at 
least 1 dacomitinib plasma concentration.
PK parameter 
All participants who take 1 dose of dacomitinib and have at 
least 1 dacomitinib plasma PK parameters of primary interest.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in 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.
9.4.1. Efficacy Analyses
An efficacy analysis is not applicable to this study. 
9.4.2. Safety Analyses
AEs, ECGs, BP, pulse rate, and safety laboratory test data will be reviewed and summarized 
on an ongoing basis during the study to evaluate the safety of participants.  Any clinical 
laboratory test, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively by cohort, where appropriate.


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Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will be required to be reported, unless 
otherwise noted.  However, any untoward findings identified on physical 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 be required to be reported, unless otherwise noted.  Demographic data collected at 
Screening will be reported.
9.4.2.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by cohort and time.
The number (%) of participants with maximum post-dose QTc values and maximum 
increases from baseline in the following categories will be tabulated by cohort: 
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.4.3. Other Analyses 
PGx data will be collected and retained for future analyses, but will not be analyzed, 
specifically, for this study. 
9.4.3.1. Pharmacokinetic Analyses
The effect of hepatic impairment on PK parameters will be assessed by constructing 
90% confidence intervals (CIs) around the estimated difference between the Test (severe 
hepatic impairment cohort; Cohort 1) and the Reference (normal hepatic function; Cohort 2) 
using a one-way analysis of variance (ANOVA) model based on natural log transformed 
data. Only participants with CYP2D6 EM and IM in each cohort will be included in this 
analysis.
One-way ANOVA will be used to compare the natural log transformed AUCinf, AUClast and 
Cmax, and AUCinf,u, AUClast,u and Cmax,u of dacomitinib and PF-05199265, as data permit, for 
severe hepatic impairment cohort (Test) to the normal hepatic function cohort (Reference). 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model.  The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios as a percentage. 


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The dacomitinib PK parameters (AUCinf, AUCinf,u, AUClast, AUClast,u, Cmax, Cmax,u, Tmax, t½, 
CL/F, CLu/F, Vz/F, and Vz,u/F) and PF-05199265 PK parameters (AUCinf, AUCinf,u, AUClast, 
AUClast,u, Cmax, Cmax,u, Tmax, t½) will be summarized descriptively by cohort.  Boxplots of 
mean, median and individual participant parameters will be made by cohort for AUCinf, 
AUCinf,u, AUClast, AUClast,u, Cmax, and Cmax,u.  Similar presentations will also be made for 
other PK parameters, if considered relevant.  Dacomitinib and PF-05199265 total and 
unbound concentrations will be listed and summarized descriptively by PK sampling time 
and cohort.  Summary profiles (means and medians) of the dacomitinib and PF-05199265
concentration-time data will be plotted by cohort on linear and semi-log scale.  Individual 
participant concentration time profiles will be also presented.  For summary statistics and 
summary plots by sampling time, the nominal PK sampling time will be used, for individual 
participant plots by time, the actual PK sampling time will be used.
9.4.3.2. Pharmacodynamic Analyses
Not applicable.
9.5. 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 dose selection decisions, and/or supporting clinical 
development.
9.5.1. Data Monitoring Committee
This study will not use a data monitoring committee (DMC).


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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, IB, and other relevant documents 
(eg, advertisements) must be reviewed and approved by the Sponsor and 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.
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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), 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 IP, 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 ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.


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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 28 days from the previous ICD signature date.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide 
this separate signature.
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 shall 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 natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the Sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the Sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. 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.


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10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic 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.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-Sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-Sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data. 
Policy 0070 applies to new marketing authorization applications submitted via the 


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centralized procedure since 01 January 2015 and applications for line extensions and for new 
indications submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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 (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, remote, or on-site monitoring), are provided in the 
monitoring plan/contracts.
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.


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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
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.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed 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.
10.1.8. Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) 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 GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the Sponsor
30 days before submission. This allows the Sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The Sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
Sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.


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10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/team SharePoint site/study portal/clinical trial management system 
(CTMS)/study team on demand (StoD) system. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and IP identifiers, participant numbers, contact information 
for the investigator site, and contact details for a contact center in the event that the 
investigator site staff cannot be reached to provide advice on a medical question or problem 
originating from another healthcare professional not involved in the participant’s 
participation in the study.  The contact number can also be used by investigator staff if they 
are seeking advice on medical questions or problems; however, it should be used only in the 
event that the established communication pathways between the investigator site and the 
study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 
a Pfizer CRU, the contact number is not intended for use by the participant directly, and if a 
participant calls that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests (Table 2) 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 concerns.
Table 2.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
PT/INR
WBC count
Total neutrophils (abs)
Eosinophils (abs)
Monocytes (abs)
Basophils (abs)
Lymphocytes (abs)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
At screening only:

FSHb

Urine drug screeningc

Hepatitis B surface antigen

Hepatitis B core antibody

Hepatitis C antibody

Human immunodeficiency 
virus
Abbreviations: abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
BUN = blood urea nitrogen; FSH = follicle-stimulating hormone; INR = international normalized ratio;
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; qual = qualitative; PT = prothrombin time; RBC = red blood cell; 
WBC = white blood cell. 
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol (THC), 
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).
Investigators must document their review of each laboratory safety report.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the clinical study report (CSR).  Samples 
to be used for this purpose will be shipped to either a Pfizer-approved Biospecimen Banking 
System (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 (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions 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/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 which 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 SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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 detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 


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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the IP under 
study during pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.


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Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  

When an AE/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/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/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

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.

The investigator will use clinical judgment to determine the relationship.

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 investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has 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 his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the IP caused the event, then the 
event will be handled as “related to IP” for reporting purposes, as defined by the 
Sponsor.  In addition, if the investigator determines that an SAE is associated with 
study procedures, the investigator must record this causal relationship in the source 
documents and CRF, and report such an assessment in the dedicated section of the 
CT SAE Report Form and in accordance with the SAE reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare professionals.

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 completed CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the 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 data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.


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SAE Reporting to Pfizer Safety via 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, 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 Guidance and Collection of Pregnancy Information
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 weeks after the last dose of study intervention,
which corresponds to the time needed to eliminate study intervention(s) (eg, 5 terminal 
half-lives) plus an additional 90 days (a spermatogenesis cycle): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual or homosexual 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 when engaging in any activity that allows for 
passage of ejaculate to another person.

Use of an additional highly effective contraceptive method with a failure rate of 
<1% per year as described below in Section 10.4.4 for a female partner of 
childbearing potential.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant, not a WOCBP (see definitions below in Section 10.4.3), is eligible to 
participate.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential (WOCBP)
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. Premenarchal.


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2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female.

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.


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5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
3. Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the IP; or the female 
becomes or is found to be pregnant after discontinuing and/or being exposed to the 
IP;


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
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
IP prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the IP, 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.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (eg, a participant reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) to 
Pfizer Safety using the EDP supplemental form.  This must be done irrespective of whether 
an AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
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).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the IP. 


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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.


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate).

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to dacomitinib or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7) will be stored for up to 
1 years or other period as per local requirements or will not be stored beyond the 
completion of this study (eg, CSR finalization)].

Samples for banking (see Section 8.7.2) will be stored indefinitely or other period 
as per local requirements. 

Participants may withdraw their consent for the storage and/or use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses. 

Banked biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank. 


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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 drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (Tbili) elevations (>2 × ULN) by several days 
or weeks.  The increase in Tbili typically occurs while AST/ALT is/are still elevated above 
3 × ULN (ie, AST/ALT and Tbili values will be elevated within the same laboratory sample).  
In rare instances, by the time Tbili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to Tbili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and Tbili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a Tbili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR Tbili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of Tbili above the normal range: Tbili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).


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Rises in AST/ALT and Tbili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and Tbili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (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 (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, 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 and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
Tbili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability of all 
the results of the investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec 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 premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS complex >120 msec).

New-onset right bundle branch block (QRS complex >120 msec).

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 (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 


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monomorphic/polymorphic ventricular tachycardia >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 Serious Adverse Events

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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10.8. Appendix 8: Modified Child-Pugh Classification (CPC) of Liver Dysfunction
CPC score is calculated from the sum of the points for each CPC criteria:
CPC Classification
Level of dysfunction
Score
C
Severe
10
Assessment Parameters
Assigned Score for Observed Findings
1 point
2 point
3 point
Encephalopathy grade
(refer to table below)
0
1 or 2
3 or 4a
Ascites
Absent
Slight
Moderateb
Serum total bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, seconds prolonged
<4
4 to 6
>6
a.
Including participants with a history of stage 3 or stage 4 encephalopathy receiving medication(s) to 
prevent recurrent encephalopathy; participants with clinically active stage 3 or 4 encephalopathy are 
excluded from participation in the study.
b.
Including participants with history of severe ascites on medication(s) to control their ascites.
Encephalopathy 
Grade
Definition
0
Normal consciousness, personality, neurological exam
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting
2
Lethargic, time-disoriented, inappropriate, asterixis, ataxia
3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity
4
Unrousable coma, no personality/behavior, decerebrate


Dacomitinib
A7471058
Final Protocol, 14 November 2018
Page 73
10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CV
percent coefficient of variation
abs
absolute
ADME
absorption, distribution, metabolism and excretion
AE
adverse event
Akt
protein kinase b
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC24
area under the concentration time curve from time 0 to 24 hours post-dose
AUCinf
area under the concentration time curve from time 0 to infinity
AUCinf, u
unbound AUCinf
AUClast
area under the concentration time curve from time 0 to the time of last quantifiable 
concentration
AUClast, u
unbound AUClast
AUCtau
area under the concentration time curve over doing interval tau
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSEP
bile salt export pump
BUN
blood urea nitrogen
CBER
Center for Biologics Evaluation and Research
CDER
Center for Drug Evaluation and Research
CK
creatine kinase
Cmax
maximum observed plasma concentration
Cmax, u
unbound Cmax
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
clearance
CL/F
apparent oral clearance
CLu/F
unbound CL/F
CPC
Child-Pugh Classification
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CTMS
clinical trial management system
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury


Dacomitinib
A7471058
Final Protocol, 14 November 2018
Page 74
Abbreviation
Term
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
eGFR
estimated glomerular filtration rate
EM
extensive metabolizer
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
fu
fraction of unbound drug in plasma
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IGF1R
insulin-like growth factor 1 receptor
IM
intermediate metabolizer
IND
investigational new drug
INR
international normalized ratio
IP 
investigational product 
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
JAK3
janus kinase 3
K2EDTA
dipotassium ethylenediamine tetraacetic acid
LFT
liver function test
MDRD
Modification of Diet in Renal Disease
MET
mesenchymal-epithelial transition
MRI
magnetic resonance imaging
N/A
not applicable
NCI
National Cancer Institute


Dacomitinib
A7471058
Final Protocol, 14 November 2018
Page 75
Abbreviation
Term
NSCLC
non-small cell lung cancer
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PCD
primary completion date
PD
pharmacodynamic(s)
PDGFR
platelet-derived growth factor receptor
PGx 
pharmacogenomic(s)
P-gp
P-glycoprotein
PI
principal investigator
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic(s)
PPI
proton-pump inhibitor
PR
pulse rate
PT
prothrombin time
QD
once daily
QTc
corrected QT
QTcB
corrected QT (Bazett method)
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
ROS1
ROS oncogene 1
RTK
receptor tyrosine kinase
rCYP
recombinant cytochrome P450
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t½
terminal phase half-life
Tbili
total bilirubin
TIPS
transjugular intrahepatic portosystemic shunt
Tmax
time to reach the maximum observed plasma concentration
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution
Vz, u/F
Unbound Vz/F
WBC
white blood cell
WOCBP
woman of childbearing potential


Dacomitinib
A7471058
Final Protocol, 14 November 2018
Page 76
11. REFERENCES
1.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med 2016;5(1):23-37.
2.
The National Cancer Institute Organ Dysfunction Working Group Criteria for 
assessment of hepatic impairment.
3.
FDA Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (Issued by 
CDER/CBER, May 2003).

SAP_001.pdf: 
Protocol A7471058 (PF-00299804) Statistical Analysis Plan
Page 1 of 17
 
Protocol A7471058
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL-GROUP 
STUDY TO EVALUATE THE PLASMA PHARMACOKINETICS AND 
SAFETY OF DACOMITINIB IN PARTICIPANTS WITH SEVERELY 
IMPAIRED HEPATIC FUNCTION RELATIVE TO PARTICIPANTS 
WITH NORMAL HEPATIC FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(FSP Statistician – Sciformix Technologies Pvt. Ltd, Mumbai)
Date:
11-JAN-2019
PPD


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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
January 11, 2019
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.1.1. Concentration Analysis Set...........................................................................7
5.1.2. Parameter Analysis Set.................................................................................7
5.2. Pharmacodynamic Analysis Set................................................................................7
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................8
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoint(s) .................................................................................................8
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
7.1. Concentrations Below the Limit of Quantification.................................................10


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7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods and Analyses............................................................................11
8.2. Safety Analysis........................................................................................................13
8.2.1. Treatment and Disposition of Subjects.......................................................13
8.2.2. Demographic and Clinical Examination Data............................................14
8.2.3. Discontinuation(s).......................................................................................14
8.2.4. Adverse Events...........................................................................................14
8.2.5. Laboratory Data..........................................................................................14
8.2.6. Vital Signs Data..........................................................................................14
8.2.7. ECG Data....................................................................................................14
8.2.8. Other Safety Data .......................................................................................15
8.2.9. Concomitant Treatments.............................................................................15
8.2.10. Screening and Other Special Purpose Data ..............................................15
8.2.11. Other Analyses..........................................................................................15
8.2.12. Child-Pugh Classification Data ................................................................15
9. REFERENCES ....................................................................................................................16
10. APPENDICES ...................................................................................................................17
LIST OF TABLES
Table 1.
Hepatic Function Categories Based on Child-Pugh Classification ............6
Table 2.
Noncompartmental PK Parameters...........................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Group......................12
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................17


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Dacomitinib (PF-00299804) is a selective, adenosine triphosphate (ATP) competitive, 
irreversible, small-molecule inhibitor of the HER (ERBB) family of receptor tyrosine kinases 
(RTKs), including the epidermal growth factor receptor (EGFR, HER1), the HER2 receptor 
(ERBB2), the HER4 receptor (ERBB4), and their oncogenic variants (eg, EGFR with del 
exon 19 or L858R mutations).  It is currently approved for the first-line treatment of patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) with 
EGFR-activating mutations.
Insufficient data are however available regarding the use of dacomitinib in patients with 
severe hepatic impairment to provide dosing recommendations in this patient population.
The purpose of this study is to evaluate the effect of severe hepatic impairment on the single 
dose PK of dacomitinib.
2.1. Study Design
This will be a Phase 1, open-label, parallel-group study to investigate the effect of severe
hepatic impairment on the plasma PK, safety and tolerability after a single oral 30 mg dose 
of dacomitinib under fasted conditions. 
At Screening, the modified Child-Pugh classification score as outlined in Appendix 8 of the 
Protocol will be utilized to assess entry criteria and to assign participants into the 
appropriate hepatic impairment group (Table 1 below).  The modified Child-Pugh 
classification criteria will permit enrollment of participants with a history of Stage 3 or Stage 
4 encephalopathy who are receiving medication(s) to prevent recurrent encephalopathy; 
participants with clinically active Stage 3 or 4 encephalopathy will be excluded from 
participation in the study.  The criteria will also allow enrollment of participants with history
of severe ascites who are on medication(s) to control their ascites.


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Table 1.
Hepatic Function Categories Based on Child-Pugh Classification
Cohort 
Description
Child-Pugh Score
Number of Participants
1
Severe hepatic impairment
Class C (10 to 15 points)
8
2
Normal hepatic function
Not applicable
8a
a.
Participants in Cohort 2 may be dosed to a maximum of 10 participants to ensure that the age of each 
participant in Cohort 2 is within 10 years and the body weight is within 15 kg to the median age 
and median body weight of participants in Cohort 1, respectively.
Approximately 18 participants will be enrolled into the study to ensure at least 6 PK 
evaluable (having data for estimating primary PK parameters for dacomitinib) participants 
in each cohort.  Participants who withdraw may be replaced upon agreement with the 
Sponsor.
The participants from the severely impaired hepatic function cohort will be recruited first, 
and a median value for age and weight will be determined for all evaluable participants 
across study sites in this cohort.  Then the control participants from the normal hepatic 
function cohort will be recruited later such that the age of each participant in Cohort 2 is 
within 10 years and the body weight is within 15 kg of the median of the participants in the 
severe hepatic impairment cohort (Cohort 1).  An attempt will be made to maintain a similar 
male/female ratio and racial make-up between Cohorts 1 and 2.  Approval from the Sponsor 
must be obtained before proceeding with dosing participants in Cohort 2. 
After the PK data from all participants with severe hepatic impairment (Cohort 1) have been 
reviewed, the Sponsor will notify the site if additional participants for Cohort 1 are required.  
If no additional participants are required, recruitment for participants with normal hepatic 
function (Cohort 2) will begin.  If the PK variability is greater than expected, additional 
participants may be enrolled in Cohort 1 and the sample size for Cohort 2 will also be 
increased accordingly. 
The end of the study is defined as the date of the last visit of the last participant in the study.  
2.2. Study Objectives
Primary Objective
To evaluate the effect of severe hepatic impairment on the single dose plasma PK of 
dacomitinib.
Secondary Objective
To assess the safety and tolerability of a single oral dose of dacomitinib in participants with 
normal hepatic function and participants with severe hepatic impairment.


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Tertiary/Exploratory Objectives

To characterize the effect of severe hepatic impairment on other plasma PK 
parameters of dacomitinib and its metabolite PF-05199265.

To analyze CYP2D6 genotype in pharmacogenetic samples.

To enable exploratory research through collection of banked biospecimens, unless 
prohibited by local regulations or ethics committee decision.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
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 dose selection decisions, 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.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
This set is defined as all participants who take 1 dose of dacomitinib and have at least 
1 dacomitinib plasma concentration.
5.1.2. Parameter Analysis Set
This set is defined as all participants who take 1 dose of dacomitinib and have at least 
1 dacomitinib plasma PK parameters of primary interest.
5.2. Pharmacodynamic Analysis Set
None.


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5.3. Safety Analysis Set
This set is defined as all participants assigned to dacomitinib and who take 1 dose of 
dacomitinib.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.
If a subject takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (e.g. lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 5.1 and 5.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.


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6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events;

laboratory data;

vital signs data;

ECG results.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of dacomitinib and PF-05199265 will be taken according to 
the Schedule of Activities given in the protocol.
The following PK parameters will be calculated for dacomitinib and PF-05199265 (if 
possible) from the concentration-time data using standard noncompartmental methods:


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Table 2.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
Dacomitinib
PF-05199265
AUCinf
*
ln
A, D
A, D
AUCinf,u
*
ln
A, D
A, D
AUClast
ln
A, D
A, D
AUClast,u
ln
A, D
A, D
Cmax
ln
A, D
A, D
Cmax,u
ln
A, D
A, D
Tmax
R
D
D
t1/2
*
ln
D
D
CL/F*
ln
D
-
CLu/F*
ln
D
-
VZ/F*
ln
D
-
VZ,u/F*
ln
D
-
Fu
R
D
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), u=unbound, *=if data permits
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. 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).
7.2. 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);


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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.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’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 subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set 
to missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods and Analyses
The effect of hepatic impairment on PK parameters will be assessed by constructing 
90% confidence intervals (CIs) around the estimated difference between the Test (severe 
hepatic impairment cohort; Cohort 1) and the Reference (normal hepatic function; Cohort 2) 
using a one-way analysis of variance (ANOVA) model based on natural log transformed 
data.  Only participants with CYP2D6 EM and IM in each cohort will be included in this 
analysis.
One-way ANOVA will be used to compare the natural log transformed AUCinf, AUClast and 
Cmax, and AUCinf,u, AUClast,u and Cmax,u of dacomitinib and PF-05199265, as data permit, for 
severe hepatic impairment cohort (Test) to the normal hepatic function cohort (Reference).  
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model.  The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios as a percentage. 


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The dacomitinib PK parameters (AUCinf, AUCinf,u, AUClast, AUClast,u, Cmax, Cmax,u, Tmax, t½, 
CL/F, CLu/F, Vz/F, and Vz,u/F) and PF-05199265 PK parameters (AUCinf, AUCinf,u, AUClast, 
AUClast,u, Cmax, Cmax,u, Tmax, t½) will be summarized descriptively by cohort.  Boxplots of 
mean, median and individual participant parameters will be made by cohort for AUCinf, 
AUCinf,u, AUClast, AUClast,u, Cmax, and Cmax,u.  Similar presentations will also be made for 
other PK parameters, if considered relevant.  Dacomitinib and PF-05199265 total and 
unbound concentrations will be listed and summarized descriptively by PK sampling time 
and cohort.  Summary profiles (means and medians) of the dacomitinib and PF-05199265 
concentration-time data will be plotted by cohort on linear and semi-log scale.  Individual 
participant concentration time profiles will be also presented.  For summary statistics and 
summary plots by sampling time, the nominal PK sampling time will be used, for individual 
participant plots by time, the actual PK sampling time will be used.
Residuals from the models 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 clinical study report.  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.
The following PK parameters will be summarized and listed by hepatic function group:
Table 3.
PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
AUCinf, AUCinf,u, AUClast, 
AUClast,u, Cmax, Cmax,u, CL/F,
CLu/F, Vz/F, and Vz,u/F
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric mean 
and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2, fu
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum.
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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Presentations for dacomitinib and PF-05199265 concentrations will include:

a listing of all concentrations sorted by hepatic function group (present in heading), 
subject id 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 hepatic function group and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.

median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function group (all hepatic function groups on the same plot 
per scale, based on the summary of concentrations by hepatic function group and time 
postdose).

mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function group (all hepatic function groups on the same plot 
per scale, based on the summary of concentrations by hepatic function group and time 
postdose).

individual concentration time plots by hepatic function group (on both linear and 
semi-log scales) against actual time postdose (there will be separate spaghetti plots 
for each hepatic function group per scale).

Box and whisker plots for individual subject parameters (AUCinf, AUCinf, u, AUClast, 
AUClast, u, Cmax, and Cmax, u) by hepatic function group and overlaid with geometric 
means.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.2. Safety Analysis
A set of summary tables split by hepatic function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering study treatments.
8.2.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by hepatic 
function group.


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Data will be reported in accordance with the sponsor reporting standards.
8.2.2. Demographic and Clinical Examination Data
A break down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.2.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by hepatic function group.
Data will be reported in accordance with the sponsor reporting standards.
8.2.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function group.
8.2.5. Laboratory Data
The baseline measurement is the last predose measurement.
For each planned timepoint, baseline values and change from baseline values within each 
hepatic function group will be summarized with descriptive statistics (using sponsor default 
standards).
Laboratory data will be listed in accordance with the sponsor reporting standards.
8.2.6. Vital Signs Data
Supine blood pressure and pulse rate will be measured as per the Schedule of Activities 
mentioned in the protocol.
The baseline measurement is the last predose measurement.
For each planned timepoint, baseline values and change from baseline values within each 
hepatic function group will be summarized with descriptive statistics (using sponsor default 
standards).
These data will be listed in accordance with the sponsor reporting standards.
8.2.7. ECG Data
The baseline measurement is the predose measurement.


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Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by cohort and time.
The number (%) of participants with maximum post-dose QTc values and maximum 
increases from baseline in the following categories will be tabulated by cohort: 
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
These data will be listed in accordance with the sponsor reporting standards.
8.2.8. Other Safety Data
None.
8.2.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.2.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine B-hCG for all females of childbearing potential, Alcohol/tobacco use and
Breath alcohol test, Hepatitis B (HepBsAg, HepBcAb), Hepatitis C (HCVAb), and HIV tests 
and urine drug testing will be obtained at Screening.
These data will not be brought in-house, and therefore will not be listed.
8.2.11. Other Analyses
PGx (pharmacogenomics) data will be collected and listed by subject per cohort in this study.
8.2.12. Child-Pugh Classification Data
This data will be listed by subject per cohort in this study.


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9. REFERENCES
None.


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC GLM code is provided below:
proc glm data=tab.pk;
class group;
model l&var=group/ss3 clparm alpha=0.1;
lsmeans group;
estimate 'Severe vs Normal'
group 1 -1;
ods output Estimates = est&var;
ods output FitStatistics = fit&var;
ods output ModelANOVA = tst&var;
ods output OverallANOVA = overall&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Severe hepatic impairment (Test)
B = Normal hepatic function (Reference);
  */;