Clinical trial NCT04056455
Conditions: Renal Impairment Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2020-03-04; Completion date: 2022-04-20
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
It is hoped that mobocertinib will eventually help people with cancer with severely reduced kidney function. The main aim of this study is to learn about the levels of mobocertinib in the blood and urine of participants with severely reduced kidney function and participants with healthy kidneys. These participants do not have cancer. The information from this study will be used to work out the best dose of mobocertinib for people with cancer with severely reduced kidney function in the future.

At the first visit, the study doctor will check who can take part. Participants who can take part will be placed into 1 of 2 treatment groups. Participants with severely reduced kidney function will be in 1 group. Participants with healthy kidneys will be in the other group. Participants in both groups will receive the same treatment and the group results will be compared.

Participants from both groups will take 1 capsule of mobocertinib. They will stay in the clinic for 10 days so the study doctors can check the amount of mobocertinib in the blood and urine of these participants over time. The study doctors will also check if the participants have any side effects from this treatment.

The clinic will call the participants 30 days after they took mobocertinib to check if they have any more side effects from their treatment.

Detailed description:
The drug being tested in this study is called mobocertinib. This study is to assess the pharmacokinetic (PK) of mobocertinib and its active metabolites (AP32960 and AP32914) in participants with severe RI compared to matched-healthy participants with normal renal function.

The study will enroll approximately 24 participants. Participants will be assigned to 1 of the following 2 treatment groups:

* Severe RI: Mobocertinib 80 mg
* Normal Renal Function: Mobocertinib 80 mg

Healthy participants with normal renal function will be recruited to match severe RI 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.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 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: Participants with severe renal impairment received a single dose of mobocertinib 80 mg, capsule, orally, on Day 1. arm 2: Participants with normal renal function received a single dose of mobocertinib 80 mg, capsule, orally, 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: 
NCT04056455
A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects With Severe
 Renal Impairment and Normal Renal Function
TAK-788-1007
Protocol Version and Date: 
Version 2.0: 14-December-2020
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects with Severe Renal 
Impairment and Normal Renal Function
Study Identifier:
TAK-788-1007
Compound:
Mobocertinib (TAK-788)
Date:
09 December 2020
Version/Amendment 
Number:
Amendment 2
Amendment History: 
Date
Amendment Number
Amendment Type
Region
12 July 2019
Initial Version
Not applicable
United States
05 Aug 2020
01
Appendix E
United States
09 December 2020
02
Appendix F
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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Mobocertinib
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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
Benefit/Risk Profile .................................................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Hypothesis...............................................................................................................22
5.2
Study Objectives......................................................................................................22
5.2.1
Study Primary Objective..................................................................................22
5.2.2
Study Secondary Objectives.............................................................................22
5.2.3
Study Exploratory Objective............................................................................22
5.3
Endpoints.................................................................................................................22
5.3.1
Primary Endpoints ...........................................................................................22
5.3.2
Secondary Endpoint.........................................................................................23
5.3.3
Exploratory Endpoint.......................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................24
6.1
Study Design ...........................................................................................................24
6.2
Dose Escalation .......................................................................................................25
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................25
6.3.1
Rationale of Study Design ...............................................................................25
6.3.2
Rationale for Dose...........................................................................................26
6.3.3
Rationale for Endpoints ...................................................................................26
6.3.3.1
Pharmacokinetic Endpoints......................................................................26
6.3.3.2
Safety Endpoints......................................................................................26
6.3.4
Future Biomedical Research ............................................................................26
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............27
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................27
6.5
Study Beginning and End/Completion .....................................................................27
6.5.1
Definition of Beginning of the Study ...............................................................27
6.5.2
Definition of End of the Study.........................................................................27
6.5.3
Definition of Study Completion.......................................................................27
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6.5.4
Definition of Study Discontinuation.................................................................27
6.5.5
Criteria for Premature Termination or Suspension of the Study........................28
6.5.6
Criteria for Premature Termination or Suspension of a Site..............................28
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Inclusion Criteria .....................................................................................................28
7.1.1
Inclusion Criteria for Healthy Subjects ............................................................28
7.1.2
Inclusion Criteria for Subjects with Renal Impairment.....................................29
7.2
Exclusion Criteria ....................................................................................................30
7.2.1
Exclusion Criteria for Healthy Subjects ...........................................................30
7.2.2
Exclusion Criteria for Subjects with Renal Impairment....................................31
7.3
Prior and Concomitant Medications and Therapies...................................................33
7.4
Excluded Medications, Supplements, Dietary Products............................................34
7.5
Diet, Fluid, Activity.................................................................................................35
7.5.1
Diet and Fluid..................................................................................................35
7.5.2
Activity ...........................................................................................................35
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................35
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................35
7.8
Subject Replacement................................................................................................36
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................36
8.1
Clinical Study Drug .................................................................................................36
8.1.1
Mobocertinib Capsules ....................................................................................36
8.1.2
Clinical Study Drug Labeling ..........................................................................36
8.1.3
Clinical Study Drug Inventory and Storage......................................................36
8.1.4
Clinical Study Drug Blinding...........................................................................37
8.1.5
Randomization Code Creation and Storage......................................................37
8.1.6
Clinical Study Blind Maintenance/Unblinding Procedure.................................37
8.1.7
Accountability and Destruction of Sponsor-Supplied Drugs.............................37
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure............................................................................37
9.1.1.1
Assignment of Screening and Allocation Numbers ..................................37
9.1.1.2
Study Drug Assignment...........................................................................37
9.1.2
Inclusion and Exclusion...................................................................................38
9.1.3
Medical History/Demography..........................................................................38
9.1.4
Concomitant Medications ................................................................................38
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9.2
Clinical Procedures and Assessments.......................................................................38
9.2.1
Full Physical Exam..........................................................................................38
9.2.2
Height and Weight...........................................................................................38
9.2.3
BMI.................................................................................................................38
9.2.4
Vital Signs.......................................................................................................38
9.2.5
12-Lead ECG...................................................................................................39
9.2.6
Pulmonary Function Test.................................................................................39
9.2.6.1
Spirometry...............................................................................................39
9.2.7
Study Drug Administration..............................................................................39
9.2.8
AE Monitoring ................................................................................................39
9.2.9
Laboratory Procedures and Assessments..........................................................40
9.2.9.1
Clinical Laboratory Tests.........................................................................40
9.3
Pharmacokinetic Samples ........................................................................................41
9.3.1
PK Measurements............................................................................................42
9.3.1.1
Plasma PK Measurements........................................................................42
9.3.1.2
Urine PK Measurements..........................................................................43
9.3.2
Microbiome Assessment..................................................................................43
9.3.3
PGx Measurements..........................................................................................43
9.3.4
Confinement....................................................................................................43
10.0
ADVERSE EVENTS ....................................................................................................44
10.1
Definitions and Elements of AEs .............................................................................44
10.1.1
SAEs ...............................................................................................................46
10.1.2
Special Interest AEs.........................................................................................47
10.2
AE Procedures.........................................................................................................47
10.2.1
Assigning Severity/Intensity of AEs ................................................................47
10.2.2
Assigning Causality of AEs .............................................................................48
10.2.3
Start Date.........................................................................................................48
10.2.4
End Date..........................................................................................................48
10.2.5
Outcome..........................................................................................................48
10.2.6
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................49
10.2.6.1
Collection Period.....................................................................................49
10.2.6.2
Reporting AEs.........................................................................................49
10.2.6.3
Reporting SAEs.......................................................................................50
10.2.6.4
Reporting Special Interest AEs ................................................................50
10.2.6.5
Reporting of Abnormal Liver Function Tests...........................................50
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10.2.7
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...51
10.2.8
Procedures for Reporting Product Complaints or Medication Errors 
(Including Overdose).......................................................................................51
11.0
STATISTICAL METHODS..........................................................................................51
11.1
Statistical and Analytical Plans ................................................................................51
11.1.1
Analysis Sets ...................................................................................................52
11.1.1.1
Pharmacokinetic Set ................................................................................52
11.1.1.2
Safety Set ................................................................................................52
11.1.1.3
Pharmacodynamic Set..............................................................................52
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................52
11.1.3
Pharmacokinetic Analysis................................................................................52
11.1.4
Pharmacodynamic Analysis.............................................................................52
11.1.5
Safety Analysis................................................................................................53
11.1.5.1
AEs .........................................................................................................53
11.1.5.2
Clinical Laboratory Evaluation ................................................................53
11.1.5.3
Vital Signs...............................................................................................53
11.1.5.4
Other Safety Parameters ..........................................................................53
11.2
Interim Analysis and Criteria for Early Termination ................................................53
11.3
Determination of Sample Size..................................................................................53
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................54
12.1
Study-Site Monitoring Visits ...................................................................................54
12.2
Protocol Deviations..................................................................................................54
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................54
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................55
13.1
IRB and/or IEC Approval ........................................................................................55
13.2
Subject Information, Informed Consent, and Subject Authorization .........................56
13.3
Subject Confidentiality ............................................................................................57
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................57
13.4.1
Publication and Disclosure...............................................................................57
13.4.2
Clinical Study Registration ..............................................................................58
13.4.3
Clinical Study Results Disclosure ....................................................................58
13.5
Insurance and Compensation for Injury....................................................................58
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................59
14.1
Administrative Information......................................................................................59
14.1.1
Study Contact Information...............................................................................59
14.1.2
INVESTIGATOR AGREEMENT ...................................................................60
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14.1.3
Study-Related Responsibilities.........................................................................61
14.1.4
List of Abbreviations .......................................................................................62
15.0
DATA HANDLING AND RECORDKEEPING............................................................64
15.1
CRFs .......................................................................................................................64
15.2
Record Retention .....................................................................................................64
16.0
REFERENCES..............................................................................................................65
17.0
APPENDICES...............................................................................................................66
LIST OF IN-TEXT TABLES
Table 1.a
Study Design for Arms 1 and 2 ............................................................................7
Table 3.a
Pharmacokinetic Plasma and Urine Sampling Schedule (Arm 1 and Arm 2).......18
Table 6.a
Study Arms and Planned Dose ...........................................................................24
Table 6.b
Study Design for Arms 1 and 2 ..........................................................................25
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................34
Table 9.a
Primary Specimen Collections ...........................................................................41
Table 10.a
Takeda Medically Significant AE List................................................................47
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................66
Appendix B
Elements of the Subject Informed Consent.........................................................68
Appendix C
Investigator Consent to the Use of Personal Information ....................................71
Appendix D
Pregnancy and Contraception.............................................................................72
Appendix E
Detailed Description of Amendments to Text: Amendment 1.............................74
Appendix F
Detailed Description of Amendments to Text: Amendment 2.............................79
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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 (TAK-788)
Study Identifier: TAK-788-1007 (CA27460)
Phase: 1
Protocol Title: A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects with Severe Renal Impairment 
and Normal Renal Function
Study Design:
This is an open-label, parallel-arm study of oral mobocertinib designed to assess the PK of mobocertinib and its active 
metabolites (AP32960 and AP32914) in subjects with severe renal impairment (RI) compared to matched-healthy 
subjects with normal renal function. 
Approximately 12 subjects will be enrolled in each arm of the study according to the following criteria:

Arm 1: Severe RI (estimated glomerular filtration rate [eGFR] 15-29 mL/min), 

Arm 2: Normal renal function (eGFR ≥90 mL/min). Healthy subjects with normal renal function will be recruited 
to match subjects with severe RI 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, a 10-day confinement period (Day −1 to Day 10) and a follow-up 
phone call 30 ± 2 days after dosing.
For assessment of renal function at screening, eGFR will be based on the eGFR value calculated from Modification of
Diet in Renal Disease (MDRD) formula divided by standard body surface area (BSA) value of 1.73 m2 for the renal 
classification category of subjects (ie, severe RI or normal renal function). For subjects with non-standard BSA, the 
eGFR value calculated by MDRD formula will be multiplied by the individual’s BSA calculated using appropriate 
formula (Dubois and Dubois, 1916) and divided by 1.73 m2. The eGFR value will be compared to the renal function 
assignment from historical values within a 6 month period from screening. The subjects to be recruited into this study 
should show a stable renal function, such as <30% difference in eGFR values, within 6 months from screening. If the 
renal function of historical and screening assessments falls in the same renal function category with <30% difference, 
the subject can be enrolled into this study if other inclusion criteria are met and none of the exclusion criteria are met. 
If no historical measurement is available, a second baseline eGFR sample will be taken during the screening period (at 
least 72 hours apart) and the two values have to show <30% difference and fall in the same renal function category of 
either severe RI or normal renal function before check-in. If the results of the 2 most recent assessments are not in 
agreement with regard to the subject’s renal function category, the third assessment has to be performed at least 72 
hours after the second assessment. If the second and third measurements differ, the subject will not be eligible for the 
study. 
Subjects will receive a single oral dose of 80 mg mobocertinib capsule on Day 1 (Table 1.a). 
Table 1.a
Study Design for Arms 1 and 2
-1
1
2
3
4
5
6
8
10
Mobocertinib PO
X
PK Blood Samples 
X
X
X
X
X
X
X
X
PK Urine Samples 
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).
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Blood samples will be collected from Days 1 to 10 and urine samples will be collected from Day 1 to the morning of 
Day 6 at predetermined time points to characterize the plasma and urine PK and plasma protein binding of 
mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with severe RI and in matched-healthy 
subjects with normal renal 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 clinical research unit (CRU) from Day -1 until the morning of Day 10 after the 
216-hour study assessments are complete. 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 Objectives:
Study Primary Objective:
To characterize the single-dose plasma and urine PK of mobocertinib and its active metabolites (AP32960 and 
AP32914) in subjects with severe RI compared to matched-healthy subjects with normal renal 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 severe RI and the matched healthy 
subjects with normal renal function.
Study Subject Population: Adult male and female subjects will be enrolled into one of the 2 arms of the study 
according to the following criteria:
Arm 1: Severe RI (eGFR 15-29 mL/min).
Arm 2: Normal renal function (eGFR ≥90 mL/min). 
Planned Number of Subjects:
A total of approximately 24 adult male and female 
subjects will be enrolled into 2 arms of the study. 
Twelve (12) subjects with severe RI will be enrolled to 
Arm 1. Twelve (12) matched-healthy subjects with 
normal renal function will be enrolled to Arm 2.
Planned Number of Sites:
At least 2
Dose Level:
80 mg mobocertinib single dose
Route of Administration:
Oral
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. 
Criteria for Inclusion:
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 <81 years, at screening. Subjects will be matched to RI 
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 RI 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 
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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.
Baseline eGFR ≥90 mL/min based on the MDRD equation at screening divided by standard BSA value of 
1.73 m2). For subjects with non-standard BSA, the eGFR value calculated by MDRD formula will be multiplied 
by the individual’s BSA calculated using appropriate formula and divided by 1.73 m2.
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 the 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 
following 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 following mobocertinib dosing as 
indicated in Appendix D.
11. Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the 
protocol.
Subjects with Renal Impairment
All RI subjects must fulfill the following inclusion criteria to be eligible for participation in the study:
1.
Adult male or female subjects aged ≥18 to <81 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 dose of mobocertinib 
and throughout the period of PK sample collection.
3.
Body mass index 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 RI, 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.
Baseline eGFR of 15-29 mL/min not on dialysis based on the MDRD equation at screening divided by standard 
BSA value of 1.73 m2. For subjects with non-standard BSA, the eGFR value calculated by MDRD formula will 
be multiplied by the individual’s BSA calculated using appropriate formula and divided by 1.73 m2. 
6.
Has a diagnosis of chronic (>6 months), stable (no significant changes in renal function [<30%] in the 30 days 
preceding screening; no acute episodes of illness within the previous 2 months due to deterioration in renal 
function) renal insufficiency. Subjects with RI may have related medical conditions consistent with their disease 
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(eg, mild diabetes) that are stable for at least 3 months prior to screening, in the opinion of the Investigator or 
designee. 
7.
For a female 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.
8.
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.
9.
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.
10. 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 
following 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.
11. Male subjects must agree not to donate sperm from dosing until at least 30 days following mobocertinib dosing as 
indicated in Appendix D.
12. Understands the study procedures in the ICF and be willing and able to comply with the protocol.
Criteria for Exclusion:
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 Investigator or designee, might confound the results of the study 
or poses an additional risk to the subjects by their participation in the study.
4.
History or presence of alcoholism or 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 child 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 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.
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
12. Positive test result for novel corona virus disease 2019 (COVID-19) testing at screening or check-in.
13. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
14. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
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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 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 Renal Impairment
All RI 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, aside from RI, 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 subjects by their participation in the study.
4. History or presence of alcoholism or 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 child asthma.
7. History of lung infection, within 3 months of screening or ongoing lung infection.
8. Fluctuating or rapidly deteriorating renal function within the screening period, and up to 30 days prior to Day 1, in 
the opinion of the Investigator and Sponsor.
9. Failed renal transplant or has had a nephrectomy.
10. Rapidly fluctuating renal function, as determined by historical measurements; or has demonstrated or suspected 
renal artery stenosis. Rapidly fluctuating renal function is defined as eGFR that differs by more than 30% within a 
6 month period before the screening. If historical measurements are not available, then the 2 screening 
measurements will be used to demonstrate stability; a second baseline eGFR sample will be taken during the 
screening period (at least 72 hours apart) and the two values have to show <30% difference and fall in the same 
renal function category of either severe RI or normal renal function before check-in. If the results of the 2 most 
recent assessments are not in agreement with regard to the subject’s renal function category, the third assessment 
has to be performed at least 72 hours after the second assessment. If the second and third measurements differ, the 
subject will not be eligible for the study.
11. Female subjects with a positive pregnancy test or who are lactating.
12. Positive results for urine or breath alcohol screen at screening or check-in.
13. 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.
14. Positive results at screening for HIV, HBsAg, or HCV. 
15. Positive test result for COVID-19 testing at screening or check-in.
16. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
17. Seated blood pressure is less than 90/40 mmHg or greater than 180/100 mmHg at screening.
18. QTcF interval is >500 msec or has ECG findings deemed abnormal with clinical significance by the Investigator 
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or designee at screening.
19. 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.
20. 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.
21. Donation of blood or significant blood loss within 56 days prior to dosing.
22. Plasma donation within 7 days prior to dosing.
23. 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 following total and unbound PK parameters in plasma will be analyzed for mobocertinib and its active 
metabolites, AP32960 and AP32914 (bound 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) 

Combined molar unbound Cmax,u, AUClast,u, and AUC,u of mobocertinib, AP32960, and AP32914.

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 CL,u/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.
The following urinary PK parameters will be analyzed for mobocertinib and its active metabolites, AP32960 and 
AP32914:

Amount of drug excreted in urine from time 0 to time t (Aet)

Fraction of administered dose excreted in urine from time 0 to time t (fe,t)

Renal clearance (CLR)
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).

Clinical laboratory values.

12-lead ECG. 

Vital signs
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Statistical Considerations:
Pharmacokinetics:
The natural log (ln)-transformed combined molar unbound Cmax,u, AUClast,u, and AUC∞,u, for mobocertinib and its 
metabolites (AP32960 and AP32914) will be compared between RI and the healthy arms using an analysis of variance 
(ANOVA) model. 
The ANOVA model will include RI 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 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 12 subjects in each renal function arm is considered adequate to provide a precise 
estimation of the combined molar AUC∞of mobocertinib and its active metabolites AP32960, and AP32914 in 
subjects with severe renal impairment compared to healthy subjects with normal renal function. The sample size 
calculation was based on the 95% confidence interval (CI) for the geometric mean of the combined molar AUC∞of 
mobocertinib and its active metabolites AP32960, and AP32914. The average interpatient coefficient of variation for 
mobocertinib, AP32960, and AP32914 apparent clearance was estimated to be
 
With a sample size of 12 in each renal function arm, the 95% 
CI for the for the geometric mean of the combined molar AUC∞is expected to be 0.6 to 1.4 with at least 80% power 
according to the variance assumptions.
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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
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, as per the scheduled 
of study procedures (Section 9.0). Subjects may be admitted earlier than Day -1 for COVID-19 testing not related to study protocol as per CRU requirements. At all 
times, subject 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 (Arm 1 and Arm 2)
FU c
Days →
-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 f
X g
Height
X
Weight
X
X f
Assessment of Renal Function h
X
X
12-Lead Safety ECGs
X
X i
X
X
X g
Vital Signs (HR and BP)
X
X i
X
X
X
X g
Vital Signs (RR and T)
X
Pulmonary Function Test j
X
Hem, Serum Chem k, and UA 
X
X
X
X g
Serum Pregnancy Test (♀only)
X
X
Serum FSH (PMP ♀only)
X
Urine/saliva Drug Screen
X
X
Urine/breath Alcohol Screen
X
X
HIV/Hepatitis Screen
X
COVID-19 Test
X
X
AE Monitoring j
X
X
ConMeds Monitoring
X
Study Drug Administration / PK
Mobocertinib Administration
X
Blood for Mobocertinib and metabolites 
(AP32960 and AP32914) PK
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 (Arm 1 and Arm 2)
FU c
Days →
-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
Blood for Protein Binding for Mobocertinib and 
metabolites (AP32960 and AP32914)
X
X
X
Urine for PK Mobocertinib and metabolites 
(AP32960 and AP32914)
X m
Other Procedures
Confinement in the CRU n
X
Stool Sample for Microbiome o
X
Blood Sample for Blood Sample for Bacterial 
Antibodies and Other Circulating Biomarkers
X
Visit 
X
a
For details on Procedures, refer to Section 9.0.
b
Within 21 days prior to study drug administration.
c
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after mobocertinib 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 other times, at the Investigator’s or designee’s discretion.
f
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 value will be used.
g
To be performed at Day 10 or prior to early termination from the study.
h
For assessment of renal function at screening, eGFR will be calculated based on the eGFR value calculated by MDRD formula divided by standard BSA value of 1.73 m2 for the 
renal classification category of subjects (ie, severe RI or normal renal function). For subjects with non-standard BSA, the eGFR value calculated by MDRD formula will be 
multiplied by the individual’s BSA calculated using appropriate formula (Dubois and Dubois 1916) and devided by 1.73 m2. The eGFR value will be compared to the renal 
function assignment from historical values within a 6 month period from screening. If the renal function of historical and screening assessments falls in the same renal function 
category, the subject can be enrolled into this study if other inclusion criteria are met. If no historical measurement is available, a second baseline eGFR sample will be taken 
during the screening period (at least 72 hours apart) and the two values have to fall in the same renal function category of either severe RI or normal renal function before 
check-in. If the results of the two most recent assessments are not in agreement with regard to the subject’s renal function category, the third assessment has to be performed at 
least 72 hours after the second assessment.
i
To be performed within 24 hours prior to dosing.
j
Pulmonary function test may be performed in the event of a pulmonary AE, if deemed clinically necessary by the Investigator or designee. 
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k
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 when 
the serum chemistry sample is being taken.
l
To be performed prior to dosing.
m
Urine collection intervals are: pre-dose (spot collection), 0 - 12 hours, 12 - 24 hours postdose, 24 -36 hours postdose, 36 -48 hours postdose, 48 -72 hours postdose, 72 -96 hours 
postdose, and 96 -120 hours post-dose. For subjects with renal insufficiency, urine samples will be collected whenever possible, as they may not be able to produce urine at each 
interval. For subjects who are anuric, urine samples for urinalysis will not be collected.
n
Subjects will start the confinement on Day -1 and be released from confinement after the 216-hour study assessments (Day 10). Subjects may be required to remain at the CRU 
for longer at the discretion of the Investigator or designee
o
Subjects will be given a stool sample container at screening and instructions on sample collection. They will provide the clinic with a stool sample at their next scheduled visit.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, ConMeds = Concomitant medication,COVID-2019 = Corinavirus 
disease 2019, CRU = Clinical research unit, ECG = Electrocardiogram, eGFR = estimated glomerular filtration rate, ET = early termination, FSH = Follicle-stimulating hormone, 
FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, MDRD = Modification of Diet in Renal Disease, PK = Pharmacokinetics, 
PMP = Postmenopausal, RI = Renal Impairment, RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis. 
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Table 3.a
Pharmacokinetic Plasma and Urine Sampling Schedule (Arm 1 and Arm 2)
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
Urine 
Concentrations of 
Mobocertinib, 
AP32960, and 
AP32914
1
0 h
(predose)
00:00
(predose)

(predose void)
0.5 h
00:30 (±5 min)

0-12 h a
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)


12-24 h a
12 h
36:00 (±30 min)

24-36 h a
3
0 h
48:00 (±30 min)

36-48 h a
4
0 h
72:00 (±60 min)

48-72 h a
5
0 h
96:00 (±60 min)

72-96 h a
6
0 h
120:00 (±60 min)

96-120 h a
8
0 h
168:00 (±60 min)

10
0 h
216:00 (±60 min)

Number of samples per 
subject: 
16
3
8
a The collection interval will be completed close to nominal time point.
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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. Systemic exposures to 
2 active metabolites, AP32960 and AP32914, accounted for approximately 62% and 9% of parent 
average concentrations, respectively. 
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 
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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 
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 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. 
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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. Preliminary 
non-compartmental analysis PK analysis in clinical study with NSCLC patients (AP32788-15-101) 
shows no effect of baseline mild or moderate RI on the combined molar concentration average (Cav) 
of mobocertinib and its active metabolites, which, together with the minor contribution of renal 
clearance (<5% of dose as unchanged mobocertinib excreted in urine in healthy subjects) to 
mobocertinib clearance, supports a reduced design PK study as per Food and Drug Administration 
(FDA) recommendations (FDA 2020). 
The purpose of this PK study (TAK-788-1007) is to assess the PK of mobocertinib and its active 
metabolites (AP32960 and AP32914) in subjects with severe RI as compared to healthy subjects 
with normal renal function. These data will be used to provide dose adjustment guidance for 
cancer patients with severe RI, since this patient population has not been studied in any 
mobocertinib clinical trials to date. 
4.3
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 drugs. An indirect 
health benefit to the healthy 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 RI is unknown. However, the risk of a single 
80 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 and urine PK of mobocertinib and its active metabolites 
(AP32960 and AP32914) in subjects with severe RI compared to matched-healthy subjects with 
normal renal function.
5.2.2
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 severe RI and 
the matched-healthy subjects with normal renal function.
5.2.3
Study Exploratory Objective
To assess the overall fecal microbiome diversity, serum bacterial antibodies and/or other 
circulating biomarkers at the baseline.
5.3
Endpoints
5.3.1
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 (bound 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). 

Combined molar unbound Cmax,u, AUClast,u, and AUC,u of mobocertinib, AP32960, and 
AP32914.

Time of first occurrence of Cmax (tmax). 

Terminal disposition phase half-life (t½z).
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
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.
The following urinary PK parameters will be analyzed for mobocertinib and its active metabolites, 
such as AP32960 and AP32914:

Amount of drug excreted in urine from time 0 to time t (Aet).

Fraction of administered dose excreted in urine from time 0 to time t (fe,t).

Renal clearance (CLR).
5.3.2
Secondary Endpoint
Pharmacokinetics:
Plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914).
Safety Endpoints

Incidence of TEAEs assessments (including physical examination findings).

Clinical laboratory testing.

12-lead ECG.

Vital signs.
5.3.3
Exploratory Endpoint 
Evaluation of baseline microbiome diversity in subjects with impaired renal impairment or 
subjects with normal renal function.
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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 
mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with severe RI 
compared to matched-healthy subjects with normal renal function. 
Table 6.a
Study Arms and Planned Dose
Study Arms
Arm
Number of 
Subjects
Classification
eGRF(a) mL/min
Dose
1
12
Severe
15-29
80 mg
2
12
Matched-Healthy (b)
≥90
80 mg
(a) Estimated glomerular filtration rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) equation as 
defined as follows (for females multiply result by 0.742, if African American multiply result by 1.212):
eGFR = (175 x (Scr,std)-1.154 x (Age)-0.203)/1.73 m2 (for subjects with standard BSA)
eGFR = (175 x (Scr,std)-1.154 x (Age)-0.203)x BSA value /1.73 m2 (for subjects with non-standard BSA)
Scr, std: serum creatinine (mg/dL) measured with a standardized assay.
BSA will be calculated using Dubois and Dubois formula (Dubois and Dubois, 1916)
(b) Healthy subjects with normal renal function will be recruited to match subjects in severe RI arm 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, a 10-day confinement period (Day −1 to 
Day 10), and a follow-up phone call 30 ± 2 days after dosing.
For assessment of renal function at screening, eGFR will based on the eGFR value calculated by 
MDRD formula divided by BSA value of 1.73 m2 for the renal classification category of subjects 
(ie, severe RI or normal renal function). For subjects with non-standard BSA, the eGFR value 
calculated by MDRD formula will be multiplied by the individual’s BSA calculated using 
appropriate formula (Dubois and Dubois, 1916) and divide by 1.73 m2. The eGFR value will be 
compared to the renal function assignment from historical values within a 6 month period from 
screening. The subjects to be recruited into this study should show a stable renal function, such as 
<30% difference in eGFR values, within 6 months from screening. If the renal function of 
historical and screening assessments falls in the same renal function category with <30% 
difference, the subject can be enrolled into this study if other inclusion criteria are met and none of 
the exclusion criteria are met. If no historical measurement is available, a second baseline eGFR 
sample will be taken during the screening period (at least 72 hours apart) and the two values have 
to show <30% difference and fall in the same renal function category of either severe RI or normal 
renal function before check-in. If the results of the 2 most recent assessments are not in agreement 
with regard to the subject’s renal function category, the third assessment has to be performed at 
least 72 hours after the second assessment. If the second and third measurements differ, the subject 
will not be eligible for the study.
Subjects will receive a single oral dose of 80 mg mobocertinib capsule on Day 1 (Table 6.b). 
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Table 6.b
Study Design for Arms 1 and 2
Study Day
S
-1
1
2
3
4
5
6
8
10
Mobocertinib PO (80 mg)
X
PK Blood Samples
X
X
X
X
X
X
X
X
PK Urine Samples
X
X
X
X
X
X
Blood Sample for Bacterial 
Antibodies and Other 
Circulating Biomarkers
X
Stool Sample for Microbiome 
Research
X
Confinement in CRU
X
X
X
X
X
X
X
X
X
CRU-clinical research unit; PK-pharmacokinetic; PO-per os (by mouth); S-screening.
Blood samples will be collected from Days 1 to 10 and urine PK samples will be collected from 
Day 1 to the morning of Day 6 at predetermined time points to characterize the plasma and urine 
PK and plasma protein binding of mobocertinib and its active metabolites (AP32960 and AP32914) 
in subjects with severe RI and in matched-healthy subjects with normal renal function. 
Spirometry, as the PFT, may be performed in the event of a pulmonary AE, if deemed clinically 
necessary by the Investigator or designee.
Subjects will be confined in the CRU from Day -1 until the morning of Day 10 after the 216-hour 
study assessments are complete. 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
There will be no dose modifications for this study.
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design
According to the FDA Draft Guidance March 2020 – Pharmacokinetics in Patients with Impaired 
Renal Function – Study Design, Data Analysis, and Impact on Dosing (FDA 2020), a “reduced 
pharmacokinetic study” may be used for drugs which are predominantly eliminated via nonrenal 
routes. If no substantial difference (eg, AUC increase of <50%) in pharmacokinetics is seen 
between subjects with severe renal impairment as compared to healthy subjects, no further study 
needs to be undertaken. The severe renal impairment group has been chosen based on the 
classification system within the aforementioned Draft Guidance. 
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As per the FDA guidance, a healthy subject control group will be enrolled with demographics 
which are reasonably matched to the mean demographic parameters to control for the influence of 
covariates in PK assessment. In the current study the covariates of BMI, age and gender will be 
matched. Following the categorization of renal function outlined in the Draft Guidance, healthy 
subjects will have an eGFR ≥90 mL/min and severely impaired subjects will have an eGFR 15-29 
mL/min (FDA 2020).
6.3.2
Rationale for Dose 
The dose selected for this study with severe renal impairment is 80 mg of mobocertinib taken 
orally; this corresponds to 50% of the highest single oral dose evaluated in healthy subjects (ie, 
160 mg) and will provide a safety margin. In the event that renal impairment delays drug clearance 
and increases overall systemic exposure, it is anticipated that a single oral dose 80 mg 
administered to patients with severe renal impairment will not exceed the historical exposure 
levels seen in healthy subjects of a single oral dose of 160 mg dose of mobocertinib. 
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 active metabolites along with the exposure parameters of mobocertinib, 
AP32960, and AP32914 individually.
Renal impairment can adversely affect some pathways of hepatic/gut metabolism that might lead 
to changes to plasma protein binding (FDA 2020). Since mobocertinib and its active metabolites 
display high binding to plasma proteins in vitro, renal impairment may affect plasma protein 
binding of mobocertinib and its active metabolites. Therefore, the statistical analyses of PK 
exposure parameters will be conducted using the unbound PK parameters.
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 
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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
The dose and administration of the study drugs to any subject may not be modified. If necessary, a 
subject may be discontinued for the reasons described in Section 7.5 and Section 7.6.
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.
6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure 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.
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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. 
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 <81 years, at screening. Subjects will be 
matched to RI 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 RI 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. Baseline eGFR ≥90 mL/min/1.73m2 based on the MDRD equation at screening divided by 
standard BSA value of 1.73 m2. For subjects with non-standard BSA, the eGFR value 
calculated by MDRD formula will be multiplied by the individual’s BSA calculated using 
appropriate formula and divided by 1.73 m2.
6. Female subjects of nonchildbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to dosing:
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
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 the 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 following 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 following 
mobocertinib 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 Renal Impairment
All RI subjects must fulfill the following inclusion criteria to be eligible for participation in the 
study:
1. Adult male or female subjects aged ≥18 to <81 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 dose of mobocertinib 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 RI, 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. Baseline eGFR 15-29 mL/min not on dialysis based on the MDRD equation at screening
divided by standard BSA value of 1.73 m2. For subjects with non-standard BSA, the eGFR 
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value calculated by MDRD formula will be multiplied by the individual’s BSA calculated 
using appropriate formula and divided by 1.73 m2.
6. Has a diagnosis of chronic (>6 months), stable (no significant changes in renal function [<30%] 
in the 30 days preceding screening; no acute episodes of illness within the previous 2 months 
due to deterioration in renal function) renal insufficiency. Subjects with RI may have related 
medical conditions consistent with their disease (eg, mild diabetes) that are stable for at least 3 
months prior to screening, in the opinion of the Investigator or designee.
7. For a female 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.
8. 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.
9. 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.
10. 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 following 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.
11. Male subjects must agree not to donate sperm from dosing until at least 30 days following 
mobocertinib dosing as indicated in Appendix D.
12. 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.
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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 Investigator or designee, might confound the 
results of the study or poses an additional risk to the subjects by their participation in the study.
4. History or presence of alcoholism or 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 child 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 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.
11. Positive results at screening for HIV, HBsAg, or HCV.
12. Positive test result for COVID-19 testing at screening or check-in.
13. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
14. Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg 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 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 Renal Impairment
All RI 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.
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2. History or presence of clinically significant medical, aside from RI, 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 subjects by their participation in the study.
4. History or presence of alcoholism or 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 child asthma.
7. History of lung infection, within 3 months of screening or ongoing lung infection.
8. Fluctuating or rapidly deteriorating renal function within the screening period, and up to 
30 days prior to Day 1, in the opinion of the Investigator and Sponsor.
9. Failed renal transplant or has had nephrectomy.
10. Rapidly fluctuating renal function, as determined by historical measurements; or has 
demonstrated or suspected renal artery stenosis. Rapidly fluctuating renal function is defined 
as eGFR that differs by more than 30% within a 6 month period before the screening. If 
historical measurements are not available, then the 2 screening measurements will be used to 
demonstrate stability; a second baseline eGFR sample will be taken during the screening 
period (at least 72 hours apart) and the two values have to show <30% difference and fall in the 
same renal function category of either severe RI or normal renal function before check-in. If 
the results of the 2 most recent assessments are not in agreement with regard to the subject’s 
renal function category, the third assessment has to be performed at least 72 hours after the 
second assessment. If the second and third measurements differ, the subject will not be eligible 
for the study.
11. Female subjects with a positive pregnancy test or who are lactating.
12. Positive results for urine or breath alcohol screen at screening or check in.
13. 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.
14. Positive results at screening for HIV, HBsAg, or HCV.
15. Positive test result for COVID-19 testing at screening or check-in.
16. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
17. Seated blood pressure is less than 90/40 mmHg or greater than 180/100 mmHg at screening.
18. QTcF interval is >500 msec or has ECG findings deemed abnormal with clinical significance 
by the Investigator or designee at screening.
19. 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 
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indicated in Section 7.3 (Prohibitions and Concomitant Medication) for the prohibited time 
period.
20. 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.
21. Donation of blood or significant blood loss within 56 days prior to dosing.
22. Plasma donation within 7 days prior to dosing.
23. 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 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, nonprescription 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 RI who are taking medications to treat manifestations of renal disease or 
medications needed to treat for stable diseases (eg, diuretics, angiotensin converting enzyme 
inhibitors, angiotensin II receptor antagonists, and beta-blockers) will be allowed to participate in 
the study at the discretion of the Investigator and following consultation with the Sponsor. For 
renal disease related medical conditions, subjects must be on a stable dose (steady dose, drug, and 
regimen) for at least 14 days and 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 (H2RAs [except cimetidine]); or multivitamins containing iron or zinc 
must be withheld at least 8 hours before dosing and at least 6 hours postdose.
Any medication (including over-the-counter) that would significantly alter CLcr values which, by 
the determination of the Investigator and the Sponsor, might interfere with the study 
(eg, cimetidine) must be discontinued at least 14 days (or 5 half-lives of the compound, whichever 
is longer) prior to dosing.
If a subject with RI 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.
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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 
nonprescription 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 nonprescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Dosing (Days -14 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 7.2 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. 
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7.5
Diet, Fluid, Activity 
7.5.1
Diet and Fluid
Water (except water provided with 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. 
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 urine or saliva 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 7.6. 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 
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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 12 PK-evaluable subjects 
complete in each arm of study.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
Mobocertinib Capsules 
A single dose of 80 mg mobocertinib (2 x 40 mg mobocertinib capsules) 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
8.1.2
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 in individual unit dose containers for each subject.
8.1.3
Clinical Study Drug Inventory and Storage
Mobocertinib capsules
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.
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8.1.4
Clinical Study Drug Blinding
This is an open-label study.
8.1.5
Randomization Code Creation and Storage 
Not applicable
8.1.6
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable
8.1.7
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused mobocertinib study drug will be retained by 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.
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.
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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 permitted or 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.
For this study, the collection of blood for mobocertinib PK 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 Exam
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
BMI
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.
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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.
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 8.0.
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 drugs and/or 
procedures as described in Section 10.0.
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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.
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
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 
Magnesium 
* At screening, eGRF will be calculated based on MDRD for renal classification assignment.
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
HCV
Urine or breath alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
Blood and fecal samples for microbiome research
COVID-19 testing (performed according to CRU 
standard procedures detailed in a separate 
document[s])
9.3
Pharmacokinetic Samples
Instructions for plasma and urine 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
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
Urine sample for mobocertinib and 
metabolites PK
Urine
Urine sample for mobocertinib and 
metabolites PK analysis
Mandatory
Stool sample for microbiome 
assessment
Feces
Fecal microbiome diversity at the 
baseline
Mandatory
Serum sample for bacterial antibodies 
and other circulating biomarkers
Serum
Serum for bacterial antibodies and 
other circulating biomarkers at 
baseline
Mandatory 
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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.
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. AUCu is calculated as AUCulast 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/AUCu (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).
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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/(AUCu 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. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
9.3.1.2
Urine PK Measurements
PK parameters for urine mobocertinib and metabolites AP32960 and AP32914 concentrations will 
be calculated as follows, as appropriate, following oral administration:
Aet:
Total amount of drug excreted unchanged in the urine from time 0 to the last 
observed non-zero concentration, obtained by adding the amounts excreted 
over each collection interval.
fe,t:
Fraction administered dose excreted in urine from time 0 to time t.
CLR:
Renal clearance calculated as Ae(t’-t”)/AUC(t’-t”) where t’-t” is the longest 
interval of time during which Ae and AUC are both obtained.
9.3.2
Microbiome Assessment
A baseline stool samples per subject will be collected for the evaluation of microbiome using 16S 
rRNA (ribosomal ribonucleic acid) sequencing and/or DNA sequencing for metagenomics as 
indicated in the Section 3.0.
A blood sample for serum bacterial antibodies and/or other circulating biomarkers will be obtained 
as indicated in the Section 3.0.
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 
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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.
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.
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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 
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 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.
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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 CRF, in order to capture this important safety information consistently in the 
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 10.2.8.

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 
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. Non-serious AEs that begin prior to 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
If a subject has elevated ALT ≥3x upper limit of normal (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 subject with ALT ≥3x ULN and total bilirubin >2 x ULN or INR >1.5x 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.
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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.
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 
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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 dose of 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 plasma concentrations of mobocertinib and metabolites (AP32960 and 
AP32914) 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 renal 
impairment and the healthy arms using an ANOVA model. The ANOVA model will include renal 
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 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 of 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.
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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
There are no interim analysis in this study.
There are no predetermined criteria for early termination of the study.
11.3
Determination of Sample Size
The planned sample size of 12 subjects in each renal function arm is considered adequate to 
provide a precise estimation of the combined molar AUC∞of mobocertinib and its active 
metabolites AP32960, and AP32914 in subjects with severe renal impairment compared to healthy 
subjects with normal renal function. The sample size calculation was based on the 95% confidence 
interval (CI) for the geometric mean of the combined molar AUC∞of mobocertinib and its active 
metabolites AP32960, and AP32914. The average interpatient coefficient of variation for 
mobocertinib, AP32960, and AP32914 apparent clearance was estimated to be 
 
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With a 
sample size of 12 in each renal function arm, the 95% CI for the for the geometric mean of the 
combined molar AUC∞is expected to be 0.6 to 1.4 with at least 80% power according to the 
variance assumptions.
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 subjects (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 (eg, 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 studies 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 studies 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 studies 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] Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events 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.
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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
Corona virus disease 2019
CRA
Clinical Research Associate
CRF
Case report form
CRU
Clinical Research Unit
CYP
Cytochrome P450
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
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
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
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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
MDRD
Modification of Diet in Renal Disease
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
PK
Pharmacokinetic(s)
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RI
Renal impairment
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
t½z
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
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 
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[R2] (Section 8) until at least 2 years after the last approval of a marketing application for a 
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.
16.0
REFERENCES
1. Dubois D, Dubois EF, 1916, A Formula to Estimate the Approximate Surface Area if Height 
and Weight Be Known, Arch Intern Med, 17:863-871.
2. 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.
3. Mobocertinib. Millennium Pharmaceuticals, Inc. Global Investigator Brochure. Edition 4.0, 01 
April 2020.
4. U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Draft Guidance for Industry: Pharmacokinetics in 
Patients with Impaired Renal Function —Study Design, Data Analysis, and Impact on Dosing. 
September 2020.
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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).
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 subjects 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 is 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 his 
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 their 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. 
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If a female is of childbearing potential and is 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 must use 
an effective non-hormonal methods of contraception. 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 
Nonhormonal 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 study medication 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. 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 Inclusion criteria 6 for healthy subjects and 7 for subjects with RI, and the 
indication in the study design in Section 1.0 – Study Summary, 

Change in the PFT associated footnote “j” in Section 3.0 – Schedule of Study Procedures,

Removal of the PFT in Section 4.3 – Benefit/Risk Profile, 

Removal of criterion 6 in Section 7.1.1. – Inclusion Criteria for Healthy Subjects, removal 
of criterion 7 in Section 7.1.2- Inclusion Criteria for Subjects with Renal Impairment

Removal of details of the PFT in Section 9.2.6 – Pulmonary Function Test

Removal of abbreviations FEV1 and FVC in Section 14.1.4 – List of Abbreviations.
Removed 
Wording:
Pulmonary Function Test (PFT) (spirometry) 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).
Inclusion criteria 6 (Section 1.0 and Section 7.1.1) and 7 (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” in Section 3.0 :
“To be conducted within 7 days prior to dosing.” was replaced by “j Pulmonary 
function test may be performed in the event of a pulmonary AE, if deemed 
clinically necessary by the Investigator or designee.”
PFT [spirometry] as part of safety monitoring: 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.
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
FEV1 (forced expiratory volume);

FVC (forced vital capacity);

FEV1/FVC.
FEV1 Forced expiratory volume
FVC Forced vial capacity (Section 9.2.6)
In Section 1.0 – Study Summary, Section 6.1 - Study Design, and Section 9.2.6 – Pulmonary 
Function Test.
Addition of the 
wording
Spirometry as the pulmonary function test may be performed in the event of a 
pulmonary AE, if deemed clinically necessary by the Investigator or designee.
In Section 3.0 – Schedule of Study Procedures – row for pulmonary function test
Merging 
columns
The columns from screening until Day 10 were merged and indicated with a 
single X.
Change 2: The name of the study drug was changed to mobocertinib to match current IB
Change of 
Wording
From TAK-788 to mobocertinib
Change 3. In Section 4.0 (Introduction), wording was updated to match the current IB and the 
study TAK-788-1008
In Section 4.1 – Background, Section 4.3 – Benefit/Risk Profile, and Section 16.0 - References
Wording 
Update
From IB Edition 3.0, Jan-2019 to IB Edition 4.0, 04-Jan-2020 and update of 
background information and benefit/risk information.
Change 4. In Section 9.2.9.1 - Clinical Laboratory Tests, renal function will be measured based on 
the MDRD; therefore, under “Chemistry”, creatinine clearance is incorrectly listed as measured by 
Cockcroft-Gault formula. Additionally, protease will not be measured during the study, and
typographical redundancy of listing amylase and lipase twice was corrected as only one sample 
will be taken.
Wording 
removed
protease
Duplicate analytes: amylase and lipase
Footnote ‘*’:“.(…) creatinine clearance will be calculated using the 
Cockcroft-Gault formula.”
Wording added
Footnote ‘*’: (…) eGRF will be calculated based on MDRD for renal 
classification assignment.”
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Change 5. In Section 3.0 - Schedule of Study Procedures - a predose blood samples for protein 
binding of mobocertinib and metabolites will not be collected; therefore, the “X” should be 
removed from predose time points in “Blood for protein binding for mobocertinib and metabolites 
(AP32960 and AP32914).
Wording 
removed
X
Change 6. In Section 9.2.4 - Vital Signs - The timing of the posture requirement is not listed in the 
protocol for vital sign measurements; therefore, the timing was added to the second paragraph.
Wording added
(subjects must be seated for at least 5 minutes prior to measurement)
Change 7. In Section 9.2.5 - 12- Lead ECG - the timing of the posture requirement is not listed in 
the protocol for ECG measurements; therefore, the sentence was added to the second paragraph.
Wording added
Subjects are required to be supine for at least 5 minutes prior to the ECG 
measurement.
Change 8. In Section 3.0 - Schedule of Study Procedures - the “Assessment of Renal Function” 
row has an incorrect footnote “g” that should be replaced by footnote “h” that lists the details of 
renal function assessment
Change 9. In Section 9.2.9.1 - Clinical Laboratory Tests (under ‘Other’) - subjects who test 
positive for HCV antibody will not be tested for RNA levels. This is in accordance with exclusion 
criterion 11 for healthy subjects and exclusion criterion 14 for subjects with RI (Sections 1.0 Study 
Summary and Section 7.2 Exclusion Criteria). 
Wording 
removed
(if antibody positive, confirm RNA negative)
Change 10. During the study, only two active metabolites of mobocertinib, AP32960 and 
AP32914, will be analyzed. Therefore, all references to possible analysis of other mobocertinib 
metabolites in Section 1 – Study Summary (under Study Design, Statistical Considerations, and 
Sample Size Justification), Section 3 - Schedule of Study Procedures, Section 4.2 - Rationale for 
the Proposed Study, Section 6.1 - Study Design, Section 6.3.5 – Critical Procedures Based on 
Study Objectives: Timing of Procedures, Section 9.3.1.1 Plasma PK Measurements, Section 
9.3.1.2. – Urine PK Measurements, Section 11.1.3 Pharmacokinetic Analysis, were removed. 
Wording 
removed
including but not limited to
Change 11. COVID-19 tests were added at screening and check-in to mitigate infection risk.
In Section 3.0 – Schedule of Study Procedures, addition of a row indicating COVID-19 testing.
Wording added
Row title COVID-19 test with ‘X’ marked at screening and check-in columns.
Addition of Exclusion criteria 12 in Section 1.0 – Study Summary and Section 7.2.1 – Exclusion 
Criteria for Healthy Subjects and exclusion criterion 15 in Section 1.0 – Study Summary and 
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Protocol Amendment 02 
09 December 2020
CONFIDENTIAL
Section 7.2.2 – Exclusion Criteria for Subjects with Renal Impairment.
Wording added
Positive test result for COVID-19 testing at screening or check-in.
In Section 9.2.9.1 - Clinical Laboratory Tests (under ‘Other’), addition of COVID-19 test
Wording added
COVID-19 testing (performed according to CRU standard procedures detailed 
in a separate document[s])
Change 12: Subjects confinement in the CRU was extended to Day 10 to reduce the risk of 
subjects’ being exposed to COVID-19. 
Confinement period, release time, and indication for return visits on Days 8 and 10 in Section 1 –
Study Summary (under Study Design), Section 2.0 – Study Schematics, Section 3 – Schedule of 
Study Procedures, Section 6.1 – Study Design, and Section 10.2.6.2 – Reporting AEs, were 
updated.
Wording 
removed
Study Design:
Subjects will be furloughed from the CRU in the morning of Day 6 after the 
120-hour PK sample collection and return to the CRU for additional PK sample 
collections in the morning of Days 8 and 10.
The study will consist of a 21-day screening period, a 6-day confinement period 
(Day −1 to Day 6) and a follow-up phone call 30 ± 2 days after dosing.
Study Schematics:
Day 2-6 cell and indication for outpatient visits on Days 8 and 10 removed.
Subjects will be confined on Day -1 and be released from confinement after the 
120-hour study assessments (Day 6) are completed and will and will return to 
the study site for subsequent procedures on Days 8 and 10, as per the scheduled 
of study procedures (Section 9.0).
Schedule of study procedures (footnote ‘n’):
Subjects will start the confinement on Day -1 and be released from confinement 
after the 120-hour study assessments (Day 6). Subjects may be required to 
remain at the CRU for longer at the discretion of the Investigator or designee.
Reporting AEs:
At each study visit, the Investigator will assess whether any subjective AEs 
have occurred.
Wording added
Study Design:
Subjects will be confined in the CRU from Day -1 and be released from 
confinement after the 216-hour study assessments (Day 10) are complete.
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.
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Protocol Amendment 02 
09 December 2020
CONFIDENTIAL
Study Schematics:
Cell title for Days 8 and 10 changed to Days 2-10.
Subjects will start the confinement on Day -1 and be released from confinement 
after the 216-hour study assessments (Day 10) are complete, as per the 
scheduled of study procedures (Section 9.0).
Schedule of study procedures (footnote ‘n’):
Subjects will start the confinement on Day -1 and be released from confinement 
after the 216-hour study assessments (Day 10). Subjects may be required to 
remain at the CRU for longer at the discretion of the Investigator or designee.
Reporting AEs:
At follow-up, the Investigator will assess whether any subjective AEs have 
occurred.
Merging cells
The columns from Day-1 check-in until Day 10 were merged with an X. An X 
will retained at screening.
Typographical and grammatical corrections, as well as formatting changes, were made throughout 
the protocol.
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Protocol Amendment 02 
09 December 2020
CONFIDENTIAL
Appendix F
Detailed Description of Amendments to Text: Amendment 2
Change 1. Severe renal group classification based on eGFR values was changed from 
<30 mL/min/1.73 m2 to 15-29 mL/min and normal renal function classification based on eGFR 
was changed from ≥90 mL/min/1.73 m2 to ≥90 mL/min due to changes in recommendations in 
the new draft FDA guidance released September 2020 Pharmacokinetics in Patients With 
Impaired Renal Function —Study Design, Data Analysis and Impact on Dosing. For assessment of 
renal function, eGFR value will be calculated based on MDRD formula divided by standard BSA
value of 1.73 m2 for the renal classification category of subjects (ie, severe RI or normal renal 
function). For subjects with non-standard BSA, the eGFR value calculated by MDRD formula will 
be multiplied by the individual’s BSA calculated using appropriate formula (Dubois and Dubois, 
1916) and divided by 1.73 m2.
The following sections were updated to reflect this change:

Section 1.0 – Study Design, Study Subject Population, Criteria for Inclusion (Healthy 
Subjects [criterion #5], Subjects with Renal Impairment [criterion #5])

Section 3.0-Schedule of Study Procedures (footnote h)

Section 6.1 - Study Design

Section 6.3.1 – Rationale of Study Design

Section 7.1.1 – Inclusion Criteria for Healthy Subjects (criterion #5)

Section 7.1.2 – Inclusion Criteria for Subjects with Renal Impairment (criterion #5)
Change 2. The planned sample size in each renal function arm was increased from 8 subjects to 12 
subjects to provide a precise estimation of combined molar AUC∞of mobocertinib and its active 
metabolites AP32960, and AP32914 in subjects with severe renal impairment compared to healthy 
subjects with normal renal function. Details for the sample size estimation were also added to the 
appropriate sections.
The following sections were updated to reflect this change:

Section 1.0 – Study Design, Planned Number of Subjects, and Sample Size Justification

Section 6.1 - Study Design (Table 6.a)

Section 7.8 – Subject Replacement

Section 11.3 – Determination of Sample Size
Change 3. Body surface area (BSA) will be calculated based on Dubois and Dubois formula and a 
reference “Dubois D, EF Dubois, 1916, A Formula to Estimate the Approximate Surface Area if 
Height and Weight Be Known, Arch Intern Med, 17:863-871” was added to the protocol.
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Study ID TAK-788-1007
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Protocol Amendment 02 
09 December 2020
CONFIDENTIAL
The following sections were updated to reflect this change:

Section 1.0 – Study Design, Criteria for Inclusion (Healthy Subjects [criterion #5], 
Subjects with Renal Impairment [criterion #5])

Section 3.0-Schedule of Study Procedures (footnote h)

Section 6.1 - Study Design

Section 16.0 - References
Change 4. The upper age limit of subjects was changed from 80 to 81 years old.
The following sections were updated to reflect this change:

Section 1.0 – Criteria for Inclusion (Healthy Subjects [criterion #1], Subjects with Renal 
Impairment [criterion #1])

Section 7.1.1 – Inclusion Criteria for Healthy Subjects (criterion #1)

Section 7.1.2 – Inclusion Criteria for Subjects with Renal Impairment (criterion #1)
Change 5. The FDA guidance released September 2020 Pharmacokinetics in Patients With 
Impaired Renal Function —Study Design, Data Analysis and Impact on Dosing was updated to 
replace FDA guidance released March 2010.
The following sections were updated to reflect this change:

Section 1.0 – Rationale for the Proposed Study

Section 6.3.1 - Rationale of Study Design

Section 6.3.3.1 – Pharmacokinetic Endpoints

Section 16.0 - References
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680f31956
Amendment 02 to A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects with Severe Renal
Impairment and Normal Renal Function
Clinical Pharmacology Approval
14-Dec-2020 13:39 UTC
Biostatistics Approval
14-Dec-2020 14:09 UTC
Clinical Science Approval
14-Dec-2020 14:14 UTC
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
NCT Number: 
Study Title: 
Study Number: 
NCT04056455
A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects With Severe
Renal Impairment and Normal Renal Function
TAK-788-1007
SAP Version and Date: 
Version 1.0: 18-Feb-2021
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1.0 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Study Number: TAK-788-1007 
Celerion Study Number: CA27460 
Study Title: A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects with Severe 
Renal Impairment and Normal Renal Function 
Phase: 1 
Version: Final 
Date: 18-Feb-2021 
Prepared by: 
, MSc 
Data Management and Biometrics 
Celerion 
, MSc 
Clinical Pharmacology & Pharmacometrics 
Data Management and Biometrics 
Celerion 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 09-Dec-2020 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
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Statistical Analysis Plan Final 
18-Feb-2021
 
CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
18-Feb-2021 
Not Applicable 
 
 
 
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CONFIDENTIAL 
1.1 
Approval Signatures 
Electronic signature can be found on the last page of this document. 
 
Study Title: 
A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects with 
Severe Renal Impairment and Normal Renal Function 
 
 
Approvals: 
 
 
 
 
 PhD 
 Statistical and Quantitative Science 
Takeda Pharmaceuticals 
 
 
Date 
 
 
 
 
 
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Statistical Analysis Plan Final 
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CONFIDENTIAL 
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 Endpoints ...........................................................................................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 ........................................................................................................14 
9.3 
Disposition of Subjects ................................................................................................14 
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 .......................................................................................15 
9.5 
Medication History and Concomitant Medications .....................................................15 
9.6 
Efficacy Analysis .........................................................................................................15 
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CONFIDENTIAL 
9.7 
Safety Analysis ............................................................................................................15 
9.7.1 
Adverse Events ....................................................................................................15 
9.7.2 
Adverse Events of Special Interest (if applicable) ..............................................16 
9.7.3 
Clinical Laboratory Assessments ........................................................................16 
9.7.4 
Vital Signs ...........................................................................................................17 
9.7.5 
Electrocardiograms ..............................................................................................17 
9.7.6 
Physical Examination ..........................................................................................17 
9.7.7 
Overdose ..............................................................................................................18 
9.7.8 
Other Safety Analysis (if applicable) ..................................................................18 
9.7.9 
Extent of Exposure and Compliance ...................................................................18 
9.8 
Pharmacokinetic Analysis ............................................................................................18 
9.8.1 
Plasma Pharmacokinetics ....................................................................................18 
9.8.2 
Urine Pharmacokinetics .......................................................................................19 
9.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................19 
9.10 
Preliminary Analyses ...................................................................................................19 
9.11 
Interim Analyses ..........................................................................................................19 
9.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................19 
10.0 
REFERENCES ..................................................................................................................20 
11.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................20 
12.0 
APPENDIX ........................................................................................................................20 
12.1 
Changes From the Previous Version of the SAP .........................................................20 
12.2 
Data Handling Conventions .........................................................................................20 
12.3 
Analysis Software ........................................................................................................20 
 
LIST OF IN-TEXT TABLES 
Table 5:1 
Study Arms and Planned Dose ...............................................................................10 
Table 5:2 
Study Design for Arms 1 and 2 ..............................................................................10 
Table 9:1 
Collection of Blood Samples for Pharmacokinetic and Plasma Protein Binding 
Analyses and Urine Samples for Pharmacokinetic Analysis .................................18 
 
 
 
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CONFIDENTIAL 
3.0 
ABBREVIATIONS 
%Dose 
percentage of dose eliminated 
λz 
terminal disposition phase rate constant 
AE 
adverse event 
Aet 
amount of drug excreted in urine from time 0 to time t 
ANOVA 
analysis of variance 
AUC∞ 
area under the total concentration versus time curve from time 0 extrapolated to infinity 
AUC∞,u 
area under the unbound concentration versus time curve from time 0 extrapolated to infinity 
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 
BMI 
below the lower limit of quantitation 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
CL/F 
apparent clearance after extravascular administration for total analyte 
CLR 
renal clearance 
CLu/F 
apparent clearance after extravascular administration for unbound analyte 
Cmax 
maximum observed total plasma concentration 
Cmax,u 
maximum observed unbound plasma concentration 
COVID-19 
coronavirus disease 2019  
CPAP 
clinical pharmacology analysis plan 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cum%Dose 
cumulative percentage of dose eliminated 
CumAe 
cumulative amount eliminated 
CV% 
arithmetic percent coefficient of variation 
DDFM 
denominator degrees of freedom 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
fet 
fraction of administered dose excreted in urine from time 0 to time t  
Geom CV% 
geometric percent coefficient of variation 
Geom Mean 
geometric mean 
HR 
heart rate 
ICF 
informed consent form 
KR 
Kenward-Roger 
LSM 
least-squares mean 
Mean 
arithmetic mean 
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CONFIDENTIAL 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
modification of diet in renal disease 
n 
number of observations 
NCI 
National Cancer Institute 
PFT 
pulmonary function test 
PK 
Pharmacokinetic 
PO 
per os (by mouth) 
PT 
preferred term (MedDRA) 
RI 
renal impairment 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Scr,std 
serum creatinine (mg/dL) measured with a standardized assay 
SD 
standard deviation 
SEM 
standard error of the mean 
SI 
International System of Units 
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 
WHO 
World Health Organization 
 
 
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CONFIDENTIAL 
4.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
4.1 
Objectives 
4.1.1 
Primary Objective 
To characterize the single-dose plasma and urine pharmacokinetics (PK) of mobocertinib and its 
active metabolites (AP32960 and AP32914) in subjects with severe renal impairment (RI) 
compared to matched-healthy subjects with normal renal 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 single oral dose in subjects with severe RI 
and the matched-healthy subjects with normal renal function. 
4.1.3 
Exploratory Objective 
To assess the overall fecal microbiome diversity, serum bacterial antibodies and/or other 
circulating biomarkers at the baseline. 
Note:  This exploratory objective will not be assessed by Celerion. 
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 (bound 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). 
• Combined molar unbound Cmax,u, AUClast,u, and AUC∞,u of mobocertinib, AP32960, 
and AP32914. 
• 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. 
The following urinary PK parameters will be analyzed for mobocertinib and its active metabolites, 
such as AP32960 and AP32914: 
• Amount of drug excreted in urine from time 0 to time t (Aet). 
• Fraction of administered dose excreted in urine from time 0 to time t (fet). 
• Renal clearance (CLR). 
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 Endpoints 
Evaluation of baseline microbiome diversity in subjects with RI or subjects with normal renal 
function. 
Note: This exploratory endpoint will not be determined by Celerion. 
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 
mobocertinib and its active metabolites (AP32960 and AP32914) in subjects with severe RI 
compared to matched-healthy subjects with normal renal function. 
 
 
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CONFIDENTIAL 
Table 5:1 
Study Arms and Planned Dose 
 
Study Arms 
Arm 
Number of 
Subjects 
Classification 
eGRF(a) mL/min 
Dose 
1 
12 
Severe 
15-29 
80 mg 
2 
12 
Matched-Healthy (b) 
≥90 
80 mg 
(a) Estimated glomerular filtration rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) 
equation as defined as follows (for females multiply result by 0.742, if African American multiply result by 
1.212): 
eGFR = (175 x (Scr,std)-1.154 x (Age)-0.203)/1.73 m2 (for subjects with standard BSA) 
eGFR = (175 x (Scr,std)-1.154 x (Age)-0.203)x BSA value /1.73 m2 (for subjects with non-standard BSA)  
Scr, std: serum creatinine (mg/dL) measured with a standardized assay. 
BSA will be calculated using Dubois and Dubois formula (Dubois and Dubois, 1916) 
(b) Healthy subjects with normal renal function will be recruited to match subjects in severe RI arm 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, a 10-day confinement period (Day −1 
to Day 10), and a follow-up phone call 30 ± 2 days after dosing. 
Subjects will receive a single oral dose of 80 mg mobocertinib capsule on Day 1. 
Table 5:2 
Study Design for Arms 1 and 2 
 
Study Day 
S 
-1 
1 
2 
3 
4 
5 
6 
8 
10 
Mobocertinib PO (80 mg) 
X 
PK Blood Samples 
X 
X 
X 
X 
X 
X 
X 
X 
PK Urine Samples 
X 
X 
X 
X 
X 
X 
Blood Sample for Bacterial 
Antibodies and Other 
Circulating Biomarkers 
X 
Stool Sample for Microbiome 
Research 
X 
Confinement in CRU 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRU-clinical research unit; PK-pharmacokinetic; PO-per os (by mouth); S-screening. 
Blood samples will be collected from Days 1 to 10 and urine PK samples will be collected from 
Day 1 to the morning of Day 6 at predetermined time points to characterize the plasma and 
urine PK and plasma protein binding of mobocertinib and its active metabolites (AP32960 and 
AP32914) in subjects with severe RI and in matched-healthy subjects with normal renal 
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. 
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CONFIDENTIAL 
Subjects will be confined in the clinical research unit (CRU) from Day -1 until the morning of 
Day 10 after the 216-hour study assessments are complete. 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. 
6.0 
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 12 subjects in each renal function arm is considered adequate to 
provide a precise estimation of the combined molar AUC∞ of mobocertinib and its active 
metabolites AP32960, and AP32914 in subjects with severe RI compared to healthy subjects with 
normal renal function. The sample size calculation was based on the 95% confidence interval 
(CI) for the geometric mean of the combined molar AUC∞ of mobocertinib and its active 
metabolites AP32960, and AP32914. The average interpatient coefficient of variation for 
mobocertinib, AP32960, and AP32914 apparent clearance was estimated to be
 
 
 
 With a sample size of 12 in each renal function arm, the 95% CI for the 
geometric mean of the combined molar AUC∞ is expected to be 0.6 to 1.4 with at least 80% 
power according to the variance assumptions. 
8.0 
ANALYSIS SETS 
8.1 
Safety Analysis Set 
All subjects who received the dose of study drug will be included in the safety evaluations. 
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CONFIDENTIAL 
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 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 included in the 
PK analysis but excluded from the statistical analysis. 
9.0 
STATISTICAL ANALYSIS  
9.1 
General Considerations 
All plasma PK analyses will be conducted using Phoenix® WinNonlin® Version 8.1 or higher. 
All urine PK analyses will be conducted using SAS® Version 9.4 or higher. All statistical 
analyses will be conducted using SAS® Version 9.4 or higher. 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. 
Plasma and urine 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 plasma 
concentration plots, and the calculation of PK parameters, unless they are obvious outliers (e.g., 
BLQ value between measurable values (applicable for plasma concentrations only)), in which 
case they will be treated as missing. 
For urine data, if a subject is unable to void in a given collection interval: 
• urine sample weight will be set to 0,  
• urine analyte concentration will be set to missing,  
• amount eliminated (Aet) and percentage of dose eliminated (%Dose) will be set to 0, 
• cumulative amount eliminated (CumAe) and cumulative percentage of dose eliminated 
(Cum%Dose) will be carried over from the previous interval. 
A subject’s plasma and/or urine 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) plasma concentration is greater than 5% of that subject’s maximum 
concentration value in that period  
• If some urine is spilled for a given subject in a given collection interval, urine sample weight, 
urine analyte concentration, Ae, CumAe, %Dose, Cum%Dose, and CLR will be presented but 
excluded from descriptive statistics 
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• A subject did not meet inclusion/exclusion criteria that may have an effect on the 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 plasma and urine 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 λz-dependent parameters 
• PK parameters presented by renal function group, including the units, precision, and 
summary statistics that will be presented in in-text and end-of-text tables 
• Concentration data presented by renal 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 plasma concentration-time and urine Cum%Dose-time figures presented as 
in-text and end-of-text figures 
• Individual plasma concentration-time and urine Cum%Dose-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 counts and percentages of each possible value will be tabulated, 
where applicable. The denominator for the percent calculation will be based on the number of 
subjects dosed. For continuous variables, the number of subjects with non-missing values, 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. 
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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 renal function arm (ie, Severe 
RI, Normal Renal Function) and overall. Study completion status, including reason for 
discontinuation, will also be listed by subject. 
9.4 
Demographic and Other Baseline Characteristics 
9.4.1 
Demographics 
Demographic and baseline characteristics will be summarized descriptively by renal function 
arm (ie, Severe RI, Normal Renal 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 any significant conditions or diseases 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. 
 
 
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9.4.3 
Baseline Characteristics 
For assessment of renal function at screening, eGFR will be calculated based on MDRD formula 
for the renal classification category of either severe renal impairment or normal renal function 
and compared to the renal function assignment from historical values within a 6 month period 
from screening. If no historical measurement is available, a second baseline eGFR sample will be 
taken during the screening period (at least 72 hours apart). If the results of the two most recent 
assessments are not in agreement with regard to the subject’s renal function category, the third 
assessment has to be performed at least 72 hours after the second assessment. Baseline renal 
function assessments will be listed by subject. 
9.5 
Medication History and Concomitant Medications  
Medication history to be obtained includes any medication taken prior to clinic check-in. 
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. 
9.6 
Efficacy Analysis 
Not applicable. 
9.7 
Safety Analysis 
For each renal function arm (ie, Severe RI, Normal Renal 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 physical examinations. All safety data will be listed by, renal function 
arm (ie, Severe RI, Normal Renal Function), subject, and assessment time points, including 
rechecks, unscheduled assessments, and early termination, chronologically.  
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. 
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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 renal function arm (ie, Severe RI, Normal Renal Function). Summary tables will 
include number of subjects reporting the AE and as percent of safety analysis set by renal 
function group (ie, Severe RI, Normal Renal Function) and overall. The most commonly 
reported non-serious TEAEs (i.e., those events reported by >5% of all subjects in each renal 
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 renal function arm 
(ie, Severe HI, Normal Renal Function).  
Additional TEAE summary tables will be presented by severity and relationship to study drug. 
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. If a subject has 
multiple AEs with different severity levels within the same term, the subject will be counted in 
the most severe category only. For each relationship to study drug, if a subject has both related 
and unrelated AEs with the same term, the subject will be counted as having related TEAEs.  
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and SAEs will be discussed in the text 
of the CSR. 
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 5, 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 Investigator.  
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by renal function arm (ie, Severe RI, 
Normal Renal Function) and assessment time points. 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 (generally Day -1). All clinical laboratory listings and tables 
will be presented with the International System of Units (SI). Postdose unscheduled or recheck 
assessments, including early termination, will not be used in analysis. 
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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 Investigator, and the corresponding 
values will be listed by subject in a table. All clinical laboratory data will be presented in by-
subject data listings. 
9.7.4 
Vital Signs 
Vital sign measurements consist of body temperature, respiratory rate, BP, and HR. Temperature 
and 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 Investigator. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for HR and 
BP results and change from baseline by renal function arm (ie, Severe RI, Normal Renal 
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, including early termination, 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 Investigator.  
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by renal function arm (ie, Severe RI, Normal Renal 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, including early termination, 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, check-in, and at Day 10 (or early 
termination). If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), 
the check-in assessment will be conducted at the discretion of the Investigator. Symptom-driven 
physical exams may be performed at other times at the discretion of the Investigator. Physical 
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exam findings will be presented in the data listings by renal function arm (ie, Severe RI, Normal 
Renal Function) and 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 pulmonary function test (PFT), may be performed in the event of a 
pulmonary AE, if deemed clinically necessary by the Investigator or designee. 
9.7.9 
Extent of Exposure and Compliance 
The date, time, and treatment administered will be listed by subject. 
9.8 
Pharmacokinetic Analysis 
Blood and urine samples for the assessment of plasma and urine mobocertinib, AP32960, and 
AP32914 concentrations, and blood samples for the assessment of 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 and Urine Samples for Pharmacokinetic Analysis 
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 
Mobocertinib, AP32960, and 
AP32914 
Urine 
Predose, 0 - 12, 12 - 24, 24 - 36, 36 - 48, 48 - 72, 72 - 96, and 
96 - 120 hours postdose. 
*The actual dates and times of sample collections will be recorded on the source document in the case report form. 
9.8.1 
Plasma Pharmacokinetics 
Plasma 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∞,u will be compared between subjects with severe RI and subjects with normal renal 
function using an analysis of variance (ANOVA) model.  
The ANOVA model will include renal function group (ie, Severe RI, Normal Renal Function) as 
a fixed effect and subject nested within group as a random 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, subject nested within arm, and inter-subject 
variance will be reported. Ratios of LSMs and 90% confidence intervals will be calculated using 
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the exponential function of the difference between group LSMs from the analysis on the 
ln-transformed Combined Molar Cmax,u, Combined Molar AUClast,u, and Combined Molar 
AUC∞,u. The above analysis will also be performed on the ln-transformed Combined Molar Cmax, 
Combined Molar AUClast, and Combined Molar 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∞,u) and total 
(Cmax, AUClast, and AUC∞) PK parameters. 
The following SAS® code will be used to perform the analysis: 
PROC MIXED DATA=XXX; 
CLASS Arm Subject; 
MODEL <ln_pkparam>=Arm/DDFM=KR; 
RANDOM Subject(Arm); 
ESTIMATE ‘Severe Renal Impairment vs. Normal Renal Function’ Arm 1 -1 / CL ALPHA=0.1 
E; 
LSMEANS Arm; 
RUN; 
9.8.2 
Urine Pharmacokinetics 
Urine PK analysis will be described in the CPAP for this study. 
No inferential statistical analyses will be performed on PK parameter data in urine. 
9.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
Not applicable. 
9.10 
Preliminary Analyses 
Plasma PK analysis will be completed as described in the CPAP and Section 9.8.1 of the SAP, 
with the following changes: 1) QCed data will be used (not QAed); 2) nominal times will be 
used for the calculation of PK parameters (not actual sampling times); 3) tables and figures will 
be created using Phoenix® WinNonLin® Version 8.1 or higher. 
9.11 
Interim Analyses 
Not applicable. 
9.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not applicable. 
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10.0 
REFERENCES 
Not applicable. 
11.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
The analyses described in this SAP do not differ from those specified in the protocol. 
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 or higher will be used for all statistical analyses provided in the CSR. 
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