Clinical trial NCT04056468
Conditions: Hepatic Impairment Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2020-10-09; Completion date: 2022-02-26
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to characterize the single-dose plasma PK of mobocertinib and its active metabolites (AP32960 and AP32914) in participants with moderate and/or severe HI compared to matched-healthy participants with normal hepatic function.

Detailed description:
29-Apr-2020 Enrollment of new participants into this study was paused due to the COVID-19 situation. The duration of this pause was dependent on the leveling and control of the COVID-19 pandemic.

The drug being tested in this study is called mobocertinib. The study will assess the PK of single dose mobocertinib and its active metabolites (AP32960 and AP32914) in participants with moderate and/or severe HI compared to matched-healthy participants with normal hepatic function.

The study will enroll approximately 24 participants. Participants will be assigned to 1 of the following 3 treatment groups in a staggered manner based on their degree of hepatic impairment which will be determined based on Child-Pugh Score as follow:

* Moderate HI (Child-Pugh B): Mobocertinib 40 mg
* Severe HI (Child-Pugh C): Mobocertinib 40 mg
* Normal Hepatic Function: Mobocertinib 40 mg

Healthy participants with normal hepatic function will be recruited to match both moderate and severe HI by age (mean plus or minus \[+-\] 10 years), gender (+-2 participants per gender), and body mass index (BMI, mean +-10 percent \[%\]).

All participants will be asked to take single dose of mobocertinib on Day 1. The dose level for severe HI may be modified based on the previous results of approximately 3 moderate HI and healthy participants who completed up to Day 10 study procedures.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 51 days. Participants will be contacted by telephone 30 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: Mobocertinib 40 milligram (mg), capsule, orally, a single dose on Day 1. arm 2: Mobocertinib 40 mg, capsule, orally, a single dose on Day 1. arm 3: Mobocertinib 40 mg, capsule, orally, a single dose on Day 1.
Interventions: intervention 1: Mobocertinib
Intervention descriptions: intervention 1: Mobocertinib capsule.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT04056468 
Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in 
Subjects With Moderate or Severe Hepatic Impairment and Normal 
Hepatic Function 
TAK-788-1008
Protocol Version and Date: 
Version 2.0: 12-Aug-2020 


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects with 
Moderate or Severe Hepatic Impairment and Normal Hepatic Function
Study Identifier:
TAK-788-1008
Compound:
Mobocertinib
Date:
07 August 2020
Version/Amendment 
Number:
Amendment 2
Amendment History: 
Date
Amendment Number
Amendment Type
Region
12 July 2019
Initial Version
Not applicable
United States
10 September 2019
01
Appendix E
United States
07 August 2020
02
Appendix F
United States
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................14
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................15
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................20
4.3
Child-Pugh Classification of Hepatic Impairment ....................................................21
4.4
Benefit/Risk Profile .................................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Hypothesis...............................................................................................................24
5.2
Study Objectives......................................................................................................24
5.2.1
Study Primary Objective .............................................................................24
5.2.2
Study Secondary Objectives........................................................................24
5.2.3
Study Exploratory Objective .......................................................................24
5.3
Endpoints.................................................................................................................24
5.3.1
Primary Endpoint........................................................................................24
5.3.2
Secondary Endpoints...................................................................................25
5.3.3
Exploratory Endpoint..................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Dose Escalation .......................................................................................................27
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................28
6.3.1
Rationale of Study Design...........................................................................28
6.3.2
Rationale for Dose ......................................................................................28
6.3.3
Rationale for Endpoints...............................................................................28
6.3.3.1
Pharmacokinetic Endpoints ....................................................................28
6.3.3.2
Safety Endpoints ....................................................................................29
6.3.4
Future Biomedical Research........................................................................29
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures........29
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.5
Study Beginning and End/Completion .....................................................................29
6.5.1
Definition of Beginning of the Study...........................................................29
6.5.2
Definition of End of the Study.....................................................................30
6.5.3
Definition of Study Completion ..................................................................30
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6.5.4
Definition of Study Discontinuation............................................................30
6.5.5
Criteria for Premature Termination or Suspension of the Study...................30
6.5.6
Criteria for Premature Termination or Suspension of a Site.........................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............31
7.1
Inclusion Criteria .....................................................................................................31
7.1.1
Inclusion Criteria for Healthy Subjects........................................................31
7.1.2
Inclusion Criteria for Subjects with Moderate or Severe Hepatic 
Impairment..................................................................................................32
7.2
Exclusion Criteria ....................................................................................................33
7.2.1
Exclusion Criteria for Healthy Subjects.......................................................33
7.2.2
Exclusion Criteria for Subjects with Moderate or Severe Hepatic 
Impairments................................................................................................34
7.3
Prior and Concomitant Medications and Therapies...................................................35
7.4
Excluded Medications, Supplements, Dietary Products............................................36
7.5
Diet, Fluid, Activity.................................................................................................37
7.5.1
Diet and Fluid .............................................................................................37
7.5.2
Activity.......................................................................................................37
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................38
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................38
7.8
Subject Replacement................................................................................................38
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................39
8.1
Clinical Study Drug .................................................................................................39
8.1.1
Clinical Study Drug Labeling......................................................................39
8.1.2
Clinical Study Drug Inventory and Storage .................................................39
8.1.3
Clinical Study Drug Blinding ......................................................................39
8.1.4
Randomization Code Creation and Storage .................................................39
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure............................40
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs ........................40
9.0
STUDY PROCEDURES...............................................................................................41
9.1
Administrative Procedures.......................................................................................41
9.1.1
Informed Consent Procedure.......................................................................41
9.1.1.1
Assignment of Screening and Allocation Numbers .................................41
9.1.1.2
Study Drug Assignment..........................................................................41
9.1.2
Inclusion and Exclusion ..............................................................................41
9.1.3
Medical History/Demography .....................................................................41
9.1.4
Concomitant Medications............................................................................41
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9.2
Clinical Procedures and Assessments.......................................................................41
9.2.1
Full Physical Examination...........................................................................42
9.2.2
Height and Weight ......................................................................................42
9.2.3
Body Mass Index ........................................................................................42
9.2.4
Vital Signs ..................................................................................................42
9.2.5
12-Lead ECG..............................................................................................42
9.2.6
Pulmonary Function Test ............................................................................43
9.2.6.1
Spirometry..............................................................................................43
9.2.7
Study Drug Administration .........................................................................43
9.2.8
AE Monitoring............................................................................................43
9.2.9
Laboratory Procedures and Assessments .....................................................43
9.2.9.1
Clinical Laboratory Tests........................................................................44
9.3
Pharmacokinetic Samples ........................................................................................45
9.3.1
PK Measurements .......................................................................................45
9.3.1.1
Plasma PK Measurements ......................................................................45
9.3.2
47
9.3.3
PGx Measurements .....................................................................................47
9.3.4
Confinement ...............................................................................................47
10.0
ADVERSE EVENTS ....................................................................................................48
10.1
Definitions and Elements of AEs .............................................................................48
10.1.1
SAEs...........................................................................................................50
10.1.2
Special Interest AEs....................................................................................51
10.2
AE Procedures.........................................................................................................51
10.2.1
Assigning Severity/Intensity of AEs............................................................51
10.2.2
Assigning Causality of AEs.........................................................................52
10.2.3
Start Date....................................................................................................52
10.2.4
End Date.....................................................................................................52
10.2.5
Outcome .....................................................................................................52
10.2.6
Collection and Reporting of AEs, SAEs, Special Interest AEs, and 
Abnormal LFTs...........................................................................................53
10.2.6.1
Collection Period....................................................................................53
10.2.6.2
Reporting AEs........................................................................................53
10.2.6.3
Reporting SAEs......................................................................................54
10.2.6.4
Reporting Special Interest AEs...............................................................54
10.2.6.5
Reporting of Abnormal Liver Function Tests..........................................54
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10.2.7
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................55
10.2.8
Procedures for Reporting Product Complaints or Medication Errors 
(Including Overdose) ..................................................................................55
11.0
STATISTICAL METHODS..........................................................................................56
11.1
Statistical and Analytical Plans ................................................................................56
11.1.1
Analysis Sets...............................................................................................56
11.1.1.1
Pharmacokinetic Set ...............................................................................56
11.1.1.2
Safety Set ...............................................................................................56
11.1.1.3
Pharmacodynamic Set ............................................................................56
11.1.2
Analysis of Demography and Other Baseline Characteristics.......................56
11.1.3
Pharmacokinetic Analysis ...........................................................................56
11.1.4
Pharmacodynamic Analysis ........................................................................57
11.1.5
Safety Analysis ...........................................................................................57
11.1.5.1
AEs ........................................................................................................57
11.1.5.2
Clinical Laboratory Evaluation...............................................................57
11.1.5.3
Vital Signs..............................................................................................57
11.1.5.4
Other Safety Parameters .........................................................................57
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................58
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
12.1
Study-Site Monitoring Visits ...................................................................................59
12.2
Protocol Deviations..................................................................................................59
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
13.1
IRB and/or IEC Approval ........................................................................................60
13.2
Subject Information, Informed Consent, and Subject Authorization .........................61
13.3
Subject Confidentiality ............................................................................................62
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................62
13.4.1
Publication and Disclosure..........................................................................62
13.4.2
Clinical Study Registration..........................................................................63
13.4.3
Clinical Study Results Disclosure................................................................63
13.5
Insurance and Compensation for Injury....................................................................63
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................64
14.1
Administrative Information......................................................................................64
14.1.1
Study Contact Information ..........................................................................64
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14.1.2
Investigator Agreement ...............................................................................65
14.1.3
Study-Related Responsibilities....................................................................66
14.1.4
List of Abbreviations...................................................................................66
15.0
DATA HANDLING AND RECORDKEEPING............................................................68
15.1
CRFs (Electronic and Paper)....................................................................................68
15.2
Record Retention .....................................................................................................68
16.0
REFERENCES..............................................................................................................70
17.0
APPENDICES...............................................................................................................71
LIST OF IN-TEXT TABLES
Table 1.a
Study Design........................................................................................................8
Table 3.a
Pharmacokinetic Plasma Concentration Sampling Schedule...............................18
Table 4.a
Derivation of Child-Pugh Classification Score 1.................................................22
Table 4.b
Determination of Encephalopathy Grade 1..........................................................22
Table 6.a
Study Arms and Planned Dose ...........................................................................26
Table 6.b
Study Design......................................................................................................27
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................37
Table 9.a
Primary Specimen Collections ...........................................................................45
Table 10.a
Takeda Medically Significant AE List................................................................51
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................71
Appendix B
Elements of the Subject Informed Consent.........................................................73
Appendix C
Investigator Consent to the Use of Personal Information ....................................76
Appendix D
Pregnancy and Contraception.............................................................................77
Appendix E
Detailed Description of Amendments to Text: Amendment 1.............................79
Appendix F
Detailed Description of Amendments to Text: Amendment 2.............................80
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1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Telephone: +1 (617) 679-7000
Compound:
Mobocertinib
Study Identifier: TAK-788-1008 (CA27459)
Phase: 1
Protocol Title: Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects with Moderate or 
Severe Hepatic Impairment and Normal Hepatic Function
Trial Design:
This is an open-label, parallel-arm study of oral Mobocertinib designed to assess the PK of single dose mobocertinib
and its active metabolites (AP32960 and AP32914) in subjects with moderate and/or severe hepatic impairment (HI) 
compared to matched-healthy subjects with normal hepatic function. 
Approximately 8 subjects will be enrolled in each arm of the study according to the following criteria:

Arm 1: Moderate HI (Child-Pugh B),

Arm 2: Severe HI (Child-Pugh C),

Arm 3: Normal hepatic function. Healthy subjects with normal hepatic function will be recruited to match both 
moderate and severe HI by age (mean ± 10 years), gender (± 2 subjects per gender), and body mass index (BMI, 
mean ± 10%). 
The study will consist of a 21-day screening period, a10-day confinement period (Day −1 to Day 10) and a follow-up 
phone call 30 ± 2 days after dosing.
For assessment of hepatic function, two hepatic function assessments are required prior to Day 1. These 2 assessments 
should be obtained during the screening period and on Day -1, at least 48 hours apart. If the Child-Pugh scores from 
these 2 assessments indicate the same liver function category for the subject (ie, normal function, moderate 
impairment, or severe impairment), mobocertinib can be administered as scheduled. If the results of the 2 assessments 
indicate different liver function categories, a third assessment must be conducted at least 24 hours after the second 
assessment. If the results of the 2 most recent assessments (the second and third) are in agreement with regard to the 
subject’s liver function category, the subject may be enrolled and should receive the Day 1 dose within 48 hours of the 
third assessment. If the second and third measurements differ, the subject will not be eligible for the study.
Subjects will be enrolled in a staggered manner. All moderate HI subjects may be enrolled concurrently however 
approximately 3 subjects in the moderate HI arm and approximately 3 subjects in the matched-normal hepatic function 
arm must complete up to Day 10 study procedures prior to enrolling the subjects to the severe HI arm. An informal 
preliminary PK data analysis of these subjects will be performed and may additionally leverage historical control PK 
data in healthy subjects to gain an initial estimate of effect of moderate HI on the PK of mobocertinib and its active 
metabolites (AP32960 and AP32914). These preliminary data along with safety data will guide the decision to enroll 
the severe HI arm (for example, a decision will be made to dose the severe HI group at the same dose as the moderate 
HI arm, a reduced dose, or to not dose this arm). Following completion of enrollment of the moderate and severe HI (if 
enrolled) arms, the remaining subjects will be enrolled to the matched-normal hepatic function arm. 
Subjects will receive a single oral dose of 40 mg mobocertinib on Day 1 (Table 1.a).
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Table 1.a
Study Design
Study Day
-1
1
2
3
4
5
6
8
10
Mobocertinib PO
X
PK Blood Samples 
X
X
X
X
X
X
X
X
Confinement in CRU
X
X
X
X
X
X
X
X
X
CRU-clinical research unit; PK-pharmacokinetics; PO-per os (by mouth).
Blood samples will be collected from Days 1 to 10 at predetermined time points to characterize the PK and plasma 
protein binding of mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with moderate and/or 
severe HI compared to matched-healthy subjects with normal hepatic function.
Spirometry, as the pulmonary function test (PFT), may be performed in the event of a pulmonary adverse event (AE), 
if deemed clinically necessary by the Investigator or designee.
Subjects will be confined in the clinic research unit (CRU) until the morning of Day 10 after the 216-hour PK sample 
collection for additional PK sample collections. A subject may be required to remain at the CRU for longer periods, at 
the discretion of the Investigator. Subjects may be admitted earlier than Day -1 for COVID-19 testing not related to 
study protocol as per CRU requirements.
A final safety follow up phone call will occur 30 ± 2 days after mobocertinib dosing to determine if any AEs have 
occurred since last study visit.
Study Primary Objective:
To characterize the single-dose plasma PK of mobocertinib and its active metabolites (AP32960 and AP32914) in 
subjects with moderate and/or severe HI compared to matched-healthy subjects with normal hepatic function.
Study Secondary Objectives:
1.
To evaluate plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914).
2.
To assess the safety of mobocertinib following single oral dose in subjects with moderate and/or severe HI as well 
as matched-healthy subjects with normal hepatic function.
Study Subject Population: Subjects will be enrolled in each arm of the study according to the following criteria:
Arm 1: Moderate HI (Child-Pugh B)
Arm 2: Severe HI (Child-Pugh C)
Arm 3: Normal hepatic function
Planned Number of Subjects:
At least 24 subjects will be enrolled into 3 arms (8 in 
each arm). 
Up to 16 healthy subjects may be enrolled into Arm 3 if 
it is not feasible to match the first 8 healthy subjects 
into both Arms 1 and 2. 
Planned Number of Sites:
At least 2
Dose Level:
40 mg Mobocertinib, single dose*
*The dose level for severe HI arm may be modified 
based on the preliminary results of approximately 
3 moderate HI and 3 healthy matched subjects who 
completed up to Day 10 study procedures.
Route of Administration:
Oral
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Duration of Treatment:
Day 1, subjects will receive a single oral dose of 
Mobocertinib
Planned Study Duration:
Approximately 51 days ± 2 days including screening period 
and follow-up.
Main Criteria for Inclusion:
Healthy Subjects: 
The subject must fulfill the following inclusion criteria to be eligible for participation in the study:
1.
Healthy, adult male or female subjects aged ≥18 to <80 years, at screening. Subjects will be matched to hepatic 
impaired subjects by age (mean ± 10 years) at screening.
2.
Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before screening. Subject 
must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior to mobocertinib dosing 
and throughout the period of PK sample collection
3.
Body mass index (BMI) ≥18.0 and ≤39.0 kg/m2, at screening. Subjects will be matched to hepatic impaired 
subjects by BMI (mean ± 10 %) at screening. At least 50% of the subjects will be required to be of BMI ≥18.0 and 
≤35.0 kg/m2, at screening.
4.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or ECGs, as deemed by the Investigator or designee. Has liver function tests including alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin 
within the upper limit of normal at screening and at check-in.
5.
Creatinine clearance (eGFR) ≥60 mL/min/1.73m2 at screening.
6.
Female subjects of nonchildbearing potential must have undergone one of the following sterilization procedures 
at least 6 months prior to dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle stimulating hormone (FSH) 
serum levels consistent with postmenopausal status.
7.
Female subjects of childbearing potential will be advised to remain sexually inactive or to keep the same birth 
control method for at least 30 days following mobocertinib dosing as indicated in Appendix D.
8.
Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days following 
mobocertinib dosing as indicated in Appendix D.
9.
Males subjects who are sexually active with a female partner of childbearing potential must use barrier 
contraception as indicated in Appendix D or abstain from sexual intercourse during the study until at least 30 days 
after mobocertinib dosing. Total abstinence (no sexual intercourse) may be considered an acceptable method of 
birth control if it agrees with his preferred and usual lifestyle.
10. Male subjects must agree not to donate sperm from dosing until at least 30 days after dosing as indicated in 
Appendix D.
11. Understands the study procedures in the ICF and be willing and able to comply with the protocol.
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Subjects with Moderate or Severe Hepatic Impairment: 
The subject must fulfill the following inclusion criteria to be eligible for participation in the study: 
1.
Adult male or female subjects aged ≥18 to <80 years, at screening.
2.
Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before screening. Subject 
must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior to mobocertinib dosing 
and throughout the period of PK sample collection.
3.
BMI ≥18.0 and ≤39.0 kg/m2, at screening. At least 50% of the subjects will be required to be of BMI ≥18.0 and 
≤35.0 kg/m2, at screening.
4.
Aside from HI, be sufficiently healthy for study participation based upon medical history, physical examination, 
vital signs, ECGs, and screening clinical laboratory profiles, as deemed by the Investigator or designee.
5.
Creatinine clearance (eGFR) ≥60 mL/min/1.73m2 at screening.
6.
Diagnosis of chronic (eg, imaging, biopsy, etc.) stable hepatic insufficiency for at least 6 months (no acute 
episodes of illness within the previous 2 months due to deterioration in hepatic function) with features of cirrhosis 
due to any etiology according to medical history.
7.
Chronic HI for at least 3 months before screening, and the HI must be stable, ie, no significant changes in hepatic 
function in the 30 days preceding screening (or since the last visit if within 6 months before screening) and 
treatment with stable doses of medication. Has a score on the Child-Pugh Class (Table 4.a) at screening as 
follows: 
Moderate HI arm, Child-Pugh Class B: ≥7 and ≤9
Severe HI arm, Child-Pugh Class C: ≥10 and ≤15
8.
Female subjects of nonchildbearing potential must have undergone one of the following sterilization procedures 
at least 6 months prior to dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum levels consistent with 
postmenopausal status.
9.
Female subjects of childbearing potential will be advised to remain sexually inactive or to keep the same birth 
control method for at least 30 days following mobocertinib dosing as indicated in Appendix D.
10. Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days following 
mobocertinib dosing as indicated in Appendix D.
11. Males subjects who are sexually active with a female partner of childbearing potential must use barrier 
contraception as indicated in Appendix D or abstain from sexual intercourse during the study until at least 30 days 
after mobocertinib dosing. Total abstinence (no sexual intercourse) may be considered an acceptable method of 
birth control if it agrees with his preferred and usual lifestyle.
12. Male must agree not to donate sperm from dosing until at least 30 days after dosing as indicated in Appendix D.
13. Understands the study procedures in the ICF and be willing and able to comply with the protocol.
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Main Criteria for Exclusion:
Healthy Subjects: 
The subject must be excluded from participating in the study if the subject: 
1.
Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an 
additional risk to the subject by their participation in the study.
4.
History or presence of alcoholism and drug abuse within the past 2 years prior to dosing.
5.
History or presence of clinically significant hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
6.
History or presence of any previous significant lung disease except childhood asthma.
7.
History of lung infection within 3 months of screening or ongoing lung infection.
8.
Female subjects with a positive pregnancy test or who are lactating.
9.
Positive results for urine or breath alcohol screen at screening or check-in.
10. Positive results for novel corona virus disease 2019 (COVID-19) testing at screening or check-in.
11. Positive results for urine or saliva drug screen at screening or check-in unless the positive drug screen is due to 
prescription drug use that is approved by the Investigator and Sponsor.
12. Positive result at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
13. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
14. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
15. QTcF interval is ≥450 msec in males or ≥470 msec in females or has ECG findings deemed abnormal with clinical 
significance by the Investigator or designee at screening.
16. Unable to refrain from or anticipates the use of any medication or substance (including prescription or 
over-the-counter, vitamin supplements, natural or herbal supplements) as indicated in Section 7.3 (Prohibitions 
and Concomitant Medication) for the prohibited time period.
17. Been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 
days prior to dosing and throughout the study.
18. Donation of blood or had significant blood loss within 56 days prior to dosing.
19. Plasma donation within 7 days prior to dosing.
20. Participation in another clinical study within 30 days prior to dosing. The 30-day window will be derived from the 
date of the last dosing in the previous study to Day 1 of the current study.
Subjects with Moderate or Severe Hepatic Impairment:
The subject must be excluded from participating in the study if the subject:
1.
Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical, besides hepatic impairment, or psychiatric condition or 
disease in the opinion of the Investigator or designee.
3.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the subject by their participation in the study.
4.
History or presence of alcoholism and drug abuse within the past 6 months prior to dosing.
5.
History or presence of clinically significant hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
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6.
History or presence of any previous significant lung disease except childhood asthma.
7.
History of lung infection within 3 months of screening or ongoing lung infection.
8.
History of liver or other solid organ transplant.
9.
Female subjects with a positive pregnancy test or who are lactating.
10. Positive results for urine or breath alcohol screen at screening or check-in.
11. Positive results for COVID-19 testing at screening or check-in.
12. Positive results for urine or saliva drug screen at screening or check-in unless the positive drug screen is due to 
prescription drug use that is approved by the Investigator and Sponsor.
13. Positive result at screening for HIV. Hepatitis B surface antigen (HBsAg) positive subjects are allowed to enroll if 
HBV DNA is below 1000 copies/mL in the plasma. Subjects who are positive for anti-HCV antibody (HCVAb) 
can be enrolled but must not have detectable HCV RNA in the plasma. 
14. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
15. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
16. QTcF interval is >500 msec or has ECG findings deemed abnormal with clinical significance by the Investigator 
or designee at screening.
17. Unable to refrain from or anticipates the use of any medication or substance (including prescription or 
over-the-counter, vitamin supplements, natural or herbal supplements) as indicated in Section 7.3 (Prohibitions 
and Concomitant Medication) for the prohibited time period.
18. Been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 
30 days prior to dosing and throughout the study.
19. Donation of blood or had significant blood loss within 56 days prior to dosing.
20. Plasma donation within 7 days prior to dosing.
21. Participation in another clinical study within 30 days prior to dosing. The 30-day window will be derived from the 
date of the last dosing in the previous study to Day 1 of the current study.
Study Endpoints:
Primary Endpoints
The primary endpoints of the study are the following total and unbound PK parameters for TAK 788 and its active 
metabolites, AP32960 and AP32914 (total and unbound parameters in parenthesis, respectively):

Maximum observed concentration (Cmax and Cmax,u).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the last 
quantifiable concentration (AUC∞and AUC∞,u).

Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast
and AUClast,u). 

Time of first occurrence of Cmax (tmax).

Terminal disposition phase half-life (t½z).

Terminal disposition phase rate constant (λz).

Apparent clearance after extravascular administration (CL/F and CLu/F) for mobocertinib only.

Apparent volume of distribution during the terminal disposition phase after extravascular administration (Vz/F 
and Vz,u/F) for mobocertinib only.
Secondary Endpoints
Pharmacokinetics:
Plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914).
Safety:

Incidence of treatment emergent AEs (TEAEs) (including physical examination findings).
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
Clinical laboratory values.

12-lead ECG. 

Vital signs.
Statistical Considerations:
Pharmacokinetics:
The natural log (ln)-transformed of the combined molar unbound Cmax,u, AUClast,u, and AUC∞,u, for mobocertinib and 
its metabolites (AP32960 and AP32914) will be compared between HI and the healthy arms using an analysis of 
variance (ANOVA) model. 
The ANOVA model will include HI versus normal conditions as a fixed effect and subject nested within group as a 
random effect. Each ANOVA analysis will calculate the least-squares mean (LSM), the difference between group 
LSMs, and the standard error associated with the difference. Residual, subject nested within group, and intersubject 
variance will be reported. Ratio of LSM and 90% confidence interval (CI) will be calculated using the exponential 
function of the difference between group LSMs from the analysis on the ln-transformed combined molar total and 
unbound Cmax,u, AUClast,u, and AUC∞,u, for mobocertinib and its metabolite (AP32960 and AP32914). The same 
analysis will be repeated for each analyte (mobocertinib, AP32960, and AP32914) separately and will be performed 
on total PK parameters as well (Cmax, AUClast, and AUC∞). 
Safety:
Safety data as well as the difference to baseline, when appropriate, will be summarized using the appropriate 
descriptive statistics.
Sample Size Justification:
The planned sample size of 8 subjects in each hepatic function arm represents a size that is considered adequate to 
provide a descriptive characterization of the PK of mobocertinib and its active metabolites (AP32960 and AP32914) 
in subjects with moderate or severe HI compared to healthy subjects with normal hepatic function.
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2.0
STUDY SCHEMATIC
Screening
Treatment
Follow-up a
Check-in and Predose 
Assessments
Mobocertinib Dosing, 
PK sampling, and 
Study Assessments
PK sampling and Study Assessments
Within 21 days prior to dosing
Day -1
Day 1
Day 2-10 a
30 days ± 2 following 
mobocertinib dose
Outpatient Visit
Confinement b 
a The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after the mobocertinib administration to determine if any adverse 
events have occurred since the last study visit.
b Subjects will start the confinement on Day -1 and be released from confinement after the 216-hour study assessments (Day 10) are complete. At all times, subjects
may be required to remain at the clinical research unit for longer at the discretion of the Investigator or designee.
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3.0
SCHEDULE OF STUDY PROCEDURES 
Study Procedures a
S b
Study Days
FU c
Days in Period →
-1
1
2
3
4
5
6
8
10
Hours →
C-I d
0
0.5
1
2
4
6
8
12
24
36
48
72
96
120
168
216
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Full Physical Examination e
X
X g
X f
Height
X
Weight
X
X g
Child-Pugh Assessment h
X
12-Lead Safety ECG
X
X i
X
X
X f
Vital Signs (HR and BP)
X
X i
X
X
X
X f
Vital Signs (RR and T)
X
Pulmonary Function Test k
X
Hem, Serum Chem j, Coag and UA 
X
X
X
X f
Serum Pregnancy Test (♀only)
X
X
Serum FSH (PMP ♀only)
X
Urine/saliva Drug Screen
X
X
Urine/breath Alcohol Screen
X
X
COVID-19 test
X
X
HIV/Hepatitis Screen
X
AE Monitoring k
X
X
ConMeds Monitoring
X
Study Drug Administration / PK
Mobocertinib Administration
X
Blood for Mobocertinib and its 
X l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Procedures a
S b
Study Days
FU c
Days in Period →
-1
1
2
3
4
5
6
8
10
Hours →
C-I d
0
0.5
1
2
4
6
8
12
24
36
48
72
96
120
168
216
Active Metabolites (AP32960 and 
AP32914) PK
Blood for Protein Binding for 
Mobocertinib and its active 
metabolites (AP32960 and 
AP32914)
X
X
X
Other Procedures
Confinement in the CRU m
X
Visit
X
a
For details on Procedures, refer to Section 9.0.
b
Within 21 days prior to study drug administration (Day 1). 
c
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after study drug administration to determine if any AEs have occurred since the 
last study visit.
d
Subjects will be admitted to the CRU on Day -1 at the time indicated by the CRU. Subjects may be admitted earlier than Day -1 for COVID-19 testing not related to study 
protocol as per CRU requirements.
e
Full physical examination will be conducted as indicated. Symptom-driven physical examination may be performed, at the Investigator’s or designee’s discretion.
f
To be performed at Day 10 or prior to early termination from the study.
g
If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), assessment will be conducted at check-in only if, in the opinion of the Investigator, there is 
reason to believe they have substantially changed, otherwise the screening result will be used. 
h
For assessment of hepatic function, two hepatic function assessments are required prior to Day 1. These 2 assessments should be obtained during screening period and on Day -1, 
at least 48 hours apart. If the Child-Pugh scores from these 2 assessments indicate the same liver function category for the subject (ie, normal function, moderate impairment, or 
severe impairment), mobocertinib can be administered as scheduled. If the results of the 2 assessments indicate different liver function categories, a third assessment must be 
conducted at least 24 hours after the second assessment. If the results of the 2 most recent assessments (the second and third) are in agreement with regard to the subject’s liver 
function category, the subject may be enrolled and should receive the Day 1 dose within 48 hours of the third assessment. If the second and third measurements differ, the subject 
will not be eligible for the study. Refer to Section 4.3.
i
To be performed within 24 hours prior to dosing. 
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j
Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours prior to the 
serum chemistry sample is taken.
k
Pulmonary function tests may be performed in the event of a pulmonary AE, if deemed clinically necessary by the Investigator or designee.
l
To be performed prior to dosing.
m
A subject may be required to remain at the CRU for longer periods, at the discretion of the Investigator.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = Coagulation, ConMeds = Concomitant medication, 
CRU = Clinical research unit, ECG = Electrocardiogram, FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, 
HR = Heart rate, PK = Pharmacokinetics, PMP = Postmenopausal, RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis. 
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Table 3.a
Pharmacokinetic Plasma Concentration Sampling Schedule
Study Day
Sample Collection 
Time
Time 
(Relative to Dosing)
h:min
Plasma 
Concentrations of 
Mobocertinib, 
AP32960, and 
AP32914
Plasma Protein 
Binding for 
Mobocertinib, 
AP32960, and 
AP32914
1
0 h
(predose)
00:00
(predose)

0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)


4 h
04:00 (±10 min)


6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

2
0 h
24:00 (±30 min)


12 h
36:00 (±30 min)

3
0 h
48:00 (±30 min)

4
0 h
72:00 (±60 min)

5
0 h
96:00 (±60 min)

6
0 h
120:00 (±60 min)

8
0 h
168:00 (±60 min)

10
0 h
216:00 (±60 min)

Number of samples per subject: 
16
3
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4.0
INTRODUCTION
4.1
Background
Aberrant activation of epidermal growth factor receptor (EGFR) and human epidermal growth 
factor 2 (HER2) plays a causal role in a subset of non–small cell lung cancer (NSCLC) and other 
cancers. As inhibition of wild-type (WT) EGFR is associated with dose-limiting toxicities, a 
tyrosine kinase inhibitor (TKI) that inhibits oncogenic EGFR and HER2 variants more potently 
than WT EGFR is more likely to be dosed at the more efficacious levels. Multiple classes of 
activating mutations have been identified in EGFR and HER2 that vary widely in their sensitivity 
to available TKIs. Mobocertinib, formerly known as AP32788 and TAK-788, was designed to be a 
potent, selective inhibitor of all activated forms of EGFR and HER2, including exon 20 insertions 
(not targeted by any approved TKI), more potently than it inhibits WT EGFR.
Non-Clinical Pharmacokinetics
Following oral administration in rats and dogs, urinary and biliary excretions of unchanged drug 
were negligible (<0.3% and 0.54% - 7.9% respectively). In Sprague-Dawley rats, mobocertinib
was eliminated almost completely (97.46% ± 1.70% of the radioactive dose) through feces, and 
urinary excretion was insignificant (1.98% ± 0.16%). Most of the dose (88.54%) was excreted in 0 
to 24 hours. In bile duct-cannulated rats, the average total recovery of administered radioactivity 
(0 - 72 hours) was 103.38% ±4.03%, with most of the elimination through bile (57.76% ± 4.19%), 
indicating that metabolism was the major clearance mechanism.
In vitro studies indicated that the metabolism of mobocertinib was primarily mediated by 
CYP3A4/5, with minor contributions from CYP2C8, 2C9, 2C19, and 2D6.
Clinical Pharmacokinetics
The clinical development program for mobocertinib includes an ongoing phase 1/2 clinical 
efficacy and safety study in patients with NSCLC (AP32788-15-101) and 2 completed clinical 
pharmacology studies: 1) Single rising dose study (Part 1), low-fat meal effect study (Part 2), and 
relative bioavailability study (Part 3) in healthy subjects (TAK-788-1001); and 2) a drug-drug 
interaction (DDI) study to characterize mobocertinib DDI with either a strong cytochrome P-450 
(CYP)3A inhibitor, itraconazole (Part 1) or with a strong CYP3A inducer, rifampin (Part 2) in 
healthy subjects (TAK-788-1006); and 2 ongoing clinical pharmacology studies: TAK-788-1002, 
and -1004. The objectives and study design of these studies are presented in mobocertinib IB 
Edition 4 (IB 2020). Only preliminary PK results from AP32788-15-101, and final PK results from 
TAK-788-1001 and TAK-788-1006 are presented in this document.
In the AP32788-15-101 study, following oral administration of mobocertinib once daily (QD), 
mobocertinib was readily absorbed with a median time to reach Cmax concentration (Tmax) of 4 
hours postdose. The single-dose Cmax and area under the plasma concentration-time curve from 
time 0 to 24 hours postdose (AUC24) following multiple doses increased in a less than dose 
proportional manner across the dose range of 5 to 180 mg.
Minimal to modest mobocertinib accumulation ratios were observed at steady state (geometric 
mean range 1.23 to 1.52) in the dose range of 20 to 120 mg QD. At 160 mg QD, the geometric 
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mean accumulation ratio following repeated doses was 1.06, suggesting autoinduction of the 
apparent oral clearance of mobocertinib likely via induction of CYP3A.
The emerging finding of autoinduction by mobocertinib at the 160 mg QD dose is consistent with 
the results of in vitro induction studies that have shown concentration-dependent CYP3A 
induction by mobocertinib and its active metabolites, suggesting a possible risk for drug-drug 
interactions due to induction of CYP3A and other co-regulated enzymes/transporters by 
mobocertinib as a potential perpetrator. The PK of the 2 active metabolites (AP32960 and 
AP32914) of mobocertinib were also evaluated in clinical studies. Systemic exposures to 
metabolites AP32960 and AP32914 in terms of molarAUC24 were approximately 
62% (%CV: 25%) and 8% (%CV: 13%) of parent AUC24 respectively. 
In the healthy subject study TAK-788-1001, a low-fat meal (ie, ≤350 calories and ≤15% calories 
from fat) did not affect the PK of mobocertinib in healthy subjects. At 160 mg mobocertinib, 90% 
CIs of the GMR with a low-fat meal versus fasted conditions for Cmax (GMR 0.964) and AUC∞
(GMR 0.951) fell completely within 80 -125% range.
In the TAK-788-1006 study, a DDI between the CYP3A4 inhibitor, itraconazole, and 
mobocertinib was observed. Following coadministration of multiple oral doses of 200 mg 
itraconazole with a single oral dose of 20 mg mobocertinib, overall (AUC∞) and peak (Cmax) 
exposures were increased by approximately 743% and 282% from the corresponding values 
obtained following mobocertinib alone. Similar results were observed for combined molar AUC∞
and combined molar Cmax data when comparing itraconazole + mobocertinib to mobocertinib
alone. A significant reduction in mobocertinib AUC∞and Cmax was observed when mobocertinib
was concomitantly administered with the strong CYP3A4 inducer, rifampin. Following 
coadministration of multiple oral doses of 600 mg rifampin with a single oral dose of 160 mg 
mobocertinib, overall (AUC∞) and peak (Cmax) exposures were reduced by approximately 96% and 
95%, respectively, compared to the corresponding values obtained following mobocertinib alone. 
Similar results were observed for combined molar AUC∞and combined molar Cmax data when 
comparing rifampin + mobocertinib to mobocertinib alone.
Refer to the Investigator’s Brochure (IB) for detailed background information and safety data on 
mobocertinib IB Edition 4 (IB 04-Jan-2020).
4.2
Rationale for the Proposed Study
Mobocertinib, formerly known as AP32788 and TAK-788, was designed to be a selective inhibitor 
of all mutant forms of EGFR and HER2, including exon 20 insertions (not indicated by any 
approved TKI), and has shown clinically more potent inhibition of these mutant variants than WT 
EGFR. Mobocertinib is neither a mutagenic nor genotoxic agent and was generally well tolerated 
in the previous clinical pharmacology studies (TAK-788-1001 and TAK-788-1002, a total of 
65 subjects) in healthy subjects in the single dose range of 20 – 160 mg.
After entering the body, drugs are eliminated by excretion and/or metabolism. Although 
elimination can occur through a variety of routes, most drugs are cleared by metabolism in the liver 
and/or small intestine and/or by elimination of unchanged drug by the kidney. Liver disease is
associated with several pathophysiologic changes that may alter the PK of a drug. These include 
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alterations in hepatic blood flow, changes in liver enzyme activity, decreased binding of drug to 
plasma proteins, and impaired biliary excretion (Rodighiero, 1999 and Verbeeck, 2008).
Accordingly, current United States (US) FDA guidance recommends a PK study in patients with 
impaired hepatic function if hepatic metabolism and/or excretion accounts for a substantial portion 
(≥20 percent of the absorbed drug) of the elimination of a parent drug or active metabolite (FDA 
2003). 
Metabolism via multiple cytochrome P450s (CYPs) appears to be the major route of elimination 
for mobocertinib and urinary excretion of the parent drug is low (<5% of dose as unchanged 
mobocertinib excreted in urine in healthy subjects). In vitro human liver microsomal metabolism 
studies have shown that mobocertinib undergoes oxidative biotransformation by hepatic 
cytochrome P450 enzymes primarily CYP3A4/5, forming 2 active metabolites (AP32960 and 
AP32914). Since mobocertinib and its 2 active metabolites inhibit EGFR exon 20 insertions with 
similar potency and comparable plasma unbound fractions in vitro, the effect of HI on the 
combined molar exposure to mobocertinib and its 2 active metabolites, adjusted for molecular 
weight, will be characterized in this study to establish scientifically guided dosing 
recommendations in these special patient populations.
The result of preliminary PK analysis based on the data from clinical study (AP32788-15-101) in 
patients with NSCLC shows that the combined molar Cav of mobocertinib and its 2 active 
metabolites (dose-normalized on C1D1) is not impacted by mild HI, supporting a common dose 
between these patients with mild HI and patients with normal hepatic function. Because the 
inclusion criteria of hepatic function based on total bilirubin laboratory values at the baseline in 
clinical study AP32788-15-101 (<1.5x upper limit of normal [ULN]) result in inclusion of patients 
with mild HI (based on NCI ODWG criteria) who would be expected to fall into the same 
categorization of mild HI determined by Child-Pugh score, (Mansfield, 2016) subjects with mild 
HI are not included in this HI study (TAK-788-1008), given the clinical safety and PK data 
available from these cancer patients in the mobocertinib clinical program. However, no 
information is available on the PK of mobocertinib and its 2 active metabolites in patients with 
moderate or severe HI. Therefore, this study will evaluate the PK of mobocertinib and its active 
metabolites following oral administration in subjects with moderate or severe HI using Child-Pugh 
scores, (FDA 2003) compared to matched-healthy subjects with normal hepatic function.
4.3
Child-Pugh Classification of Hepatic Impairment
The Child-Pugh classification (Table 4.a) will be used to categorize HI due to its widespread use 
and acceptance by regulatory agencies (including the US FDA [FDA 2003] and the European 
Medicines Agency [EMA 2005]. This study design is supported by FDA guidelines for drugs that 
undergo substantial hepatic metabolism and for which a dosage guideline is sought for subjects 
with HI.
In the current study, subjects with chronic, stable HI with features of cirrhosis due to any etiology 
will be enrolled, and the Child-Pugh scale will be used to classify the severity of liver disease. The 
scale employs 5 clinical measures of liver disease listed in Table 4.a. Each measure is scored 1 to 
3, with 3 indicating most severe derangement. The bilirubin score in the table is dependent upon 
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the type of cirrhosis (primary biliary cirrhosis versus all other causes). Subjects’ scores of 5 to 6, 7 
to 9, and 10 to 15 on this scale are classified as having mild (Child-Pugh A), moderate (Child-Pugh
B), and severe (Child-Pugh C) hepatic failure, respectively.
Table 4.a
Derivation of Child-Pugh Classification Score 1
Parameter
1 Point
2 Points
3 Points
Serum albumin (g/dL) 
>3.5
2.8 to 3.5
<2.8
Total serum bilirubin (mg/dL) 
<2.0
2.0 to 3.0
>3.0
Prothrombin time (sec prolonged) 
or international normalized ratio (ratio) 
<4
<1.70
4 to 6
1.70 to 2.30
>6
>2.30
Ascites
Absent
Slight
Moderate or Subject on 
medication(s) to control 
ascites
Hepatic encephalopathy (see Table 4.b)
None
Grade 1 or 2
Grade 3 or 4 or subject 
receiving medication(s) 
to prevent 
encephalopathy
Table 4.b
Determination of Encephalopathy Grade 1
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
3a
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity
4a
Unrousable coma, no personality/behavior, decerebrate
a Subjects with clinically active Grade 3 or 4 encephalopathy are excluded.
1 Adapted from FDA Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function: Study 
Design, Data Analysis, and Impact on Dosing and Labeling (FDA 2003).
Two hepatic function assessments are required prior to Day 1. These 2 assessments should be 
obtained during the screening period and on Day -1, at least 48 hours apart. If the Child-Pugh 
scores from these 2 assessments indicate the same liver function category for the subject 
(ie, normal function, moderate impairment, or severe impairment), mobocertinib can be 
administered as scheduled. If the results of the 2 assessments indicate different liver function 
categories, a third assessment must be conducted at least 24 hours after the second assessment. If 
the results of the 2 most recent assessments (the second and third) are in agreement with regard to 
the subject’s liver function category, the subject may be enrolled and should receive the Day 1 
dose within 48 hours of the third assessment. If the second and third measurements differ, the 
subject will not be eligible for the study.
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4.4
Benefit/Risk Profile
The clinical safety data available as of 27 January 2020 indicated no particular safety findings that 
are unique to mobocertinib compared with other approved EGFR TKIs. The most common 
treatment-emergent AEs (TEAE) occurring in ≥20% of patients by preferred term overall were 
diarrhea (84.7%), nausea (45.3%), decreased appetite (31.0%), vomiting (31.0%), fatigue (30.0%), 
and anemia (23.2%). There is some variety in the characterization of TEAEs of the skin resulting 
in different PTs to describe it. The most common skin-related PTs were rash (30.5%), dry skin 
(23.6%), maculo-papular rash (17.2%), paronychia (14.8%), dermatitis acneiform (12.3%), and 
pruritus (10.8%) (IB 2020).
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the subjects enrolled in this study is the free medical tests received at screening 
and during the study.
The risk of dosing mobocertinib in subjects with hepatic impairment (HI) is unknown in this study. 
The risk of dosing mobocertinib in subjects with RI is unknown. However, the risk of a single 40 
mg dose of mobocertinib administered in this study is anticipated to be similar to those previously 
reported studies in the mobocertinib IB (IB 2020).
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, 12-lead ECG, vital signs, clinical laboratory tests, AE questioning, and physical 
examination are adequate to protect the subject’s safety and should detect all TEAEs.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Not applicable
5.2
Study Objectives
5.2.1
Study Primary Objective
To characterize the single-dose plasma PK of mobocertinib and its active metabolites (AP32960 
and AP32914) in subjects with moderate and/or severe HI compared to matched-healthy subjects 
with normal hepatic function.
5.2.2
Study Secondary Objectives
The secondary objectives of the study are:
1. To evaluate plasma protein binding of mobocertinib and its active metabolites (AP32960 and 
AP32914).
2. To assess the safety of mobocertinib following single oral dose in subjects with moderate 
and/or severe HI as well as matched-healthy subjects with normal hepatic function.
5.2.3
Study Exploratory Objective
 
5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoints of the study are the following total and unbound PK parameters for 
mobocertinib and its active metabolites, AP32960 and AP32914 (total and unbound parameters in 
parenthesis, respectively):

Maximum observed concentration (Cmax and Cmax,u).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration (AUCand AUC,u).

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast and AUClast,u). 

Time of first occurrence of Cmax (tmax). 

Terminal disposition phase half-life (t½z).

Terminal disposition phase rate constant (λz).


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
Apparent clearance after extravascular administration (CL/F and CLu/F) for mobocertinib
only.

Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F and Vz,u/F) for mobocertinib only.
5.3.2
Secondary Endpoints 
Pharmacokinetics:
Plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914).
Safety:

Incidence of TEAEs assessments (including physical examination findings).

Clinical laboratory testing.

12-lead ECG.

Vital signs.
5.3.3
Exploratory Endpoint 
 


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is an open-label, parallel-arm study of oral mobocertinib designed to assess the PK of single 
dose mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with moderate 
and/or severe HI compared to matched-healthy subjects with normal hepatic function. 
The planned doses of mobocertinib per study arm are outlined in Table 6.a. 
Table 6.a
Study Arms and Planned Dose
Study Arms
Arm
Number of 
Subjects
Classification
Child-Pugh 
Category (a)
Dose (b)
1
8
Moderate
B
40 mg
2
8
Severe
C
40 mg (may be 
reduced) (d)
3
8-16 (d)
Matched-Healthy (c)
40 mg
(a) Refer to Section 4.3 for the classification system.
(b) Single orally administered dose at Hour 0 on Day 1. Subjects will be enrolled in a staggered manner beginning with 
approximately 3 subjects in moderate impairment arm followed by approximately 3 subjects in matched-normal 
hepatic function arm.
(c) Healthy subjects with normal hepatic function will be recruited to match both moderate and severe HI arms by age 
(mean ± 10 years), gender (± 2 subjects per gender), and body mass index (BMI, mean ± 10%).
(d) If the dose of Arm 2 is reduced then an additional 8 healthy matched subjects will be dosed in Arm 3 at the 
corresponding dose level to the Arm 2.
The study will consist of a 21-day screening period, a 10-day confinement period (Day −1 to 
Day 10) and a follow-up phone call 30 ± 2 days after dosing.
For assessment of hepatic function, two hepatic function assessments are required prior to Day 1. 
These 2 assessments should be obtained during screening period and on Day -1, at least 48 hours 
apart. If the Child-Pugh scores from these 2 assessments indicate the same liver function category 
for the subject (ie, normal function, moderate impairment, or severe impairment), mobocertinib
can be administered as scheduled. If the results of the 2 assessments indicate different liver 
function categories, a third assessment must be conducted at least 24 hours after the second 
assessment. If the results of the 2 most recent assessments (the second and third) are in agreement 
with regard to the subject’s liver function category, the subject may be enrolled and should receive 
the Day 1 dose within 48 hours of the third assessment. If the second and third measurements 
differ, the subject will not be eligible for the study.
Subjects will be enrolled in a staggered manner. All moderate HI subjects may be enrolled 
concurrently however approximately 3 subjects in the moderate HI arm and approximately 
3 subjects in the matched-normal hepatic function arm must complete up to Day 10 study 
procedures prior to enrolling the subjects to the severe HI arm. An informal preliminary PK data 
analysis of these subjects will be performed and may additionally leverage historical control PK 


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data in healthy subjects to gain an initial estimate of effect of moderate HI on the PK of 
mobocertinib and its active metabolites (AP32960 and AP32914). These preliminary data along 
with safety data will guide the decision to enroll the severe HI arm (for example, a decision will be 
made to dose the severe HI group at the same dose as the moderate HI arm, a reduced dose, or to 
not dose this arm). Following completion of enrollment of the moderate and severe HI (if enrolled) 
arms, the remaining subjects will be enrolled to the matched-normal hepatic function arm. 
Subjects will receive a single oral dose of 40 mg mobocertinib on Day 1 (Table 6.b).
Table 6.b
Study Design 
Study Day
Screening
-1
1
2
3
4
5
6
8
10
Mobocertinib PO
X
PK Blood Samples 
X
X
X
X
X
X
X
X
Confinement in CRU
X
X
X
X
X
X
X
X
X
CRU-clinical research unit; PK-pharmacokinetics; PO-per os (by mouth).
Blood samples will be collected from Days 1 to 10 at predetermined time points to characterize the 
PK and plasma protein binding of mobocertinib and its active metabolites (AP32960 and 
AP32914) in subjects with moderate and/or severe HI compared to matched-healthy subjects with 
normal hepatic function.
Subjects will be confined in the CRU until the morning of Day 10 after the 216-hour PK sample. A
subject may be required to remain at the CRU for longer periods, at the discretion of the 
Investigator. Subjects may be admitted earlier than Day -1 for COVID-19 testing not related to 
study protocol as per CRU requirements.
A final safety follow up phone call will occur 30 ± 2 days after mobocertinib dosing to determine if 
any AEs have occurred since last study visit.
6.2
Dose Escalation
An informal preliminary PK data analysis will be performed on approximately 3 moderate HI 
subjects and 3 healthy matched subjects who completed study procedures up to Day 10 and may 
additionally leverage historical control PK data in healthy subjects to gain an initial estimate of 
effect of moderate HI on the PK of mobocertinib and its active metabolites (AP32960 and 
AP32914). These preliminary data along with safety data will guide the decision to enroll the 
severe HI arm (for example, a decision will be made to dose the severe HI group at the same dose 
as the moderate HI arm, a reduced dose, or to not dose this arm). 


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6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
This study design is supported by the Food and Drug Administration (FDA) guidelines for drugs 
which undergo substantial hepatic metabolism and for which an indication is sought for subjects 
with hepatic insufficiency (FDA 2003). The FDA guidance recommends that a cohort of subjects 
with normal hepatic function representative of the typical patient population be used as a reference 
arm in HI PK studies. Demographically matched adult healthy subjects will be used as the 
reference arm to detect clinically relevant PK differences. These subjects will be matched to 
subjects with impaired hepatic function by age, BMI, and gender.
6.3.2
Rationale for Dose 
The dose selected for this study with moderate and/or severe HI is 40 mg of mobocertinib taken 
orally; this corresponds to 25% of the highest single oral dose evaluated in healthy subjects 
(ie, 160 mg) and will provide a safety margin. In the event that HI reduces drug clearance and 
increases overall systemic exposure, it is anticipated that a single oral dose 40 mg administered to 
patients with severe HI will not exceed the historical exposure levels seen in healthy subjects of a 
single oral dose of 160 mg dose of mobocertinib. 
Following review of the preliminary PK and safety data of approximately 3 moderate HI subjects 
and 3 healthy matched subjects who completed up to Day 10 study procedures, a decision to dose 
the severe HI at the same dose as the moderate HI arm will be made to ensure a similar safety 
margin in the severe HI group; alternatively a reduced dose may also be proposed or the severe HI 
group may not be dosed.
6.3.3
Rationale for Endpoints
6.3.3.1
Pharmacokinetic Endpoints
Given that mobocertinib, AP32960, and AP32914 are pharmacologically active, with similar 
in-vitro potency to inhibit EGFR/HER2 exon 20 insertions, the statistical analyses of PK exposure 
parameters will be performed on the molecularly weight adjusted combined exposure of 
mobocertinib and its 2 active metabolites along with the exposure parameters of mobocertinib, 
AP32960, and AP32914 individually.
It is well known that hepatic dysfunction will impact expression and activity of drug metabolizing 
enzymes by which unbound drugs, if they are substrates of these enzymes, are mediated. As 
mobocertinib and its 2 active metabolites display high binding to plasma proteins in vitro, plasma 
protein binding of mobocertinib and its 2 active metabolites may vary with hepatic dysfunction in 
humans. Therefore, the statistical analyses of PK exposure parameters will be conducted using the 
unbound PK values.


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6.3.3.2
Safety Endpoints 
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring of 
adverse events, vital signs, ECGs, laboratory assessments and physical examinations.
6.3.4
Future Biomedical Research
Any residual plasma samples will be stored by the Sponsor or Bioanalytical facility for the 
maximal 5 years determined by Sponsor following dosing and may be used in the future to perform 
metabolite profiling. Tubes or container will be identified with a barcode using an appropriate 
label.
No diseases/conditions, deoxyribonucleic acid, or ribonucleic acid will be the focus of these 
analyses. The analyses will focus on metabolite profiling for mobocertinib compound. Samples 
will not be submitted to a public database. The Sponsor and contract research organizations 
involved in the clinical conduct, bioanalytical analyses and PK and statistical analysis of the data 
will have access to the samples and/or the data that resulted from the analysis, if performed. 
By signing the ICF, subjects agree to the possible future analysis of these samples. At any time, the 
subjects can contact the CRU staff to request destruction of the residual samples once PK 
assessments required to meet the primary objective of the study are completed. Any additional 
research on these samples unspecified by this protocol will require approval from the subjects.
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
mobocertinib and its active metabolites (AP32960 and AP32914) and samples are required to be 
collected, as appropriate, as close to the scheduled times defined in this protocol as possible.
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
Severe HI arm only: The dose of mobocertinib may be reduced following review of preliminary 
PK and safety data of approximately 3 HI subjects and 3 healthy subjects. If reduced, the dose for 
the matched-healthy subjects will be modified as well.
The dose and administration of mobocertinib for subjects in the moderate HI arm and their 
matched-healthy subjects may not be modified.
If necessary, a subject may be discontinued for the reasons described in Section 7.6 and 
Section 7.7.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first subject.


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6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure at the clinic as 
outlined in the Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in the follow-up phone call 
for the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
6.5.4
Definition of Study Discontinuation
Celerion and/or the clinical site reserves the right to terminate the study in the interest of subject 
welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.5.6
Criteria for Premature Termination or Suspension of a Site
There is no predetermined criteria for termination of suspension of a site. 
Termination or suspension of a site may occur at any time at the discretion of the Sponsor. 


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
7.1.1
Inclusion Criteria for Healthy Subjects
All healthy subjects must fulfill the following inclusion criteria to be eligible for participation in 
the study: 
1. Healthy, adult male or female subjects aged ≥18 to <80 years, at screening. Subjects will be 
matched to hepatic impaired subjects by age (mean ± 10 years) at screening.
2. Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before 
screening. Subject must agree to consume no more than 5 cigarettes or equivalent/day from the 
7 days prior to mobocertinib dosing and throughout the period of PK sample collection
3. BMI ≥18.0 and ≤39.0 kg/m2, at screening. Subjects will be matched to hepatic impaired 
subjects by BMI (mean ± 10 %) at screening. At least 50% of the subjects will be required to be 
of BMI ≥18.0 and ≤35.0 kg/m2, at screening.
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee. Has liver 
function tests including ALT, AST, ALP, and total bilirubin within the upper limit of normal at 
screening and at check-in.
5. Creatinine clearance (eGFR) ≥60 mL/min/1.73m2 at screening.
6. Female subjects of nonchildbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum levels 
consistent with postmenopausal status.
7. Female subjects of childbearing potential will be advised to remain sexually inactive or to keep 
the same birth control method for at least 30 days following mobocertinib dosing as indicated 
in Appendix D.
8. Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days 
following mobocertinib dosing as indicated in Appendix D.
9. Males subjects who are sexually active with a female partner of childbearing potential must 
use barrier contraception as indicated in Appendix D or abstain from sexual intercourse during 
the study until at least 30 days after mobocertinib dosing. Total abstinence (no sexual 


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intercourse) may be considered an acceptable method of birth control if it agrees with his 
preferred and usual lifestyle.
10. Male subjects must agree not to donate sperm from dosing until at least 30 days after dosing as 
indicated in Appendix D.
11. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.1.2
Inclusion Criteria for Subjects with Moderate or Severe Hepatic Impairment
All HI subjects must fulfill the following inclusion criteria to be eligible for participation in the 
study: 
1. Adult male or female subjects aged ≥18 to <80 years, at screening.
2. Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before 
screening. Subject must agree to consume no more than 5 cigarettes or equivalent/day from the 
7 days prior to mobocertinib dosing and throughout the period of PK sample collection.
3. BMI ≥18.0 and ≤39.0 kg/m2, at screening. At least 50% of the subjects will be required to be of 
BMI ≥18.0 and ≤35.0 kg/m2, at screening.
4. Aside from HI, be sufficiently healthy for study participation based upon medical history, 
physical examination, vital signs, ECGs, and screening clinical laboratory profiles, as deemed 
by the Investigator or designee.
5. Creatinine clearance (eGFR) ≥60 mL/min/1.73m2 at screening.
6. Diagnosis of chronic (eg, imaging, biopsy, etc.) stable hepatic insufficiency for at least 
6 months (no acute episodes of illness within the previous 2 months due to deterioration in 
hepatic function) with features of cirrhosis due to any etiology according to medical history.
7. Chronic HI for at least 3 months before screening, and the HI must be stable, ie, no significant 
changes in hepatic function in the 30 days preceding screening (or since the last visit if within 
6 months before screening) and treatment with stable doses of medication. Has a score on the 
Child-Pugh Class (Table 4.a) at screening as follows: 

Moderate HI arm, Child-Pugh Class B: ≥7 and ≤9.

Severe HI arm, Child-Pugh Class C: ≥10 and ≤15.
8. Female subjects of nonchildbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;


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or be postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum levels 
consistent with postmenopausal status.
9. Female subjects of childbearing potential will be advised to remain sexually inactive or to keep 
the same birth control method for at least 30 days following mobocertinib dosing as indicated 
in Appendix D.
10. Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days 
following mobocertinib dosing as indicated in Appendix D.
11. Males subjects who are sexually active with a female partner of childbearing potential must 
use barrier contraception as indicated in Appendix D or abstain from sexual intercourse during 
the study until at least 30 days after mobocertinib dosing. Total abstinence (no sexual 
intercourse) may be considered an acceptable method of birth control if it agrees with his 
preferred and usual lifestyle.
12. Male must agree not to donate sperm from dosing until at least 30 days after dosing as 
indicated in Appendix D.
13. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
7.2.1
Exclusion Criteria for Healthy Subjects
All healthy subjects must be excluded from participating in the study if the subject: 
1. Mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History of any illness that, in the opinion of the PI or designee, might confound the results of 
the study or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism and drug abuse within the past 2 years prior to dosing.
5. History or presence of clinically significant hypersensitivity or idiosyncratic reaction to the 
study drug or related compounds.
6. History or presence of any previous significant lung disease except childhood asthma.
7. History of lung infection within 3 months of screening or ongoing lung infection.
8. Female subjects with a positive pregnancy test or who are lactating.
9. Positive results for urine or breath alcohol screen at screening or check-in.
10. Positive results for COVID-19 testing at screening or check-in.


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11. Positive results for urine or saliva drug screen at screening or check-in unless the positive drug
screen is due to prescription drug use that is approved by the Investigator and Sponsor.
12. Positive result at screening for HIV, HBsAg, or HCV.
13. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
14. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
15. QTcF interval is ≥450 msec in males or ≥470 msec in females or has ECG findings deemed 
abnormal with clinical significance by the Investigator or designee at screening.
16. Unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section 7.3 (Prohibitions and Concomitant Medication) for the prohibited time 
period.
17. Been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to dosing and throughout the study.
18. Donation of blood or had significant blood loss within 56 days prior to dosing.
19. Plasma donation within 7 days prior to dosing.
20. Participation in another clinical study within 30 days prior to dosing. The 30-day window will 
be derived from the date of the last dosing in the previous study to Day 1 of the current study.
7.2.2
Exclusion Criteria for Subjects with Moderate or Severe Hepatic Impairments
All HI subjects must be excluded from participating in the study if the subject: 
1. Mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical, besides hepatic impairment, or 
psychiatric condition or disease in the opinion of the Investigator or designee.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism and drug abuse within the past 6 months prior to dosing.
5. History or presence of clinically significant hypersensitivity or idiosyncratic reaction to the 
study drug or related compounds.
6. History or presence of any previous significant lung disease except childhood asthma.
7. History of lung infection within 3 months of screening or ongoing lung infection.
8. History of liver or other solid organ transplant.
9. Female subjects with a positive pregnancy test or who are lactating.
10. Positive results for urine or breath alcohol screen at screening or check-in.


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11. Positive results for COVID-19 testing at screening or check-in.
12. Positive results for urine or saliva drug screen at screening or check-in unless the positive drug 
screen is due to prescription drug use that is approved by the Investigator and Sponsor.
13. Positive result at screening for HIV. HBsAg positive subjects are allowed to enroll if HBV 
DNA is below 1000 copies/mL in the plasma. Subjects who are positive for HCVAb can be 
enrolled but must not have detectable HCV RNA in the plasma. 
14. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
15. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
16. QTcF interval is >500 msec or has ECG findings deemed abnormal with clinical significance 
by the Investigator or designee at screening.
17. Unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section 7.3 (Prohibitions and Concomitant Medication) for the prohibited time 
period.
18. Been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to dosing and throughout the study.
19. Donation of blood or had significant blood loss within 56 days prior to dosing.
20. Plasma donation within 7 days prior to dosing.
21. Participation in another clinical study within 30 days prior to dosing. The 30-day window will 
be derived from the date of the last dosing in the previous study to Day 1 of the current study.
7.3
Prior and Concomitant Medications and Therapies
Concomitant therapies include any therapies, over-the-counter medications, herbal products, 
vitamin and/or mineral supplements used by a subject from Day 1 through the last PK sample on 
Day 10. A record of all medications used will be maintained for each subject throughout the study. 
Reported information will include a description of the type of drug, treatment period, dosing 
regimen, the route of administration, and drug indication. 
Subjects will be instructed to inform the study Investigator of the details (indication, dose and 
dates of administration) if they take any medication prior to clinic check-in, and these details will 
be recorded in the CRF. 
Healthy subjects will be restricted of using any prescription medications/products and any 
over-the-counter, non-prescription preparations (including herbal products, natural or herbal 
supplements) from at least 14 days before dosing and throughout the study. However, healthy 
subjects that are on stable medication for at least 30 days prior to dosing may be enrolled upon 
approval by the Investigator (or designee) and Sponsor.
Subjects with HI who are taking medications to treat manifestations of hepatic disease or 
medications needed to treat for stable diseases (eg, diuretics, angiotensin converting enzyme 


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inhibitors, angiotensin II receptor antagonists, beta-blockers, lactulose, rifaximin or antibiotics 
used for spontaneous bacterial peritonitis like fluoroquinolones) will be allowed to participate in 
the study at the discretion of the Investigator and following consultation with the Sponsor. 
Subjects must be on a stable dose (steady dose, drug, and regimen) for at least 14 days able to 
withhold the use for at least 4 hours post-dose. Phosphate binders containing aluminum, calcium, 
or lanthanum salts; iron supplements or other metal cations; H2-receptor antagonists (except 
cimetidine); or multivitamins containing iron or zinc must be withheld at least 8 hours before 
dosing and at least 6 hours postdose.
If a subject with HI is prescribed prohibited medication, upon discussion between the Sponsor and 
the Investigator, the Investigator may substitute the previously prescribed medication to an 
allowed one for the purpose of this study.
For all subjects, any drugs known to be strong or moderate inhibitors of CYP3A enzymes and/or 
P-gp will be restricted for 14 days, and any drugs known to be strong or moderate inducers of 
CYP3A enzymes and/or P-gp, including St. John’s Wort, will be restricted for 28 days, before 
dosing and throughout the study. Use of weak inhibitors or inducers may be deemed acceptable 
following consultation with the Sponsor and the Investigator or designee. Appropriate sources (eg, 
Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamic interaction with 
study drug.
For all subjects, following dosing, acetaminophen (up to 2 g per 24 hours) may be administered at 
the discretion of the Investigator or designee. Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior to 
dosing.
All medications taken by subjects during the course of the study will be recorded.
Concurrent medication during the course of the study including both prescription and 
non-prescription drugs may be permitted based on the timing of study drug administration and its 
pharmacology, but must first be discussed with the Investigator or designee and Sponsor prior to 
dosing, unless appropriate medical care necessitates that therapy should begin before the 
Investigator or designee and Sponsor can be consulted. 
7.4
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.


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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Dosing (Days -28 to 
predose [Day 1])
After Dosing (Day 1) through 
Follow-up 
Alcohol
Prohibited from 48 hours prior to dosing
Prohibited up to Day 10, 
inclusively
Xanthine and/or Caffeine
Prohibited from 24 hours prior to dosing a
Prohibited up to Day 10, 
inclusively a
Medications 
See Sections 7.2 and 7.3
See Sections 7.1 and 7.3
Food substance
Grapefruit/Seville orange
Prohibited from 28 days prior to dosing
Prohibited up to Day 10, 
inclusively
a small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction. 
If deviations occur, the Investigator will decide on a case-by-case basis whether the subject may 
continue participation in the study based on the time the drugs were administered and their 
pharmacology.
7.5
Diet, Fluid, Activity 
7.5.1
Diet and Fluid
Water (except water provided with oral dosing) will be restricted 1 hour prior to and 1 hour after 
study drug administration, but will be allowed ad libitum at all other times. Other fluids may be 
given as part of meals and snacks but will be restricted at all other times throughout the 
confinement period.
On Day 1, subjects will fast overnight for at least 10 hours prior to oral study drug administration 
and will continue to fast for at least 4 hours postdose. When confined, standard meals and snacks 
will be provided at appropriate times, except when they are required to fast. When confined in the 
CRU, subjects will be required to fast from all food and drink except water between meals and 
snacks. Each meal and/or snacks served at the CRU will be standardized and will be similar in 
caloric content and composition.
7.5.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose on Day 1, except 
when they are supine or semi-reclined for study procedures or AEs.
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the study.
Depending on the CRU rules and regulations, subjects may be prohibited from smoking during 
their confinement or during portions of their confinement. 


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7.6
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the Investigator or designee for the 
following reasons:

AEs.

A positive pregnancy test for females.

Positive drug or alcohol results.

Difficulties in blood collection.
A subject may be withdrawn by the Investigator (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.3. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the Investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
7.8
Subject Replacement
Replacement of discontinued or withdrawn subjects due to any reason will be assessed on a case 
by case basis by the Sponsor and Investigator to ensure approximately 8 PK-evaluable subjects 
complete in each arm of the study. In the event of a dose change for the severe HI arm, additional 
healthy-matched subjects may be enrolled at the discretion of the Sponsor up to 8 subjects.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
A single 40 mg dose of mobocertinib (1 x 40 mg mobocertinib capsule) will be administered on 
Day 1.
Mobocertinib drug product is a nonsterile, oral, capsule dosage form. Mobocertinib succinate salt 
is the active pharmaceutical ingredient encapsulated in a hard gelatin capsule shell with no 
excipients.
Mobocertinib (AP32788) 40 mg: Size 1, white, opaque, hard gelatin capsules, 30 capsules per 
bottle.
Mobocertinib (AP32788) 20 mg: Size 2, Swedish-orange, opaque, gelatin capsules, 30 capsules 
per bottle.
The 20 mg capsules of mobocertinib has been provided to allow dose modification for the severe 
HI group if the moderate HI group interim data indicates the 40 mg dose is not well tolerated.
8.1.1
Clinical Study Drug Labeling
Mobocertinib capsule containers will be affixed with a clinical label in accordance with local 
regulatory requirements.
The pharmacy at the CRU will provide the dose in individual unit dose containers for each subject.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of mobocertinib products to allow completion of this 
study. 

Store below 30°C (86°F).

Do not refrigerate or freeze – Normal room temperature.

Keep away from cold or heat sources.

Keep out of reach and sight of children.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
8.1.4
Randomization Code Creation and Storage 
Not applicable.


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8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused mobocertinib study drug will be retained by the CRU, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records.


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9.0
STUDY PROCEDURES
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same Investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 13.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
9.1.1.1
Assignment of Screening and Allocation Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of dosing, different from the screening number.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
All subjects will receive mobocertinib as detailed in Section 8.1.
9.1.2
Inclusion and Exclusion 
Subjects must satisfy all of the inclusion criteria and meet none of the exclusion criteria as outlined 
in Sections 7.1 and 7.2, respectively in their applicable study arm.
9.1.3
Medical History/Demography
Medical history and demographic data, including subject number, sex, age, race, ethnicity, and 
history of tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Sections 7.2 and 7.3. All medications 
taken by subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to subject safety.


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For this study, the collection of blood for mobocertinib and its metabolites is the critical parameter 
and needs to be collected as close to the exact time point as possible. All other procedures should 
be completed as close to the prescribed/scheduled time as possible, but can be performed prior to 
or after the prescribed/scheduled time (refer to Table 3.a).
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Full Physical Examination
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
Body Mass Index
Subject BMI will be calculated based on the height and weight measured at screening.
9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and heart rate measurements will be performed with subjects in a seated position, 
(subjects must be seated for at least 5 minutes prior to measurement), except when they are supine 
or semi-reclined because of study procedures and/or AEs (eg, nausea, dizziness) or if deemed 
necessary by the Investigator or designee.
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing for the 
predose time point. When scheduled postdose, vital signs will be performed within approximately 
15 minutes of the scheduled time point.
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
Investigator or designee.
ECGs will be performed with subjects in a supine position. Subjects are required to be supine for at 
least 5 minutes prior to the ECG measurement. All ECG tracings will be reviewed by the 
Investigator or designee.


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ECGs will be measured within 24 hours prior to Day 1 dosing for the predose time point. When 
scheduled postdose, ECGs will be performed within approximately 20 minutes of the scheduled 
time point.
9.2.6
Pulmonary Function Test
9.2.6.1
Spirometry
Spirometry as the PFT may be performed in the event of a pulmonary AE, if deemed clinically 
necessary by the Investigator or designee.
9.2.7
Study Drug Administration
Mobocertinib oral capsules will be provided as described in Section 8.1.
Subjects will be instructed not to crush, split, or chew the mobocertinib capsules.
Mobocertinib will be administered following an overnight fast.
Mobocertinib will be administered with approximately 240 mL of water. The exact clock time of 
oral dosing will be recorded.
The pharmacy at the CRU will provide study drug in individual unit dose containers for each 
subject as appropriate.
9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drug and/or 
procedures as described in Section 10.0.
9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.


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9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Coagulation
Coagulation will consist of the following tests:
Prothrombin time 
International normalized ratio
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to when the serum chemistry sample is 
taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Amylase
Albumin
Lipase
Sodium
Blood Urea Nitrogen
Potassium
Bilirubin (total and direct)
Chloride
Alkaline phosphatase
Glucose 
Aspartate aminotransferase
Creatinine *
Alanine aminotransferase (ALT)
Magnesium
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.


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Other 
HIV test
Urine or saliva drug screen
–
Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)
–
Amphetamines
–
Barbiturates
–
Benzodiazepines
–
Cocaine
–
Cannabinoids
HBsAg (if HI patients are positive for HBV, DNA 
copies are below 1000 copies/mL in plasma)
HCV (if antibody positive, confirm RNA negative)
Urine or breath alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
COVID-19 testing (performed according to CRU 
standard procedures, provided in a separate 
document[s])
9.3
Pharmacokinetic Samples
Instructions for plasma samples processing and handling will be provided in a separate document. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Description of Intended Use
Sample 
Collection
Plasma sample for Mobocertinib and 
metabolites PK Total
Plasma
Plasma sample for Mobocertinib and 
metabolites PK analysis
Mandatory
Plasma sample for Mobocertinib and 
metabolites protein binding
Plasma
Plasma sample for Mobocertinib and 
metabolites protein binding
Mandatory
9.3.1
PK Measurements 
9.3.1.1
Plasma PK Measurements
Total and unbound plasma PK parameters for mobocertinib and metabolites (AP32960 and 
AP32914) will be calculated as follows, as appropriate, following oral administration:
AUClast:
The area under the concentration versus time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method for total analyte.


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AUClast,u:
The area under the concentration versus time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method for unbound analyte.
AUC:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUCis calculated as AUClast plus the ratio of the 
last measurable blood concentration to the elimination rate constant for total 
analyte.
AUC∞,u:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUC∞,u is calculated as AUClast,u plus the ratio of the 
last measurable blood concentration to the elimination rate constant for 
unbound analyte.
AUC%extrap:
Percent of AUC∞extrapolated, represented as (1 - AUClast/AUC∞)*100.
CL/F
Apparent total plasma clearance after oral (extravascular) administration, 
calculated as Dose/AUC(mobocertinib only).
CLu/F
Apparent total plasma clearance after oral (extravascular) administration, 
calculated as Dose/AUC,u (mobocertinib only).
Cmax:
Maximum observed concentration for total analyte.
Cmax,u:
Maximum observed concentration for unbound analyte.
tmax:
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value.
t½z:
Apparent first-order terminal elimination half-life will be calculated as 
0.693/λz.
Where λz is the apparent first order terminal elimination rate constant 
calculated from a semilog plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares- regression 
analysis using the maximum number of points in the terminal log-linear 
phase (eg, three or more non-zero plasma concentrations).
Vz/F
Apparent volume of distribution during the terminal elimination phase after 
oral (extravascular) administration, calculated as Dose/(AUCx λz) 
(mobocertinib only).
Vz,u/F
Apparent volume of distribution during the terminal elimination phase after 
oral (extravascular) administration, calculated as Dose/(AUC,u x λz) 
(mobocertinib only).
No value for λz, AUC, AUC,u, AUC%extrap, CL/F, CLu/F, Vz/F, Vz,u/F, or t½z will be reported for 
cases that do not exhibit a terminal log-linear phase in the concentration versus time profile. 
No PK parameters will be calculated for subjects with detectable concentrations at 2 or fewer 
consecutive time points. 


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Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
9.3.2
 
 
 
9.3.3
PGx Measurements 
Not applicable
9.3.4
Confinement
Subjects will be housed on Day -1, at the time indicated by the CRU, until the morning of Day 10 
after the 216-hour PK sample is collected and study procedures are complete, as indicated in the 
Section 3.0. At all times, a subject may be required to remain at the CRU for longer at the 
discretion of the Investigator or designee.


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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 


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of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, Investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the Investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 


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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.6.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject 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.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1.1 and 10.2.6.3).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
There are no AEs of Special Interest for this study.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5.0, dated 27 November 2017 [CTCAE 2017]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on subject/event outcome or action criteria described above and is usually associated with 
events that pose a threat to a subject’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to <2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.


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10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
Investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.


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
Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.6 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.6.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call 30 days (± 2 days) after mobocertinib dosing. For subjects who discontinue 
prior to the administration of mobocertinib, AEs will be followed until the subject discontinues 
study participation. 
10.2.6.2 Reporting AEs
At follow-up, the Investigator will assess whether any subjective AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Subjects may 
report AEs occurring at any other time during the study. Subjects experiencing an SAE prior to the 
first exposure to investigational product must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to Baseline or there is a satisfactory 
explanation for the change. Nonserious AEs that begin prior to the first exposure to investigational 
product, related or unrelated to the study procedure, need not be followed-up for the purposes of 
the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
Investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with Study drug.

Outcome of event.

Seriousness.


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10.2.6.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the Investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the Investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.6.4 Reporting Special Interest AEs 
Not applicable
10.2.6.5 Reporting of Abnormal Liver Function Tests
Healthy-Matched Subjects
If a healthy subject has elevated ALT ≥3x ULN with concurrent elevated total bilirubin >2x ULN 
or elevated international normalized ratio (INR) >1.5, contact the sponsor’s medical monitor 
within 24 hours. 
For any healthy subject with ALT ≥3x ULN and total bilirubin >2x ULN or INR >1.5x ULN for 


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which an alternative etiology has not been found, report the event as an SAE (Section 10.2.6.3) 
and contact the sponsor immediately.
Hepatic Impairment Subjects
If a HI subject has elevated ALT ≥6x ULN with concurrent elevated total bilirubin >4x ULN or
elevated INR >3x ULN, contact the sponsor’s medical monitor within 24 hours. 
For any HI subject with ALT ≥6x ULN and total bilirubin >4x ULN or INR >3x ULN for which an 
alternative etiology has not been found, report the event as an SAE (Section 10.2.6.3) and contact 
the sponsor immediately.
10.2.7 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, Investigators and IRBs or
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the Study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
10.2.8
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
Email
Fax
Mobocertinib
Dohmen Life Science 
Services, or DLSS 
(formerly known as 
MedComm)
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@
takeda.com 
1-800-881-
6092
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP will be prepared by Celerion and 
agreed upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis will also 
be reflected in a protocol amendment. Additional statistical analyses other than those described in 
this section may be performed if deemed appropriate.
11.1.1 Analysis Sets
11.1.1.1 Pharmacokinetic Set
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile 
(eg, exposure to treatment, availability of measurements and absence of major protocol violations) 
will be included in the statistical analyses. Any subject who experiences emesis within 8 hours 
post dosing with mobocertinib will be excluded in the final data analysis.
11.1.1.2 Safety Set
All subjects who received the study drug will be included in the safety evaluations.
11.1.1.3 Pharmacodynamic Set
Not applicable.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3 Pharmacokinetic Analysis
PK parameters for mobocertinib and metabolites (AP32960 and AP32914) in plasma will be 
calculated as described in Section 9.3.1.1, and outlined in the SAP.
The ln-transformed of the combined molar unbound Cmax,u AUClast,u, and AUC∞,u, for mobocertinib
and its metabolites (AP32960 and AP32914) will be compared between hepatic impairment and 
the healthy arms using an ANOVA model. 
The ANOVA model will include hepatic impairment versus normal conditions as a fixed effect 
and subject nested within group as a random effect. Each ANOVA analysis will calculate the 
LSM, the difference between group LSMs, and the standard error associated with the difference. 
Residual, subject nested within group, and intersubject variance will be reported. Ratio of LSM 


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and 90% CI will be calculated using the exponential function of the difference between group 
LSMs from the analysis on the ln-transformed combined molar unbound Cmax,u AUClast,u, and 
AUC∞,u, for mobocertinib, AP32960, and AP32914. 
The same analysis will be repeated for each analyte (mobocertinib, AP32960, and AP32914) 
separately and will be performed on total PK parameters as well (Cmax, AUClast, and AUC∞).
11.1.4 Pharmacodynamic Analysis 
Not applicable.
11.1.5 Safety Analysis
All safety data will be populated in the individual CRFs. 
Dosing dates and times will be listed by subject.
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.
11.1.5.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by population for the number of subjects 
reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing including 
verbatim term, coded term, treatment, severity, and relationship to treatment will be provided.
11.1.5.2 Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by population and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.5.3 Vital Signs
Vital signs assessments will be summarized by population and point of time of collection.
11.1.5.4 Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs will be summarized by population and point of time of collection.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization drug dictionary and will be listed 
by subject.
11.2
Interim Analysis and Criteria for Early Termination
An informal preliminary PK data analysis will be performed on approximately 3 moderate HI 
subjects and 3 healthy matched subjects who completed study procedures up to Day 10 and may 
additionally leverage historical control PK data in healthy subjects to gain an initial estimate of 


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effect of moderate HI on the PK of mobocertinib and its active metabolites (AP32960 and 
AP32914). These preliminary data along with safety data will guide the decision to enroll the 
severe HI arm (for example, a decision will be made to dose the severe HI group at the same dose 
as the moderate HI arm, a reduced dose, or to not dose this arm).
There are no predetermined criteria for early termination of the study.
11.3
Determination of Sample Size
The planned sample size of 8 subjects in each hepatic function arm represents a size that is 
considered adequate to provide a descriptive characterization of the PK of mobocertinib and its 
active metabolites in subjects with moderate or severe hepatic impairment compared to healthy 
subjects with normal hepatic function.
At least 24 subjects will be enrolled into 3 arms (approximately 8 subjects in each arm) in the 
study. The target numbers for the matched-healthy subjects with normal hepatic function are 
8 subjects; however up to 16 healthy subjects may be enrolled into Arm 3 if it is not feasible to 
match the first 8 healthy subjects into both Arms 1 and 2.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The Investigator and study site guarantee access to source documents by the Sponsor or its 
designee (Clinical Research Organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the Investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to Study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The Investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council on Harmonisation (ICH) Harmonised Tripartite Guideline 
for GCP. Each Investigator will conduct the study according to applicable local or regional 
regulatory requirements and align his or her conduct in accordance with the “Responsibilities of 
the Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
Investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the Study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the Investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.


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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The Investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the Investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The Investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the Sponsor may allow a designee of the Investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and
subject information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the Investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1 Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


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13.4.2 Clinical Study Registration 
In order to ensure that information on clinical study reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical study it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for Americas Investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting study 
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Study Results Disclosure 
Takeda will post the results of clinical study on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the Investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
SAE Reporting Contact Information
Cognizant
US and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Please refer to Safety Management Plan.


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14.1.2 Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure and any 
other product information provided by the Sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 [R2] GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.7 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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14.1.3 Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4 List of Abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUClast
Area under the concentration-time curve, from time 0 to the last observed non-zero 
concentration total
AUClast,u
Area under the concentration-time curve from time 0 to time t the last observed non-zero 
concentration unbound
AUC
Area under the concentration-time curve, from time 0 extrapolated to infinity total
AUC,u
Area under the concentration-time curve, from time 0 extrapolated to infinity unbound
BMI
Body mass index
bpm
Beats per minute
Cav
Average concentration 
CFR
Code of Federal Regulations
CI
Confidence interval
CL/F
Apparent clearance after extravascular administration total
CLu/F
Apparent clearance after extravascular administration unbound
cm
Centimeter
Cmax
Maximum observed concentration total
Cmax,u
Maximum observed concentration unbound
COVID-19
Novel Corona Virus Vaccine 2019
CRA
Clinical Research Associate
CRF
Case report form
CRU
Clinical Research Unit
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
EGFR
Epidermal growth factor receptor 
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HER2
Human epidermal growth factor 2


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HI
Hepatic impairment
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
kg
Kilogram
LFT
Liver function test
LSM
Least-squares mean
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
NSCLC
Non–small cell lung cancer
P-gp
P-glycoprotein
PFT
Pulmonary Function Test(s)
PK
Pharmacokinetic(s)
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
t½
Apparent first-order terminal elimination half-life
tmax
Time to reach Cmax
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
ULN
Upper limit of normal
US
United States
USA
United States of America
Vz/F
Apparent volume of distribution after extravascular administration total
Vz,u/F
Apparent volume of distribution after extravascular administration unbound
WT
Wild-type
λz
Apparent first order terminal elimination rate constant


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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan.
15.1
CRFs (Electronic and Paper)
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor or its 
designee will train appropriate site staff in the use of the CRF. These forms are used to transmit the 
information collected in the performance of this study to the Sponsor and regulatory authorities. 
CRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal Investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the Investigator/designee with use of change and modification 
records of the CRFs. The Principal Investigator must review the data change for completeness and 
accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The Investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 [R2] Section 4.9.5 requires the Investigator to retain essential documents specified in ICH E6 
[R2] (Section 8) until at least 2 years after the last approval of a marketing application for a 


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specified drug indication being investigated or, if an application is not approved, until at least 
2 years after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6 [R2] Section 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the Clinical Study Site 
Agreement between the Investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The Investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.


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16.0
REFERENCES
1. European Medicines Agency Committee for Medicinal Products for Human Use: Guideline on 
the Evaluation on the Pharmacokinetics of Medicinal Products in Patients with Impaired 
Hepatic Function, February, 2005.
2. Mansfield AS. The effect of hepatic impairment on outcomes in phase 1 clinical trials in cancer 
subjects. Clin. Cancer Res. 2016;22(22):5472-5479.
3. National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 
Revised: Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_8.5x11.pdf.
4. Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet 
1999;37(5):399-431.
5. Mobocertinib. Millennium Pharmaceuticals, Inc. Global Investigator Brochure. Edition 4.0, 
04 January 2020.
6. U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function 
— Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003.
7. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. 
Eur J Clin Pharmacol 2008;64(12):1147-61.


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the Investigator may participate in this study.
The Investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
Investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 


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2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The Investigator should 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.


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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 


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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for at 
least 30 days after the dose of study drug. Regular pregnancy tests will be performed 
throughout the study for all female subjects of childbearing potential. If a subject is found to be 
pregnant during study, study drug will be discontinued and the Investigator will offer the 
subject the choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for at least 30 days 
after the dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, the Investigator will offer the subject the choice to receive unblinded treatment 
information. 
27. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.


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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of Investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting Investigator site contact information, study details and results on publicly accessible 
clinical study registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Mobocertinib may pose a risk to developing fetuses or to babies who are being breastfed. Because 
mobocertinib may affect an unborn baby, female participants should not become pregnant while in 
this study, and male participants should not conceive with their female partner(s) while in this 
study. Women who are pregnant or breastfeeding will not be allowed to take part in this study.
Women of childbearing potential and male patients must use medically acceptable birth control. 
Avoiding sexual activity is the only certain way to prevent pregnancy. 
Males Subjects and Their Female Partners:
It is not known whether the study medication will affect sperm or an unborn baby. Based on animal 
studies, taking mobocertinib may lead to testicular changes that could impact reproduction. For 
this reason, to be in the study males must agree not to father a child or donate sperm during the 
study and for at least 30 days after mobocertinib dosing. 
If a male has not had a vasectomy and are sexually active with any person who is pregnant, or 
could get pregnant, he must use a condom with spermicidal cream or jelly each time he has sex 
during the study and for at least 30 days after mobocertinib dosing. If a male is surgically sterilized 
(ie, have had a vasectomy) he must agree to use an appropriate method of barrier contraception 
(latex condom with a spermicidal agent) during the entire study, and for at least 30 days after 
mobocertinib dosing. Or, he should completely avoid having heterosexual intercourse.
If a female partner does become pregnant while a male subject is taking part in the study, the 
subject must tell the study doctor immediately.
In this situation, the female partner should be under medical supervision during her pregnancy, and 
the baby should be under supervision after it is born. The female partner may be asked to give her 
consent to the collection of information related to both herself as well as the baby.
Acceptable birth control for males with female partners includes any of the following:

total abstinence (no sexual intercourse) if it agrees with his preferred and usual lifestyle.

a barrier method (latex condom with a spermicidal agent).
Males must use acceptable birth control during the study treatment period and for at least 30 days 
after mobocertinib dosing and should tell their female partner(s) that they are in research study.
Females:
Females must agree not to become pregnant, breastfeed a baby or donate an egg or eggs (ova) 
during the study and for at least 30 days after mobocertinib dosing. Women of childbearing 
potential must use acceptable birth control from the time of signing the informed consent form 
until at least 30 days after mobocertinib dosing.
If a female has been surgically sterilized or is postmenopausal, she does not need to meet any 
contraception requirements to take part in this study. If a female is of childbearing potential and is 


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sexually active with a male partner, she must be willing to use an acceptable method of 
contraception during the study and for at least 30 days after mobocertinib dosing.
Mobocertinib may decrease effectiveness of hormonal contraceptives, therefore, women of 
childbearing potential must use effective contraception without hormones. Acceptable birth 
control for women of childbearing potential with male partners must include one form of highly 
effective non-hormonal contraception and one additional effective (barrier) method, as described 
below:
Highly effective non-hormonal methods
Additional effective (barrier) methods 
Non-hormonal intrauterine device 
Male or female condom with or without spermicide 
(female and male condoms should not be used together)
Vasectomised sole sexual partner (removal of the tube 
that carries sperm from the testicle to the penis)
Sexual abstinence (no sexual intercourse)
Cap, diaphragm or sponge with spermicide
Total abstinence (no sexual intercourse) may be considered an acceptable method of birth control 
if it agrees with her preferred and usual lifestyle. 
In order to enter the study, all females must have a pregnancy test to confirm that she is not 
pregnant. This test will be repeated just before she starts taking the study medication and at 
check-in. If a pregnancy test during the study shows that she may be pregnant, she will be 
withdrawn from the study and the treatment will end. She will be asked for the results of any tests 
and procedures carried out during pregnancy and up to the birth. She may also be asked for the 
results from any evaluation of the baby after the birth.


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Appendix E
Detailed Description of Amendments to Text: Amendment 1
Change 1. The criterion 17 of exclusion for hepatic impairment subjects should be an inclusion 
criterion for the same group of subjects. 
Move criterion 17 in Section 7.2.2 – Exclusion Criteria for Hepatic Impairment Subjects to 
become criterion 6 in Section 7.1.2 – Inclusion Criteria for Hepatic Impairment Subjects and 
updating in the corresponding places in Section 1.0 – Study Summary 
Moved 
Wording 
and 
Reworded:
Diagnosis of chronic (eg, imaging, biopsy, etc.) stable hepatic insufficiency for at 
least 6 months (no acute episodes of illness within the previous 2 months due to 
deterioration in hepatic function) with features of cirrhosis due to any etiology 
according to medical history.
Change 2. The exclusion criterion 12 of Section 7.2.2 - Exclusion Criteria for Hepatic Impairment 
Subjects allows for hepatic impairment subjects to be hepatitis B positive if the viral titer is below 
1000 copies/mL of plasma at the time of testing and therefore should be harmonized with test 
HBsAg under “Other” in Section 9.2.9.1 - Clinical Laboratory Tests. 
The Section 9.2.9.1 - Clinical Laboratory Tests, “Other” test HBsAg
Added 
Wording
(if HI patients are positive for HBV, DNA copies are below 1000 copies/mL in 
plasma)
Change 3. Scheduling coagulation at the same time as the other clinical laboratory tests 
throughout the study.
Coagulation as a clinical laboratory test was missing from the Section 1.0 - The Schedule of Study 
Procedures.
Wording 
Added
Add “Coag” to the row with “Hem, Serum Chem k, and UA” and add the definition 
of the abbreviation to the list of abbreviations below Coag = Coagulation.


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Appendix F
Detailed Description of Amendments to Text: Amendment 2
Change 1. Due to the COVID-19 pandemic of 2020, the mandatory measurement of the PFT was 
removed from the protocol to diminish the risk of airborne virus transmission during the study 
conduct. 
The following sections were updated to reflect this change:

Removal of Criteria 6 and 8 in Section 1.0 – Study Summary (Inclusion Criteria), 

Removal of the PFT associated footnote “j” in Section 3.0 – Schedule of Study Procedures, 

Removal of reference to PFT in Section 4.4 – Benefit/Risk Profile,

Removal of reference to the PFT in Section 5.3.3 – Study Design, 

Removal of Criterion 6 in Section 7.1.1 – Inclusion Criteria for Healthy Subjects, 

Removal of Criterion 8 in Section 7.1.2 - Inclusion Criteria for Hepatic Impairment 
Subjects, 

Removal of details of the PFT in Section 9.2.6.1 – Pulmonary Function Test,

Removal of abbreviations FEV1 and FVC in Section 14.1.4 – List of Abbreviations.
Removed 
Wording:
Pulmonary Function Test (PFT) (spirometry only) is required to be performed 
and be assessed as normal at screening. Post-dose PFTs will be performed only if 
indicated on the basis of pulmonary symptoms at the discretion of the 
Investigator or designee (Section 1.0 and Section 6.0).
Criterion 6 (Section 1.0 and Section 7.1.1) - Normal baseline spirometry for FVC 
and FEV1/FVC within 7 days prior to dosing based on the following normal FVC 
and FEV1/FVC range:

18 - 39 years of age: ≥80% of predicted normal

40 - 59 years of age: ≥75% of predicted normal

60 - <80 years of age: ≥70% of predicted normal
Criterion 8 (Section 1.0 and Section 7.1.2) - Normal baseline spirometry for FVC 
and FEV1/FVC within 7 days prior to dosing based on the following normal
FVC and FEV1/FVC range:

18 - 39 years of age: ≥80% of predicted normal

40 - 59 years of age: ≥75% of predicted normal

60 - <80 years of age: ≥70% of predicted normal
Pulmonary Function Test associated footnote “j” – “To be conducted within 
7 days prior to dosing (Section 3.0).”


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Spirometry measures will be taken at screening (within 7 days prior to dosing) 
using a standard calibrated spirometer to determine the parameters detailed 
below. Spirometry may be repeated during the study in response to pulmonary 
symptoms at the discretion of the Investigator or designee.

FEV1 (forced expiratory volume);

FVC (forced vital capacity);

FEV1/FVC.
FEV1 Forced expiratory volume
FVC Forced vial capacity (Section 9.2.6.1)
Section 1.0 – Study Summary, Section 3.0 – Schedule of Study Procedures (additional footnote 
“k”), and Section 9.2.6.1 – Pulmonary Function Test.
Addition of 
wording
Spirometry as the pulmonary function test (PFT) may be performed in the event 
of a pulmonary adverse event (AE), if deemed clinically necessary by the 
Investigator or designee.
Section 3.0 – Schedule of Study Procedures – row for pulmonary function test (this test is 
performed in response to AEs only).
Merging 
columns
The columns from screening until Day 10 were merged and indicated with a 
single X.
Change 2. The reference to more than two specific metabolites for the PK analysis was removed 
and only the two known metabolites (AP32960 and AP32914) will be assessed in subjects with 
moderate and/or severe hepatic impairment (HI) compared to matched-healthy subjects with 
normal hepatic function. The following sections were updated to reflect this change:

Section 1.0 – Study Summary, 

Section 3.0 - Schedule of Study Procedures, 

Section 6.1 Study Design, 

Section 6.2 - Dose Escalation, 

Section 6.3.5 - Critical Procedures Based on Study Objectives: Timing of Procedures, 

Section 9.3.1.1 - Plasma PK Measurements, 

Section 11.1.3 - Pharmacokinetic Analysis, 

Section 11.2 - Interim Analysis and Criteria for Early Termination.
Removed 
Wording 
“including but not limited to”


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Change 3. Due to the COVID-19 pandemic, all return visits on study were updated to full
confinement. The following sections were updated to reflect this change:

Section 1.0 – Study Summary, 

Table 1.a – Study Design, 

Section 2.0 – Study Schematic, 

Section 3.0 Schedule of Study Procedures, 

Section 6.1- Study Design, 

Table 6.b - Study Design.

Section 9.3.4 - Confinement
Wording 
update
The wording was updated as appropriate for confinement up to Day 10
Flow Chart 
Updated
Removal of “X” for Day 8 and 10 return visits and columns from Day -1 to 
Day 10 merged and indicated with a single X for full confinement.
Wording 
update
Reference to verbiage for return visits and/or returns to CRU are removed since 
there are no more return visits, in the appropriate protocol sections.
Change 4. Section 1.0 – Study Summary and In Sections 7.1.2 and 7.2.1, the title of the inclusion 
and exclusion was updated for specificity in relation to hepatic subject participation in.
Wording 
update
From “Hepatic Impairment Subjects” to “Subjects with Moderate or Severe 
Hepatic Impairment”
Change 5. In Section 9.2.9.1 - Clinical Laboratory Tests: COVID-19 testing was added
A caveat for positive results for COVID-19 testing at screening or check-in has been added as an 
exclusion criterion to Section 1.0 (Study Summary, Exclusion Criteria), Section 7.2.1 (Exclusion 
Criteria for Healthy Subjects), and Section 7.2.2 (Exclusion Criteria for Hepatic Impairment 
Subjects).
Addition of 
wording
Exclusion Criterion 10 (Healthy Subjects) and Criterion 11 (Subjects with 
Moderate or Severe Hepatic Impairment) – “Positive results for COVID-19 
testing at screening or check-in.”
Change 6. In Section 4.0 (Introduction), wording was updated to match the current IB and the 
study TAK-788-1007
Wording 
update
Updated From IB Edition 3.0, Jan-2019 to IB Edition 4.0, 04-Jan-2020 and the 
background information has been updated.


Mobocertinib
Study No. TAK-788-1008
Page 83 of 83
Protocol Incorporating Amendment No. 02
07 August 2020
CONFIDENTIAL
Change 7. The name of the study drug was changed from TAK-788 to mobocertinib. 
Change 8. In Section 9.2.4 – Vital Signs, the rest period before taking vital signs was added to the 
text.
Wording 
Added 
(subjects must be seated for at least 5 minutes prior to measurement.)
Change 9. In Section 9.2.5 - 12-Lead ECG, the rest period duration for ECG measurement was 
added. 
Wording 
Adding 
Subjects are required to be supine for at least 5 minutes prior to the ECG 
measurement.
Change 10. In Section 4.4 – Benefit/risk profile, the TEAEs and safety information was updated in 
accordance with the new IB.
Change 11. In addition to the aforementioned changes, minor updates were made throughout the 
protocol for grammar and formatting.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680e27429
Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects with Moderate or Severe Hepatic
Impairment and Normal Hepatic Function
Clinical Science Approval
11-Aug-2020 14:06 UTC
Clinical Pharmacology Approval
11-Aug-2020 20:30 UTC
Biostatistics Approval
12-Aug-2020 01:01 UTC

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
Study Title: 
Study Number: 
NCT04056468 
Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in 
Subjects With Moderate or Severe Hepatic Impairment and Normal 
Hepatic Function 
TAK-788-1008
SAP Version and Date: 
Version 2.0: 12-Apr-2022 


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN 
Study Number: TAK-788-1008 
Celerion Study Number: CA27459
Study Title: Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects with 
Moderate or Severe Hepatic Impairment and Normal Hepatic Function  
Phase: 1 
Version: Final Version 2 
Date: 12-Apr-2022 
 
 
 
Prepared by:  
, MS 
 
Data Management and Biometrics 
Celerion  
 
, MSc 
, Clinical Pharmacology & Pharmacometrics 
Data Management and Biometrics 
Celerion 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 07-Aug-2020 
 
 
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REVISION HISTORY 
Version  
Approval Date
Primary Rationale for Revision 
Final
27-Jan-2021 
Not Applicable 
Final Version 2
12-Apr-2022 
Updated following completion of the ad hoc topline pharmacokinetic 
analysis conducted to compare the total combined molar exposure of 
mobocertinib, AP32960, and AP32914 between the moderate hepatic 
impairment group and the normal hepatic function group as of a 29 June 
2021 data cut-off date, and following the enrollment of Arm 3. 
 
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1.1
Approval Signatures 
Electronic signature can be found on the last page of this document. 
 
Study Title:
Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in 
Subjects with Moderate or Severe Hepatic Impairment and Normal 
Hepatic Function
 
Approvals: 
 
, PhD
, Statistical and Quantitative Science 
Takeda Pharmaceuticals 
 
Date
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2.0
TABLE OF CONTENTS 
1.0
TITLE PAGE .......................................................................................................................1
1.1 
Approval Signatures.......................................................................................................3
2.0
TABLE OF CONTENTS.....................................................................................................4
3.0
ABBREVIATIONS .............................................................................................................6
4.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8
4.1 
Objectives ......................................................................................................................8
4.1.1
Primary Objective ..................................................................................................8
4.1.2
Secondary Objectives ............................................................................................8
4.1.3
Exploratory Objective ...........................................................................................8
4.2 
Endpoints .......................................................................................................................8
4.2.1
Primary Endpoints .................................................................................................8
4.2.2
Secondary Endpoints.............................................................................................9
4.2.3
Exploratory Endpoint ............................................................................................9
4.3 
Estimand(s) ....................................................................................................................9
5.0
STUDY DESIGN.................................................................................................................9
6.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................11
6.1 
Statistical Hypotheses ..................................................................................................11
6.2 
Statistical Decision Rules ............................................................................................11
6.3 
Multiplicity Adjustment ...............................................................................................11
7.0
SAMPLE-SIZE DETERMINATION................................................................................11
8.0
ANALYSIS SETS .............................................................................................................11
8.1
Safety Analysis Set ......................................................................................................11
8.2 
Pharmacokinetic Analysis Set......................................................................................12
9.0
STATISTICAL ANALYSIS .............................................................................................12
9.1 
General Considerations ................................................................................................12
9.1.1
Handling of Treatment Misallocations ................................................................13
9.2 
Study Information ........................................................................................................13
9.3 
Disposition of Subjects ................................................................................................13
9.4 
Demographic and Other Baseline Characteristics .......................................................14
9.4.1
Demographics......................................................................................................14
9.4.2
Medical History and Concurrent Medical Conditions.........................................14
9.4.3
Baseline Characteristics.......................................................................................14
9.5 
Medication History and Concomitant Medications.....................................................14
9.6 
Efficacy Analysis .........................................................................................................15
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9.7
Safety Analysis ............................................................................................................15
9.7.1
Adverse Events....................................................................................................15
9.7.2
Adverse Events of Special Interest (if applicable) ..............................................17
9.7.3
Clinical Laboratory Assessments ........................................................................17
9.7.4
Vital Signs ...........................................................................................................18
9.7.5
Electrocardiograms..............................................................................................18
9.7.6
Physical Examination ..........................................................................................18
9.7.7
Overdose..............................................................................................................18
9.7.8
Other Safety Analysis (if applicable) ..................................................................18
9.7.9
Extent of Exposure and Compliance ...................................................................19
9.8 
Pharmacokinetic Analysis............................................................................................19
9.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................20
9.10 
Preliminary Analyses...................................................................................................20
9.11 
Interim Analyses..........................................................................................................20
9.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees].................................................................................................................20
10.0
REFERENCES ..................................................................................................................20
11.0
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................21
12.0
APPENDIX ........................................................................................................................21
12.1 
Changes From the Previous Version of the SAP .........................................................21
12.2 
Data Handling Conventions.........................................................................................21
12.3
Analysis Software........................................................................................................21
LIST OF IN-TEXT TABLES
Table 5:1 
Study Arms and Planned Dose ..............................................................................10
Table 5:2 
Study Design..........................................................................................................10
Table 9:1 
Collection of Blood Samples for Pharmacokinetic and Plasma Protein Binding 
Analyses.................................................................................................................19
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3.0
ABBREVIATIONS
z
terminal disposition phase rate constant 
AE
adverse event 
AESI
adverse event of special interest
ANOVA 
analysis of variance 
AUC  
area under the concentration versus time curve from time 0 extrapolated to infinity for total 
analyte
AUC ,u 
area under the concentration versus time curve from time 0 extrapolated to infinity for unbound 
analyte 
AUClast
area under the concentration versus time curve from time 0 to the time of the last quantifiable 
concentration for total analyte 
AUClast,u
area under the concentration versus time curve from time 0 to the time of the last quantifiable 
concentration for unbound analyte 
BLQ
below the lower limit of quantitation
BOCF 
baseline observation carried forward 
CI
confidence interval
CL/F 
apparent clearance after extravascular administration for total analyte 
CLu/F
apparent clearance after extravascular administration for unbound analyte 
Cmax 
maximum observed plasma concentration for total analyte 
Cmax,u
maximum observed plasma concentration for unbound analyte 
COVID-19
coronavirus disease 2019 
CRU 
clinical research unit 
CTCAE
Common Terminology Criteria for Adverse Events 
CV% 
arithmetic percent coefficient of variation 
DMC 
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form 
Geom CV%
geometric percent coefficient of variation
Geom Mean
geometric mean
HI 
hepatic impairment 
IRC
Internal Review Committee 
LSM 
least-squares mean
Mean 
arithmetic mean
MedDRA 
Medical Dictionary for Regulatory Activities
n
number of observations 
NCI ODWG
National Cancer Institute Organ Dysfunction Working Group 
PK 
pharmacokinetic(s) 
PO 
per os (by mouth)
PT
Preferred Term (MedDRA)
SAE 
serious adverse event
SAP
statistical analysis plan 
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SD
standard deviation
SEM 
standard error of the mean
SOC 
System Organ Class
t½z
terminal disposition phase half-life
TEAE 
treatment-emergent adverse event
TFLs
tables, figures, and listings
tmax
time of first occurrence of Cmax and Cmax,u
Vz
apparent volume of distribution during the terminal disposition phase after extravascular 
administration for total analyte 
Vz,u/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration for unbound analyte 
 
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4.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
4.1 
Objectives 
4.1.1 
Primary Objective 
To characterize the single-dose plasma pharmacokinetics (PK) of mobocertinib and its active 
metabolites (AP32960 and AP32914) in subjects with moderate and/or severe hepatic 
impairment (HI) compared to matched-healthy subjects with normal hepatic function. 
4.1.2
Secondary Objectives 
1. To evaluate plasma protein binding of mobocertinib and its active metabolites (AP32960 and 
AP32914). 
2. To assess the safety of mobocertinib following a single oral dose in subjects with moderate 
and/or severe HI as well as matched-healthy subjects with normal hepatic function. 
4.1.3
Exploratory Objective 
 
 
 
4.2
Endpoints
4.2.1 
Primary Endpoints
The primary endpoints of the study are the following total and unbound PK parameters for 
mobocertinib and its active metabolites, AP32960 and AP32914 (total and unbound parameters 
in parenthesis, respectively):
 Maximum observed concentration (Cmax and Cmax,u). 
 Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC and AUC ,u). 
 Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast and AUClast,u).
 Time of first occurrence of Cmax (tmax).
 Terminal disposition phase half-life (t½z). 
 
z). 
 Apparent clearance after extravascular administration (CL/F and CLu/F) for mobocertinib 
only. 
 Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F and Vz,u/F) for mobocertinib only.
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4.2.2
Secondary Endpoints
Pharmacokinetics 
Plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914).
Safety 
 Incidence of treatment-emergent adverse events (TEAEs) assessments (including physical 
examination findings). 
 Clinical laboratory testing.
 12-lead electrocardiogram (ECG). 
 Vital signs. 
4.2.3 
Exploratory Endpoint 
 
 
 
4.3
Estimand(s) 
Not applicable. 
5.0 
STUDY DESIGN 
This is an open-label, parallel-arm study of oral mobocertinib designed to assess the PK of single 
dose mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with moderate 
and/or severe HI compared to matched-healthy subjects with normal hepatic function. 
The planned doses of mobocertinib per study arm are outlined in Table 5:1.
 
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Table 5:1 
Study Arms and Planned Dose
Study Arms 
Arm
Number of 
Subjects
Classification
Child-Pugh 
Category (a)
Dose (b)
1
8
Moderate
B
40 mg
2
8
Severe
C
40 mg (may have been reduced) (d)
3
8/8 (d)
Matched
Healthy (c) 
40 mg (n=8)/reduced dose to match dose in 
Arm 2, if needed (n=8) (d) 
(a) Refer to Section 4.3 of protocol amendment 2 for the classification system. 
(b) Single orally administered dose at Hour 0 on Day 1. Subjects were enrolled in a staggered manner beginning 
with approximately 3 subjects in the moderate impairment arm followed by approximately 3 subjects in the 
matched-normal hepatic function arm. 
(c) Healthy subjects with normal hepatic function were recruited to match both moderate and severe HI arms by age 
(mean ± 10 years), gender (± 2 subjects per gender), and body mass index (BMI, mean ± 10%). 
(d) If the dose of Arm 2 was reduced, then an additional 8 healthy matched subjects were to be dosed in Arm 3 at the 
corresponding dose level to Arm 2.  
 
The study consists of a 21-day screening period, a 10-
Day 10) and a follow-up phone call 30 ± 2 days after dosing.
Subjects were enrolled in a staggered manner. All subjects who qualified for the moderate HI
arm may have been enrolled concurrently; however, approximately 3 subjects in the moderate HI 
arm and approximately 3 subjects in the matched-normal hepatic function arm must have 
completed up to Day 10 study procedures prior to enrolling subjects to the severe HI arm. An 
informal preliminary PK data analysis of these subjects was performed and may have 
additionally leveraged historical control PK data in healthy subjects to gain an initial estimate of 
the effect of moderate HI on the PK of mobocertinib and its active metabolites (AP32960 and 
AP32914). These preliminary data along with safety data guided the decision to enroll the severe 
HI arm at the same dose as the moderate HI arm. Following completion of enrollment of the 
moderate and severe HI arms, the remaining subjects were enrolled to the matched-normal 
hepatic function arm.  
Subjects received a single oral dose of 40 mg mobocertinib on Day 1 (Table 5:2). 
Table 5:2 
Study Design  
Study Day
Screening
-1
1
2
3
4
5
6
7 
8
9
10
Mobocertinib PO
 
X
 
 
PK Blood Samples 
 
X
X
X
X
X
X
X
X 
Confinement in CRU 
 
X
X
X
X
X
X
X
X
X
X
X 
CRU-clinical research unit; PK-pharmacokinetics; PO-per os (by mouth). 
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Blood samples were to be collected from Days 1 to 10 at predetermined time points to 
characterize the PK and plasma protein binding of mobocertinib and its active metabolites 
(AP32960 and AP32914) in subjects with moderate and/or severe HI compared to 
matched-healthy subjects with normal hepatic function. 
Subjects were confined in the clinical research unit (CRU) until the morning of Day 10 after the 
216-hour PK sample. A subject may have been required to remain at the CRU for longer periods, 
at the discretion of the Investigator. Subjects may have been admitted earlier than Day -1 for 
COVID-19 testing not related to study protocol as per CRU requirements. 
A final safety follow up phone was made 30 ± 2 days after mobocertinib dosing to determine if 
any adverse events (AEs) have occurred since last study visit. 
6.0
STATISTICAL HYPOTHESES AND DECISION RULES  
6.1
Statistical Hypotheses 
Not applicable. 
6.2 
Statistical Decision Rules 
Not applicable. 
6.3 
Multiplicity Adjustment 
Not applicable. 
7.0 
SAMPLE-SIZE DETERMINATION 
The planned sample size of 8 subjects in each hepatic function arm represents a size that is 
considered adequate to provide a descriptive characterization of the PK of mobocertinib and its 
active metabolites in subjects with moderate or severe hepatic impairment compared to healthy 
subjects with normal hepatic function. 
At least 24 subjects were to be enrolled into 3 arms (approximately 8 subjects in each arm) in the 
study. The target number for the matched-healthy subjects with normal hepatic function was 
8 subjects; however, up to 16 healthy subjects may have been enrolled into Arm 3 if it was not 
feasible to match the first 8 healthy subjects into both Arms 1 and 2.
8.0 
ANALYSIS SETS 
8.1 
Safety Analysis Set 
All subjects who received the study drug will be included in the safety evaluations.
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8.2
Pharmacokinetic Analysis Set  
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol-specified dosing and display an evaluable PK 
profile (eg, exposure to treatment, availability of sufficient PK measurements and absence of 
major protocol violations) will be included in the statistical analyses. Any subject who 
experiences emesis within 8 hours post dosing with mobocertinib may be included in the PK 
analysis but excluded from the statistical analysis.
9.0
STATISTICAL ANALYSIS
9.1
General Considerations
All PK analyses will be conducted using Phoenix® WinNonlin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4. All relevant data recorded in the 
electronic case report form (eCRF) will be listed by subject. All tables, figures, and listings 
(TFLs) shells and numbering list will be included and specified in the TFL Shells document. 
Concentration values below the lower limit of quantitation (BLQ) will be presented as ‘BLQ’ in 
the concentration table listings and footnoted accordingly. BLQ values will be treated as zero for 
the calculation of summary statistics, the generation of concentration plots, and the calculation of 
PK parameters, unless they are obvious outliers (e.g., BLQ value between measurable values), in 
which case they will be treated as missing. 
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical analyses if one or more of the following criteria are met:  
 A predose (0 hr) concentration is greater than 5% of that subject’s maximum concentration 
value in that period  
 A subject did not meet inclusion/exclusion criteria that may have an effect on PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist) 
 A subject deviates substantially from the protocol-defined study procedures, including but 
not limited to dosing, dose timing, sample collection, etc (as determined by the Takeda 
Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist) 
The details on PK parameter calculations and TFLs will be outlined in the Clinical 
Pharmacology Analysis Plan (CPAP) and TFL Shell document including specifics on the 
following: 
 Insufficient data to determine a reliable t1/2z value and other 
z-dependent parameters
 PK parameters presented by hepatic function group, including the units, precision, and 
summary statistics that will be presented in in-text and end-of-text tables 
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 Concentration data presented by hepatic function group, including the units, precision, and 
summary statistics that will be presented in end-of-text tables 
 Concentration data file used for PK analysis 
 PK parameter WinNonlin® output file used to generate the TFLs
 Analysis of variance (ANOVA) results presented in in-text and end-of-text tables 
Arithmetic mean concentration-time figures presented as in-text and end-of-text figures
Individual concentration-time figures.
All concentration and PK parameter data and their descriptive statistics (with the exception of the 
number of observations) will be presented to 3 significant digits. The number of observations (n) 
will be presented as an integer (no decimal places). 
For demographic and safety data where appropriate, variables will be summarized descriptively. 
For the categorical variables, the count and proportions of each possible value will be tabulated, 
where applicable. The denominator for the proportion will usually be based on the number of 
subjects dosed. For continuous variables, the number of subjects with non-missing values, mean, 
geometric mean, % CV of geometric mean, SD, minimum, median, and maximum values will be 
tabulated. The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than minimum/maximum, 
SD in one more precision level than mean/median, and n will be presented as an integer. Counts 
and percentages will be presented as integers. 
9.1.1 
Handling of Treatment Misallocations 
Not applicable. 
9.2 
Study Information 
A study information table will be generated including the following items: date of first subject’s 
signed informed consent form, date of first dose, date of last dose, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, the 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Dictionary, and SAS version used for creating the datasets. 
9.3
Disposition of Subjects 
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized by hepatic function arm (ie, 
Moderate HI, Severe HI, Normal Hepatic Function) and overall. Study completion status, 
including reason for discontinuation, will also be listed by subject. 
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9.4
Demographic and Other Baseline Characteristics
9.4.1
Demographics
Demographic and baseline characteristics will be summarized descriptively by hepatic function 
arm (ie, Moderate HI, Severe HI, Normal Hepatic Function) and overall. Summary statistics (n, 
mean, SD, minimum, median, and maximum) will be generated for continuous variables (age 
[recorded in the eCRF], weight, height and body mass index [BMI]) and the number and 
percentage of subjects within each category will be presented for categorical variables (sex, race, 
and ethnicity). Height, weight, and BMI recorded at screening will be used in the baseline 
summaries. Demographics data will also be listed as recorded in the eCRF, including the date of 
informed consent. 
9.4.2 
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
informed consent form (ICF). Concurrent medical conditions are those significant ongoing 
conditions or diseases that are present at signing the ICF. Each subject’s medical history and 
concurrent medical conditions will be listed. Any medical condition started after taking the study 
drug(s) will be classified as an adverse event. All medical history will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®) Version 23.0. If appropriate, the 
medical history listing will include whether the event was medical or surgical, the body system 
or organ class involved, coded term, start date (if known) and end date or whether the condition 
was ongoing, and a description of the condition or event. There will be no statistical analysis of 
medical history.
9.4.3
Baseline Characteristics
Child-Pugh scores will be assessed at screening to classify subjects into hepatic function arms.  
The overall scores will be summarized by hepatic function arm.  Individual results will be listed 
by hepatic function arm and subject.  
9.5 
Medication History and Concomitant Medications  
Medication history to be obtained includes any medication relevant to eligibility criteria and 
safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant medication 
includes any medication other than study drug taken at any time between Day 1 through the end 
of the study (including follow-up visit). All medication history and concomitant medications 
recorded during the study will be coded with the WHO Drug Dictionary March 2020 B3 Global 
and listed. If appropriate, the listing will include the medication name, coded term, dosage, route 
of administration, start date and end date, or whether it continued after study completion, and 
indication for use. 
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9.6
Efficacy Analysis 
Not applicable. 
9.7 
Safety Analysis 
For each hepatic function arm (ie, Moderate HI, Severe HI, Normal Hepatic Function) safety and 
tolerability will be assessed through incidence, severity and type of adverse events. Safety will 
also be assessed through changes from baseline in subjects’ vital signs, safety ECGs and clinical 
laboratory assessments; along with symptom-driven physical examinations. All safety data will 
be listed by hepatic function arm (ie, Moderate HI, Severe HI, Normal Hepatic Function), 
subject, and assessment time points, including rechecks, unscheduled assessments, and early 
termination, chronologically.  
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. 
9.7.1 
Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity, relationship to study drug (related or not related) and action relative 
to the study drug as recorded in the eCRF. All AEs occurring during this study will be coded 
using the MedDRA® Dictionary Version 23.0. However, only TEAEs occurring after dosing will 
be summarized. A TEAE is defined as any AE newly occurring or worsening from the first dose 
until a follow-up phone call 30 days (±2 days) after the last dose of study drug. If a subject 
experiences an exacerbation or complication of a concurrent medical condition that should be 
recorded as an AE. 
All AEs, including TEAEs, will be severity graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, with grading levels 1 to 
5 which correspond to mild, moderate, severe or medically significant but not immediately life-
threatening, life-threatening consequences, and fatal. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. Summaries will be 
presented by hepatic function arm (ie, Moderate HI, Severe HI, Normal Hepatic Function). 
Summary tables will include number of subjects reporting the AE and as percent of safety 
analysis set by hepatic function group (ie, Moderate HI, Severe HI, Normal Hepatic Function) 
and overall. The most commonly reported non-serious TEAEs (i.e., those events reported 
by >5% of all subjects in each hepatic function arm, excluding serious adverse events [SAEs]) 
will also be summarized. In addition, TEAEs will be summarized as number of AEs and 
percentage of AEs for each hepatic function arm (ie, Moderate HI, Severe HI, Normal Hepatic 
Function) for the overview of TEAEs.  
Additional TEAE summary tables will be presented by severity and relationship to study drug.
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Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAE. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the CSR. 
In summary, AEs will be summarized by each hepatic function group and overall as follows:
• 
Overview of TEAEs - number and percentage of subjects, number of events; 
• 
TEAEs by system organ class (SOC), and preferred term (PT) - number and percentage of 
subjects; 
• 
Most frequent TEAEs by PT [excluding SAEs]
subjects in any hepatic function arm) - number and percentage of subjects;  
• 
TEAEs by relationship to study drug and by SOC, and PT - number and percentage of 
subjects; 
• 
TEAEs by severity and by SOC, and PT - number and percentage of subjects; 
• 
TEAEs for severity grade 3 or higher by relationship and by SOC, and PT - number and 
percentage of subjects; 
• 
TEAEs leading to study discontinuation by SOC, and PT - number and percentage of 
subjects; 
• 
Serious TEAEs by SOC, and PT - number and percentage of subjects;
• 
Serious TEAEs by relationship to study drug and by SOC, and PT - number and percentage 
of subjects; 
• 
Serious TEAEs by severity and by SOC, and PT - number and percentage of subjects;
• 
TEAEs resulting in death by PT - number and percentage of subjects; 
Key guidelines for determining the incidence of AEs are as follows:  
• 
AEs with missing or unknown severity will be considered as severe (or Grade 3).  
• 
AEs with missing or unknown relationship to study drug will be counted as related. 
• 
AEs with missing date will be counted as treatment-emergent, unless the date is known to be 
prior to dosing. 
• 
AEs with a start date on Day 1 but missing start time will be counted as treatment-emergent. 
• 
A subject with 2 or more AEs within the same level of the MedDRA term will be counted 
only once in that level. 
• 
SOCs will be sorted in alphabetical order. Within an SOC, PTss will be sorted in descending 
order of total number of subjects with the preferred term among all the hepatic function arms.
• 
For the summary of TEAEs by SOC and PT and severity, if a subject experiences more than 
1 episode of a particular coded adverse event, the subject will be counted only once by the 
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maximum severity grade of the episode (preferred term). Similarly, if a subject has more than 
1 adverse event within an SOC, the subject will be counted only once by the maximum 
severity in that SOC. 
• 
In selected summaries, adverse events will be summarized by the number of events reported 
in addition to the number and percentage of subjects with events. 
Data listings for TEAEs, TEAEs leading to study discontinuation, SAEs, and deaths will be 
presented. The AEs will be listed by hepatic function arm, subject number, and onset date of the 
adverse event. The listing will contain: subject identifier, adverse event (PT and reported term), 
SOC, onset date, end date or whether the event was ongoing, duration, frequency, severity, 
action taken concerning study drug, causality to study drug, the outcome, whether the adverse 
event was a SAE. 
9.7.2 
Adverse Events of Special Interest (if applicable) 
Not applicable. 
9.7.3 
Clinical Laboratory Assessments 
Hematology, serum chemistry, coagulation, and urinalysis will be performed at screening, check-
in (Day -1), Day 3, and Day 10 (or at early termination if applicable). Urine drug screening will 
be carried out at screening and check-in (Day-1) only. In addition, laboratory safety tests may be 
performed at various unscheduled time points, if deemed necessary by the Principal Investigator 
(PI). 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by hepatic function arm (ie, Moderate 
HI, Severe HI, Normal Hepatic Function) and assessment time points. Change from baseline will 
be summarized in a similar manner. Baseline is defined as the last assessment including rechecks 
taken prior to dosing (generally Day -1). All clinical laboratory listings and tables will be 
presented in conventional units. Postdose unscheduled or recheck assessments will not be used in 
analysis. 
For each laboratory test, a shift table will be developed comparing the frequency and percentage 
of the results at baseline (above normal (H), normal (N), or below normal (L)) with the postdose 
time points. For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range 
values and corresponding recheck results will be listed.  
Out-of-normal range flags will be listed with the corresponding categorical references as follows: 
high (H) and low (L) for numerical results and did-not-match (*) for categorical results. All 
clinically significant laboratory tests, as indicated by the PI, and the corresponding values will be 
listed by subject in a table. All clinical laboratory data will be presented in by-subject data 
listings. 
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9.7.4
Vital Signs 
Vital sign measurements consist of body temperature, respiratory rate, BP, and HR. 
Temperature, respiratory rate will be collected at screening only. BP and HR will be collected at 
screening, prior to dosing on Day 1, Day 1 hours 4 and 12, Day 2 (24 Hours), and Day 10 (or at 
early termination if applicable).  Additional unscheduled vital signs may be recorded at other 
times if deemed necessary by the PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for HR and 
BP results and change from baseline by hepatic function arm (ie, Moderate HI, Severe HI, 
Normal Hepatic Function) and time point of collection. Change from baseline will be 
summarized in a similar manner. Baseline is defined as the last assessment, including rechecks 
(by replacement), taken prior to dosing. Postdose unscheduled or recheck assessments will not be 
used in analysis. Vital sign data will also be displayed in a data listing by subject. 
9.7.5 
Electrocardiograms 
Single 12-lead ECGs will be collected at screening, prior to dosing on Day 1, Day 1 Hour 4, Day 
2 (Hour 24), and Day 10 (or at early termination if applicable). Additional unscheduled ECGs 
may be recorded at other times if deemed necessary by the PI.  
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by hepatic function arm (ie, Moderate HI, Severe HI, Normal 
Hepatic Function) and time point of collection. Change from baseline will be summarized in a 
similar manner. Baseline is defined as the last assessment, including rechecks (by replacement), 
taken prior to dosing. Postdose unscheduled or recheck assessments will not be used in analysis. 
ECG data will also be displayed in a data listing by subject. 
9.7.6 
Physical Examination 
Physical examination will be performed at screening and check-in. If the screening assessment 
was conducted within 4-7 days prior to dosing (Day 1), screening result may be used at the 
discretion of the PI. Symptom-driven physical exams may be performed at other times at the 
discretion of the PI. Physical exam findings will be presented in the data listings by arm and 
subject. Reproductive system findings will also be listed by subject. 
9.7.7 
Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs.  
9.7.8 
Other Safety Analysis (if applicable) 
Spirometry as the PFT may be performed in the event of a pulmonary AE, if deemed clinically 
necessary by the Investigator or designee. 
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9.7.9
Extent of Exposure and Compliance 
The date, time, and treatment administered will be listed by subject. 
9.8
Pharmacokinetic Analysis 
Blood samples for the assessment of plasma mobocertinib, AP32960, and AP32914 
concentrations and plasma protein binding will be collected as outlined in Table 9:1 below:  
Table 9:1 
Collection of Blood Samples for Pharmacokinetic and Plasma Protein 
Binding Analyses
Analyte
Matrix
Scheduled Time (Hours)* 
Mobocertinib, AP32960, and 
AP32914 
Plasma
Predose, and 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168, and 
216 hours postdose 
Protein Binding
Plasma
2, 4, and 24 hours postdose 
*The actual date and time of sample collection was recorded on the source document in the case report form. 
Additional details regarding the PK analysis will be described in the CPAP for this study.
The ln-transformed Combined Molar Cmax,u, Combined Molar AUClast,u, and Combined Molar 
AUC
 for mobocertinib and its metabolites (AP32960 and AP32914) will be compared 
between the HI groups and the matched healthy group using an analysis of variance (ANOVA)
model. 
The ANOVA model will include each HI versus healthy condition as a fixed effect. Each 
ANOVA analysis will calculate the least-squares means (LSMs), the difference between group 
LSMs, and the standard error associated with the difference. Residual variance will be reported. 
Ratios of LSMs and 90% confidence intervals will be calculated using the exponential function 
of the difference between group LSMs from the analysis on the ln-transformed Combined Cmax,u, 
Combined AUClast,u, and Combined AUC
. The above analysis will also be performed on the 
ln-transformed Combined Cmax, Combined AUClast, and Combined AUC . 
The same analysis will be repeated for each analyte (mobocertinib, AP32960, and AP32914) 
separately and will be performed on both unbound (Cmax,u, AUClast,u, and AUC
) and total 
(Cmax, AUClast, and AUC ) PK parameters. Additional ANOVA analyses may also be performed 
stratifying patients using the National Cancer Institute Organ Dysfunction Working Group (NCI 
ODWG) criteria for hepatic function. 
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The following SAS® code will be used to perform the analysis:
PROC MIXED DATA=XXX;
CLASS Arm;
MODEL <ln_pkparam>=Arm/DDFM=KR; 
ESTIMATE ‘Moderately Impaired vs. Matched Healthy’ Arm 1 0 -1 / CL ALPHA=0.1 E; 
ESTIMATE ‘Severely Impaired vs. Matched Healthy’ Arm 0 1 -1 / CL ALPHA=0.1 E; 
LSMEANS Arm;
RUN;
Where ‘Arm’ is as described in Table 5:1, ie, 1=Moderate, 2=Severe, 3=Healthy 
9.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
Not applicable. 
9.10 
Preliminary Analyses 
No preliminary analyses will be performed. 
9.11 
Interim Analyses 
An informal preliminary PK data analysis was to be performed on approximately 3 moderate HI 
subjects and 3 healthy matched subjects who completed study procedures up to Day 10 and may 
have additionally leveraged historical control PK data in healthy subjects to gain an initial 
estimate of the effect of moderate HI on the PK of mobocertinib and its active metabolites 
(AP32960 and AP32914). These preliminary data along with safety data were to guide the 
decision to enroll the severe HI arm (for example, a decision was to be made to dose the severe 
HI group at the same dose as the moderate HI arm, a reduced dose, or to not dose this arm). 
To address a specific request from a regulatory agency, an ad hoc topline PK analysis was 
conducted to compare the total combined molar exposure of mobocertinib, AP32960, and 
AP32914 between the moderate HI group (n=8) and the normal hepatic function group (n=6) as 
of a 29 June 2021 data cut-off date.
There are no predetermined criteria for early termination of the study. 
9.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not applicable.
10.0 
REFERENCES 
Not applicable.
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11.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Protocol Amendment 2 stated that the ANOVA model will include HI versus normal conditions 
as a fixed effect and subject nested within group as a random effect. However, the random effect 
was not needed since we only have one measurement (eg, Combined Cmax,u) per subject per 
analysis. Therefore, “CLASS Arm Subject;” was replaced with “CLASS Arm” and “RANDOM 
Subject(Arm);” was removed from the model. 
12.0 
APPENDIX  
12.1 
Changes From the Previous Version of the SAP 
Not applicable. 
12.2 
Data Handling Conventions  
Not applicable. 
12.3 
Analysis Software  
SAS® Version 9.4 will be used for all statistical analysis provided in the CSR. 
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