A Phase 2 Open-label, Single Arm Study of MK-7119 in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic HER2+ Breast Carcinoma
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Pfizer

Product: Tucatinib  
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Protocol/Amendment No.: 001-09 
 
 
MK-7119-001-09 Final Protocol 
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Title Page 
 
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF SEAGEN INC. 
Protocol Number: 
MK-7119-001 
Version: 
Amendment 09/28-Feb-2024 
Protocol Title: 
A phase 2 open-label, single arm study of tucatinib (ONT-380, 
MK-7119) in combination with trastuzumab and capecitabine 
in participants with previously treated locally advanced 
unresectable or metastatic HER2+ breast carcinoma 
Investigational 
Product: 
Tucatinib 
Phase: 
2 
Sponsor: 
Seagen Inc.*  
21823 30th Drive SE 
Bothell, WA 98021, USA 
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 
 
*Please note that as of 14 December 2023, Seagen Inc. became part of Pfizer Inc. 
 
This document contains information proprietary to the Sponsor, Inc. The information is being 
provided to you for the purpose of conducting a clinical trial for the Sponsor, Inc. You may disclose 
the contents of this document to study personnel under your supervision and to your Institutional 
Review Board (IRB) or Ethics Committee (EC) for the same purpose. You may not disclose the 
contents of this document to any other party, unless government regulations or laws require such 
disclosure, without prior written permission from the Sponsor, Inc. Any supplemental information 
that may be added to this document is proprietary to the Sponsor, Inc. and should be handled using 
the disclosure procedure described above. 
 
 

Product: Tucatinib  
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Investigator Signatory 
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol. 
 
 
Typed Name: 
Title: 
 
Date 

Product: Tucatinib  
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Protocol/Amendment No.: 001-09 
 
 
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DOCUMENT HISTORY 
Document 
Date of Issue 
Overall Rationale 
Amendment 9 
28-Feb-2024 
To change the Sponsor entity name and update title 
of amendment to include tucatinib and ONT-380. 
Amendment 8 
29-Aug-2022 
To change the Sponsor entity name and address, and 
to update that newly-obtained tumor biopsy during 
the prescreening period is not allowed. 
Amendment 7 
18-Apr-2022 
Number of Planned Participants enrolled in this 
study is changed. 
Amendment 6 
30-SEP-2021 
Contraceptive period, pregnancy reporting period 
and duration of pregnancy test after receiving last 
dose of  trastuzumab for female participants is 
updated from 80 days to 7 months. 
Amendment 5 
2-JUL-2021 
South Korea and Taiwan were included to 
participate in this study. 
Amendment 4 
16-MAR-2021 
Amended Inclusion criteria and Data Analysis 
method section based on the PMDA’s advice. 
Amendment 3 
6-JAN-2021 
Sponsor change 

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Amendment: 09 
Overall Rationale for the Amendments: 
To change the Sponsor entity name, update title of amendment to include tucatinib and ONT-380, and provide to updated text 
regarding overall status of ongoing and completed tucatinib clinical trials. 
Summary of Changes Table:  
Section # and Name 
Description of Change  
Brief Rationale  
Title page, Protocol Synopsis, 
and footers 
Sponsor entity name change.  
Updated amendment version. 
Update title to include the Seagen nomenclature of Tucatinib and 
ONT-380 (Note: MK-7119 is retained parenthetically). 
Effective as of 
Amendment 9, the sponsor 
has been updated, 
amendment version is 
updated, and the code name 
for tucatinib was updated. 
Investigator Signatory page 
Remove sponsor signatory  
A standalone sponsor 
signatory page will be done. 
Section 1.3.3 
Removed summary statement of tucatinib clinical studies; existing 
text refers to the IB as the source for additional information on 
tucatinib clinical trials. 
Update 

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PROTOCOL SYNOPSIS 
Protocol Number 
001 
Version 
Amendment 09 / 28-Feb-2024 
Phase 
2 
Product Name 
Tucatinib (ONT-380 or MK-7119) 
Sponsor 
Seagen Inc. (hereafter called the Sponsor) 
 
 
Protocol Title 
A phase 2 open-label, single arm study of tucatinib (ONT-380, MK-7119) in combination with 
trastuzumab and capecitabine in participants with previously treated locally advanced unresectable or 
metastatic HER2+ breast carcinoma 
Study Objectives 
Primary 
● Assess the objective response rate (ORR) of tucatinib in combination with trastuzumab and 
capecitabine by independent central review (ICR) per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 in Japanese population. 
Secondary 
● Assess ORR of tucatinib in combination with trastuzumab and capecitabine by ICR per RECIST 
v1.1 in all participants population. 
● Assess ORR of tucatinib in combination with trastuzumab and capecitabine by investigator 
assessment (INV) per RECIST v1.1 in Japanese population and all participants population. 
● Assess the duration of response (DOR) of tucatinib in combination with trastuzumab and 
capecitabine by ICR and INV per RECIST v1.1 in Japanese population and all participants 
population . 
● Assess the progression free survival (PFS) of tucatinib in combination with trastuzumab and 
capecitabine by ICR and INV per RECIST v1.1 in Japanese population and all participants 
population. 
● Assess the overall survival (OS) of tucatinib in combination with trastuzumab and capecitabine in 
Japanese population and all participants population. 
● Assess the safety of tucatinib in combination with trastuzumab and capecitabine in Japanese 
population and all participants population. 
Exploratory 
● Evaluate the pharmacokinetics (PK) of tucatinib administered in combination with trastuzumab and 
capecitabine in Japanese population, South Korean population and all participants population. 
Study Population 
Inclusion Criteria 
1. Participants must have histologically confirmed human epidermal growth factor receptor 
(HER)2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or 

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immunohistochemistry (IHC) methodology according to the American Society of Clinical 
Oncology/College of American Pathologists. 
a. Tissue blocks or slides must be submitted to confirm HER2 positivity (using IHC, ISH or 
fluorescence in situ hybridization [FISH]) by a Sponsor-designated central laboratory  
b. Centrally confirmed HER2 results (either IHC, ISH, or FISH) from a previous study can be 
used to determine eligibility for this study with approval from the Sponsor 
2. Received previous treatment with taxane anti-cancer agent, trastuzumab, pertuzumab, and 
trastuzumab emtansine (T-DM1) with the exception is when the use of taxanes is contraindicated 
or judged not to be the best treatment at the discretion of the investigator.  
3. Radiographically and/or histologically confirmed disease progression on last systemic anticancer 
treatment for unresectable locally advanced or metastatic HER2+ breast carcinoma.  
Note: Clinical exam, rising tumor markers and/or photography are not acceptable as methods for 
documentation of progressive disease 
4. Measurable disease as assessed by RECIST v1.1  
5. Age of majority at time of consent 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 
7. Life expectancy ≥6 months, in the opinion of the investigator 
8. Has adequate organ function (refer to Table 2 in detail). Specimens must be collected within 10 
days prior to the start-of-study interventions. 
9. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or 
multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study 
treatment 
10.  A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
one of the following conditions applies  
・ 
Is not a WOCBP 
OR 
・ 
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of 
<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in APPENDIX D during the intervention period and for at least 30 days after 
receiving the last dose of tucatinib, 7 months after receiving the last dose of trastuzumab, or 
180 days after receiving the last dose of Capecitabine whichever occurs last and agrees not to 
donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of 
reproduction during this period. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first 
dose of study intervention.  
・ 
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours for urine or within 72 hours for serum before 
the first dose of study treatment 

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・ 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy 
test is required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. 
・ 
Additional requirements for pregnancy testing during and after study intervention are in 
Section 7.4.5. 
・ 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
・ 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
11. Male participants are eligible to participate if they agree to the following during the intervention 
period and for at least 7 days after receiving the last dose of tucatinib or 90 days after receiving 
the last dose of Capecitabine whichever occurs last for male partner (no contraception 
requirement for trastuzumab for male).: 
・ 
Refrain from donating sperm 
PLUS either: 
・ 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agree to remain abstinent 
OR 
・ 
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [APPENDIX D]) as detailed below: 
・ 
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile-vaginal 
penetration. 
・ 
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. 
12. Participant must provide written informed consent  
13. Participant must be willing and able to comply with study procedures 
Central Nervous System (CNS) Inclusion – Based on screening contrast brain magnetic resonance 
imaging (MRI), participants must have one of the following: 
14. No evidence of brain metastases 
15. Untreated brain metastases not needing immediate local therapy. For participants with untreated 
CNS lesions >2.0 cm on screening contrast brain MRI, discussion with and approval from the 
Sponsor is required prior to enrollment. 
16. Previously treated brain metastases 
a. Brain metastases previously treated with local therapy may either be stable since treatment or 
may have progressed since prior local CNS therapy, provided that there is no clinical 
indication for immediate re-treatment with local therapy in the opinion of the investigator 

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b. Participants treated with CNS local therapy for newly identified lesions or previously treated 
progressing lesions found on contrast brain MRI performed during screening for this study 
may be eligible to enroll if all of the following criteria are met: 
i. 
Time since whole brain radiation therapy (WBRT) is ≥14 days prior to first dose 
of study treatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to 
first dose of study treatment, or time since surgical resection is ≥28 days 
ii. Other sites of disease assessable by RECIST v1.1 are present 
c. Relevant records of any CNS treatment must be available to allow for classification of target 
and non-target lesions 
Exclusion Criteria 
1. Prior treatment with: 
a. Lapatinib within 12 months of starting study treatment.  
Note:In cases where lapatinib was given for ≤21 days and was discontinued for reasons other 
than disease progression or severe toxicity, the participant is eligible. 
Note:In cases where lapatinib was given as a part of the last systemic anticancer treatment for 
unresectable locally advanced or metastatic HER2+ breast carcinoma, the participant is not 
eligible according to Inclusion Criteria 3. 
b. Neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) 
or HER2 tyrosine kinase inhibitor (TKI) at any previous time 
c. Tucatinib or enrolled on a tucatinib clinical trial and received Tucatinib. 
2. Previous treatment with capecitabine (or other fluoropyrimidine [eg, 5-fluorouracil]) for 
metastatic disease (except in cases where capecitabine was given for ≤21 days and was 
discontinued for reasons other than disease progression or severe toxicity). Note: participants who 
have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to 
starting study treatment are eligible. 
3. History of exposure to the following cumulative doses of anthracyclines: 
a. Doxorubicin >360 mg/m2 
b. Epirubicin >720 mg/m2 
c. Mitoxantrone >120 mg/m2 
d. Idarubicin >90 mg/m2 
e. Liposomal doxorubicin (e.g. Doxil, Caelyx, and/or Myocet) > 550 mg/m2 
4. History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or 
biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to trastuzumab 
that were successfully managed, or known allergy to one of the excipients in the study drugs 
5. Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS 
radiation, or experimental agent ≤3 weeks of first dose of study treatment or are currently 
participating in another interventional clinical trial. An exception for the washout of hormonal 
therapies is gonadotropin releasing hormone (GnRH) agonists used for ovarian suppression in 
premenopausal women, which are permitted concomitant medications. 

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6. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the 
following exceptions: 
● 
Alopecia and neuropathy, which must have resolved to ≤ Grade 2 
● 
Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of 
occurrence, and must have resolved completely 
● 
Anemia, which must have resolved to ≤ Grade 2 
7. Clinically significant cardiopulmonary disease such as: 
● 
Ventricular arrhythmia requiring therapy 
● 
Symptomatic hypertension or uncontrolled hypertension as determined by investigator 
● 
Any history of symptomatic CHF or symptomatic decreases in ejection fraction 
● 
Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE v4.03] 
Grade 3 or above) due to complications of advanced malignancy 
● 
Any history of interstitial lung disease or pneumonitis that is grade 2 or greater. 
● 
Hypoxia requiring supplementary oxygen therapy 
8. Known myocardial infarction or unstable angina within 6 months prior to first dose of study 
treatment 
9. Any uncontrolled Grade 3 or higher (per the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events [NCI CTCAE], version 4.03) viral, bacterial, or fungal infection 
within 14 days prior to the first dose of study treatment. Antimicrobial prophylaxis or ongoing 
treatment of resolving/controlled infection is permitted. 
10. Positive for Hepatitis B by surface antigen expression, or positive for Hepatitis C infection, or the 
presence of known chronic liver disease. Participants who have been treated for Hepatitis C 
infection are permitted if they have documented sustained virologic response of 12 weeks. As 
reactivation of these viruses has not been studied with the combination of tucatinib, trastuzumab, 
and capecitabine, there is a possible risk of reactivation. 
・ 
Participants who are positive for either antibodies to Hepatitis B surface antigen (HBsAb) or 
antibodies to Hepatitis B core antigen (HBcAb) should be screened using polymerase chain 
reaction (PCR) measurement of Hepatitis B DNA levels. Participants with Hepatitis B DNA 
levels by PCR that require nucleoside analogue therapy are not eligible for the trial. The latest 
local guidelines should be followed regarding the monitoring of Hepatitis B DNA levels by 
PCR for participants on study treatment. 
11. Known to be positive for human immunodeficiency virus (HIV) 
12. Participants who are pregnant, breastfeeding, or planning to become pregnant from time of 
informed consent until 30 days after receiving the last dose of tucatinib, 7 months after receiving 
the last dose of trastuzumab, or 180 days after receiving the last dose of Capecitabine whichever 
occurs last 
13. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are 
allowed) 
14. Unable to swallow pills or significant gastrointestinal disease which would preclude the adequate 
oral absorption of medications 

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15. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong 
CYP3A4 or a moderate or strong CYP2C8 inducer within 5 days prior to first dose of study 
treatment. Use of sensitive CYP3A substrates should be avoided 2 weeks prior to the start of 
study treatment and requires Sponsor consultation. 
16. Known dihydropyrimidine dehydrogenase deficiency 
17. Unable for any reason to undergo contrast MRI of the brain 
18. Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact 
safety or compliance with study procedures 
19. Evidence within 2 years of the start of study treatment of another malignancy that required 
systemic treatment 
CNS Exclusion – Based on screening brain MRI, participants must not have any of the following: 
20. Any untreated brain lesions >2.0 cm in size, unless discussed with the Sponsor and approval for 
enrollment is given 
21. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total 
daily dose of >2 mg of dexamethasone (or equivalent). However, participants on a chronic stable 
dose of ≤2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and 
approval by the Sponsor. 
22. Any brain lesion thought to require immediate local therapy, including (but not limited to) a 
lesion in an anatomic site where increase in size or possible treatment-related edema may pose 
risk to participant (e.g. brain stem lesions). Participants who undergo local treatment for such 
lesions identified by screening contrast brain MRI may still be eligible for the study based on 
criteria described under CNS inclusion criteria 16b. 
23. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
24. Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest neurologic 
progression due to brain metastases notwithstanding CNS-directed therapy 
Number of Planned Participants 
Approximately 55 participants will enroll in this study (Japanese population: approximately 42 
participants, South Korean population:approximately 10 participants, Taiwanese 
population:approximately 3 participants). 
Study Design 
This is a single-arm, multicenter, phase 2 study designed to evaluate the efficacy and safety of 
tucatinib in combination with trastuzumab and capecitabine in participants with unresectable locally 
advanced or metastatic HER2+ BC who have had prior treatment with taxane anti-cancner agent, 
trastuzumab, pertuzumab, and TDM1. This study consists of Japanese population, South Korean 
population and Taiwanese population. 
In Japanese population, prior to enrollment on the main portion of the trial, a safety run-in will be 
conducted in approximately 3 to 6 participants to assess the safety and tolerability of the standard 
doses and schedule for the combination of tucatinib, trastuzumab, and capecitabine. The inclusion and 
exclusion criteria, treatment doses and schedule, study assessments, and safety reporting rules will be 
identical to the main portion of the trial, with the exception of additional study visits and laboratory 

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assessments performed during the first 2 cycles of study treatment. Participants in the safety run-in 
will be carefully monitored through the first cycle of treatment and evaluated for adverse events 
(AEs) that are unexpected based on the known safety profile of each individual agent and of the 
combination of tucatinib, trastuzumab, and capecitabine. Investigators must ensure that participants 
enrolled in the safety run-in portion of the trial do not have other medical, social, or psychosocial 
factors that, in the opinion of the investigator, could impact safety or compliance with study 
procedures required per the protocol (such as compliance with additional study visits, laboratory 
assessments, oral medications and close out-patient monitoring). During the first cycle, the participant 
may be hospitalized for a minimum of 24 hours with discharge permitted if a participant has no 
ongoing ≥ Grade 3 AEs and is otherwise considered appropriate for discharge by the investigator 
based on history, physical exam (including vital signs), and laboratory evaluations (including 
complete blood count, serum chemistry, and liver function tests). History includes assessment of any 
new or ongoing AEs and concomitant medication use. For participants undergoing outpatient follow-
up,  the investigator must ensure that the participant will be followed closely in the outpatient setting 
by methods they determine to be appropriate to assure the participant’s safety, and participants should 
be instructed to contact the investigator immediately in the event they experience an adverse event. In 
case of emergency, adequate means of communication between the site and the participant should be 
ensured by the investigator regardless of time of day or in the event of a holiday. The pace of 
enrollment will be monitored by the Sponsor, where there will be at least 7 days between the start of 
study treatment for each participant enrolled in the safety run-in.  
While on study treatment, all participants will be assessed for progression every 6 weeks for the first 
24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. After completion 
of study treatment and after occurrence of disease progression, participants will continue to be 
followed for survival until death, study closure, or withdrawal of consent. 
A safety monitoring committee (SMC) consisting of the study clinical director, medical expert, 
investigators, study statistician, and other study team members will monitor the safety of participants 
on an ongoing basis throughout the study. For the safety run-in, the SMC will conduct an evaluation 
of overall safety after 3 participants have enrolled and completed one cycle of study treatment. If the 
overall safety is deemed acceptable by the SMC in the first 3 participants enrolled, the SMC may 
recommend opening the efficacy-evaluable portion of the trial. Additionally, based on the observed 
data, the SMC may also determine that an additional 3 participants should be enrolled in the safety 
run-in and may consider further safety measures. In this case, after evaluation of the totality of safety 
data in all participants enrolled, the SMC may recommend proceeding with the trial, enrolling 
additional participants to evaluate an alternative dosing regimen, or not to proceed with the trial. In 
the event a significant safety concern was to occur in the interim between scheduled SMC meetings, 
enrollment will be paused and an ad hoc meeting of the SMC will be called.  
Investigational Product, Dose, and Mode of Administration 
Treatment will be administered in 21-day cycles. 
Tucatinib 300 mg (150 mg tablet× 2 tablets) will be given orally twice a day ( total 600mg per day). 
Depending on the outcome of the safety run-in, the tucatinib starting dose may be adjusted. 
Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of each 21-day cycle. 
Trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV) followed by 6 mg/kg once 
every 21 days. 

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Duration of Treatment 
Study treatment will continue until unacceptable toxicity, disease progression, death, withdrawal of 
consent, or study closure. In the absence of clear evidence of radiographic disease progression (per 
RECIST v1.1), development of CNS symptoms, or radiographic changes thought to pose potential 
immediate risk to the participant, all efforts should be made to continue treatment until unequivocal 
evidence of radiologic progression occurs, as defined in RECIST v1.1. 
Efficacy Assessments 
Efficacy assessments will include measurement of all known sites of metastatic or locally advanced 
unresectable disease (including at a minimum the chest, abdomen, and pelvis) by high quality spiral 
contrast computed tomography (CT), positron emission tomography (PET)/CT (if high quality CT 
scan included) and/or contrast MRI scan as appropriate, as well as appropriate imaging of any other 
known sites of disease at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks 
thereafter, irrespective of dose holds or interruptions. Efficacy assessments for each participant will 
continue until investigator-assessed disease progression (per RECIST v1.1), the start of subsequent 
anti-cancer therapy, death, withdrawal of consent, or study closure. Contrast MRI of the brain will be 
required on this same schedule only in those participants with prior history of brain metastases or 
with brain metastases or equivocal brain lesions at screening. Contrast brain MRI may also be 
performed in participants without known brain metastases if there is clinical suspicion of new brain 
lesions. Additional imaging such as nuclear medicine bone scan or other unscheduled scans may be 
performed at the discretion of the investigator. Treatment decisions will be made based upon local 
assessment of radiologic scans. Follow-up for survival will continue until death, study closure, or 
withdrawal of consent. 
Pharmacokinetic Assessments 
PK assessments of trough levels of tucatinib and ONT-993 (which is the predominant circulating 
metabolite) will be performed on Day 1 of Cycles 2-6 prior to administration of tucatinib. On Day 1 
of Cycle 3, PK assessments of peak levels of tucatinib and ONT-993 will be performed 1–4 hours 
after administration of tucatinib. For the safety run-in only, additional PK assessments may be 
performed on Cycle 1 days 1, 8 and 15, and Cycle 2 days 8 and 15. 
Safety Assessments 
Participants will be assessed throughout the study for safety. Safety assessments including physical 
exam and collection of adverse events (AEs) and laboratory abnormalities will be performed at a 
minimum of once every 3 weeks throughout study treatment and 30 days after the last dose of study 
drugs. Laboratory assessments will be performed locally. During Cycle 1, an in-person safety 
assessment will be performed on Days 1 and 12. During Cycle 2, an in-person safety assessment will 
be performed on Day 1 and liver function tests (AST/ALT and total bilirubin) will be collected on 
Cycle 2 Day 12. An in-person safety assessment will then be performed on Day 1 of each cycle 
throughout the remainder of the study or as clinically indicated. Assessment of cardiac ejection 
fraction will be performed by MUGA or ECHO at screening and at least once every 12 weeks 
thereafter until study discontinuation irrespective of dose delays or interruption, and 30 days after the 
last dose of study drugs (unless done within 12 weeks prior to 30-day follow-up visit). 
 

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Statistical Methods 
Data collected in this study will be presented using summary tables, participant data listings, and 
figures. Continuous variables will be summarized using descriptive statistics, specifically the mean, 
median, standard deviation, minimum, and maximum. Categorical variables will be summarized by 
frequencies and percentages. For time-to-event endpoints, the median survival time will be estimated 
using the Kaplan Meier method; the associated 90% confidence interval (CI) will be calculated based 
on the complementary log-log transformation. 
The primary efficacy analysis will be performed in Japanese population by testing the null hypothesis 
of ORR being less than or equal to 20% against the alternative hypothesis that ORR is greater than 
20% at overall 1-sided 5% level of significance, i.e., H0: P≤0.20 vs Ha: P>0.20. The point estimate 
and the 2-sided 90% exact Clopper Pearson CI for the confirmed ORR, as assessed by ICR will be 
provided. The study will be considered positive if the lower bound of the 2-sided 90% exact Clopper-
Pearson CI for confirmed objective response rate (cORR) is greater than 20%, so that the null 
hypothesis that the cORR is less than or equal to 20% can be rejected. cORR will be also estimated in 
all participants population including participants enrolled in Japan, South Korea and Taiwan as a 
secondary endpoint. 
Approximately 42 participants will be enrolled in Japan including 4 participants in the safety run-in. 
With 38 participants, the study will have approximately 80% power to detect a 20% increase in ORR 
from 20% to 40% and approximately 90% power to detect a 25% increase in ORR from 20% to 45%, 
at one-sided significance level of 0.05.  
On 02-Aug-2021 the SMC conducted an evaluation of overall safety after 4 Japanese participants 
were enrolled in the safety run-in and  the safety and tolerability was deemed acceptable by the SMC; 
hence the enrollment of the safety run-in was completed and that of the main study was initiated on 
the following day. 
A total of approximately 13 participants from South Korea and Taiwan are planned to be enrolled at 
this time. 
The primary analysis will be conducted when all of the treated participants in Japanese population 
have been followed for at least 8 months (or all responders have been followed for a minimum of 6 
months after their initial response, whichever comes first), have discontinued from the study, or had 
30 days safety follow-up after disease progression, whichever comes first. In addition, for the purpose 
of regulatory submission in South Korea and Taiwan, the additional analyses may be conducted 
subsequently to the initial analysis. 

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TABLE OF CONTENTS 
DOCUMENT HISTORY ....................................................................................................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................................................... 5 
TABLE OF CONTENTS ..................................................................................................................................... 14 
LIST OF IN-TEXT TABLES ............................................................................................................................... 17 
LIST OF IN-TEXT FIGURES ............................................................................................................................. 17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................................... 18 
1 
INTRODUCTION ......................................................................................................................................... 21 
1.1 
Background Information on the Target Disease ................................................................................. 21 
1.1.1 
HER2+ Breast Cancer .......................................................................................................... 21 
1.2 
Current Treatment Options for HER2+ Metastatic or Recurrent Breast Cancer ................................ 21 
1.2.1 
Treatment Options for HER2+ Breast Cancer with Brain Metastases ................................. 23 
1.2.2 
Tucatinib .............................................................................................................................. 23 
1.3 
Data Overview .................................................................................................................................... 24 
1.3.1 
Nonclinical ........................................................................................................................... 24 
1.3.2 
Clinical ................................................................................................................................. 24 
1.3.3 
Tucatinib Clinical Development in Breast Cancer ............................................................... 24 
1.3.4 
Tucatinib Safety and Pharmacokinetic Data in Japanese Participants .................................. 25 
1.4 
Risk Benefit Assessment .................................................................................................................... 26 
2 
OBJECTIVES ............................................................................................................................................... 27 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 28 
3.1 
Summary of the Safety Run-in (Japanese participants only) .............................................................. 28 
3.1.1 
Dose Limiting Toxicity ........................................................................................................ 29 
3.1.2 
Summary of Study Design ................................................................................................... 31 
3.1.3 
Study Stopping Rules and Discontinuation Criteria ............................................................. 33 
3.1.4 
End of Study ......................................................................................................................... 33 
3.1.5 
Retreatment .......................................................................................................................... 33 
3.2 
Discussion and Rationale for Study Design........................................................................................ 33 
3.2.1 
Rationale for Study Population ............................................................................................ 33 
3.2.2 
Rationale for Selection of Doses .......................................................................................... 35 
3.2.3 
Blinding and Unblinding ...................................................................................................... 37 
4 
STUDY POPULATION................................................................................................................................ 37 
4.1 
Inclusion Criteria ................................................................................................................................ 37 
4.2 
Exclusion Criteria ............................................................................................................................... 41 
4.3 
Childbearing Potential ........................................................................................................................ 44 
4.4 
Removal of Participants from Therapy or Assessment ....................................................................... 44 
4.4.1 
Discontinuation of Study Treatment .................................................................................... 44 
4.4.2 
Participant Withdrawal from Study ...................................................................................... 45 
5 
TREATMENTS ............................................................................................................................................ 46 
5.1 
Treatments Administered.................................................................................................................... 46 
5.2 
Investigational Product (Tucatinib) .................................................................................................... 46 
5.2.1 
Description ........................................................................................................................... 46 
5.2.2 
Method of Procurement ........................................................................................................ 46 
5.2.3 
Dose and Administration ...................................................................................................... 46 
5.2.4 
Storage and Handling ........................................................................................................... 47 
5.2.5 
Packaging and Labeling ....................................................................................................... 47 
5.2.6 
Study Drug Accountability ................................................................................................... 47 
5.3 
Trastuzumab ....................................................................................................................................... 48 
5.3.1 
Description ........................................................................................................................... 48 
5.3.2 
Method of Procurement ........................................................................................................ 48 

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5.3.3 
Dose, Preparation, and Administration................................................................................. 48 
5.3.4 
Storage and Handling ........................................................................................................... 48 
5.3.5 
Packaging and Labeling ....................................................................................................... 48 
5.4 
Capecitabine ....................................................................................................................................... 48 
5.4.1 
Description ........................................................................................................................... 48 
5.4.2 
Method of Procurement ........................................................................................................ 49 
5.4.3 
Dose, Preparation, and Administration................................................................................. 49 
5.4.4 
Storage and Handling ........................................................................................................... 49 
5.4.5 
Packaging and Labeling ....................................................................................................... 49 
5.5 
Dose Modifications............................................................................................................................. 49 
5.5.1 
Tucatinib Dose Reductions .................................................................................................. 50 
5.5.2 
Trastuzumab Dose Modifications......................................................................................... 51 
5.5.3 
Capecitabine Dose Modifications......................................................................................... 53 
5.5.4 
Dose Modifications for Hepatotoxicity ................................................................................ 54 
5.5.5 
Dose Modifications for Left Ventricular Dysfunction ......................................................... 55 
5.6 
Concomitant Therapy ......................................................................................................................... 55 
5.6.1 
Required Concomitant Therapy ........................................................................................... 56 
5.6.2 
Allowed Concomitant Therapy ............................................................................................ 56 
5.6.3 
Prohibited Concomitant Therapy ......................................................................................... 57 
5.6.4 
Potential Concomitant Drug Interactions ............................................................................. 57 
5.7 
Management of Overdose ................................................................................................................... 58 
5.8 
Treatment Compliance ....................................................................................................................... 58 
6 
STUDY ACTIVITIES ................................................................................................................................... 59 
6.1 
Schedule of Events ............................................................................................................................. 59 
6.2 
Screening Visit (Days –28 to 1) .......................................................................................................... 59 
6.3 
Treatment Period ................................................................................................................................ 61 
6.3.1 
Cycle 1 Day 1 ....................................................................................................................... 61 
6.3.2 
Cycle 1 Day 8 (±2 days, safety run-in participants only) ..................................................... 62 
6.3.3 
Cycle 1 Day 12 (± 3 days, not applicable for safety run-in participants) ............................. 63 
6.3.4 
Cycle 1 Day 15 (±2 days, safety run-in participants only) ................................................... 63 
6.3.5 
Cycle 2 Day 1 and Day 1 of All Subsequent Cycles (-1 to + 3 Days, - 1 day allowance is not 
applicable for Cycle 2 Day 1 of safety run-in participants) .................................................. 64 
6.3.6 
Cycle 2 Day 8 (±2 days, safety run-in participants only) ..................................................... 64 
6.3.7 
Cycle 2 Day 12 (± 3 days, not applicable for safety run-in participants) ............................. 65 
6.3.8 
Cycle 2 Day 15 (±2 days, safety run-in participants only) ................................................... 65 
6.3.9 
Response Assessments: Every Six Weeks (- 7 days) as Determined by Cycle 1 Day 1, 
through Week 24, then Every 9 Weeks (- 7 days) through End of Treatment ...................... 66 
6.3.10 
Every 12 Weeks as Determined by Screening Exam (-7 days) ............................................ 66 
6.4 
End of Treatment Visit (30 to 37 Days After Last Dose of Study Drug) ........................................... 66 
6.5 
Long-Term Follow-up ........................................................................................................................ 67 
6.6 
End of Study/End of Follow-up .......................................................................................................... 68 
7 
STUDY ASSESSMENTS ............................................................................................................................. 69 
7.1 
Screening/Baseline Assessments ........................................................................................................ 69 
7.1.1 
Confirmation of HER2 Expression for Study Eligibility ..................................................... 69 
7.1.2 
Treatment for Brain Metastases Prior to Study Entry .......................................................... 70 
7.2 
Response/Efficacy Assessments ......................................................................................................... 70 
7.2.1 
Isolated Progression in the Brain .......................................................................................... 71 
7.3 
Pharmacokinetic Assessments ............................................................................................................ 72 
7.4 
Safety Assessments............................................................................................................................. 72 
7.4.1 
Adverse Events ..................................................................................................................... 72 
7.4.2 
Vital Signs ............................................................................................................................ 80 
7.4.3 
Clinical Laboratory Tests ..................................................................................................... 80 
7.4.4 
Physical Examination ........................................................................................................... 81 

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7.4.5 
Pregnancy Testing ................................................................................................................ 81 
7.4.6 
Cardiac Function .................................................................................................................. 81 
7.5 
Appropriateness of Measurements...................................................................................................... 82 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 83 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 83 
8.2 
Data Management Procedures ............................................................................................................ 84 
8.3 
Access to Source Data ........................................................................................................................ 84 
8.4 
Accuracy and Reliability of Data........................................................................................................ 84 
8.5 
Data Quality Assurance ...................................................................................................................... 84 
8.6 
Data Handling and Record Keeping ................................................................................................... 85 
8.6.1 
Data Handling ...................................................................................................................... 85 
8.6.2 
Investigator Record Retention .............................................................................................. 86 
9 
DATA ANALYSIS METHODS ................................................................................................................... 86 
9.1 
Determination of Sample Size ............................................................................................................ 86 
9.2 
Study Endpoint Definitions ................................................................................................................ 87 
9.2.1 
Objective Response Rate ...................................................................................................... 87 
9.2.2 
Duration of Response ........................................................................................................... 87 
9.2.3 
Progression Free Survival .................................................................................................... 87 
9.2.4 
Overall Survival ................................................................................................................... 87 
9.3 
Statistical and Analytical Plans .......................................................................................................... 87 
9.3.1 
General Considerations ........................................................................................................ 87 
9.3.2 
Participant Disposition ......................................................................................................... 89 
9.3.3 
Participant Characteristics .................................................................................................... 89 
9.3.4 
Treatment Compliance ......................................................................................................... 89 
9.3.5 
Efficacy Analyses ................................................................................................................. 89 
9.3.6 
Pharmacokinetic Analyses ................................................................................................... 90 
9.3.7 
Safety Analyses .................................................................................................................... 90 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 92 
10.1 Informed Consent ............................................................................................................................... 92 
10.2 Ethical Review .................................................................................................................................... 92 
10.3 Regulatory Considerations.................................................................................................................. 93 
10.3.1 
Investigator Information ....................................................................................................... 93 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 93 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 93 
10.5 Clinical Trial Agreement .................................................................................................................... 93 
11 REFERENCES .............................................................................................................................................. 94 
APPENDIX A: 
SCHEDULE OF EVENTS ................................................................................................... 99 
APPENDIX B: 
ADDITIONAL PK ASSESSMENTS FOR PARTICIPANTS IN SAFETY RUN-IN ONLY . 
 
 ............................................................................................................................................ 105 
APPENDIX C: 
PERFORMANCE STATUS SCALES CONVERSION .................................................... 106 
APPENDIX D: 
GUIDANCE ON CONTRACEPTION .............................................................................. 107 
APPENDIX E: 
CYP3A4 INDUCERS AND THEIR ELIMINATION HALF-LIVES ............................... 110 
APPENDIX F: 
CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION HALF-LIVES........ 111 
APPENDIX G: 
CLINICAL SUBSTRATES FOR CYP3A-MEDIATED METABOLISM ........................ 112 
APPENDIX H: 
RECIST VERSION 1.1 ...................................................................................................... 113 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1:  
Objectives and corresponding endpoints ....................................................................................... 27 
Table 2: 
Adequate Organ Function Laboratory Values ............................................................................... 38 
Table 3: 
Recommended Tucatinib dose reduction schedule ........................................................................ 50 
Table 4: 
Dose modifications of tucatinib and trastuzumab for clinical adverse events other than left 
ventricular dysfunction related to either tucatinib and/or trastuzumab, or hepatocellular toxicity*
 ....................................................................................................................................................... 52 
Table 5: 
Dose modification of capecitabine for clinical adverse events considered related to capecitabine
 ....................................................................................................................................................... 53 
Table 6: 
Dose modifications of tucatinib and capecitabine for liver function abnormalities ....................... 54 
Table 7: 
Dose modifications for left ventricular dysfunction ...................................................................... 55 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study schema ................................................................................................................................. 32 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
AE of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BC 
breast cancer 
β-hCG 
beta human chorionic gonadotropin  
BID 
twice a day 
CBC 
complete blood count 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system 
cORR 
confirmed objective response rate 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic CRF 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ESMO 
European Society for Medical Oncology 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony stimulating factor 
GFR 
glomerular filtration rate 

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GnRH 
gonadotropin releasing hormone 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IAR 
infusion-associated reactions 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICR 
independent central review 
IEC 
independent ethics committee 
INR 
international normalized ratio 
INV 
investigator assessment 
IRB 
institutional review board 
ISH 
in situ hybridization 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
JBCS 
Japanese Breast Cancer Society 
LAM 
lactational amenorrhea method  
LFT 
liver function tests 
LMD 
leptomeningeal disease 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
MDRD 
Modification of Diet in Renal Disease [study] 
MUGA 
multiple-gated acquisition scan 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
P-gp 
P-glycoprotein 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 

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PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Scr 
serum creatinine 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SMC 
Safety Monitoring Committee 
SRS 
stereotactic radiosurgery 
SRT 
stereotactic radiation therapy 
T-DM1 
trastuzumab emtansine 
TKI 
tyrosine kinase inhibitors 
ULN 
upper limit of normal 
WBRT 
whole brain radiation therapy 
 

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1 
INTRODUCTION 
1.1 Background Information on the Target Disease 
1.1.1 HER2+ Breast Cancer 
Breast cancer (BC) is the most common form of cancer and the second leading cause of 
cancer-related death in women worldwide (Ferlay 2019). In Japan, BC is the fourth most 
common cancer, with an incidence of 92,266 cases in 2019 (Kantar Health 2019), and 
accounts for 9% of all cancer-related deaths (JBCS. Review 1 Changes in breast cancer 
morbidity and breast cancer mortality among Japanese women. 2018. 
http://jbcs.gr.jp/guidline/2018/index/ekigakuyobo/s1/ Accessed: Feb 11, 2020). Over the past 
several years, the incidence of BC in Japan has been increasing (annual percent change of 
6.4% between 2003 and 2011 (Sauvaget 2016), with BC accounting for nearly half of the 
increase in all cancer diagnoses in Japanese women. The BC mortality rate had been steadily 
increasing from the 1960s, but plateaued starting in 2008. By age group, recent mortality 
rates for BC have decreased in Japanese women 30–54 years old, but have remained steady 
among older age groups (Katanoda 2015). 
Human epidermal growth factor receptor (HER)-2 is a transmembrane tyrosine kinase 
receptor that mediates cell growth, differentiation, and survival. HER2 overexpression or 
amplification is a critical driver of HER2+ (positive) malignancies (Lee-Hoeflich 2008). 
BC that is HER2+ accounts for 15%–20% of primary BC cases worldwide and is often 
associated with a higher initial disease stage and a more aggressive phenotype that is more 
likely to recur when compared to HER2-negative BC (Musolino 2011). Although, there have 
been significant advances in HER2-targeted therapy, HER2+ metastatic breast cancer (mBC) 
almost invariably progresses (Swain 2013). Up to 50% of patients with HER2+ BC develop 
brain metastases during the course of their disease, which have been associated with faster 
disease progression, shorter overall survival (OS), and lower quality of life when compared 
with non-central nervous system (CNS) metastases (Bendell 2003; Olson 2013; Pestalozzi 
2013; Freedman 2019; Hurvitz 2019). 
1.2 Current Treatment Options for HER2+ Metastatic or Recurrent Breast 
Cancer 
In Japan, the introduction of HER2-targeted therapy using either antibody-based therapies or 
small molecule tyrosine kinase inhibitors (TKI) has led to significant and ongoing 
improvements in disease-free survival, progression-free survival (PFS), and OS in the 
neoadjuvant, adjuvant, and metastatic settings (Slamon 2001; Geyer 2006; Baselga 2012; 
Verma 2012). Trastuzumab, a humanized antibody that binds to the extracellular domain of 
HER2, was the first anti-HER2 agent approved by the Ministry of Health, Labour and 
Welfare (MHLW) for use in HER2+ BC, and remains the backbone of treatment in the 
neoadjuvant, adjuvant, and metastatic settings (Slamon 2001; Vogel 2002). Additionally, 
upon improvements in both PFS and OS, the addition of pertuzumab and taxane anti-cancer 

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agent to trastuzumab-based therapy in the first-line setting, and the use of single-agent 
trastuzumab emtansine (T-DM1) as second-line treatment, have become important standards 
of care for patients with metastatic disease.  There are no effective treatments for the patients 
who have been difficult to treat with these standar-of-care therapy, and anti HER2 antibodies 
and chemotherapy combination or lapatinib and chemotherapy combination have been used 
for these patients. However, the response rate is approximately 22-23%, and the prognosis 
has not been imporved (Murthy 2020b; Yokoe 2021; Masuda 2020; Charles 2006). In recent 
years, the anti HER2 Antibody-Drug Conjugate (ADC), Trastuzumab deruxtecan, was 
approved in March 2020 for new therapeutic options after second-line treatment. The 
response rate of Trastuzumab deruxtecan was 60.9% (95%CI : 53.4-68.0) and the median 
PFS was 16.4 months (95% CI: 12.7-Not reached). However, as some patients are resistant to 
trastuzumab derxtecan or difficult to administer,  the development of effective therapeutic 
agents with novel mechanisms of action continues to be essential for further prognostic 
improvement in this patient population.  
BC practice guidelines from the JBCS (23 Oc 2019 update; JBCS. CQ22. What is the 
recommended treatment for first-line treatment of HER2-positive inoperable or metastatic or 
recurrent breast cancer? 2018 http://jbcs.gr.jp/guidline/2018/index/yakubutu/y2-cq-22 
Accessed: Feb 12, 2020) strongly recommend a combination of trastuzumab + pertuzumab + 
docetaxel as first-line treatment for HER2+ metastatic or recurrent BC. This recommendation 
is based on results from the phase 3 CLEOPATRA study, in which 808 patients were 
randomized to receive pertuzumab + trastuzumab + docetaxel or placebo + trastuzumab + 
docetaxel. PFS in the experimental arm was superior to the control arm (median 18.7 months 
vs. 12.4 months; hazard ratio [HR] 0.69; 95% confidence interval [CI]: 0.58, 0.81) (Swain 
2013). Median OS was also significantly longer in those patients who received pertuzumab 
(median 56.5 months vs. 40.8 months; HR 0.68; 95% CI: 0.56, 0.84; P<0.001) (Swain 2019). 
The combination of pertuzumab + trastuzumab + paclitaxel is also an option for first-line 
treatment for HER2+ mBC in Japan, as data from a phase 2 study showed this combination 
to be active and tolerable (Dang 2015). 
The JBCS strongly recommends T-DM1 for use in patients with HER2+ metastatic or 
recurrent BC that has progressed during or after trastuzumab administration. This 
recommendation is primarily based on results from the phase 3 EMILIA study, in which 
991 patients with HER2+ locally advanced, metastatic, or recurrent BC who had previously 
been treated with trastuzumab and a taxane were randomized to receive T-DM1 or 
capecitabine + lapatinib (Verma 2012). Those randomized to T-DM1 had statistically 
significant improvements in PFS (median 9.6 months vs. 6.4 months; HR 0.65; 95% CI: 0.55, 
0.77; P<0.001), OS (median 30.9 months vs. 25.1 months; HR 0.68; 95% CI: 0.55, 0.85; 
P<0.001) and objective response rate (ORR) (43.6% vs. 30.8%; P<0.001) as compared to the 
control group. In addition, T-DM1 is weakly recommended in later lines of therapy based on 
results from the phase 3 TH3RESA study of T-DM1 vs. physician’s choice in patients with 
previously treated HER2+ mBC and the EMILIA study where 39% of patients (n=500) were 

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treated in the third-line or later. Currently, no randomized clinical trial has evaluated T-DM1 
as second-line treatment in patients with disease progression after trastuzumab + pertuzumab 
+ chemotherapy. 
Continuation of anti-HER2 therapy past progression is recommended in the third-line setting 
by the JBCS. An exploratory analysis from the GBG 26/BIG 03-05 study showed an 
improved post-progression survival (PPS) for patients who received anti-HER2 treatment as 
part of third-line treatment (n=52) vs. those who did not (n=88) (PPS: 18.8 months [95% CI: 
12.9, 24.8] vs. 13.3 months [95% CI: 10.2, 14.7]; HR 0.63; P=0.02). However, no OS benefit 
was observed in those who received anti-HER2 treatment (von Minckwitz 2011).  
Globally, the current standard of care for HER2+ metastatic or recurrent breast cancer also 
consists of treatment with trastuzumab + pertuzumab and a taxane as first-line treatment, 
followed by T-DM1 in second line (Cardoso 2020, NCCN Guidelines® 2021). Trastuzumab 
deruxtecan is recommended as third line treatment in the ESMO and NCCN guidelines. 
However, Trastuzumab deruxtecan has not been approved in South Korea and Taiwan. 
1.2.1 Treatment Options for HER2+ Breast Cancer with Brain Metastases 
HER2+ BC patients with brain metastases have a worse prognosis than those without CNS 
disease. In a population-based registry of HER2+ mBC patients enrolled at diagnosis, 
evidence of brain metastases led to a shortened survival relative to patients without brain 
metastases (Brufsky 2011). Among 377 patients with brain metastases, the median OS from 
the date of initial mBC diagnosis was 26.3 months (range: 1.0–60.9 months) compared to 
44.6 months (range: 0.5–59.7 months) in the 635 patients who did not have CNS metastases 
(Brufsky 2011). 
Treatment of brain metastases often includes surgical resection, radiosurgery, and/or whole 
brain radiotherapy, combined with continuation of systemic anti-cancer therapy. 
Unfortunately, CNS-directed therapy often result in significant neurologic toxicities, which 
may impair quality of life. Stereotactic radiosurgery (SRS) has been increasingly used to 
avoid the neurologic toxicities of whole brain radiotherapy, but has been associated with 
inferior control of distant brain relapse outside the local radiation fields (Chang 2009; Brown 
2016; Kaidar-Person 2016). Patients with brain metastases have historically been excluded 
from clinical trials and, as a result, no systemic agents are approved for treatment of HER2+ 
brain metastases (Lin 2015). Development of treatments for this patient population remains 
an important unmet medical need, which will require including these patients in clinical 
trials. 
1.2.2  Tucatinib  
On 17 April 2020, tucatinib was approved by the US Food and Drug Administration (FDA) 
under the trade name Tukysa, based on results from the HER2CLIMB trial. Tucatinib was 
approved for treatment of adult patients with advanced unresectable or metastatic 
HER2-positive breast cancer, including patients with brain metastases, who have received 

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one or more prior anti-HER2-based regimens in the metastatic setting in combination with 
trastuzumab and capecitabine.  
Tucatinib is an orally-available (PO), reversible HER2 small molecule TKI. Two key 
features of tucatinib are its potency and selectivity for HER2 compared to the closely-related 
tyrosine kinase epidermal growth factor receptor (EGFR). In comparison to other approved 
HER2 TKIs for patients with mBC, tucatinib is approximately 6-fold more potent in its 
inhibition of HER2 compared to lapatinib. In addition, tucatinib is highly selective for HER2 
compared to EGFR. With >1000-fold more selectivity for HER2 compared to EGFR, 
tucatinib has the potential to inhibit HER2 signaling while avoiding known EGFR-related 
side effects (e.g., severe skin rash and gastrointestinal toxicity). This unique feature also 
differentiates tucatinib from other HER2 inhibitors, including both neratinib and lapatinib, 
which inhibit HER2 and EGFR with similar potency and are associated with side effects 
related to EGFR inhibition. 
Clinical trials are ongoing to examine the safety and efficacy of tucatinib when combined 
with other HER2-directed therapies. A complete summary of the clinical and nonclinical data 
for tucatinib and its trials in human patients is provided in the Investigator’s Brochure. 
1.3 Data Overview 
A complete summary of the clinical and nonclinical data relevant to the evaluation of 
tucatinib in human participants is provided in the Investigator’s Brochure. 
1.3.1 Nonclinical 
The pharmacological and toxicological properties of tucatinib were evaluated in accordance 
with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) S9 guidance. The tucatinib Investigator’s Brochure 
provides a complete summary of nonclinical pharmacology, pharmacokinetic (PK), and 
toxicology study data. 
1.3.2 Clinical 
1.3.3  Tucatinib Clinical Development in Breast Cancer 
A complete summary of the current tucatinib clinical development program is provided in the 
tucatinib Investigator’s Brochure. 
The efficacy and safety of the combination of tucatinib + trastuzumab + capecitabine has 
been evaluated in a phase 1b dose finding trial (ONT-380-005) and a pivotal, randomized, 
double-blind, placebo-controlled, active comparator study (HER2CLIMB; ONT-380-206). 
The phase 1b dose-escalation trial (ONT-380-005) evaluated tucatinib in combination with 
trastuzumab and/or capecitabine in participants with HER2+ mBC (Murthy 2018). Sixty 
participants who received prior treatment with both trastuzumab and T-DM1 for metastatic 
disease were enrolled, including 27 participants treated with tucatinib 300 mg twice a day 

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(BID), trastuzumab, and capecitabine (1000 mg/m2 twice daily for 14 days of each 3 week 
cycle). This study informed dose selection of 300 mg BID tucatinib for the pivotal trial 
HER2CLIMB. Median PFS for participants treated with tucatinib 300 mg + trastuzumab + 
capecitabine was 7.8 months. Among those with measurable disease, the ORR for tucatinib 
300 mg + trastuzumab + capecitabine was 61%. Treatment was generally tolerable with a 
manageable safety profile and is consistent with what was observed in the HER2CLIMB 
trial. 
Results from the pivotal HER2CLIMB trial clearly demonstrated the benefit of adding 
tucatinib to trastuzumab and capecitabine in HER2+ mBC (Murthy 2020b). HER2CLIMB 
enrolled 612 participants who had been treated with 3 prior HER2-directed agents 
(trastuzumab, pertuzumab, and T-DM1). Participants were randomized in a 2:1 ratio to 
receive tucatinib (300 mg BID) or placebo in combination with trastuzumab (8 mg/kg 
intravenously [IV] followed by 6 mg/kg every 3 weeks) and capecitabine (1000 mg/m2 twice 
daily for 14 days of each 3 week cycle). The primary endpoint of PFS was highly statistically 
significant in favor of the tucatinib combination, with an HR of 0.54 (95% CI: 0.42, 0.71; 
P<0.001). Additionally, all multiplicity-adjusted secondary endpoints supported the primary 
endpoint and demonstrated benefit with tucatinib, including OS (HR 0.66; 95% CI; 0.50, 
0.88; P=0.005), PFS in participants with brain metastases (HR 0.48; 95% CI; 0.34, 0.69; 
P<0.001) and confirmed ORR (40.6% [95% CI; 35.3, 46.0] in the tucatinib arm vs. 22.8% 
[95% CI; 16.7, 29.8] in the control arm, P<0.001). Tucatinib treatment was generally 
tolerable with a manageable safety profile and low rate of treatment-emergent adverse events 
(TEAEs) leading to discontinuation of treatment. 
The pivotal HER2CLIMB trial met the primary endpoint of PFS, demonstrating that the 
addition of tucatinib to trastuzumab and capecitabine reduced the risk of disease progression 
or death by approximately half in heavily pretreated patients with HER2+ locally advanced 
unresectable or mBC. Tucatinib treatment reduced the risk of disease progression or death by 
a greater amount in participants with brain metastases. Most importantly, tucatinib also 
reduced the risk of death by approximately a third in the overall population. Tucatinib 
treatment was generally tolerable with a manageable safety profile and low rate of treatment-
emergent adverse events (TEAEs) leading to discontinuation of treatment. 
Based on the statistically significant and clinically meaningful results for the primary and all 
alpha-controlled secondary endpoints, the Sponsor made the decision to unblind this trial and 
allow participants on the control arm to cross over to receive tucatinib. 
1.3.4  Tucatinib Safety and Pharmacokinetic Data in Japanese Participants 
To support clinical development of tucatinib in Japan, a phase 1 safety, tolerability, and PK 
trial was conducted in healthy Japanese and Caucasian participants in the US 
(SGNTUC-015). The results of this trial show there were no meaningful differences in PK or 
safety profiles between Caucasian and Japanese participants at the clinically relevant dose of 
300 mg BID. Therefore, no starting dose adjustment is recommended for tucatinib based on 

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age, albumin, creatinine clearance, body weight, or race in Japanese participants. 
Additionally, a population PK analysis was performed on the HER2CLIMB trial where race 
was not identified as a covariate in the model. 
1.4 Risk Benefit Assessment 
In the global HER2CLIMB trial, all subgroups analyzed, including race (white vs, 
non-white), demonstrated a PFS benefit with tucatinib treatment consistent with the overall 
outcome. Additionally, data from the SGNTUC-015 PK trial demonstrated no marked 
differences in tucatinib exposure or safety between Japanese and Caucasian healthy 
volunteers at the clinically relevant 300 mg dose level. Taken together, these data support a 
positive benefit/risk profile for evaluation of tucatinib in combination with trastuzumab and 
capecitabine in Japanese participants with HER2+ mBC. 

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2 
OBJECTIVES 
Table 1:  
Objectives and corresponding endpoints 
Objective 
Corresponding Endpoint 
Primary 
 
● Assess ORR per Response Evaluation  
Criteria in Solid Tumors (RECIST) v1.1 in 
Japanese population. 
● Confirmed objective response rate 
(cORR) per RECIST v1.1, as 
determined by ICR 
Secondary 
 
● Assess ORR per Response Evaluation  
Criteria in RECIST v1.1 by ICR in all 
participants population. 
● cORR per RECIST v1.1, as 
determined by ICR 
● Assess ORR per RECIST v1.1 by  
investigator assessment (INV) in Japanese 
population and all participants population. 
● cORR per RECIST v1.1 as 
determined by INV 
● Assess duration of response (DOR) per  
RECIST v1.1 in Japanese population and all 
participants population. 
● DOR per RECIST v1.1, as 
determined by ICR and INV 
● Assess PFS per RECIST v1.1 in Japanese 
population and all participants population. 
● PFS per RECIST v1.1, as 
determined by ICR and INV 
● Assess overall survival (OS) in Japanese 
population and all participants population. 
● OS 
● Evaluate the safety of tucatinib in  
combination with trastuzumab and  
capecitabine in Japanese population and all 
participants population. 
● Type, incidence, severity, 
seriousness, and relatedness of 
adverse events (AEs) and lab 
abnormalities 
● Frequency of dose modifications 
and treatment discontinuations 
● Vital signs and other relevant 
safety variables  
Exploratory 
 
● Evaluate the pharmacokinetics (PK) of tucatinib 
administered in combination with trastuzumab 
and capecitabine in Japanese population, South 
Korean population and all participants population. 
● PK 
 

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3 
INVESTIGATIONAL PLAN 
3.1 Summary of the Safety Run-in (Japanese participants only) 
Prior to enrollment of participants into the main portion of the trial, a safety run-in will be 
conducted in approximately 3 to 6 participants to assess the safety and tolerability of the 
standard doses and schedule for the combination of tucatinib, trastuzumab, and capecitabine. 
The inclusion and exclusion criteria (Section 4), treatment doses (Section 5), schedule and 
study assessments (Sections 6 and APPENDIX A), and safety reporting rules (Section 7.4) 
will be identical to the main portion of the trial, with the exception of additional study visits 
and laboratory assessments performed during the first 2 cycles of study treatment (Section 6). 
The starting dose for participants in the safety run-in will receive tucatinib 300 mg (150 mg 
tablet × 2 tablets) orally twice a day (total 600 mg per day), trastuzumab loading dose of 8 
mg/kg IV followed by 6 mg/kg once every 21 days, and capecitabine 1000 mg/m2 PO BID 
for Days 1-14 only of a 21-day cycle. 
Participants in the safety run-in will be carefully monitored through the first cycle of 
treatment (21 days) and evaluated for AEs that are unexpected based on the known safety 
profile of each individual agent and of the combination of tucatinib, trastuzumab, and 
capecitabine. Participants will be enrolled at a limited number of sites for this safety run-in. 
Investigators must ensure that participants enrolled in the safety run-in portion of the trial do 
not have other medical, social, or psychosocial factors that, in the opinion of the investigator, 
could impact safety or compliance with study procedures required per the protocol (such as 
compliance with additional study visits, laboratory assessments, oral medications and close 
out-patient monitoring) (Section 4.2). During the first cycle, the participant may be 
hospitalized for a minimum of 24 hours with discharge permitted if a participant has no 
ongoing ≥ Grade 3 AEs and is otherwise considered appropriate for discharge by the 
investigator based on history, physical exam (including vital signs), and laboratory 
evaluations (including complete blood count, serum chemistry, and liver function tests). 
History includes assessment of any new or ongoing AEs and concomitant medication use. 
For participants undergoing outpatient follow-up, the investigator must ensure that the 
participant will be followed closely in the outpatient setting by methods they determine to be 
appropriate to assure the participant’s safety, and participants should be instructed to contact 
the investigator immediately in the event they experience an AE. In case of emergency, 
adequate means of communication between the site and the participant should be ensured by 
the investigator regardless of time of day or in the event of a holiday. The pace of enrollment 
will be monitored by the Sponsor, where there will be at least 7 days between the start of 
study treatment for each participant enrolled in the safety run-in.  
A safety monitoring committee (SMC) consisting of the study clinical director, medical 
expert, investigators, study statistician, and other study team members will conduct an 
evaluation of overall safety after 3 participants have enrolled and completed one cycle of 
study treatment. If the overall safety is deemed acceptable by the SMC in the first 3 

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participants enrolled, the SMC may recommend opening the main portion of the trial. 
Additionally, based on the observed data, the SMC may also determine that additional 
participants should be enrolled in the safety run-in and may consider further safety measures. 
In this case, after evaluation of the totality of safety data in all participants enrolled, the SMC 
may recommend proceeding with the trial, enrolling additional participants to evaluate an 
alternative dosing regimen, or not to proceed with the trial. In the event a significant safety 
concern was to occur in the interim between scheduled SMC meetings, enrollment will be 
paused and an ad hoc meeting of the SMC will be called.  
A participant will be considered evaluable for the safety run-in if they receive at least 75% of 
the intended dose amounts of each study treatment in Cycle 1 or if they experience a toxicity 
as described in (Section 3.1.1). Participants will be replaced if they are not eligible for 
evaluation due to circumstances completely unrelated to either study treatment (e.g., receipt 
of prohibited concomitant medication or the participant does not meet eligibility criteria) or if 
they do not complete the 21-day evaluation period for reasons other than treatment-related 
toxicity (e.g., withdrawal of consent). For participants that experience a toxicity as described 
in Section 3.1.1 during the safety run-in part of the trial, the decision whether to continue 
treatment at the same or a reduced dose (or to discontinue one or more of the individual 
drugs) will be made by the treating investigator based on the individual participant’s benefit-
risk assessment. Dose modifications due to AEs will be permitted and guidelines regarding 
the resumption or discontinuation of study treatment will be followed per Section 5.5. Data 
from participants who are not DLT-evaluable will be included in safety evaluation for SMC 
awareness. 
3.1.1 Dose Limiting Toxicity 
The SMC will base their decision on an evaluation of the totality of data in the safety run-in 
participants to assess the overall safety and tolerability of the combination, in the context of 
the expected safety profile for the individual drugs. 
The SMC will adjudicate determinations of DLT in participants from initiation of treatment 
through the end of the DLT period. Among the first 3 DLT evaluable participants, 
● 
If 0 of 3 participants experience a DLT, and the overall safety is deemed acceptable 
by the SMC, the SMC may recommend that the combination is safe and tolerable in 
participants, and participants may participate in the main portion of the trial. 
● 
If 1 of 3 participants experiences a DLT, the SMC may recommend enrollment of 3 
additional participants.  
● 
If ≥2 of 3 participants experience a DLT, the SMC may recommend a lower dose of 
tucatinib. In the dose de-escalation stage, tolerability will be evaluated by enrolling 3 
participants, such as before the dose de-escalation stage. 

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In the event the cohort is expanded to a total of 6 DLT-evaluable participants (including the 3 
participants enrolled before expansion), 
● 
If ≤1 of 6 participants experiences a DLT, and the overall safety is deemed acceptable 
by the SMC, the SMC may recommend that the combination is safe and tolerable in 
participants and participants may participate in the main portion of the trial at the 
current dose.  
● 
If ≥2 of 6 participants experience a DLT, the SMC may recommend a lower dose of 
tucatinib. In the dose de-escalation stage, tolerability will be evaluated by enrolling 3 
participants, such as before the dose de-escalation stage. 
If a second dose de-escalation of tucatinib is required, the SMC may recommend that 
enrollment of participants not proceed to the main portion of the trial. 
The SMC will take into consideration the occurrence of the following toxicities during 
Cycle 1 if assessed by the investigator to be clinically significant, unexpected, and related to 
tucatinib or the combination of tucatinib, trastuzumab, and capecitabine. The events 
unrelated to tucatinib or the combination such as disease progression, medical illness, 
environmental factors, unrelated trauma etc. will be excluded. Grading will be according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), version 4.03. These events should be taken into consideration in the 
evaluation performed by the SMC. 
Non-hematologic 
● 
Any treatment-related AE ≥Grade 3 except: 
○ 
Grade 3 fatigue lasting ≤3 days 
○ 
Grade 3 diarrhea, nausea, or vomiting without optimal use of anti-emetics or 
anti-diarrheals that had recovered to ≤ Grade 1 or pretreatment level within 10 
days of initiating appropriate supportive therapy 
○ 
Grade 3 rash without optimal use of corticosteroids or anti-infectives that had 
recovered to ≤ Grade 1 or pretreatment level within 10 days of initiating 
appropriate supportive therapy  
● 
>14-day delay in start of Cycle 2 due to AEs related to tucatinib or the addition of 
tucatinib to trastuzumab and capecitabine 
● 
Missing >25% of tucatinib, capecitabine, or trastuzumab doses as a result of 
treatment-related toxicities during the first cycle 
● 
Any treatment-related toxicity that leads to treatment discontinuation (tucatinib 
and/or capecitabine and/or trastuzumab) during Cycle 1 

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Hematologic 
● 
Grade 4 thrombocytopenia (<25 X 103/µL) lasting for >7 days or requiring platelet 
transfusion 
● 
Grade 3 thrombocytopenia (<50 X 103/µL ) with significant bleeding (≥ Grade 3) 
● 
≥Grade 3 febrile neutropenia 
● 
Grade 4 neutropenia (<500/mm3) lasting for >7 days. Prophylactic use of colony 
stimulating factors (e.g., G-CSF) for primary prevention of neutropenia is prohibited 
during the DLT evaluation period. 
● 
Grade 4 anemia or anemia requiring blood transfusion 
Hepatic 
● 
Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
increased (>20 x upper limit of normal [ULN]) 
● 
Grade 4 blood bilirubin increased (> 10 x ULN) 
● 
Grade 3 ALT or AST or blood bilirubin increased that has not returned to ≤ Grade 1 
or baseline by start of Cycle 2 
● 
ALT and/or AST >3xULN AND total bilirubin >2x ULN 
Note: Asymptomatic ≥ Grade 3 laboratory abnormalities will not be considered, except for 
hematologic and hepatic abnormalities outlined above. 
3.1.2 Summary of Study Design 
This is a single-arm, multicenter, phase 2 study with a safety run-in designed to evaluate the 
efficacy and safety of tucatinib in combination with trastuzumab and capecitabine in 
participants with locally advanced unresectable or metastatic HER2+ BC who have had prior 
treatment with taxane anti-cancer agent, trastuzumab, pertuzumab, and T-DM1. This study 
consists of Japanese population, South Korean population and Taiwanese population. 
Treatment will be administered in 21-day cycles. Tucatinib 300 mg (150 mg × 2 tablets) will 
be given orally twice a day (total 600 mg per day). Depending on the outcome of the safety 
run-in, the tucatinib starting dose may be adjusted. Trastuzumab will be given as a loading 
dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days. Capecitabine will be given at 
1000 mg/m2 PO BID on Days 1–14 of each cycle. Dose holding of tucatinib, trastuzumab, 
and capecitabine will be allowed as needed for participant safety. Additionally, dose 
discontinuation of trastuzumab and/or capecitabine is permitted. Participants who discontinue 
capecitabine and/or trastuzumab may continue on study treatment. Participants who 
discontinue tucatinib will be allowed to remain on study treatment. 

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While on study treatment, participants will be assessed for progression every 6 weeks for the 
first 24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. After 
completion of study treatment and after occurrence of disease progression, participants will 
continue to be followed for survival until death, study closure or withdrawal of consent. 
A SMC consisting of the study clinical director, medical expert, investigators, study 
statistician, and other study team members will monitor the safety of participants on an 
ongoing basis throughout the study. 
Approximately 55 participants (Japanese population: approximately 42 participants 
including 4 participants in the safety run-in, South Korean population: approximately 10 
participants and Taiwanese population: approximately 3 participants) will be enrolled into 
this study. On 02-Aug-2021 the SMC conducted an evaluation of overall safety after 4 
Japanese participants were enrolled in the safety run-in and the safety and tolerability was 
deemed acceptable by the SMC; hence the enrollment of the safety run-in was completed and 
that of the main study was initiated on the following day. A study schema is provided in 
Figure 1. See APPENDIX A for a schedule of events. 
 
Figure 1: 
Study schema 
 
a 
Treatment will continue until unacceptable toxicity, disease progression, death, withdrawal of 
consent, or study closure. Participants with CNS progression may undergo local therapy to CNS 
lesions and continue on study treatment with approval from the Sponsor for clinical benefit. 
b 
Includes measurement of all known sites of unresectable locally advanced/metastatic disease via 
radiographic imaging. Assessment for brain metastases is performed with contrast magnetic 
resonance imaging (MRI) of the brain for all participants regardless of prior history of brain 
metastases (Section 7.2). 
c 
Response assessments are performed every 6 weeks for the first 24 weeks, and then every 9 
weeks thereafter, irrespective of dose holds or interruptions. Participants without brain metastases 

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at baseline do not require contrast MRIs while on treatment. Response assessments should be 
done at the End of Treatment Visit if not done within the previous 30 days only in participants 
having ended study treatment for reasons other than radiographic disease progression. A contrast 
brain MRI is required at the End of Treatment Visit for participants with known brain metastases 
at baseline or a history of brain metastases, unless already done within 30 days of ending study 
treatment or if progression in the brain has already been documented while on study (Section 
6.4).  
d 
Assessment of overall survival and collection of information regarding any additional anti-cancer 
therapies administered after discontinuation of study treatment.  
e 
For participants who discontinue study treatment prior to disease progression by investigator 
assessment (per RECIST v1.1), response assessments are performed every 9 weeks (±1 week) 
until disease progression, death, withdrawal of consent, or study closure. Contrast brain MRI is 
required on this same schedule only in those participants with known brain metastases at baseline 
or a history of brain metastases (Section 6.5). 
 
3.1.3 Study Stopping Rules and Discontinuation Criteria 
Reasons for terminating the study may include but are not limited to the following: 
● 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to participants, either through a safety review by the Sponsor or a safety 
assessment by the SMC.  
● 
Participant enrollment is unsatisfactory.  
3.1.4 End of Study 
The study ends when the last participant completes the last visit, last contact, discontinues 
from the study, or is lost to follow-up, whichever occurs first. In addition, the Sponsor may 
terminate the study at any time (Section 10.3.2). 
3.1.5 Retreatment 
Retreatment with tucatinib is not permitted. 
3.2 Discussion and Rationale for Study Design 
3.2.1 Rationale for Study Population 
The study population is designed to mirror the study population of the pivotal HER2CLIMB 
study. The key eligibility criteria will be nearly identical to the HER2CLIMB study with the 
exception that measurable disease by RECIST v1.1 will be required at study entry. Eligible 
participants for this study are those with progressive, unresectable locally advanced or 
metastatic HER2+ BC who have had prior treatment with taxane anti-cancer agent, 
trastuzumab, pertuzumab, and T-DM1 (Freedman 2012; Cardoso 2014; Giordano 2014; 
Ramakrishna 2014). 

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There is currently no single standard of care therapy for these patients. Treatment options 
that do exist include continued use of a HER2-directed agent either in combination with a 
cytotoxic agent (e.g., trastuzumab and capecitabine, or vinorelbine, or lapatinib and 
capecitabine) or with a second HER2-directed agent (i.e., trastuzumab + lapatinib), with no 
currently available data to recommend one regimen over another. Treatment selection is 
generally based upon physician and patient preference (Giordano 2014). There are currently 
limited published data reporting a median PFS or OS for pertuzumab and T-DM1 
experienced patients who require further treatment. The most similar reference population 
from recent clinical studies may be the control arm of the TH3RESA trial, which evaluated 
T-DM1 vs. physician’s choice of therapy in patients receiving third-line treatment or beyond 
for metastatic HER2+ BC. The median PFS in the physician’s choice control group was only 
3.3 months. Given that, and the fact that none of these patients had yet been exposed to 
T-DM1, the actual PFS for patients receiving third-line therapy after current first- and 
second-line standard of care may be even shorter (Krop 2014). A well-tolerated regimen 
which could improve upon overall PFS and OS in patients who have failed current standard 
of care for metastatic disease would therefore help address an important unmet medical need. 
In the HER2CLIMB study, the addition of tucatinib to the combination of trastuzumab and 
capecitabine resulted in statistically significant and clinically meaningful improvements in 
PFS, OS, PFS in participants with brain metastases, and confirmed ORR, and therefore may 
be able to meet this need. 
Certain participants with brain metastases are also eligible for this trial, including participants 
with untreated brain metastases not requiring immediate radiotherapy and patients with prior 
radiotherapy with stable to minimally progressive metastases. Treatment options for patients 
with HER2+ disease and brain metastases are currently limited, and there is no currently 
recommended systemic therapy (Ramakrishna 2014). Treatment modalities include radiation 
therapy (either whole brain radiation therapy [WBRT], SRS or stereotactic radiation therapy 
[SRT]) or surgery for selected patients. Radiation therapy can be associated with significant 
morbidity due to treatment-related injury. There is therefore a need for alternative treatment 
options. Systemic treatment options that have demonstrated some activity include single 
agent cytotoxic agents, including capecitabine, as well as combination treatment with 
capecitabine and lapatinib. However, the toxicity associated with these regimens can be 
substantial, particularly for the combination of capecitabine and lapatinib which has been 
associated with >50% rate of Grade 3 events (Verma 2012), and none of these systemic 
regimens have been approved for use in the setting of brain metastases. Data from 
HER2CLIMB have shown clinical activity in participants with either untreated brain 
metastases or brain metastases progressing after prior radiation therapy. As there are 
currently no approved systemic therapies for participants with brain metastases from HER2+ 
mBC, this clinical scenario represents a significant unmet medical need. An effective 
systemic treatment with CNS activity could potentially improve overall PFS and OS for 
participants with brain metastases, as well as allow participants to delay exposure to radiation 
therapy and its associated negative neurologic toxicities. In addition, patients with 

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progression after prior radiotherapy represent a particular unmet need, since additional 
treatment options are even more limited due to the increased risks of tissue necrosis from 
additional radiation to previously irradiated brain tissue. 
Participants with asymptomatic brain lesions found during screening not thought to need 
immediate local therapy are eligible for this study. These participants are being included as 
there are currently no data showing that early initiation of radiation therapy leads to 
improved OS, or that delay of initiation of radiation therapy until after a trial of systemic 
therapy has a negative impact on OS (Ramakrishna 2014). 
To mimic the study population in HER2CLIMB, participants with high-risk brain metastases, 
including those with lesions identified during screening that are thought to require immediate 
local therapy, those with rapidly progressing lesions, those requiring >2 mg dexamethasone 
or equivalent corticosteroid at the start of the study for control of neurologic symptoms, and 
those with larger untreated lesions, may be excluded from the trial. However, high-risk 
patients who could benefit from immediate CNS-directed therapy, such as those who have 
untreated lesions in anatomically sensitive areas, may undergo surgery or radiation therapy 
after screening and then enter the study (7 or more days after SRS/SRT, 14 or more days 
after WBRT and 28 or more days after surgical resection) if neurologically stable and on 
reduced dose of steroids as protocol specified. 
The SMC will be monitoring safety data in an ongoing fashion to ensure that participants are 
not put at excessive risk. 
To ensure that participants without true HER2 overexpression who are unlikely to benefit 
from HER2 directed therapy are excluded from this trial, HER2+ status will be confirmed 
using a centralized laboratory according to current ASCO/CAP Guidelines (Wolff 2013). 
3.2.2 Rationale for Selection of Doses 
In participants that have previously been treated with trastuzumab, pertuzumab, and T-DM1, 
the combination of tucatinib, trastuzumab, and capecitabine has now been evaluated in 
431 participants from the Phase 1b (ONT-380-005) and HER2CLIMB studies (Murthy 2018; 
Murthy 2020b). The selected doses for this study are based upon these data and identical to 
those used in the HER2CLIMB study. 
The addition of tucatinib to trastuzumab and capecitabine provides dual HER2 inhibition 
through 2 different mechanisms of action. Dual blockade of HER2 has been shown in 
multiple settings to provide benefit over single agent blockade, even in the setting of 
previous progression on trastuzumab-containing regimens (Blackwell 2010; Baselga 2012; 
Blackwell 2012; Gianni 2012). Furthermore, the greater selectivity of tucatinib compared to 
other oral anti-HER2 agents offers the potential to provide HER2 blockade with fewer 
toxicities, and allows for the addition of capecitabine, a cytotoxic agent. The Phase 1b 
ONT-380-005 dose-escalation study of tucatinib in combination with trastuzumab and 
capecitabine in participants with advanced HER2+ BC established the RP2D of tucatinib at 

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300 mg BID for the triplet combination. In HER2CLIMB, tucatinib 300 mg BID in 
combination with trastuzumab and capecitabine demonstrated statistically significant and 
clinically meaningful efficacy outcomes with a manageable safety profile in participants with 
metastatic or locally advanced unresectable BC previously treated with trastuzumab, 
pertuzumab, and T-DM1 (Murthy 2020a). This is the approved tucatinib dosing regimen in 
the US. Moreover, the established clinical dosing regimen of tucatinib 300 mg BID is 
supported by data from the SGNTUC-015 PK study, which demonstrated no marked 
differences in tucatinib exposure or safety between Japanese and Caucasian healthy 
volunteers at the 300 mg dose level. 
The dosing of trastuzumab of 8 mg/kg IV followed by 6 mg/kg once every 21 days is the full 
dose approved for single-agent use and is the same as the HER2CLIMB trial. 
The dosing of capecitabine at 1000 mg/m2 is the same as was utilized in the ONT-380-005 
and HER2CLIMB studies. This dose has been shown to have similar efficacy to the 
single-agent approved dose of 1250 mg/m2 BID when used as monotherapy, with less 
toxicity (Rossi 2007). When given as a single agent, capecitabine at the lower dose of 
1000 mg/m2 has been shown to have similar efficacy as well as higher overall dose intensity 
when compared to 1250 mg/m2 due to the frequent need for dose interruptions and dose 
reductions in patients started at the higher dose (Bajetta 2005; Pivot 2015). 
3.2.2.1 
Rationale for Regimen in Participants with Brain Metastases 
Patients with brain metastases have frequently been excluded from trials with systemic 
cancer therapies due to difficulties in imaging assessment in the brain and a lack of flexibility 
with regard to treatment discordant responses in CNS and non-CNS locations. Until tucatinib 
received US FDA approval in April 2020, there were no systemic therapies are currently 
approved for the treatment of brain metastases in patients with HER2+ mBC. Effective 
systemic therapies are needed which could potentially delay the use of radiation or treat 
lesions which have progressed after radiation. Results from the HER2CLIMB clinical study 
indicate that the addition of tucatinib to capecitabine and trastuzumab reduced the risk of 
disease progression or death in participants with brain metastases (Murthy 2020b). Therefore, 
participants with brain metastases will also be included in this study. 
As there are often differences in response to systemic therapies in intracranial vs. extracranial 
locations due to differences in penetration, tumor heterogeneity, and other factors, patients 
who have non-CNS disease control but with isolated CNS progression are often given local 
therapy to the CNS with continuation of systemic therapy until non-CNS progression. This 
allows the continuation of a therapy that is effective systemically while allowing control of 
brain metastases, and mirrors clinical practice and established guidelines (Park 2009; 
Network 2013; Ramakrishna 2014). In this trial, participants who have isolated CNS-only 
(brain or dura) progression on trial may be eligible to continue on study drugs for clinical 
benefit after undergoing local therapy to the CNS, as described in Section 7.2.1. For the 

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analysis of overall PFS, these participants will be considered to have progressed at the time 
of initial CNS progression as outlined in Section 9.3. 
3.2.3 Blinding and Unblinding 
This is an open-label study. 
4 
STUDY POPULATION 
Participants must meet all of the enrollment criteria to be eligible for this study. Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of a 
good clinical practice audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Participants must have histologically confirmed HER2+ breast carcinoma, with HER2+ 
defined by in situ hybridization (ISH) or immunohistochemistry (IHC) methodology 
according to the American Society of Clinical Oncology/College of American 
Pathologists. 
a. Tissue blocks or slides must be submitted to confirm HER2 positivity (using IHC, 
ISH or fluorescence in situ hybridization [FISH]) by a Sponsor-designated central 
laboratory  
b. Centrally confirmed HER2+ results (either IHC, ISH, or FISH) from a previous study 
can be used to determine eligibility for this study with approval from the Sponsor 
2. Received previous treatment with taxane anti-cancer agent, trastuzumab, pertuzumab, and 
T-DM1. with the exception is when the use of taxanes is contraindicated or judged not to 
be the best treatment at the discretion of the investigator. 
3. Radiographically and/or histologically confirmed disease progression on last systemic 
anticancer treatment for unresectable locally advanced or metastatic HER2+ breast 
carcinoma.  
Note: Clinical exam, rising tumor markers and/or photography are not acceptable as 
methods for documentation of progressive disease 
4. Measurable disease as assessed by RECIST v1.1  
5. Age of majority at time of consent 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 
7. Life expectancy ≥6 months, in the opinion of the investigator 
8. Has adequate organ function, as defined in the following table (Table 2). Specimens must 
be collected within 10 days prior to the start-of-study interventions. 

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Table 2: 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological1 
 
Absolute neutrophil count (ANC) 
≥1,500/µL 
Platelets 
≥100,000/µL (with stable platelet count 
from 75-100 x 103/µL may be included 
with approval from the Sponsor) 
Hemoglobin 
≥9.0 g/dL 
Renal 
 
Estimated glomerular filtration rate 
(GFR) using the Modification of Diet in 
Renal Disease (MDRD) study equation 
≥50 mL/min/1.73m2 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN, except for participants with 
known Gilbert’s disease, who may enroll if 
the conjugated bilirubin is ≤1.5 x ULN. 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 
Coagulation 
 
International normalized ratio (INR) 
and Activated partial thromboplastin 
time (aPTT) 
≤1.5 × ULN unless on medication known 
to alter INR and aPTT.  
Note: Warfarin and other coumarin 
derivatives are prohibited. 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR = glomerular filtration rate; ULN = upper limit of normal. 
1In participants transfused or who receive colony stimulating factors (eg, G-CSF) before study 
entry, transfusion or colony stimulating factor must be administered ≥14 days prior to start of 
therapy to establish adequate hematologic parameters independent from transfusion or growth 
factor support 
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and guidelines 
for the administration of specific chemotherapies. 
 
9. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) 
or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first 
dose of study treatment 
 
 

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10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies  
・ Is not a WOCBP 
OR 
・ Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in APPENDIX D during the intervention period and for 
at least 30 days after receiving the last dose of  tucatinib, 7 months after receiving the 
last dose of trastuzumab, or 180 days after receiving the last dose of Capecitabine 
whichever occurs last and agrees not to donate eggs (ova, oocytes) to others or 
freeze/store for her own use for the purpose of reproduction during this period. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.  
・ 
A WOCBP must have a negative highly sensitive pregnancy test ([urine or 
serum] as required by local regulations) within 24 hours for urine or within 72 
hours for serum before the first dose of study intervention. 
・ 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
・ 
Additional requirements for pregnancy testing during and after study 
intervention are in Section 7.4.5. 
・ 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
・ 
Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
11. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after receiving the last dose of tucatinib or 90 
days after receiving the last dose of Capecitabine whichever occurs last for male partner 
(no contraception requirement for trastuzumab for male).: 
➢ Refrain from donating sperm 
PLUS either: 

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➢ Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
OR 
➢ Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [APPENDIX D]) as detailed below: 
・ 
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration. 
➢ Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
12. Participant must provide written informed consent 
13. Participant must be willing and able to comply with study procedures 
CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), 
participants must have one of the following: 
14. No evidence of brain metastases 
15. Untreated brain metastases not needing immediate local therapy. For participants with 
untreated CNS lesions >2.0 cm on screening contrast brain MRI, discussion with and 
approval from the the Sponsor is required prior to enrollment. 
16. Previously treated brain metastases 
a. Brain metastases previously treated with local therapy may either be stable since 
treatment or may have progressed since prior local CNS therapy, provided that there 
is no clinical indication for immediate re-treatment with local therapy in the opinion 
of the investigator 
b. Participants treated with CNS local therapy for newly identified lesions or previously 
treated progressing lesions found on contrast brain MRI performed during screening 
for this study may be eligible to enroll if all of the following criteria are met: 
i. Time since WBRT is ≥14 days prior to first dose of study treatment, time since 
SRS is ≥7 days prior to first dose of study treatment, or time since surgical 
resection is ≥28 days 
ii. Other sites of disease assessable by RECIST v1.1 are present 

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c. Relevant records of any CNS treatment must be available to allow for classification 
of target and non-target lesions 
4.2 Exclusion Criteria 
1. Prior treatment with: 
a. Lapatinib within 12 months of starting study treatment. 
Note:In cases where lapatinib was given for ≤21 days and was discontinued for 
reasons other than disease progression or severe toxicity, the participant is eligible. 
Note:In cases where lapatinib was given as a part the last systemic anticancer treatment for 
unresectable locally advanced or metastatic HER2+ breast carcinoma, the participant is not 
eligible according to Inclusion Criteria 3. 
b. Neratinib, afatinib, or other investigational HER2/EGFR or HER2 TKI at any 
previous time 
c.  Tucatinib or enrolled on a tucatinib clinical trial and received Tucatinib. 
2. Previous treatment with capecitabine (or other fluoropyrimidine [e.g., 5fluorouracil]) for 
metastatic disease (except in cases where capecitabine was given for ≤21 days and was 
discontinued for reasons other than disease progression or severe toxicity). Note: 
participants who have received capecitabine for adjuvant or neoadjuvant treatment at 
least 12 months prior to starting study treatment are eligible. 
3. History of exposure to the following cumulative doses of anthracyclines: 
a. Doxorubicin >360 mg/m2 
b. Epirubicin >720 mg/m2 
c. Mitoxantrone >120 mg/m2 
d. Idarubicin >90 mg/m2 
e. Liposomal doxorubicin (eg Doxil, Caelyx, and/or Myocet) >550 mg/m2 
4. History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or 
biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to 
trastuzumab that were successfully managed, or known allergy to one of the excipients in 
the study drugs 
5. Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS 
radiation, or experimental agent ≤3 weeks of first dose of study treatment or are currently 
participating in another interventional clinical trial. An exception for the washout of 

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hormonal therapies is gonadotropin releasing hormone (GnRH) agonists used for ovarian 
suppression in premenopausal women, which are permitted concomitant medications. 
6. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the 
following exceptions: 
● 
Alopecia and neuropathy, which must have resolved to ≤ Grade 2 
● 
Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the 
time of occurrence, and must have resolved completely 
● 
Anemia, which must have resolved to ≤ Grade 2 
7. Clinically significant cardiopulmonary disease such as: 
● 
Ventricular arrhythmia requiring therapy 
● 
Symptomatic hypertension or uncontrolled hypertension as determined by 
investigator 
● 
Any history of symptomatic CHF or symptomatic decreases in ejection fraction 
● 
Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] 
v4.03 Grade 3 or above) due to complications of advanced malignancy 
● 
Any history of interstitial lung disease or pneumonitis that is grade 2 or greater 
● 
Hypoxia requiring supplementary oxygen therapy 
8. Known myocardial infarction or unstable angina within 6 months prior to first dose of 
study treatment 
9. Any uncontrolled Grade 3 or higher (per the NCI CTCAE, v4.03) viral, bacterial, or 
fungal infection within 14 days prior to the first dose of study treatment. Antimicrobial 
prophylaxis or ongoing treatment of resolving/controlled infection is permitted. 
10. Positive for Hepatitis B by surface antigen expression, or positive for Hepatitis C 
infection, or the presence of known chronic liver disease. Participants who have been 
treated for Hepatitis C infection are permitted if they have documented sustained 
virologic response of 12 weeks. As reactivation of these viruses has not been studied with 
the combination of tucatinib, trastuzumab, and capecitabine, there is a possible risk of 
reactivation. 
• Participants who are positive for either antibodies to Hepatitis B surface antigen 
(HBsAb) or antibodies to Hepatitis B core antigen (HBcAb) should be screened using 
polymerase chain reaction (PCR) measurement of Hepatitis B DNA levels. 
Participants with Hepatitis B DNA levels by PCR that require nucleoside analogue 

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therapy are not eligible for the trial. The latest local guidelines should be followed 
regarding the monitoring of Hepatitis B DNA levels by PCR for participants on study 
treatment 
11. Known to be positive for human immunodeficiency virus (HIV) 
12. Participants who are pregnant, breastfeeding, or planning to become pregnant from time 
of informed consent until 30 days after receiving the last dose of tucatinib, 7 months after 
receiving the last dose of trastuzumab, or 180 days after receiving the last dose of 
Capecitabine whichever occurs last. 
13. Require therapy with warfarin or other coumarin derivatives (non-coumarin 
anticoagulants are allowed) 
14. Unable to swallow pills or significant gastrointestinal disease which would preclude the 
adequate oral absorption of medications 
15. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a 
strong CYP3A4 or a moderate or strong CYP2C8 inducer within 5 days prior to first dose 
of study treatment. Use of sensitive CYP3A substrates should be avoided 2 weeks prior 
to the start of study treatment and requires Sponsor consultation. 
16. Known dihydropyrimidine dehydrogenase deficiency 
17. Unable for any reason to undergo contrast MRI of the brain 
18. Other medical, social, or psychosocial factors that, in the opinion of the investigator, 
could impact safety or compliance with study procedures 
19. Evidence within 2 years of the start of study treatment of another malignancy that 
required systemic treatment 
CNS Exclusion – Based on screening brain MRI, participants must not have any of the 
following: 
20. Any untreated brain lesions >2.0 cm in size, unless discussed with the Sponsor and 
approval for enrollment is given 
21. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a 
total daily dose of >2 mg of dexamethasone (or equivalent). However, participants on a 
chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) may be eligible 
with discussion and approval by the Sponsor. 
22. Any brain lesion thought to require immediate local therapy, including (but not limited 
to) a lesion in an anatomic site where increase in size or possible treatment-related edema 
may pose risk to participant (e.g., brain stem lesions). Participants who undergo local 

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treatment for such lesions identified by screening contrast brain MRI may still be eligible 
for the study based on criteria described under CNS inclusion criteria 16b. 
23. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
24. Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest 
neurologic progression due to brain metastases notwithstanding CNS-directed therapy 
4.3 Childbearing Potential 
Please refer to APPENDIX D. 
4.4 Removal of Participants from Therapy or Assessment 
The Sponsor must be notified if a participant is withdrawn from study treatment or from the 
study. The reason(s) for withdrawal must be documented in the participant’s medical records 
and case report form (CRF). 
In the absence of radiographic disease progression per RECIST v1.1, development of CNS 
symptoms, or radiographic changes thought to pose potential immediate risk to the 
participant, all efforts should be made to continue treatment until unequivocal evidence of 
radiologic progression occurs, as defined in RECIST v1.1. 
4.4.1 Discontinuation of Study Treatment 
A participant’s study treatment may be discontinued for any of the following reasons: 
● 
Progressive disease (PD) 
● 
AE 
● 
Pregnancy 
● 
Investigator decision that the study drug needs to be discontinued including the safety 
point of view 
● 
Investigator decision due to clinical progression 
● 
Withdrawal of consent 
● 
death 
● 
Participant decision, non-AE 
Note: Ensure that participants who decide to stop treatment because of an AE are not 
included in this rationale. 
● 
Study termination by Sponsor 
● 
Other, non-AE 

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Participants who withdraw consent from the interventional portion of the study should 
specify whether to allow continued follow-up and further data collection subsequent to their 
withdrawal of consent, including but not limited to follow-up through medical records, public 
records, or other public platform. Every attempt should be made to follow the participant 
until progression, death, or administrative study closure.  
4.4.2 Participant Withdrawal from Study 
Any participant may be discontinued from the study for any of the following reasons: 
● 
Participant withdrawal of consent 
● 
Study termination by Sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
 

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5 
TREATMENTS 
5.1 Treatments Administered 
Participants in the study will receive a combination treatment of tucatinib, trastuzumab, and 
capecitabine. All treatments will be given on a 21-day cycle. 
5.2 Investigational Product (Tucatinib) 
5.2.1 Description 
Tucatinib is a kinase inhibitor that selectively inhibits HER2, and displays limited activity 
against the related kinase EGFR. 
Tucatinib is supplied by the Sponsor as both a coated yellow oval capsule-shaped tablet in a 
150 mg dosage strength and a round convex tablet in a 50 mg dosage strength. The tablets are 
manufactured from a drug product intermediate amorphous dispersion of tucatinib in 
polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the 
pharmaceutical excipients (microcrystalline cellulose, sodium chloride, potassium chloride, 
sodium bicarbonate, silicon dioxide, crospovidone, and magnesium stearate), and 
compressed into tablets. 
5.2.2 Method of Procurement 
The investigational product (tucatinib) will be provided by the Sponsor. 
5.2.3 Dose and Administration 
Participants will receive tucatinib 300 mg (150 mg×2 tables) orally twice a day (total 600 mg 
per day). Depending on the outcome of the safety run-in, the tucatinib starting dose may be 
adjusted. Capecitabine and tucatinib may be taken together or in sequence. 
Participants will be instructed to store and take the tucatinib treatment as follows: 
● 
Bottles of tucatinib tablets should be stored in the refrigerator and should not be left 
in hot places (for example, in a car on a hot day). 
● 
Tucatinib tablets will be taken by mouth twice each day (one dose in the morning, 
and one dose in the evening). 
● 
Instructions will be given as to how many tablets to take each morning and each 
evening. All the prescribed number of tablets for morning and evening doses should 
be taken within a 10-minute timeframe. 
● 
It is recommended that tucatinib tablets be taken at the same times each day, 
± 2 hours. 
○ 
It is recommended that if a participant misses a scheduled dose of tucatinib and 
less than 6 hours have passed since the scheduled dosing time, the dose should be 

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immediately taken. It is recommended that if more than 6 hours have passed since 
the scheduled dosing time, the participant should not take the missed dose but 
should wait and take the next regularly scheduled dose. 
● 
Tucatinib doses should be ingested with a full 8 oz. glass of water, if possible. Doses 
may be taken either with or without food. 
● 
Tucatinib bottle and all remaining pills should be brought to the clinic for each study 
visit. 
● 
It is important for us to know that a participant is receiving the correct amount of drug 
while participating on the study. If the participant was not able to take the fully 
prescribed dose or any single tablet of tucatinib as instructed on any day, the 
participant should contact the study coordinator with the reasons that the correct 
number of tablets or dose were not taken. Missed doses or tablets, or doses that are 
vomited, will not be replaced. 
To minimize risks to participants, safety data will be reviewed on an ongoing basis 
throughout the study by the Sponsor. 
5.2.4 Storage and Handling 
Tablets of tucatinib are packaged in round, high-density polyethylene bottles containing a 
desiccant, with an induction sealed liner and child-resistant plastic closure cap. Bottles of 
tucatinib or tablets are to be stored under refrigeration at 2–8°C in a secure, access-limited 
location. 
The tablets are coated with a non-hazardous film to prevent any exposure to the active 
pharmaceutical ingredient during routine handling. Avoid breaking or crushing tablets. In the 
event the tablets are broken or crushed, wash hands and exposed skin thoroughly with soap 
and water. 
5.2.5 Packaging and Labeling 
Each bottle of investigational study drug will be labeled in compliance with applicable 
regulatory requirements. 
5.2.6 Study Drug Accountability 
Tucatinib used during the course of the study should be handled according to the Pharmacy 
Instructions. Tucatinib is to be tracked and documented from the time of receipt at the site, 
through participant dosing, and until the Sponsor approves of the final return or destruction. 
All supplies, including partially used or empty bottles, should be tracked. 
The Sponsor or designee will conduct drug accountability monitoring during the course of 
the study and will conduct final drug accountability monitoring at site closure. All used and 
unused tucatinib bottles should be handled according to the Sponsor’s instructions. 

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5.3 Trastuzumab 
5.3.1 Description 
Trastuzumab is a humanized IgG-1 kappa monoclonal antibody which binds to the 
extracellular domain of the HER2 protein. It mediates antibody-dependent cellular 
cytotoxicity by inhibiting proliferation of cells which over express HER2 protein. 
5.3.2 Method of Procurement 
Trastuzumab is provided locally by the study site. 
5.3.3 Dose, Preparation, and Administration 
Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 
21 days. However, a loading dose of trastuzumab will not be given to participants who have 
received trastuzumab within 4 weeks of Cycle 1 Day 1. These participants will receive 
trastuzumab at 6 mg/kg each cycle, including Cycle 1. Trastuzumab may also be given on a 
weekly basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab infusion 
has been delayed, and weekly infusions are required to resynchronize the cycle length to 
21 days, after discussion with the Sponsor. Trastuzumab infusion rates will be per 
institutional guidelines. If dosing of trastuzumab has been held for >4 weeks, the IV loading 
dose of 8 mg/kg should be given per approved dosing instructions. 
Approved trastuzumab biosimilars may be used in the study as either the initial therapy or at 
a later time if crossover to a biosimilar is determined appropriate by the investigator. 
However, a trastuzumab biosimilar may only be used during the study if approved for use by 
national regulatory authorities. 
Trastuzumab should be prepared and administered per instructions in the package insert. 
5.3.4 Storage and Handling 
Trastuzumab should be stored according to the package insert. 
5.3.5 Packaging and Labeling 
Each vial of trastuzumab will be labeled in compliance with applicable regulatory 
requirements. 
5.4 Capecitabine 
5.4.1 Description 
Capecitabine is a PO fluoropyrimidine carbamate with antineoplastic activity. Capecitabine 
is metabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate and 5-
fluorouridine triphosphate, which inhibit DNA synthesis and inhibit RNA and protein 
synthesis, respectively. 

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Capecitabine drug product is supplied as a biconvex, oblong film-coated tablet for oral 
administration. Each white colored tablet contains 300 mg of capecitabine*. Refer to the 
package insert for information regarding the inactive ingredients and film coating. 
*Colour, shape and the unit dose strength of Capecitabine may depend on the market 
availability for each country. 
5.4.2 Method of Procurement 
Capecitabine is provided locally by the study site. 
5.4.3 Dose, Preparation, and Administration 
Capecitabine will be given at 1000 mg/m2 PO BID for Days 1-14 only of a 21-day cycle. 
As capecitabine is an oral drug available in fixed doses, the dose administered may not 
exactly match the calculated dose. Determination of the rounding of capecitabine doses for 
administration should be made according to local institutional practices, with documentation 
of both the calculated and administered dose. 
Capecitabine should be prepared and administered per instructions in the package insert. 
Capecitabine will be administered PO based on instructions provided by the investigator. Per 
package insert, it is recommended that capecitabine be administered with food. 
5.4.4 Storage and Handling 
Capecitabine should be stored according to the package insert. 
5.4.5 Packaging and Labeling 
Each bottle of capecitabine will be labeled in compliance with applicable regulatory 
requirements. 
5.5 Dose Modifications 
Table 3,  through Table 5 provide dose modification recommendations for tucatinib, 
trastuzumab, and capecitabine. Participants who discontinue either capecitabine or 
trastuzumab may remain on study treatment. In instances where capecitabine and 
trastuzumab have been discontinued, participants may remain on study treatment with 
tucatinib alone. Participants who discontinue tucatinib will be allowed to remain on study 
treatment. 
All AEs and clinically significant laboratory abnormalities should be assessed by the 
investigator for relationship to tucatinib, trastuzumab, and capecitabine. An AE may be 
considered related to tucatinib alone, trastuzumab alone, capecitabine alone, 2 of the 3 drugs, 
all 3 drugs, or to none. In the event that the relationship is unclear, discussion should be held 
with the Sponsor to discuss which study drug(s) should be held and/or modified. Dosing 
should be modified as described below. 

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Any study drug should be discontinued if a delay of that drug greater than 6 weeks is 
required due to treatment-related toxicity, unless a longer delay is approved by the Sponsor. 
Protocol-defined visits and cycle numbering should continue as planned during a 21-day 
cycle even during dose holds or delays. 
Capecitabine should only be taken on Days 1 to 14 of a cycle. No doses should be given on 
Day 15 through Day 21 of a cycle. 
Dose reductions or treatment interruption/discontinuation for reasons other than those 
described below may be made by the investigator if it is deemed in the best interest of 
participant safety.  
Doses held for toxicity will not be replaced. 
Study treatment may be held up to 6 weeks to allow local CNS therapy. Oral study drugs 
(tucatinib and capecitabine) are to be held 1 week prior to planned CNS-directed therapy. 
The potential for radiosensitization with tucatinib is unknown. Capecitabine is a known 
radiation sensitizer and therefore needs to be held prior to CNS-directed radiotherapy. 
Trastuzumab has been shown not to potentiate radiation and therefore may continue as per 
protocol schedule during radiotherapy. Oral study drugs may be re-initiated 7 days or more 
after completion of SRS/SRT, 14-days or more after WBRT and 28-days or more after 
surgical resection. Plans for holding and re-initiating study drugs before and after local 
therapy will require discussion with, and documented approval from, the Sponsor. 
5.5.1  Tucatinib Dose Reductions 
Refer to Table 3, Table 4 and  Table 6 for the tucatinib dose modification requirements. Dose 
reductions larger than those required by these tables may be made at the discretion of the 
investigator. Up to 3 dose reductions of tucatinib are allowed, but dose reductions to below 
150 mg BID are not allowed. Participants who, in the opinion of the investigator, would 
require a dose reduction to <150 mg BID, or who would require a potential fourth dose 
reduction of tucatinib, should discontinue study treatment. 
Tucatinib dose should not be re-escalated after a dose reduction is made. 
 
Table 3: 
Recommended Tucatinib dose reduction schedule 
Starting Dosea 
1st Dose 
Reduction 
2nd Dose Reduction 
3rd Dose Reduction 
300 mg orally 
twice a day 
(total 600 mg 
per day)b 
250 mg orally 
twice a day (total 
500 mg per day) 
200 mg orally twice a 
day (total 400 mg per 
day) 
150 mg orally twice 
a day (total 300 mg 
per day) 

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a 
Dose reductions of greater steps than those listed in this table (i.e. more than 50 mg per dose 
reduction) may be made if considered clinically appropriate by the investigator. However, 
tucatinib may not be dose reduced below 150 mg BID. 
b 
Depending on the outcome of the safety run-in, the tucatinib starting dose may be adjusted. 
 
5.5.2 Trastuzumab Dose Modifications 
There are no dose reductions for trastuzumab. Trastuzumab may also be given on a weekly 
basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab infusion has been 
delayed, and weekly infusions are required to resynchronize the cycle length to 21 days, after 
discussion with the Sponsor. If trastuzumab cannot be restarted at the same dose after being 
held for an AE, it must be discontinued. If dosing of trastuzumab has been held for >4 weeks, 
the IV loading dose of 8 mg/kg should be given per approved dosing instructions. As 
trastuzumab may be given as an IV infusion, infusion-associated reactions (IARs), may 
occur.  
If a significant IAR occurs, the infusion should be interrupted and appropriate medical 
therapies should be administered (see below). Permanent discontinuation should be 
considered in participants with severe IAR. This clinical assessment should be based on the 
severity of the preceding reaction and response to administered treatment for the adverse 
reaction. 
If participants develop an IAR, participants should be treated according to the following 
guidelines, or according to institutional guidelines, at discretion of the investigator: 
1. Stop infusion and notify physician. 
2. Assess vital signs. 
3. Administer acetaminophen 650 mg PO. 
4. Consider administration of: meperidine 50 mg IM, diphenhydramine 50 mg IV, ranitidine 
50 mg IV or cimetidine 300 mg IV, dexamethasone 10 mg IV or famotidine 20 mg IV. 
5. If vital signs stable, resume trastuzumab infusion. 
No standard premedication is required for future treatments if participants have developed an 
infusion syndrome. Participants may be given acetaminophen prior to treatments. Serious 
reactions have been treated with supportive therapy such as oxygen, beta-agonists, 
corticosteroids, and withdrawal of study agent as indicated. 

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Table 4: 
Dose modifications of tucatinib and trastuzumab for clinical 
adverse events other than left ventricular dysfunction related to 
either tucatinib and/or trastuzumab, or hepatocellular toxicity* 
 
 Tucatinib  
Trastuzumab 
Clinical Adverse Event 
Related to  Tucatinib 
Related to Trastuzumab 
≥ Grade 3 AEs other than Grade 3 
fatigue lasting ≤3 days; alopeciaa; 
nausea; vomiting; diarrhea; rash; 
correctable electrolyte 
abnormalities which return to 
≤ Grade 1 within 7 days. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 3 nausea, vomiting, or 
diarrhea WITHOUT optimal use 
of anti-emetics or anti-diarrheals. 
Hold until severity ≤ Grade 1 or 
pretreatment level. Initiate 
appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Grade 3 nausea, vomiting, or 
diarrhea WITH optimal use of 
anti-emetics or anti-diarrheals. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 4 nausea, vomiting, or 
diarrhea regardless of use of 
anti-emetics or anti-diarrheals. 
Do not administer until severity  
≤ Grade 1. 
Reduce to next lowest dose level. 
Do not administer until severity ≤ 
Grade 1. Restart without dose 
reduction. 
Grade 3 rash WITHOUT optimal 
use of topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. Initiate 
appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Grade 3 rash WITH optimal use 
of topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 4 rash regardless of use of 
topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reductions. 
a.  No dose modifications are required for alopecia 
*Note that if the AE in question does not recover to the Grade required for restarting study 
medication as outlined in the table, the participant may need to discontinue the drug completely. 
Participants requiring a hold of tucatinib for > 6 weeks must discontinue study treatment, unless a 
longer delay is approved by the Sponsor.  

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5.5.3 Capecitabine Dose Modifications 
Capecitabine doses must be modified as described below in Table 5. 
Capecitabine must be held for any participant who experiences a Grade 2 or greater AE 
considered related to capecitabine or to the combination of tucatinib and capecitabine and/or 
trastuzumab (attribution as determined by the investigator). Held doses of capecitabine 
should not be made up within each cycle.  
Capecitabine dose should not be re-escalated after a dose reduction is made. 
Table 5: 
Dose modification of capecitabine for clinical adverse events 
considered related to capecitabine 
CTCAE v4.03  
Toxicity Grades 
During a Course of Therapy 
Dose Adjustment for Next 
Treatment (% of Starting 
Dose)a 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2b 
 
 
1st appearance 
Interrupt until resolved to Grade ≤1. 
100% 
2nd appearancec 
Interrupt until resolved to Grade ≤1. 
75% 
3rd appearancec 
Interrupt until resolved to Grade ≤1. 
50% 
4th appearancec 
Discontinue permanently. 
NA 
Grade 3 
 
 
1st appearance 
Interrupt until resolved to Grade ≤1. 
75% 
2nd appearancec 
Interrupt until resolved to Grade ≤1. 
50% 
3rd appearancec 
Discontinue permanently. 
NA 
Grade 4 
 
 
1st appearance 
Discontinue permanently. 
 
NA=not applicable 
a 
Dose modification table is based upon XELODA® package insert; dose rounding should be 
performed per institutional guidelines 
b 
In certain instances of asymptomatic or mildly symptomatic Grade 2 laboratory abnormalities (for 
example, anemia), investigators may choose to maintain capecitabine dose level and/or to resume 
capecitabine prior to resolution to Grade 1. This should be done only when the risk to participant 
from capecitabine dose interruption and/or reduction outweighs the risk to the participant from 
the adverse event, and when the action is consistent with usual and customary clinical practice. 
c 
For the purpose of this study, 2nd, 3rd, and 4th appearances refers to the appearance of the same 
event, not any event of the same grade severity. 
 

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5.5.4 Dose Modifications for Hepatotoxicity 
Dose modification may be required in the case of liver function abnormalities.  
For dose modifications of tucatinib and capecitabine, see Table 6 below. Dose modification 
of trastuzumab is not required but dosing can be held at investigator discretion. For 
participants with documented Gilbert’s disease, please contact the Sponsor for guidance 
regarding dose modifications in these participants. 
Table 6: 
Dose modifications of tucatinib and capecitabine for liver function 
abnormalities 
Liver Function Abnormalities 
Action for tucatinib Regardless 
of Relationship to Drug 
Capecitabine 
Grade 2 elevation of ALT and/or 
AST  
(>3–≤5 x ULN) 
Dose modification not required 
If abnormalities 
are considered 
related to 
capecitabine, 
please follow 
guidelines as per 
Table 5. 
If abnormalities 
are not considered 
related to 
capecitabine, 
modifications are 
not mandated but 
may be made at the 
discretion of the 
investigator. 
Grade 3 elevation of ALT and/or 
AST 
(>5–20 x ULN) 
Hold until severity ≤ Grade 1 
Restart at next lowest dose level 
Grade 4 elevation of ALT and/or 
AST 
(>20 x ULN) 
Discontinue drug 
Elevation of ALT and/or AST  
(>3 x ULN) 
AND 
Bilirubin (>2 x ULN) 
Discontinue drug 
 
Grade 2 elevation of bilirubin  
(>1.5–3 x ULN)  
Hold until severity ≤ Grade 1 
Restart at same dose level 
Grade 3 elevation of bilirubin 
(>3–≤10 x ULN)  
Hold until severity ≤ Grade 1 
Restart at next lowest dose level 
Grade 4 elevation of bilirubin 
 (>10 x ULN) 
Discontinue drug 
 
 

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5.5.5 Dose Modifications for Left Ventricular Dysfunction 
Trastuzumab dose modification guidelines for left ventricular dysfunction are provided in 
Table 7. 
Table 7: 
Dose modifications for left ventricular dysfunction 
Symptomatic 
CHF 
LVEF < 40% 
LVEF Below 
Institutional Limits of 
Normal and 
≥10% Points Below  
Pretreatment Baseline, 
or ≥16% Absolute 
Decrease from 
Pretreatment Baseline 
LVEF 40% 
to 
≤45% and 
decrease is 
<10% points 
from 
baseline 
LVEF 
>45% 
Discontinue 
trastuzumab. 
Do not 
administer 
trastuzumab. 
Repeat LVEF 
assessment 
within 4 
weeks. 
If LVEF < 
40% is 
confirmed, 
discontinue  
trastuzumab. 
Do not administer 
trastuzumab. 
Repeat LVEF 
assessment within 4 
weeks. 
If the LVEF has not 
recovered to within 
normal limits and 
within15% points from 
baseline, discontinue 
trastuzumab. 
Continue 
treatment 
with 
trastuzumab. 
Repeat 
LVEF 
assessment 
within 4 
weeks. 
Continue 
treatment 
with 
trastuzumab. 
 
Permanently discontinue trastuzumab for persistent (i.e., > 4 weeks) LVEF decline or for 
suspension of dosing on >3 occasions for LVEF decline. 
5.6 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered from Cycle 1, 
Day 1 (predose) through the safety reporting period will be recorded in the electronic CRF 
(eCRF). Any concomitant medication given for a study protocol-related AE should be 
recorded from the time of informed consent through the safety reporting period. Concomitant 
medications can be administered at the investigator’s discretion to conform to standard 
practice during the treatment period.  
Any planned surgery (major or minor) not directly related to cancer that occurs on study 
requires consultation with the Sponsor. Participants are required to suspend study treatment 3 
to 7 days prior to surgery and depending upon the nature of the surgery resume study 
treatment 3 to 21 days postoperatively. For emergency surgeries, contact the Sponsor as soon 
as feasible to discuss resumption of study treatment postoperatively. 

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5.6.1 Required Concomitant Therapy 
There are no required concomitant therapies. 
5.6.2 Allowed Concomitant Therapy  
Participants may continue to use any ongoing medications not prohibited by the 
inclusion/exclusion criteria. However, efforts should be made to maintain stable doses of 
concomitant medications during the course of study treatment. 
● 
During study treatment, participants may receive supportive care to include 
bisphosphonates, denosumab, hematologic/anti-infectious support and pain 
management  
● 
Supportive care medications such as anti-diarrheals, anti-emetics, antacids, and 
laxatives are permitted. Prophylactic use of anti-diarrheals is not required but may be 
permitted at the discretion of the investigator 
● 
Use of topical 10% urea cream or other topical emollients are permitted for 
prophylaxis and treatment of PPE related to capecitabine use  
● 
Prophylactic and symptomatic treatment of nausea and vomiting may be used per 
standard of care  
● 
Thoracentesis or paracentesis may be performed, if needed for comfort 
● 
If surgery or localized radiation become indicated (either for palliation or 
down-staging of previously unresectable tumor), these concomitant procedures are 
permitted for non-target non-CNS lesions only in situations where other disease 
remains assessable by RECIST v1.1 (APPENDIX H). These interventions should be 
avoided if clinically feasible until after the second response assessment. The Sponsor 
should be consulted prior to the intervention occurring  
● 
Acetaminophen may be used to manage drug-related AEs such as fever, myalgias or 
arthralgias and anti-histamines may be used to manage drug-related AEs such as 
pruritus 
● 
Influenza vaccinations (without live virus) are permitted during the study 
● 
Participants requiring systemic corticosteroids for control of brain metastases at a 
dose >2 mg of dexamethasone (or equivalent) on the first day of study treatment are 
not eligible to begin study treatment, and should not be allocated until doses <2 mg 
can be achieved. After initiation of study treatment, corticosteroids may be initiated 
for control of CNS symptoms only after consultation and approval of the Sponsor. 
● 
Premedication with corticosteroids solely for contrast use in scans or MRI can be 
used without prior the Sponsor approval. Participants requiring systemic steroids for 

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control of other comorbidities (e.g., asthma or auto-immune diseases) may be eligible 
after consultation and approval of Sponsor  
● 
Transfusion support with blood products. (However, note that no transfusions are 
permitted from <14 days prior to starting study treatment until the initiation of study 
treatment in order to establish adequate hematologic parameters for study eligibility 
independent of transfusion support) 
5.6.3 Prohibited Concomitant Therapy  
The following therapies are prohibited during the study (unless otherwise noted): 
● 
Investigational drugs and devices 
● 
Anti-cancer therapy, including but not limited to chemotherapy and hormonal therapy 
● 
Radiation therapy, except for palliative radiotherapy at focal non-CNS sites which are 
not considered target lesions per RECIST v1.1, which may be given after consultation 
with the Sponsor, provided that there remain other sites of assessable disease 
accessible by RECIST v1.1 (follow guidance for holding and resuming study 
treatment as per CNS radiation in Section 5.5). 
● 
Warfarin or other coumarin derivatives (non-coumarin anti-coagulants are permitted) 
● 
Vaccination with live vaccines 
● 
Strong inhibitors or moderate inducers of CYP2C8 are prohibited as concomitant 
medications during study treatment and within 2 weeks of discontinuation of tucatinib 
treatment. Partial and more complete lists of strong inhibitors and inducers may be 
found in other reference material. For additional information, including drug 
elimination halflives of strong inhibitors and inducers, see APPENDIX F. 
● 
Strong inducers of CYP3A4 are prohibited as concomitant medications during study 
treatment and within two weeks of discontinuation of study treatment–Partial and 
more complete lists of strong inducers may be found in other reference material. For 
additional information including drug elimination half-lives of strong inducers, see 
APPENDIX E. 
5.6.4 Potential Concomitant Drug Interactions  
For sensitive substrates of CYP3A (APPENDIX G); tucatinib exhibits inhibition of human 
CYP3A enzymes, and therefore has the potential to interact with other medications that are 
substrates of CYP3A. Therefore, concomitant use of tucatinib with sensitive CYP3A 
substrates should be avoided. Consider using an alternate medication which is not a sensitive 
CYP3A substrate. If unavoidable, consider dose reduction of CYP3A substrates with narrow 
therapeutic indices and/or increased monitoring for potential adverse reactions as described 
in the medication’s prescribing information. 

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Concomitant use of tucatinib with digoxin, a P-glycoprotein (P-gp) substrate, increases 
digoxin concentrations, which may increase the risk for digoxin related adverse reactions. 
Concomitant use of tucatinib with digoxin or P-gp substrates with a narrow therapeutic index 
(such as, but not limited to, dabigatran, fexofenadine, and cyclosporine) should be used with 
caution. Refer to the prescribing information of digoxin or other P-gp substrates for dosage 
adjustment recommendations due to drug interactions. 
5.7 Management of Overdose 
In the event of an overdose of tucatinib, defined as any dose greater than the prescribed dose, 
study personnel should: 
● 
Care for and medically stabilize the participant until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of tucatinib. 
● 
Notify the Sponsor as soon as they become aware of the overdose, to discuss details 
of the overdose (e.g., exact amount of tucatinib administered, participant weight) and 
AEs, if any. 
Refer to the package insert for overdose information for trastuzumab and capecitabine, and 
study personnel should notify the Sponsor as soon as they become aware. 
5.8 Treatment Compliance 
Study drug administration will be documented in source documents and the CRF. 
Compliance will be assessed on a participant-by-participant basis. The pharmacist or 
designee will record the number of tucatinib tablets dispensed to each individual participant, 
and the number of tablets returned to the clinic at the end of each cycle.  
Data regarding the administration and dose of trastuzumab, as well as the number of tablets 
of capecitabine taken will also be collected by the site after each cycle. Dose modifications 
and interruptions of any study drug will be documented in the source documents and the 
eCRF. 

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6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
AEs and concomitant medications will be recorded from Day 1 of Cycle 1 (predose) through 
the safety reporting period (see Section 7.4.1.3). Any study protocol-related AE (defined in 
Section 7.4.1.1) as well as any concomitant medications given for treatment of the AE, 
should be recorded from the time of informed consent. 
All assessments performed on Day 1 of all treatment cycles (as well as on Day 8 and Day 15 
during Cycle 1 and 2 for the safety run-in participants only) should be performed prior to 
administration of study drugs with the exception of AE documentation, concomitant 
medication documentation, and post-dose PK in Cycle 3 only. Study assessments will 
continue regardless of any dose holds or delays. 
A schedule of events is provided in APPENDIX A. Study activities are listed by visit in this 
section and descriptions of all study assessments are presented in Section 7. 
Study assessments below are applicable to both participants enrolled in the safety run-in and 
the main study except where noted.  
6.2 Screening Visit (Days –28 to 1) 
Optional prescreening to confirm HER2 positivity by central review is permitted at any time 
prior to study screening, after signing a prescreening consent form (Not applicable to safety 
run-in participants). 
● 
Informed consent* 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Confirm HER2+ status (confirmatory HER2 testing may be obtained greater than 
28 days prior to Cycle 1 Day 1 if prescreening consent form is signed [prescreening 
not applicable to safety run-in participants]) 
○ 
Archival tissue blocks or slides may be submitted to confirm HER2 positivity* 
̵ 
A Sponsor-designated central laboratory may use IHC, ISH or FISH to 
confirm HER2 positivity 
̵ 
Centrally confirmed HER2+ results from a previous study using IHC, ISH, or 
FISH may be used with approval from the Sponsor 
○ 
If archival tissue is unavailable, a fresh tumor biopsy must be obtained and 
submitted for central assessment for HER2 testing (A newly-obtained biopsy of 
tumor sample must be performed  after obtaining informed consent of this study.) 
● 
Physical examination including height and weight (Section 7.4.4) 

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● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
Documentation of medical history and disease history (Section 7.1) 
● 
Electrocardiogram (ECG) (Section 7.4.6.2) 
● 
ECHO, or MUGA to include at a minimum LVEF; note that whichever testing 
modality is chosen in screening should be used for all subsequent cardiac assessments 
throughout the study for comparison* (Section 7.4.6.1). 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Section 7.4.3) 
○ 
Complete blood count (CBC) with differential** 
○ 
Serum chemistry** 
○ 
Liver function tests (LFTs) ** 
○ 
Coagulation panel** 
○ 
Hepatitis B and C screening (if positive, contact the Sponsor; see Section 7.4.3)* 
● 
Urine sample for urinalysis** 
● 
For participants of childbearing potential serum or urine pregnancy test within 24 
hours for urine or within 72 hours for serum before the first dose of study treatment. 
(Section 7.4.5) 
● 
Contrast computed tomography (CT), positron emission tomography (PET)/CT (if 
high quality CT scan included), or MRI scan as appropriate to document sites of 
extracranial disease and assessment of tumor burden. At minimum, scans must 
include chest, abdomen, and pelvis, as well as appropriate imaging of any other 
known sites of disease (Section 7.2). 
● 
Contrast MRI of the brain for all participants for assessment of brain tumor burden; 
CT of the brain will not be allowed, and participants with known contraindications to 
undergoing contrast MRI imaging will be excluded from the study (Section 7.2).* 
● 
For participants with brain metastases discovered during screening or a history of 
brain metastases, confirm relevant MRI brain reports and CNS treatment records can 
be obtained (Section 7.2). 
 

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* For participants who have unsuspected brain metastases discovered at screening and go 
on to receive immediate local therapy to the CNS, certain screening evaluations may not 
need to be repeated outside the 28 day screening window with Sponsor approval. This 
includes the following: informed consent, ECHO/MUGA, hepatitis screening, and 
confirmatory HER2 testing. All other safety labs and assessments will need to be 
repeated if outside the 28 day window for these participants. In addition, an additional 
contrast MRI brain following local therapy will not be required prior to starting study 
treatment if radiation treatment was given. A postoperative contrast MRI brain scan is 
required prior to starting study treatment if surgical resection was performed. 
**  Test within 10 days prior to the first dose of study treatment. 
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
However, re-screening is not allowed for those participants whose initial HER2 testing is 
confirmed negative per central laboratory. Results from assessments during the initial 
screening period are acceptable in lieu of a repeat screening test if performed within the 
specified time frame and the corresponding inclusion/exclusion criteria is met. Participants 
who are rescreened will retain their original screening number. 
 
6.3 Treatment Period 
6.3.1 Cycle 1 Day 1 
● 
Physical examination including predose weight* (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (-1 days, results must be reviewed and eligibility confirmed prior to 
first dose, Section 7.4.3) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
PK samples (safety run-in only; see APPENDIX B for timepoints) 
● 
For participants of childbearing potential serum or urine pregnancy test (within 24 
hours for urine or within 72 hours for serum before the first dose of study treatment.; 
Section 7.4.5) 

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● 
Administer study drugs (study drugs may be administered in any order and can be 
given simultaneously) 
○ 
Dispense tucatinib and administer the first dose  
○ 
Administer the first dose of capecitabine at 1000 mg/m2 
○ 
Administer trastuzumab at 8 mg/kg given IV, unless participant has received 
trastuzumab within 4 weeks of first dose of trastuzumab on study. In this case, 
participant will not receive loading dose, and will instead receive trastuzumab 
6 mg/kg 
● 
Provide tucatinib day-of dosing instructions for the Cycle 1 Day 8 visit (safety run-in 
only), so that the visit’s predose blood sample can be collected within the required 
time window (i.e., 2 hours prior to tucatinib dosing) 
*Predose assessments do not need to be repeated if performed within 1 day prior to Cycle 
1 Day 1. 
Safety run-in participants only: for hospitalized participants, an assessment of concomitant 
medications, AEs, physical exam, vital signs, and laboratory evaluations (including CBC, 
serum chemistry, and liver function tests) must be performed prior to discharge.  
6.3.2 Cycle 1 Day 8 (±2 days, safety run-in participants only) 
● 
Physical examination (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Section 7.4.3) (Must be performed within 1 day prior to dosing. 
Review results prior to the administration of study treatment, in order to confirm 
continued study treatment and allow for potential dose adjustments) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
PK samples (APPENDIX B) 
● 
Provide tucatinib day-of dosing instructions for the Cycle 1 Day 15 visit, so that the 
visit’s predose blood sample can be collected within the required time window (i.e., 
2 hours prior to tucatinib dosing) 

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6.3.3 Cycle 1 Day 12 (± 3 days, not applicable for safety run-in participants) 
● 
Physical examination (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Section 7.4.3) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
● 
Provide tucatinib day-of dosing instructions for the Cycle 2 Day 1 visit, so that the 
visit’s predose blood sample can be collected within the required time window (i.e., 
2 hours prior to tucatinib dosing) 
6.3.4 Cycle 1 Day 15 (±2 days, safety run-in participants only) 
● 
Physical examination (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Section 7.4.3) (Must be performed within 1 day prior to dosing. 
Review results prior to the administration of study treatment, in order to confirm 
continued study treatment and allow for potential dose adjustments) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
PK samples (APPENDIX B) 
● 
Provide tucatinib day-of dosing instructions for the Cycle 2 Day 1 visit, so that the 
visit’s predose blood sample can be collected within the required time window (i.e., 
2 hours prior to tucatinib dosing) 

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6.3.5 Cycle 2 Day 1 and Day 1 of All Subsequent Cycles (-1 to + 3 Days, - 1 
day allowance is not applicable for Cycle 2 Day 1 of safety run-in 
participants) 
● 
Physical examination including predose weight (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Must be performed within 1 day prior to dosing. Review results prior 
to the administration of study treatment, in order to confirm continued study 
treatment and allow for potential dose adjustments)  
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
Samples for PK (Cycles 2-6 only, pre-dose sample; Cycle 3 only, 1-4 hours post 
dose, Section 7.3) 
● 
For participants of childbearing potential serum or urine pregnancy test within 24 
hours for urine or within 72 hours for serum before the study treatment. on Cycle 2 
Day 1 (Section 7.4.5) 
● 
Administer study drugs (study drugs may be administered in any order and can be 
given simultaneously) 
○ 
Dispense tucatinib and administer the first dose of the cycle 
○ 
Administer first dose of capecitabine of the cycle 
○ 
Administer trastuzumab 
● 
Provide tucatinib day-of dosing instructions for the Cycle 2 Day 8 visit (safety run-in 
participants only), so that the visit’s predose blood sample can be collected within the 
required time window (i.e., 2 hours prior to tucatinib dosing) 
6.3.6 Cycle 2 Day 8 (±2 days, safety run-in participants only) 
● 
Physical examination (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 

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● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (APPENDIX C) 
● 
Blood samples (Section 7.4.3) (Must be performed within 1 day prior to dosing. 
Review results prior to the administration of study treatment, in order to confirm 
continued study treatment and allow for potential dose adjustments) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
PK samples (APPENDIX B) 
● 
Provide tucatinib day-of dosing instructions for the Cycle 2 Day 15 visit, so that the 
visit’s predose blood sample can be collected within the required time window (i.e., 
2 hours prior to tucatinib dosing) 
6.3.7 Cycle 2 Day 12 (± 3 days, not applicable for safety run-in participants) 
● 
Blood samples (Section 7.4.3) 
○ 
LFTs 
6.3.8 Cycle 2 Day 15 (±2 days, safety run-in participants only) 
● 
Physical examination  (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 
● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECOG performance status (-3 days, APPENDIX C) 
● 
Blood samples (Section 7.4.3) (Must be performed within 1 day prior to dosing. 
Review results prior to the administration of study treatment, in order to confirm 
continued study treatment and allow for potential dose adjustments) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
PK samples (APPENDIX B) 

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● 
Provide tucatinib day-of dosing instructions for the Cycle 3 Day 1 visit, so that the 
visit’s predose blood sample can be collected within the required time window (i.e., 
2 hours prior to tucatinib dosing) 
6.3.9 Response Assessments: Every Six Weeks (- 7 days) as Determined by 
Cycle 1 Day 1, through Week 24, then Every 9 Weeks (- 7 days) through 
End of Treatment 
● 
Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate 
to document site of extracranial disease and assessment of tumor burden. At 
minimum, scans must include chest, abdomen, and pelvis, as well as appropriate 
imaging of any other known sites of disease (Section 7.2). 
● 
Contrast MRI of the brain (only in participants with presence or history of brain 
metastases) and assessment of CNS lesions (brain or dura) (Section 7.2). 
● 
If cycles are delayed for any reason continue with initial scan schedule as determined 
by the date of Cycle 1 Day 1. 
● 
If an interim unscheduled assessment is performed, scans should continue to be done 
on schedule. In cases of medical contraindication for repeat scans, please contact the 
Sponsor to discuss as, in some instances, assessments done at an unscheduled 
timepoint may not need to be repeated if medically contraindicated as approved by 
the Sponsor. 
6.3.10 Every 12 Weeks as Determined by Screening Exam (-7 days) 
● 
ECHO or MUGA, using the same cardiac testing modality performed in 
screening/baseline (Section 7.4.6.1). 
● 
If there is an interim assessment, subsequent cardiac ECHO or MUGA should be 
performed every 12 weeks as determined by the date of the most recent interim 
assessment  
6.4 End of Treatment Visit (30 to 37 Days After Last Dose of Study Drug) 
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of study drug 
unless delayed due to an AE. Note: The time to EOT visit may be longer than 37 days, but in 
no case should it be <30 days. However, EOT evaluations must be performed before 
initiation of a new therapy. If EOT evaluations are completed before 30 days after the last 
study treatment, the participant will be contacted 30 to 37 days following the last treatment to 
assess for AEs.  
● 
Physical examination including weight (Section 7.4.4) 
● 
Vital signs (Section 7.4.2) 

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● 
Documentation of AEs and concomitant medications (Section 7.4.1.1) 
● 
ECHO or MUGA, using the same cardiac testing modality performed in 
screening/baseline. Not required if done within previous 12 weeks (excluding the 
Screening/Baseline assessment) 
● 
ECOG performance status (APPENDIX C) 
● 
ECG (Section 7.4.6.2) 
● 
Blood samples for laboratory testing (Section 7.4.3) 
○ 
CBC with differential 
○ 
Serum chemistry 
○ 
LFTs 
○ 
Coagulation 
● 
For participants of childbearing potential serum or urine pregnancy test (if not done 
within the last 60 days) (Section 7.4.5) 
● 
Contrast CT, PET/CT (if high quality CT scan included) and/or non-brain MRI scan 
if not done within the previous 30 days only in participants having ended study 
treatment for reasons other than radiographic disease progression. At minimum, 
contrast scans must include chest, abdomen, and pelvis, as well as appropriate 
imaging of any other known sites of disease (Section 7.2). 
● 
Contrast MRI of the brain for participants with brain metastases at baseline and 
assessment of CNS lesions. Not required if brain MRI was performed within 30 days 
of discontinuing study treatment, or if progression in the brain has already been 
documented while on study. 
6.5 Long-Term Follow-up 
For participants who discontinue study treatment prior to disease progression (per RECIST 
v1.1), the following assessments must be obtained every 9 weeks (±1 week) starting from the 
date of the last imaging scan, until investigator-assessed disease progression (per RECIST 
v1.1), the start of subsequent anti-cancer therapy, death, withdrawal of consent, or study 
closure, in order to document a PFS event date: 
● 
High-quality spiral contrast CT (preferred): PET/CT (if high quality CT scan is 
included), and/or non-brain MRI scan as appropriate. The same imaging modalities 
used in Screening/Baseline should be repeated, unless otherwise clinically indicated. 

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● 
Contrast MRI of the brain (only in participants with brain metastases at baseline, as 
defined in Section 7.2) and assessment of CNS lesions (brain and/or dura) 
Once a participant experiences PD (per RECIST v1.1) or clinical progression as assessed by 
the investigator, participants will continue in long-term survival follow-up. The following 
information must be collected starting 90 days (±7 days) from the date of the last imaging 
scan and continuing every 90 days (±7 days) until death, withdrawal of consent, or study 
closure. 
● 
Participant contact or in-person assessment of OS and/or disease recurrence, as well 
as collection of information regarding any additional anti-cancer therapies 
administered after completion of study treatment. Review of medical records, public 
records, or other public platforms may be used to obtain this information if reasonable 
efforts to contact the participant are unsuccessful. 
6.6 End of Study/End of Follow-up 
The date the participant met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 

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7 
STUDY ASSESSMENTS 
Study assessments below are applicable to both participants enrolled in the safety run-in and 
the main study except where noted.  
7.1 Screening/Baseline Assessments 
Screening/Baseline assessments will be conducted to establish study baseline status and 
determine study eligibility. Only participants who meet all inclusion and exclusion criteria 
specified in Sections 4.1 and 4.2 will be enrolled in this study. 
Tumor tissue must be submitted to the Sponsor-designated central laboratory for 
confirmatory HER2 testing to determine participant eligibility; confirmatory HER2 testing 
may be performed on archival tissue or a newly-obtained biopsy of an accessible tumor 
lesion that has not been previously irradiated (see Section 7.1.1). A newly-obtained biopsy of 
tumor sample must be performed  after obtaining informed consent of this study. 
Participant medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications. 
All measurable and evaluable lesions will be assessed and documented at Screening/Baseline 
(Section 7.2). A contrast MRI of the brain is performed to evaluate for the presence of brain 
metastases (Section 7.2). Participants with brain metastases at study entry may be eligible for 
study participation if they meet the inclusion/exclusion criteria and the conditions described 
in Section 7.2. All sites of disease identified at screening/baseline must be chosen as either 
target lesions or non-target lesions. 
A physical examination including height and weight (Section 7.4.4), vital signs 
(Section 7.4.2), ECOG performance status (APPENDIX C), clinical laboratory testing, 
urinalysis (Section 7.4.3), ECG, ECHO/MUGA assessment, and pregnancy testing 
(Section 7.4.5) will be done at Screening/Baseline. 
7.1.1 Confirmation of HER2 Expression for Study Eligibility 
Archival or freshly-obtained tumor tissue (most recent tumor tissue sample preferred) must 
be submitted to the Sponsor-designated central laboratory for confirmatory HER2 testing 
prior to enrollment. The central laboratory will require sufficient tumor tissue to generate  
unstained charged slides for HER2 expression testing (refer to laboratory manual in detail). 
Archived tumor samples must be formalin-fixed and paraffin-embedded. If archival tissue 
that meets sample requirements is not available, fresh tissue from a tumor site (metastatic site 
preferred as applicable) suitable for biopsy must be obtained and submitted for confirmatory 
HER2 testing. 
A central laboratory will be used for confirmatory HER2 testing. HER2 expression will be 
analyzed using IHC or ISH, and positivity will be assessed according to current ASCO/CAP 
guidelines. 

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A tumor suitable for biopsy should be accessible, not previously irradiated, and without 
contraindication to biopsy, in the opinion of the investigator. Tissue samples obtained via 
resection, excision, punch (skin lesions only), or core needle from a tumor site are suitable 
for testing. Fine needle aspiration, brushing, cell pellets from pleural effusion, forceps, and 
lavage samples are not acceptable. Tumor tissue should be of good quality based on total and 
viable tumor content; e.g., samples should contain a minimum of 100 tumor cells that 
preserve cellular context and tissue architecture, regardless of the needle gauge used to 
collect the sample or the retrieval method. 
See the Central Laboratory Manual for more details. 
7.1.2 Treatment for Brain Metastases Prior to Study Entry 
Participants with brain metastases at study entry may be eligible for study participation if 
they meet the eligibility criteria described in Sections 4.1 and 4.2. In order to minimize the 
risk of symptomatic cerebral edema in participants with brain metastases in this study, 
participants with high-risk metastases, including those requiring immediate local therapy, 
those with rapidly progressing lesions, those requiring corticosteroids at the start of the study 
(>2 mg of dexamethasone or equivalent per day) for control of CNS symptoms, and those 
with larger untreated lesions, are excluded from the trial. However, if these participants are 
amenable to immediate CNS-directed therapy with either surgery or radiation, they may 
undergo local therapy and then be eligible for the trial. Under select circumstances 
participants may receive corticosteroid therapy for acute management of symptomatic local 
edema, as long as contrast brain MRI does not show clear evidence of CNS progression. All 
such instances require approval from the Sponsor.  
Immediate local therapy to the CNS may delay the screening process beyond the 28-day 
screening window, in which case the requirement for a repeat contrast MRI after completion 
of local therapy and prior to starting study treatment is as follows:  
● 
For participants who receive brain radiotherapy during the screening period, the 
original baseline contrast brain MRI will serve as the baseline for comparison for 
further response assessments. 
● 
For participants who undergo surgical resection of brain metastases during the 
screening period, a post-operative contrast brain MRI will be performed and will 
serve as the baseline for comparison for further response assessments. 
For participants with brain metastases discovered during screening or a history of brain 
metastases, relevant MRI brain reports and CNS treatment records should be obtained and 
available for CRF source verification. 
7.2 Response/Efficacy Assessments 
Following initiation of study treatment, measurement of all known sites of metastatic or 
locally advanced unresectable disease (including at a minimum the chest, abdomen, and 

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pelvis) by high quality spiral contrast CT, PET/CT (if high quality CT scan included) and/or 
contrast MRI scan as appropriate, as well as appropriate imaging of any other known sites of 
disease will be obtained at the end of every 6 weeks for 24 weeks, then every 9 weeks while 
on study treatment. These scans will remain on this schedule irrespective of dose holds or 
interruptions. Additional imaging, such as nuclear bone scans, may be done as appropriate at 
the discretion of the investigator. All body contrast CT or MRI scans, bone imaging, and skin 
lesion photographs, including baseline scans will be collected for retrospective ICR. All 
treatment decisions will be made on the basis of the local investigator. Results of centralized 
review will not be available to investigators for clinical decision making. 
All brain contrast MRI images will be performed locally and collected for centralized 
independent review. However, all treatment decisions will be made on the basis of local 
review of radiologic imaging. Participants with any history of brain metastases, any brain 
metastases at baseline, or brain lesions of equivocal significance at baseline will continue to 
have follow-up brain contrast MRIs on the same schedule as non-CNS disease re-staging. In 
participants with baseline brain lesions, all brain lesions should be included in the baseline 
RECIST lesion selection as either a target or non-target lesions. Participants without brain 
metastases at baseline will not require follow-up brain contrast MRIs while on treatment 
unless clinically indicated. 
In the event of equivocal progression, for example a new lesion which is small in size 
(defined as a equivocal new lesion) and there is no imminent threat to participant safety, all 
efforts should be made to continue the participant until unequivocal radiologic progression or 
clinical progression is documented. Demonstration of an unequivocal new lesion constitutes 
disease progression. 
All scans will be assessed per RECIST v1.1. Refer to APPENDIX H for further details. 
7.2.1 Isolated Progression in the Brain 
In participants with isolated progression in the brain per RECIST v1.1 (including either 
parenchymal brain or dural metastases but not skull-based or leptomeningeal metastases) and 
does not have progression of disease outside the CNS, the participant may be eligible to 
continue on study treatment after completion of local treatment (radiotherapy or surgery) to 
the brain/dural metastases to allow for clinical benefit with Sponsor approval. This approach 
approximates standard clinical practice in this clinical scenario.  
Every effort should be made to avoid radiation or surgery to target lesions in the brain in the 
absence of PD by RECIST v1.1 unless clinically necessary in the opinion of the investigator. 
Target lesions, once treated with local CNS therapy, cannot be adequately assessed for 
subsequent response to systemic therapy. Because of this, if a participant continues on study 
therapy after local CNS treatment to a target lesion, special consideration must be given for 
evaluation of the treated target lesion and the impact on the overall RECIST v1.1 assessment. 

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Following CNS-directed therapy for isolated CNS disease progression, RECIST v1.1 criteria 
would continue to measure CNS target lesions(s) if previously identified and used in the 
overall estimation of the sum of diameters measuring total disease burden. However, 
following treatment, measurement of the treated CNS target lesion(s) would use the 
immediate pre-CNS treatment measurement. If a subsequent decrease in the size of a treated 
CNS lesion post-treatment is seen, the immediate pre-CNS treatment longest diameter would 
be used for RECIST measurement. Should a treated CNS lesion enlarge following CNS-
directed therapy that was identified as a target lesion, the new and larger longest diameter is 
to be used for RECIST measurement. 
Additionally, treatment changes which may mimic progression will be taken into account, 
and participants with possible “pseudo-progression” should continue on study until 
unequivocal evidence of radiographic or clinical progression is present. In the absence of 
clear evidence of PD (per RECIST v1.1), development of CNS symptoms or radiographic 
changes thought to pose potential immediate risk to participant, all efforts should be made to 
continue treatment until unequivocal evidence of radiologic progression occurs, as defined in 
RECIST v1.1. 
After discontinuing study treatment, participants may receive further care as determined by 
their physician. 
7.3 Pharmacokinetic Assessments 
PK assessments of trough levels of tucatinib and ONT-993 (which is the predominant 
circulating metabolite) will be performed on Day 1 of Cycles 2-6 prior to administration of 
tucatinib. On Day 1 of Cycle 3, PK assessments of peak levels of tucatinib and ONT-993 will 
be performed 1-4 hours after administration of tucatinib. 
Participants in the safety run-in, additional PK samples will be collected as specified in 
APPENDIX B. 
7.4 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including serious adverse events (SAEs), recording of concomitant 
medication, and measurements of protocol-specified physical examination findings and 
laboratory tests.  
Safety will be monitored over the course of the study by an SMC as described in Section 3. 
7.4.1 Adverse Events 
7.4.1.1 Definitions 
Adverse Event 

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According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 CFR 312.32, investigational new drug (IND) Safety Reporting, an AE is any untoward 
medical occurrence in a participant or clinical investigational participant administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events CRF: 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 that increase in 
CTCAE grade should be recorded. 
● 
Medical conditions present or ongoing predose on study Day 1 that worsen in 
severity, increase in frequency, become related to study drug, or worsen in any other 
way but do not meet the threshold for increase in CTCAE grade should be recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (during and post-dose) through the end of the safety reporting period (see 
Section 7.4.1.3). Complications that occur in association with any procedure (e.g., 
biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 
or results in study termination or interruption/discontinuation of study treatment. 
When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (e.g., record “anemia” 
rather than “low hemoglobin”). 
 
 

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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the participant at immediate risk of death. This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe. 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed 
consent in the study or routine check-ups are not SAEs by this 
criterion. Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization. Hospitalizations or prolonged 
hospitalizations for scheduled therapy of the underlying cancer or 
study target disease need not be captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or 
substantial disruption of the participant’s ability to conduct normal 
life functions. 
Congenital 
anomaly or birth 
defect: 
An adverse outcome in a child or fetus of a participant exposed to 
the molecule or study treatment regimen before conception or during 
pregnancy. 
Medically 
significant: 
The AE did not meet any of the above criteria, but could have 
jeopardized the participant and might have required medical or 
surgical intervention to prevent one of the outcomes listed above or 
involves suspected transmission via a medicinal product of an 
infectious agent. Potential drug-induced liver injury (DILI) also is 
considered a medically significant event (see Section 7.4.1.2 for the 
definition of potential DILI). 
 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose 

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Overdose, Medication Error, Misuse, and Abuse 
Overdose of tucatinib is defined in Section 5.7. Refer to the package inserts for overdose 
information for trastuzumab and capecitabine.   
Medication error refers to an unintentional error in dispensing or administration of the 
investigational medicinal product not in accordance with the protocol. 
Misuse is defined as any situation where the investigational medicinal product is 
intentionally and inappropriately used not in accordance with the protocol. 
Abuse is defined as the persistent or sporadic intentional excessive use of the investigational 
medicinal product, which is accompanied by harmful physical or psychological effects.  
Overdoses, medication errors, abuse or misuse will be collected as part of investigational 
medicinal product dosing information and/or as a protocol violation, as required. 
Any AE associated with medication error, misuse or abuse of study drug should be recorded 
on the AE eCRF with the diagnosis of the AE. In addition, any overdose event should be 
reported to the Sponsor within 24 hours of receipt of the information regardless of whether 
the event is an adverse event or not. 
Adverse Event Severity 
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03.  
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAEs, above). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (tucatinib, trastuzumab, capecitabine) 
should be evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such 
as: 
● A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
● One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal 
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7.4.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during 
participant questioning, discovered during physical examination, laboratory testing and/or 
other means by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug. Record each sign or symptom as an individual AE in addition to the IRR term. If 
multiple signs or symptoms occur with a given infusion-related event, each sign or symptom 
should be recorded separately with its level of severity.  
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 

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● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of 
Disease”, or “Malignant disease progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported as AEs or SAEs. 
Pregnancy 
Notification to Drug Safety 
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 30 days after receiving the last dose of  tucatinib, 7 months after receiving the 
last dose of trastuzumab, or 180 days after receiving the last dose of Capecitabine whichever 
occurs last for female participants, and at least 7 days after receiving the last dose of  
tucatinib or 90 days after receiving the last dose of Capecitabine whichever occurs last for 
male participant’s partner. Only report pregnancies that occur in a participant’s partner if the 
estimated date of conception is after the participant’s first study drug dose. Report to the 
Sponsor’s Drug Safety Department via eCRF,  Email or fax within 24 hours of becoming 
aware of a pregnancy. All pregnancies will be monitored for the full duration; all perinatal 
and neonatal outcomes should be reported. Infants should be followed for a minimum of 8 
weeks. 
Collection of Data on the CRF 
All pregnancies (as described above) that occur within 30 days of the last dose of study 
drug(s) will also be recorded on the Adverse Events CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.4.1.1) should be reported as SAEs. 
Potential Drug-induced Liver Injury 
Hy’s Law can be used to estimate severity and the likelihood that a study drug may cause an 
increased incidence of severe hepatotoxicity. 

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The absence of hepatotoxicity in clinical trials provides a limited predictive value for 
potential DILI in the clinical setting(s) being studied. However, finding 1 Hy’s Law case in 
clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe DILI. 
Definition 
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (ALT and/or AST) elevation >3 x ULN 
AND 
2. Total bilirubin >2 x ULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements 
Any potential Hy’s Law case should be handled as a SAE and reported to the Sponsor 
within 24 hours. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary 
data. 
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI 
In general, an increase of serum ALT or AST to >3 x ULN should be followed by repeat 
testing within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, 
to confirm the abnormalities and to determine whether they are worsening. 
For potential Hy’s Law case, appropriate medical assessment should be initiated to 
investigate potential confounding factors and alternative causes of hepatotoxicity. During this 
investigation, consider withholding study drug. The study site refers to the  guidance of 
“Event of Clinical Interest (ECI) Guidance for Potential DILI (Drug-Induced Liver Injury) in 
Clinical Trials” for assessment and follow up. 
7.4.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through 
30 days after the last study treatment. However, all study protocol-related AEs are to be 
recorded from the time of informed consent. All SAEs that occur after the safety reporting 

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period and are considered study treatment-related in the opinion of the investigator should 
also be reported to the Sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the participant dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure.  
7.4.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the Sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
Participant number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
● 
Investigator causality assessment 
The completed SAE form is to be reported via the EDC system within 24 hours. If the EDC 
system is not operational, email or fax the completed paper SAE report form to the Sponsor’s 
Drug Safety Department within 24 hours. (see email or fax number specified on the SAE 
report form)  
Relevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available. 
7.4.1.5 Adverse Events of Special Interest 
An AE of special interest (AESI) can be any serious or nonserious AE that is of scientific or 
medical concern as defined by the Sponsor and specific to the program, for which ongoing 
monitoring and rapid communication to the Sponsor may be appropriate.  
The AESIs will need to be reported to the Sponsor irrespective of regulatory seriousness 
criteria or causality within 24 hours (Section 7.4.1.4). 
Hepatotoxicity 

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● 
AST or ALT elevations that are >3 X ULN with concurrent elevation (within 21 days 
of AST and/or ALT elevations) of total bilirubin >2 X ULN, except in participants 
with documented Gilbert’s syndrome  
Measurement of conjugated and unconjugated bilirubin should be considered in cases of 
hyperbilirubinemia to assist in determination of its etiology. The Sponsor will subsequently 
determine whether the elevations are associated with other possible causes of 
aminotransferase elevation and hyperbilirubinemia, such as viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
7.4.2 Vital Signs 
Vital signs measures are to include respiratory rate, pulse rate, systolic and diastolic blood 
pressure while participant is in a seated position, pulse oximetry, and temperature. 
7.4.3 Clinical Laboratory Tests 
The following laboratory assessments will be performed by the local laboratory to evaluate 
safety at scheduled timepoints (see APPENDIX A) and make clinical decisions during the 
course of the study: 
● 
The serum chemistry panel is to include the following tests: albumin,  blood urea 
nitrogen, calcium, chloride, creatinine, glucose, inorganic phosphorus, magnesium, 
potassium, sodium, and total protein. 
● 
The CBC with differential is to include the following tests: white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), RBC count, platelet count, hemoglobin, and hematocrit. 
● 
LFTs are to include the following: AST/SGOT, ALT/SGPT, total bilirubin, and 
alkaline phosphatase. 
● 
The estimated GFR should be calculated using the MDRD equation as applicable, 
with serum creatinine (Scr) reported in mg/dL.  
 
GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American or 0.808 if Japanese (Matsuo 2009)) 
If any of the above is not applicable, MDRD equation should be used to calculate 
estimated GFR in accordance with local regulations or institutional guidelines. 
● 
The coagulation panel is to include the following tests: INR, prothrombin time, and 
PTT or aPTT 
● 
Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B 
surface antigen (HBsAb), antibodies to Hepatitis B core antigen (HBcAb), Hepatitis 
B DNA levels by PCR (as applicable; refer to latest local guidelines for the 

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management of Hepatitis B virus infection), and antibodies to Hepatitis C (anti-
HCV). If positive, contact the Sponsor. 
● 
Routine Urinalysis is color, appearance, specific gravity, pH, leukocyte esterase, 
nitrites, protein, glucose, ketones, urobilinogen, bilirubin, and blood. 
● 
A serum or urine β-hCG/hCG pregnancy test (minimum sensitivity of 25 mIU/mL or 
equivalent units) for participants of childbearing potential (Section 7.4.5) 
7.4.4 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. For adult participants only, 
measurements of height obtained within the prior 12 months may be utilized. 
7.4.5 Pregnancy Testing 
For participants of childbearing potential, a serum or urine β-hCG/hCG pregnancy test 
(minimum sensitivity of 25 mIU/mL or equivalent units) will be performed at baseline, 
within 24 hours for urine or within 72 hours for serum  prior to Day 1 of each treatment 
cycle, and at the EOT Visit if not done within the last 60 days. A negative pregnancy result is 
required before the participant may receive study treatment. 
Participants with false positive results and documented verification that the participant is not 
pregnant are eligible for study participation. Similarly, participants with false positive results 
that develop during study treatment are allowed to continue treatment with documented 
verification that the participant is not pregnant. 
After the last dose of study treatment, pregnancy tests will be performed at 30 days after 
receiving the last dose of  tucatinib, 7 months after receiving the last dose of trastuzumab, or 
180 days after receiving the last dose of Capecitabine whichever occurs last. Pregnancy tests 
may also be repeated as requested per institutional review board/independent ethics 
committee (IRB/IEC) or if required by local regulations. 
7.4.6 Cardiac Function 
7.4.6.1 MUGA or ECHO 
Assessment of cardiac ejection fraction will be performed by MUGA or ECHO at screening 
and at least once every 12 weeks thereafter until study discontinuation, and at EOT (unless 
done within 12 weeks prior to the EOT Visit, excluding screening/baseline assessment). If 
there is an interim assessment, subsequent cardiac ECHO or MUGA should be performed 
every 12 weeks as determined by the date of the most recent interim assessment. The 
modality chosen in screening should be used for all subsequent cardiac assessments 
throughout the study for comparison. 

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7.4.6.2 Electrocardiogram 
ECGs will be performed at baseline predose on Cycle 1 Day 1 and at EOT visit. To correct 
for heart rate, QT intervals should be calculated using the Fridericia formula (QTcF).  
7.5 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Response will be assessed according to RECIST v1.1 which are standardized criteria for 
evaluating response in solid tumors. The intervals of evaluation in this protocol are 
considered appropriate for disease management. 

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8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
Prior to the enrollment of participants at the site, the Sponsor or its designated clinical and 
medical personnel will review the following items with the investigator and clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/ package insert 
● 
Recording and reporting AEs and SAEs 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional review board/independent ethics committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good clinical practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Participant coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Sponsor representative will typically 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability. The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents. The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study participants, and must cooperate with the monitor to ensure that any 
problems noted in the course of the trial are resolved. The investigator must maintain a 

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comprehensive and centralized filing system of all study-related documentation that is 
suitable for inspection by the Sponsor or its designated monitors and by quality assurance 
auditors, or representatives of regulatory authorities. 
8.2 Data Management Procedures 
The Sponsor will provide CRF Completion Guidelines for electronic CRF (eCRF) data entry 
of all required protocol assessments and procedures. Study specific data management 
procedures will be maintained in the data management plan. Queries resulting from edit 
checks and/or data verification procedures will be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the Sponsor’s representatives to monitor the study as frequently 
as the Sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect participant confidentiality are to be employed 
during monitoring. The CRFs and related source documents will typically be reviewed in 
detail by the monitor at each site visit. Original source documents or certified copies are 
needed for review. This review includes inspection of data acquired as a requirement for 
participation in this study and other medical records as required to confirm that the 
information collected is correct. Other study records, such as correspondence with the 
Sponsor and the IRB/IEC and screening and drug accountability logs will also be inspected. 
All source data and study records must also be available for inspection by representatives of 
regulatory authorities and the IRB/IEC. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5 Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

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Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the Sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 

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8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by the Sponsor, whichever is longer. The investigator 
must contact the Sponsor prior to destroying any records associated with the study. If the 
investigator withdraws from the study (due to relocation, retirement, etc.), the records shall 
be transferred to a mutually agreed upon designee, such as another investigator or IRB/IEC. 
Notice of such transfer will be provided in writing to the Sponsor. 
9 
DATA ANALYSIS METHODS 
The primary objective of this study is to assess the primary endpoint, ORR of tucatinib in 
combination with trastuzumab and capecitabine by ICR per RECIST v1.1 in Japanese 
population, hence, the primary analysis population of the endpoint is the response evaluable 
set as defined in the section 9.3.1.7 but only includes Japanese participants. Analysis of ORR 
in all participants population including participants enrolled in Japan, South Korea and 
Taiwan is included in the secondary endpoints.  
9.1 Determination of Sample Size 
The study is designed to estimate the confirmed ORR in Japanese population and to detect an 
improvement in the ORR compared with a historical 20% response rate. The rationale for the 
historical response rate is based on the observed response rate from the control arm of 
HER2CLIMB trial and responses of patients treated with drug therapy after multiple 
treatment lines of anthracyclines, taxanes, trastuzumab, pertuzumab or T-DM1 (Murthy 
2020b; Yokoe 2021; Masuda 2020; Charles 2006). 
Approximately 42 participants will be enrolled in Japan including 4 participants in safety 
run-in. The primary efficacy analysis will be performed based on the participants enrolled on 
the main portion of the trial. With 38 participants, the study will have approximately 80% 
power to detect a 20% increase in ORR from 20% to 40% and approximately 90% power to 
detect a 25% increase in ORR from 20% to 45%, at one-sided significance level of 0.05, 
based on exact methods using EAST®, Version 6.0, by Cytel Inc. 
On 02-Aug-2021 the SMC conducted an evaluation of overall safety after 4 Japanese 
participants were enrolled in the safety run-in and the safety and tolerability was deemed 
acceptable by the SMC; hence the enrollment of the safety run-in was completed and that of 
the main study was initiated on the following day. 
A total of approximately 13 participants from South Korea and Taiwan are planned to be 
enrolled.  

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9.2 Study Endpoint Definitions 
9.2.1 Objective Response Rate 
The primary endpoint in this study is the confirmed ORR by ICR. The ORR is defined as the 
proportion of participants with confirmed complete response (CR) or partial response (PR), 
per RECIST v1.1. Only response assessments before first documented PD or new anti-cancer 
therapies will be considered. Participants with missing data are considered non-responders. 
9.2.2 Duration of Response 
DOR is defined as the time from the first objective response (CR or PR that is subsequently 
confirmed) to documented PD per RECIST v1.1 or death from any cause, whichever occurs 
first. Only those who achieve a confirmed response will be included in the analysis. 
9.2.3 Progression Free Survival 
PFS time is defined as the time from the first date of study treatment to the date of 
documented disease progression using RECIST v1.1 or death from any cause, whichever 
occurs first. Participants who are alive and have not progressed at the time of the analysis 
will be censored at the time of their last tumor assessment documenting absence of PD. 
Participants lacking an evaluation of tumor response after their start of study treatment will 
have their event time censored at 1 day. 
9.2.4 Overall Survival 
OS is defined as the time from start of study treatment to date of death due to any cause. In 
the absence of confirmation of death, survival time will be censored at the last date the 
participant is known to be alive. Participants lacking data beyond their start of study 
treatment will have their survival time censored at 1 day. 
9.3 Statistical and Analytical Plans 
The statistical and analytical plans are presented below. 
Since the primary objective of this study is to assess ORR in Japanese population, all the 
analyses, i.e., efficacy endpoints, safety endpoints as well as demographics and other 
baseline characteristics, will be performed in Japanese population. All of the analyses will 
also be conducted in all participants population, i.e., population which include participants 
enrolled in Japan, South Korea and Taiwan. The details will be provided in a supplemental 
statistical analysis plan (sSAP).  
9.3.1 General Considerations 
In general, descriptive statistics will be presented that include the number of observations, 
mean, median, standard deviation, minimum and maximum for continuous variables, and the 
number and percentages (of non-missing) per category for categorical variables.  

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The 2-sided 90% exact CI using Clopper-Pearson method (Clopper 1934) will be calculated 
for the response rates. 
For time-to-event end points, the median survival time will be estimated using the Kaplan-
Meier method; the associated 90%CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
9.3.1.1 Randomization and Blinding 
Blinding will not be performed. 
9.3.1.2 Adjustments for Covariates 
No adjustment for covariates is planned in the analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
With the exception of ORR and time-to-event endpoints, no imputation will be conducted for 
missing data unless otherwise specified in the sSAP. 
9.3.1.4 Multicenter Studies 
This study will be conducted at multiple study centers; however, it is not anticipated that any 
center will accrue enough participants to warrant an analysis by center. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No multiple comparisons are planned and no alpha adjustment is needed because only 
1 primary endpoint will be estimated in this single arm study. 
9.3.1.6 Data Transformations and Derivations 
Time variables based on 2 dates, e.g., start date and end date, will be calculated as (end date 
– start date + 1 [in days]) unless otherwise specified in the sSAP. Unless otherwise specified, 
baseline values used in all analyses will be the most recent non-missing measurement prior to 
the first dose of study drug. 
9.3.1.7 Analysis Sets 
The all treated participants set, response evaluable set, safety run-in set and PK analysis set 
are defined below.  
The all treated participants set will include all participants who receive any amount of study 
drug. Safety, PFS, and OS will be analyzed using this analysis set. 
Response evaluable set will include all participants who meet all following criteria: (1) had 
measurable disease at baseline, (2) received any amount of study treatment, and (3) had at 
least one post baseline disease assessment or discontinued due to clinical progression, 
toxicity, or death. ORR will be analyzed using the response evaluable analysis set. 

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Safety run-in set will include all participants who were treated during the safety run-in period 
and meet the safety evaluable criteria as defined in section 3.1. Dose limiting toxicity (DLT) 
information will be summarized for this analysis set. 
The PK analysis set will include all participants in the safety set from whom at least one 
post-baseline PK assessment was reported. The PK analysis set will be used for PK analysis. 
Japanese population is defined as Japanese participants enrolled in Japanese sites in the 
respective data sets. All participants population include all participants enrolled in Japan, 
South Korea and Taiwan. 
Additional analysis sets of participants may be defined in the sSAP. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Detailed methodology will be provided in the sSAP. 
9.3.1.9 Timing of Analyses 
The primary analysis will be conducted when all of the treated participants in Japanese 
population have been followed for at least 8 months (or all responders have been followed 
for a minimum of 6 months after their initial response, whichever comes first), have 
discontinued from the study, or had 30 days safety follow-up after disease progression, 
whichever comes first. In addition, for the purpose of regulatory submission in South Korea 
and Taiwan, the additional analyses may be conducted subsequently to the initial analysis. 
9.3.2 Participant Disposition 
An accounting of study participants by disposition will be tabulated and the number of 
participants in each analysis set will be summarized. Participants who discontinue study 
treatment and participants who withdraw from the study will be summarized with reason for 
discontinuation or withdrawal. 
9.3.3 Participant Characteristics 
Demographics and other baseline characteristics will be summarized. Details will be 
provided in the sSAP. 
9.3.4 Treatment Compliance 
Treatment administration will be summarized for safety analysis set. Summary statistics for 
duration of treatment (weeks or months) and the number of cycles per participant will be 
presented. Details will be provided in the sSAP. 
9.3.5 Efficacy Analyses 
Efficacy analyses will be performed in Japanese population and all participants population of 
the respective analysis sets. 

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9.3.5.1 Primary Efficacy Analyses 
Since the primary objective of this study is to assess ORR in Japanese population, the 
primary analysis will be conducted in Japanese population of the response evaluable set. 
Analyses of ORR in all participants population are conducted as a secondary endpoint. 
The cORR by ICR and its exact 2-sided 90% CI using the Clopper-Pearson method (Clopper 
1934) will be calculated.  
The primary efficacy analysis will be performed by testing the null hypothesis of ORR being 
less than or equal to 20% against the alternative hypothesis that ORR is greater than 20% at 
overall 1-sided 5% level of significance, i.e., H0: P≤0.20 vs. Ha: P>0.20. 
The study will be considered positive if the lower bound of the 2-sided 90% exact Clopper-
Pearson CI for cORR is greater than 20%, so that the null hypothesis that the cORR is less 
than or equal to 20% can be rejected. 
The participants in response evaluable set who are enrolled after safety run-in period will be 
used for the primary efficacy analysis. In addition, all participants in response evaluable set 
which includes participants in safety run-in period may be used as supportive analysis. 
9.3.5.2 Secondary Efficacy Analyses 
cORR by ICR in all participants population will be analyzed using the same method as for 
the primary endpoint. 
ORR by INV will be analyzed using the same method as for the primary endpoint. 
Secondary time-to-event analyses for DOR by ICR and investigator, PFS by ICR and 
investigator and OS, will be analyzed using Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided. 
9.3.6 Pharmacokinetic Analyses 
Individual (participant) plasma tucatinib concentrations at each sampling time will be listed 
and summarized with descriptive statistics. Additional exploratory PK analyses may be 
conducted, including exploratory analyses investigating the relationship between tucatinib 
exposure and efficacy and safety endpoints. Summaries by ethnicity (Japanese and Korean) 
may be provided as appropriate. These analyses will be described in a separate PK analysis 
plan. 
9.3.7 Safety Analyses 
Safety analysis will be performed in Japanese population as well as all participants 
population of the all treated participants set.  

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9.3.7.1 Extent of Exposure 
Duration of treatment and number of cycles will be summarized. Details will be provided in 
the sSAP. 
9.3.7.2 Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all AEs, 
treatment -emergent AEs, treatment-related AEs, grade 3 and higher AEs, SAEs, 
treatment -related SAEs, AEs leading to deaths, and AEs leading to study treatment 
discontinuation. AEs will be defined as treatment emergent if they are newly occurring or 
worsen following study treatment. 
AEs will be listed and summarized by Medical Dictionary for Regulatory Activities 
(MedDRA), preferred term, severity, and relationship to study drug. In the event of multiple 
occurrences of the same AE with the same preferred term in 1 participant, the AE will be 
counted once as the occurrence. 
DLTs will be listed and summarized for the participants in the safety run-in period. 
9.3.7.3 Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. 
9.3.7.4 Clinical Laboratory Results 
For laboratory results, summary statistics for maximum post baseline toxicity grades and for 
change from baseline may be tabulated as appropriate. Laboratory values will be listed with 
grade per NCI CTCAE v4.03 and flagged when values are outside the normal reference 
range. 
9.3.7.5 Other Safety Analyses 
The frequency and percentage of participants with post-baseline clinically significant vital 
signs will be summarized. Abnormal physical examination findings may be collected as AEs. 
ECOG performance status will be listed. 
Cardiac ejection fraction data and change from baseline will be summarized. 

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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), good clinical practice guideline in Japan (J-GCP), and 
all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the participant in simple terms using the IRB/IEC approved informed consent document and 
for ensuring participants are re-consented when the informed consent document is updated 
during the study, if required. The investigator will ensure that written informed consent is 
obtained from each participant, or legally acceptable representative, if applicable to this 
study, by obtaining the signature and date on the informed consent document prior to the 
performance of protocol evaluations or procedures. 
10.2 Ethical Review 
The investigator will provide the Sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
The investigator must provide the following documentation to the Sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 

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10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study participant) must be approved by the Sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling participants who have met protocol eligibility criteria. Protocol deviations must be 
reported to the Sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The Sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and 
participant medical records in the participant files as original source documents for the study. 
If requested, the investigator will provide the Sponsor, its licensees and collaborators, 
applicable regulatory agencies, and applicable IRB/IEC with direct access to original source 
documents or certified copies. 
Records containing participant medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the participant 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the Sponsor should be completed in strict accordance with the instructions 
provided by the Sponsor, including the instructions regarding the coding of participant 
identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 
10.5 Clinical Trial Agreement 
Payments by the Sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 

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Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for 
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Lancet Oncol. 2009;10(11):1037-44. 
 
Charles E Geyer, John Forster, Deborah Lindquist, et al. Lapatinib plus capecitabine for 
HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-43.   
 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26(4):404-13. 
 

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Collett D. Interval-censored survival data. Modelling survival data in medical research. 
London, Chapman & Hall. 1994:237-51. 
 
Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along 
with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer. J Clin Oncol. 2015;33(5):442-7. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
 
F. Cardoso, S.Paluch-Shimon, E.Senkus et al. 5th ESO-ESMO international consensus 
guidelines for advanced breast cancer (ABC 5). Ann Oncol . 2020 Dec;31:1623-1649. 
 
Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Population Fact 
Sheets, World. Lyon, France: International Agency for Research on Cancer. 
https://gco.iarc.fr/today, Accessed: 12 Nov, 2019. 2019. 
 
Freedman RA, Anders CK. Treatment of breast cancer brain metastases. Curr Breast Cancer 
Rep. 2012;4(1):1-9. 
 
Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and 
capecitabine for patients with human epidermal growth factor receptor 2-positive breast 
cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-9. 
 
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive 
advanced breast cancer. N Engl J Med. 2006;355(26):2733-43. 
 
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 
trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast 
cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 
2012;13(1):25-32. 
 
Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced 
human epidermal growth factor receptor 2-positive breast cancer: American Society of 
Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2078-99. 
 
Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: the 
University of Washington Metabolism and Transport Drug Interaction Database. Hum 
Genomics. 2010;5(1):61-72. 
 
Hurvitz SA, O'Shaughnessy J, Mason G, et al. Central nervous system metastasis in patients 
with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival 
from SystHERs. Clin Cancer Res. 2019;25(8):2433-41. 
 

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Kaidar-Person O, Anders CK, Zagar TM. Whole brain radiotherapy for brain metastases: is 
the debate over? JAMA. 2016;316(4):393-5. 
 
Kantar Health. CancerMPact® Treatment Architecture: Japan, Breast cancer. Dec. 2019. 
 
Katanoda K, Hori M, Matsuda T, et al. An updated report on the trends in cancer incidence 
and mortality in Japan, 1958-2013. Jpn J Clin Oncol. 2015;45(4):390-401. 
 
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pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother. 
1996;40(9):2087-93. 
 
Krop IE, Kim SB, Gonzalez-Martin A, et al. Trastuzumab emtansine versus treatment of 
physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689-99. 
 
Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast 
cancer: implications for targeted therapy. Cancer Res. 2008;68(14):5878-87. 
 
Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: 
proposal from the RANO group. Lancet Oncol. 2015;16(6):e270-8. 
 
Masuda N, Yoshinami T, Yasojima H, et al. Real-world effectiveness of post-T-DM1 
treatments in HER2-positive metastatic breast cancer: KBCSG-TR1917 observational study. 
Journal of Clinical Oncology 38, no. 15_suppl. Published online May 25, 2020. Accessed: 18 
February, 2021. 
 
Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum 
creatinine in Japan. Am J Kidney Dis. 2009;53(6):982-92. 
 
Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in 
advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-
randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(7):880-8. 
 
Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and 
trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and 
without brain metastases (HER2CLIMB). Cancer Res. 2020a;80(4 Suppl):Abstract GS1-01. 
 
Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-
positive metastatic breast cancer. N Engl J Med. 2020b;382(7):597-609. 
 
Musolino A, Ciccolallo L, Panebianco M, et al. Multifactorial central nervous system 
recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and 
clinical data from a population-based cancer registry study. Cancer. 2011;117(9):1837-46. 
 

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Natioinal Comprehensive Cancer Network®. NCCN Cllinical Practice Guidelines in 
Oncology (NCCN Guidelines®). Breast Cancer Version Apr, 2021. 
 
Network NCC. NCCN Guidelines®& Clinical Resources. 2013. Accessed: August 15. 
http://www.nccn.org/. 
 
Olson EM, Abdel-Rasoul M, Maly J, et al. Incidence and risk of central nervous system 
metastases as site of first recurrence in patients with HER2-positive breast cancer treated 
with adjuvant trastuzumab. Ann Oncol. 2013;24(6):1526-33. 
 
Park IH, Ro J, Lee KS, et al. Trastuzumab treatment beyond brain progression in HER2-
positive metastatic breast cancer. Ann Oncol. 2009;20(1):56-62. 
 
Yokoe T, Kurozumi S, Nozawa K, et al. Clinical benefit of treatment after trastuzumab 
emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study 
in Japan (WJOG12519B). Breast Cancer. 2021 Jan 2. doi: 10.1007/s12282-020-01192-y. 
Epub ahead of print. Accessed: 18 February, 2021. 
 
Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in patients with HER2-
positive early breast cancer who have and have not received adjuvant trastuzumab: a 
retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol. 2013;14(3):244-8. 
 
Pivot X, Manikhas A, Zurawski B, et al. CEREBEL (EGF111438): a phase III, randomized, 
open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in 
patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J 
Clin Oncol. 2015;33(14):1564-73. 
 
Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management 
for patients with advanced human epidermal growth factor receptor 2-positive breast cancer 
and brain metastases: American Society of Clinical Oncology clinical practice guideline. J 
Clin Oncol. 2014;32(19):2100-8. 
 
Rossi D, Alessandroni P, Catalano V, et al. Safety profile and activity of lower capecitabine 
dose in patients with metastatic breast cancer. Clin Breast Cancer. 2007;7(11):857-60. 
 
Sauvaget C, Nishino Y, Konno R, et al. Challenges in breast and cervical cancer control in 
Japan. Lancet Oncol. 2016;17(7):e305-12. 
 
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 
2001;344(11):783-92. 
 
Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-
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randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461-
71. 
 
Swain SM, Miles D, Kim SB, et al. End-of-study analysis from the phase III, randomized, 
double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), 
trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast 
cancer (MBC). J Clin Oncol. 2019;37(15 Suppl):Abstract 1020. 
 
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med. 2012;367(19):1783-91. 
 
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single 
agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 
2002;20(3):719-26. 
 
von Minckwitz G, Schwedler K, Schmidt M, et al. Trastuzumab beyond progression: overall 
survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. 
Eur J Cancer. 2011;47(15):2273-81. 
 
Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-
4013. 
 
Yokoe T, Kurozumi S, Nozawa K, et al. Clinical benefit of treatment after trastuzumab 
emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study 
in Japan (WJOG12519B). Breast Cancer. 2021 Jan 2. doi: 10.1007/s12282-020-01192-y. 
Epub ahead of print. Accessed: 18 February, 2021. 

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APPENDIX A: 
SCHEDULE OF EVENTS 
Safety Run-in Only 
 
Visit Window 
Screening 
Cycles 1-2 
Subsequent 
21-Day Cycles 
Response Assessments 
EOT 
LTFU 
D1cc 
D8 
D15z 
D1 
Every 6 wks, 
through Wk 
24 
Every 9 wks, 
beginning Wk 
24 
30–37 Days  
Post Last 
Dose  
of Study 
Drug 
Every 90 
Days Post 
EOT 
Visita 
D -28 to 1 
 
(±2D) 
(±2D) 
(-1D to +3D) 
-7D 
-7D 
Baseline  
and  
Safety 
Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
Confirmatory HER2+ 
testing 
Xb 
 
 
 
 
 
 
 
 
Medical history, disease 
history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc, aa 
X 
X 
X 
 
 
X 
 
Vital signsd 
X 
X aa 
X 
X 
X 
 
 
X 
 
Weight 
X 
Xe 
 
 
Xe 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
X 
 
ECHO/MUGAg 
X 
 
 
 
 
Xh 
Xh 
Xi 
 
ECOG performance 
status 
X 
Xc 
X 
X 
X 
 
 
X 
 
Labsj 
Xbb 
Xx, aa 
Xx 
Xx 
Xx 
 
 
X 
 
Urinalysis 
Xbb 
 
 
 
 
 
 
 
 
Coagulation 
Xbb 
 
 
 
 
 
 
X 
 
Hepatitis B and C 
screeningl 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
(participants of 
childbearing potential)m 
Xn 
Xn 
 
 
Xn 
 
 
Xo 
Xf 
Participant contact/clinic 
visit 
X 
X 
Xz 
Xz 
Xz 
X 
X 
X 
Xp 

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Visit Window 
Screening 
Cycles 1-2 
Subsequent 
21-Day Cycles 
Response Assessments 
EOT 
LTFU 
D1cc 
D8 
D15z 
D1 
Every 6 wks, 
through Wk 
24 
Every 9 wks, 
beginning Wk 
24 
30–37 Days  
Post Last 
Dose  
of Study 
Drug 
Every 90 
Days Post 
EOT 
Visita 
D -28 to 1 
 
(±2D) 
(±2D) 
(-1D to +3D) 
-7D 
-7D 
Con meds and AEsq 
Collect if related to 
study procedures from 
time of informed 
consent 
Collect Day 1 predose through EOT visit or 30 days after last dose of study treatment, whichever is 
later 
 
Response 
Assessments 
CT, PET/CT, or MRIr 
X 
 
 
 
 
Xr 
Xr 
Xr 
Xr,y 
Contrast MRI brain 
X 
 
 
 
 
Xs 
Xs 
Xs 
Xs,y 
Treatments 
 
Tucatinib u 
 
X 
 
 
X 
 
 
 
 
Capecitabinev 
 
X 
 
 
X 
 
 
 
 
Trastuzumabw 
 
X 
 
 
X 
 
 
 
 
PK 
Blood samplest 
 
X 
X 
X 
Xk 
 
 
 
 
 
 
a 
More frequent long-term follow-up may be requested for OS event tracking. If a 30-Day Follow-up Visit was not done, the long-term follow-up should begin every 90 days (± 7 days) 
starting from the date of the last dose of study treatment 
b 
Archival tissue specimen may be submitted. If archival tissue is unavailable, a fresh tumor biopsy must be obtained. HER2 positive results must be obtained prior to C1D1. 
c 
Does not need to be repeated if performed within 1 day of Cycle 1 Day 1.  
d 
Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure while participant is in a seated position, pulse oximetry, and temperature 
e 
Weight taken pre-dose 
f 
Only required at 30 days after receiving the last dose of tucatinib, 7 months after receiving the last dose of trastuzumab, or 180 days after receiving the last dose of Capecitabine 
whichever occurs last 
g 
Use the same modality performed at screening visit 
h 
Every 12 weeks determined by the date of screening exam 
i 
If not done within the previous 12 weeks 
j 
Blood samples for CBC with differential, serum chemistry, and liver function tests 
k 
Through Cycle 6 only: Pre-dose at Cycles 3-6 and 1-4 hour post-dose on Day 1 at Cycle 3 only 
l 
Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B surface antigen (HBsAb), antibodies to Hepatitis B core antigen (HBcAb), Hepatitis B DNA levels 
by PCR (as applicable; refer to latest local guidelines for the management of Hepatitis B virus infection), and antibodies to Hepatitis C (anti-HCV). If positive, contact the Sponsor 
m 
Urine or serum pregnancy test; a positive urine test must be confirmed with a serum pregnancy test 
n 
Serum or urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to Day 1 of each treatment cycle  
o 
If not done within the last 60 days 
p 
Review of medical records, public records, or other public platforms may be used to obtain this information if reasonable efforts to make phone/personal contact are unsuccessful. 

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q 
Including concomitant procedures and hospitalization 
r 
Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate to document sites of extracranial disease and assessment of tumor burden. At minimum, scans 
must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease. If cycles are delayed for any reason or there is an interim unscheduled 
assessment, scans should continue to be performed according to the original schedule. Use the same modality performed at screening/baseline. If bone imaging is collected, any 
RECIST appropriate imaging modality may be used. Not required at EOT if imaging was performed within 30 days of discontinuing study treatment. 
s 
Contrast MRI of the brain and assessment of brain lesions per RECIST; only in participants with known brain metastases at baseline or a history of brain metastases. At EOT, MRI of 
the brain required unless already done within 30 days of ending study treatment or progression in the brain has already been documented while on study.  
t 
See APPENDIX B for additional PK assessment 
u 
Tucatinib is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib for next cycle 
v 
Capecitabine is administered PO BID, on Day 1 through Day 14. On Day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for next cycle. 
w 
Trastuzumab is administered intravenously, once every 21 days 
x 
All lab results must be reviewed prior to administration of study treatment, in order to confirm continued study treatment and allow for potential dose adjustments. 
y 
Scans should be performed every 9 weeks (±1 week) for participants who discontinued treatment prior to disease progression. A contrast MRI of the brain should only be performed in 
participants with brain metastases at baseline or a history of brain metastases. 
z 
Provide tucatinib day-of dosing instructions for the next visit (Cycles 1-6), so that the visit’s predose blood sample can be collected within the required time window (i.e., 2 hours prior 
to tucatinib dosing) 
aa 
For hospitalized participants, an assessment of concomitant medications, AEs, physical exam, vital signs, and laboratory evaluations (including CBC, serum chemistry, and liver 
function tests) must be performed prior to discharge. 
bb 
Test within 10 days prior to the first dose of study treatment. 
cc 
The visit window of Cycle 2 Day 1 is +3. 

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Main Study 
 
Visit Window 
Screening 
Cycles 1-2 
Subsequent 
21-Day 
Cycles 
Response Assessments 
EOT 
LTFU 
D1 
D12 
D1 
Every 6 wks, 
through Wk 
24 
Every 9 wks, 
beginning Wk 
24 
30–37 Days Post 
Last Dose of 
Study Drug 
Every 90 
Days Post 
EOT Visita 
D -28 to 1 
(-1D to 
+3D)bb 
(±3D) 
(-1D to 
+3D) 
-7D 
-7D 
Baseline 
 and  
Safety 
Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
Confirmatory HER2+ testing 
Xb 
 
 
 
 
 
 
 
Medical history, disease 
history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
Xz 
X 
 
 
X 
 
Vital signsd 
X 
X 
Xz 
X 
 
 
X 
 
Weight 
X 
Xe 
 
Xe 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
X 
 
ECHO/MUGAg 
X 
 
 
 
Xh 
Xh 
Xi 
 
ECOG performance status 
X 
Xc 
Xz 
X 
 
 
X 
 
Labsj 
Xcc 
Xx 
Xt 
Xx 
 
 
X 
 
Urinalysis 
Xcc 
 
 
 
 
 
 
 
Coagulation 
Xcc 
 
 
 
 
 
X 
 
Hepatitis B and C screeningl 
X 
 
 
 
 
 
 
 
Pregnancy test (participants 
of childbearing potential)m 
Xn 
Xn 
 
Xn 
 
 
Xo 
Xf 
Participant contact/clinic visit 
X 
X 
Xaa 
X 
X 
X 
X 
Xp 
Con meds and AEsq 
Collect if related to study 
procedures from time of 
informed consent 
Collect Day 1 predose through EOT visit or 30 days after last dose of study treatment, 
whichever is later 
 
CT, PET/CT, or MRIr 
X 
 
 
 
Xr 
Xr 
Xr 
Xr,y 

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Visit Window 
Screening 
Cycles 1-2 
Subsequent 
21-Day 
Cycles 
Response Assessments 
EOT 
LTFU 
D1 
D12 
D1 
Every 6 wks, 
through Wk 
24 
Every 9 wks, 
beginning Wk 
24 
30–37 Days Post 
Last Dose of 
Study Drug 
Every 90 
Days Post 
EOT Visita 
D -28 to 1 
(-1D to 
+3D)bb 
(±3D) 
(-1D to 
+3D) 
-7D 
-7D 
Response 
Assessments 
Contrast MRI brain 
X 
 
 
 
Xs 
Xs 
Xs 
Xs,y 
Treatments 
 
Tucatinib u 
 
X 
 
X 
 
 
 
 
Capecitabinev 
 
X 
 
X 
 
 
 
 
Trastuzumabw 
 
X 
 
X 
 
 
 
 
PK 
Blood samplesdd 
 
Xbb 
 
Xk 
 
 
 
 
 
a 
More frequent long-term follow-up may be requested for OS event tracking. If a 30-Day Follow-up Visit was not done, the long-term follow-up should begin every 
90 days (± 7 days) starting from the date of the last dose of study treatment 
b 
Archival tissue specimen may be submitted. If archival tissue is unavailable, a fresh tumor biopsy must be obtained 
c 
Does not need to be repeated if performed within 1 day of Cycle 1 Day 1.  
d 
Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure while participant is in a seated position, pulse oximetry, and temperature 
e 
Weight taken pre-dose 
f 
Only required at 30 days after receiving the last dose of tucatinib, 7 months after receiving the last dose of trastuzumab, or 180 days after receiving the last dose 
of Capecitabine whichever occurs last 
g 
Use the same modality performed at screening visit 
h 
Every 12 weeks determined by the date of screening exam 
i 
If not done within the previous 12 weeks 
j 
Blood samples for CBC with differential, serum chemistry, and liver function tests 
k 
Through Cycle 6 only: Pre-dose at Cycles 3-6 and 1-4 hour post-dose on Day 1 at Cycle 3 only 
l 
Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B surface antigen (HBsAb), antibodies to Hepatitis B core antigen (HBcAb), 
Hepatitis B DNA levels by PCR (as applicable; refer to latest local guidelines for the management of Hepatitis B virus infection), and antibodies to Hepatitis C 
(anti-HCV). If positive, contact the Sponsor 
m 
Urine or serum pregnancy test; a positive urine test must be confirmed with a serum pregnancy test 
n 
Serum or urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to Day 1 of each treatment cycle  
o 
If not done within the last 60 days 
p 
Review of medical records, public records, or other public platforms may be used to obtain this information if reasonable efforts to make phone/personal contact 
are unsuccessful. 
q 
Including concomitant procedures and hospitalization 

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r 
Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate to document sites of extracranial disease and assessment of tumor burden. At 
minimum, scans must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease. If cycles are delayed for any reason 
or there is an interim unscheduled assessment, scans should continue to be performed according to the original schedule. Use the same modality performed at 
screening/baseline. If bone imaging is collected, any RECIST appropriate imaging modality may be used. Not required at EOT if imaging was performed within 
30 days of discontinuing study treatment. 
s 
Contrast MRI of the brain and assessment of brain lesions per RECIST; only in participants with known brain metastases at baseline or a history of brain 
metastases. At EOT, MRI of the brain required unless already done within 30 days of ending study treatment or progression in the brain has already been 
documented while on study.  
t 
On Cycle 2 only collect labs for LFTs 
u 
Tucatinib is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib for next cycle 
v 
Capecitabine is administered PO BID, on Day 1 through Day 14. On Day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for 
next cycle. 
w 
Trastuzumab is administered intravenously, once every 21 days 
x 
All lab results must be reviewed prior to administration of study treatment, in order to confirm continued study treatment and allow for potential dose 
adjustments. 
y 
Scans should be performed every 9 weeks (±1 week) for participants who discontinued treatment prior to disease progression. A contrast MRI of the brain should 
only be performed in participants with brain metastases at baseline or a history of brain metastases. 
z 
Cycle 1 only 
aa 
Provide tucatinib day-of dosing instructions for the next Day 1 visit (Cycles 2-6), so that the visit’s predose blood sample can be collected within the required 
time window (i.e., 2 hours prior to tucatinib dosing) 
bb 
Cycle 2 only 
cc 
Test within 10 days prior to the first dose of study treatment. 
dd 
Predose blood sample(Cycles 2-6) can be collected within the required time window (i.e., 2 hours prior to tucatinib dosing). 
 

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APPENDIX B: 
ADDITIONAL PK ASSESSMENTS FOR PARTICIPANTS IN 
SAFETY RUN-IN ONLY 
Cycle 
Study 
Days 
Time 
Window 
Relative Time 
Blood 
Sample 
1 
1 
 
Predose 
Within 
24 hr 
START of first dose of tucatinib in Cycle 1 
Day 1 
X 
0.5 hr  
post dose 
±5 min 
START of first dose of tucatinib in Cycle 1 
X 
1 hr  
post dose 
±5 min 
START of first dose of tucatinib in Cycle 1 
X 
2 hr  
post dose 
±15 min 
START of first dose of tucatinib in Cycle 1 
X 
3 hr  
post dose 
±15 min 
START of first dose of tucatinib in Cycle 1 
X 
4 hr  
post dose 
±15 min 
START of first dose of tucatinib in Cycle 1 
X 
6 hr  
post dose 
±15 min 
START of first dose of tucatinib in Cycle 1 
X 
8 hr  
post dose 
±15 min 
START of first dose of tucatinib in Cycle 1 
X 
10 hr  
post dose 
±30 min 
START of first dose of tucatinib in Cycle 1 
X 
12 hr  
post dose 
±30 min 
START of first dose of tucatinib in Cycle 
1; prior to second dose on Cycle 1 Day 1 
X 
8 
Predose 
±48 
hours 
START of first dose of tucatinib in Cycle 
1; prior to dose on Cycle 1 Day 8 
X 
15 
Predose 
±48 
hours 
START of first dose of tucatinib in Cycle 
1; prior to dose on Cycle 1 Day 15 
X 
2 
8 
Predose 
±48 
hours 
START of first dose of tucatinib in Cycle 
2; prior to dose on Cycle 2 Day 8 
X 
15 
Predose 
±48 
hours 
START of first dose of tucatinib in Cycle 
2; prior to dose on Cycle 2 Day 15 
X 
 

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APPENDIX C: 
PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky  
 
ECOG 
Percent 
Description 
 
Score 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
 
0 
Normal activity. Fully active, 
able to carry on all pre-disease 
performance without 
restriction. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities. Up and 
about more than 50% of waking 
hours. 
50 
Requires considerable 
assistance and frequent 
medical care. 
 
40 
Disabled, requires special care 
and assistance. 
 
3 
In bed >50% of the time. 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to 
bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
 
0 
Dead. 
 
5 
Dead. 
 
 
 

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APPENDIX D: 
GUIDANCE ON CONTRACEPTION 
Definition 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below Premenopausal female with 1 of the following): 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
・ 
Premenarchal 
・ 
Premenopausal female with 1 of the following: 
・ Documented hysterectomy 
・ Documented bilateral salpingectomy 
・ Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
・ 
Postmenopausal female 
・ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
・ 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, confirmation with two FSH measurements in 
the postmenopausal range is required. 
・ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 

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Women of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
・ 
Premenopausal female with 1 of the following: 
・ Documented hysterectomy 
・ Documented bilateral salpingectomy 
・ Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
・ 
Postmenopausal female 
・ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. However, in the absence of 12 
months of amenorrhea, confirmation with two FSH measurements in the postmenopausal 
range is required.  
・ Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Contraceptives allowed during the study includea: 
Highly Effective Contraceptive Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly. 
・ Progestogen-only subdermal contraceptive implantb,c 
・ IUSc,d 
・ Non-hormonal IUD 

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・ Bilateral tubal occlusion 
・ Azoospermic partner (vasectomized or secondary to medical cause) 
This is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. A spermatogenesis 
cycle is approximately 90 days. 
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview. 
Sexual Abstinence 
・ Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
a. Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants of clinical studies. 
b. If locally required, in accordance with CTFG guidelines, acceptable contraceptive 
implants are limited to those which inhibit ovulation. 
c.    IUS is a progestin releasing IUD. 
Note: The following are not acceptable methods of contraception: 
・Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and LAM. 
・Male condom with cap, diaphragm, or sponge with spermicide. 
・Male and female condom should not be used together (due to risk of failure with friction). 
 
 

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APPENDIX E: 
CYP3A4 INDUCERS AND THEIR ELIMINATION HALF-LIVES 
CYP3A4 inducers include but are not limited to the following. There could also be additional 
new drugs and marketed drugs that could be identified as inducers with continued research. 
Druga, b 
Elimination Half-lifec (hours) 
Strong Inducers 
Barbiturates 
Variable 
Carbamazepine 
25–65 hours (single dose), 12–17 hours (repeat dose) 
Phenytoin 
7–42 hours 
Rifampin 
3–4 hours (single dose), 2–3 hours (repeat dose) 
St. John’s Wort 
9–43 hoursd 
Note: Any additional CYP3A4 inducers that are identified or become commercially available while the 
clinical trial is ongoing are also prohibited. 
a 
FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm#potency) 
b 
EMA. “Guideline on the investigation of drug interactions” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC5001296
06.pdf) 
c 
Drug package insert 
d 
(Kerb 1996) 
 
 
 

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APPENDIX F: 
CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION 
HALF-LIVES 
CYP2C8 inhibitors and inducers include but are not limited to the following. There could 
also be additional new drugs and marketed drugs that could be identified as 
inhibitors/inducers with continued research. 
Druga, b 
Elimination Half-lifec (hours) 
Strong Inhibitors 
Clopidogrel 
6 hours 
Gemfibrozil 
1–2 hours 
Moderate Inducer 
Rifampin 
3–5 hours 
Note: Any additional CYP2C8 inhibitors/inducers that are identified or become commercially 
available while the clinical trial is ongoing are also prohibited. 
a 
FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm#potency) 
b 
EMA. “Guideline on the investigation of drug interactions” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500
129606.pdf)  
c 
Drug package insert 
 
 
 

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APPENDIX G: 
CLINICAL SUBSTRATES FOR CYP3A-MEDIATED 
METABOLISM 
The following table provides examples of clinical substrates for CYP3A-mediated 
metabolism and is not intended to be an exhaustive list. 
Sensitive 
(AUC increase ≥5-fold with  
strong index inhibitor) 
Moderate Sensitive 
(AUC increase 2 to 5-fold with  
strong index inhibitor) 
alfentanil, avanafil, buspirone, 
conivaptan, darifenacin, darunavir
a, 
ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin
b, midazolam, 
naloxegol, nisoldipine, saquinavir
a, 
simvastatin
b, sirolimus, tacrolimus, 
tipranavir
a, triazolam, vardenafil 
alprazolam, aprepitant, atorvastatin
c, 
colchicine, eliglustat
d, pimozide, 
rilpivirine, rivaroxaban, tadalafil 
budesonide, dasatinib, dronedarone, 
eletriptan, eplerenone, felodipine, 
indinavir
a, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, 
tolvaptan 
Note: Sensitive substrates are drugs that demonstrate an increase in area under the concentration-time 
curve (AUC) of ≥5fold with strong index inhibitors of a given metabolic pathway in clinical drug-
drug interaction (DDI) studies. Moderate sensitive substrates are drugs that demonstrate an increase 
in AUC of ≥2 to < 5fold with strong index inhibitors of a given metabolic pathway in clinical DDI 
studies. Sensitive substrates of CYP3A with ≥ 10fold increase in AUC by co-administration of strong 
index inhibitors are shown above the dashed line. Other elimination pathways may also contribute to 
the elimination of the substrates listed in the table above and should be considered when assessing the 
drug interaction potential. 
a 
Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
b 
Acid form is an organic anion transporting polypeptide 1B1 (OATP1B1) substrate. 
c 
Listed based on pharmacogenetic studies. 
d 
Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
 
Drug-drug interaction (DDI) data were collected based on a search of the University of 
Washington Metabolism and Transport Drug Interaction Database (Hachad 2010). 
Source: 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte
ractionsLabeling/ucm093664.htm#table3-1) 
 

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APPENDIX H: 
RECIST VERSION 1.1 
Response Evaluation Criteria in Solid Tumors 
Term 
Definition 
Complete response 
(CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes must have reduction in short axis to <10 mm. 
Partial response (PR) 
A ≥30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive disease 
(PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. The appearance of one or 
more new lesions is also considered progression. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Measurable lesion 
Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a 
minimum size of 10 mm by CT scan (CT slice thickness no 
greater than 5 mm). 
From RECIST v1.1 (Eisenhauer 2009)