A Single Arm, Open Label Phase 2 Study of Tucatinib in Combination With Trastuzumab Deruxtecan in Subjects With Previously Treated Unresectable Locally-Advanced or Metastatic HER2+ Breast Cancer
Phase: PHASE2
Conditions: HER2 Positive Breast Cancer
Sponsor: Seagen, a wholly owned subsidiary of Pfizer

PF-07265792 (Tucatinib)
Protocol C4251006 (SGNTUC-025)
Amendment 03, 16 Oct 2024
PFIZER CONFIDENTIAL
Page 1 of 132
Protocol Number:
C4251006/SGNTUC-025
Version:
Amendment 03; 16-Oct-2024
Protocol Title:
A Single Arm, Open Label Phase 2 Study of Tucatinib in 
Combination with Trastuzumab Deruxtecan in Subjects with 
Previously Treated Unresectable Locally-Advanced or 
Metastatic HER2+ Breast Cancer 
Investigational 
Product:
PF-07265792 (Tucatinib)
Brief Title:
A study of tucatinib plus trastuzumab deruxtecan in HER2+ 
breast cancer
Phase:
2
IND Number:
119421
sponsor:
Seagen Inc., a wholly owned subsidiary of Pfizer
21823 30th Drive SE
Bothell, WA 98021, USA
This document and accompanying materials contain confidential information belonging to 
Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing these documents, 
you agree to hold this information in confidence and not copy or disclose it to others (except 
where required by applicable law) or use it for unauthorized purposes. In the event of any 
actual or suspected breach of the obligation, Pfizer must be promptly notified.
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Document History
Document 
Version Date
Original
10-Jun-2020
Amendment 1
16-Oct-2020
Amendment 2
03-Dec-2021
Amendment 3
16-Oct-2024
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Protocol Amendment Summary of Changes Table
Amendment 03 (DD-Oct-2024)
Overall Rationale for the Amendment: The primary purpose of this amendment is to 
incorporate a long-term extension phase and to align with the Pfizer protocol template and 
standard operating procedures.
Description of Change
Brief Rationale
Section # and Name 
Substantial Modification(s)
Added that participants still receiving clinical benefit 
and remaining on study treatment as of Amendment 3 
may continue to receive study intervention during the 
LTEP.
To allow participants 
who are still receiving 
clinical benefit to 
remain on treatment.
Synopsis (Post-safety 
Lead-in, Duration of 
Treatment)
Section 3.1 Summary 
of Study Design
Added: “During the LTEP, efficacy assessments will be 
performed per institutional guidelines and investigator-
determined usual and customary clinical care.” 
To clarify collection of 
efficacy assessments 
during the LTEP. 
Synopsis (Efficacy 
Assessments), Section 
7.2 Response/Efficacy 
Assessments
Clarified that only pregnancies and SAEs will be 
collected by the sponsor during the LTEP. All other 
assessments, including additional safety assessments, 
will be performed per institutional guidelines and 
investigator-determined usual and customary clinical 
care. Pregnancy testing will continue as outlined in the 
schedule of events for participants of child-bearing 
potential.
Clarification of data 
collection during 
LTEP.
Synopsis (Safety 
Assessments), Section 
7.7 Safety 
Assessments
Added: “As of Amendment 3, all participants still on 
study who are not entering the LTEP will have a last 
visit/contact. The study will end when the last LTEP 
participant has had their last visit/contact. The sponsor 
will provide continued access to study intervention
during the LTEP for any participant who is still on 
tucatinib with or without T-DXd and receiving clinical 
benefit based on the investigator’s assessment.”
Defined end of study 
for participants 
entering LTEP.
Section 3.1.4 End of 
Study
Updated definition of women of childbearing and non-
childbearing potential.
To align with Pfizer’s 
Protocol Template.
Section 4.4 
Childbearing Potential
Added that for participants continuing to LTEP, data will 
only be documented in the participant’s medical record.
Clarification of data 
collection during 
LTEP.
Section 4.5 Removal 
of Participants from 
Therapy or 
Assessment
Language revised to have overdose reported to Safety 
only when associated with an SAE.
To align with Pfizer’s 
safety reporting 
process.
Section 5.4.4, 5.3.4 
Overdose
Added that treatment administration data will no longer 
be collected during the LTEP.
Clarification of data 
collection during 
LTEP.
Section 5.8 Treatment 
Compliance
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Description of Change
Brief Rationale
Section # and Name 
Added LTEP for participants still receiving clinical 
benefit and remaining on treatment with tucatinib with 
or without T-DXd. Only pregnancies and SAEs will be 
collected by the sponsor. All other assessments, 
including efficacy assessments, will be performed per 
institutional guidelines and investigator-determined 
usual and customary clinical care. Pregnancy testing will 
continue as outlined in the schedule of events for 
participants of child-bearing potential.
LTEP added to allow 
participants still 
receiving clinical 
benefit to remain on 
study treatment and 
clarification of data 
collection during the 
LTEP. 
Section 6.7 Long-term 
Extension Phase 
(LTEP), Appendix I
Added that pregnancy testing will continue every 3 
weeks for participants of child-bearing potential during 
the LTEP
To clarify that 
pregnancy testing per 
protocol specified 
frequency will continue 
during the LTEP.
Section 6.3.5 Cycle 3 
and Beyond, Day 1 (–
1 day to +3 days)
Clarified that during the LTEP, brain metastases 
evaluations will be performed per institutional guidelines 
and investigator-determined usual and customary clinical 
care.
To clarify that brain 
metastases evaluations 
will be conducted 
during the LTEP.
Section 7.2.1 
Evaluation of Brain 
Metastases
Clarified that during the LTEP, only AESIs that meet 
SAE criteria will be reported to Pfizer Safety using 
PSSA only and will not be recorded within the CRF.
Clarification of data 
collection during 
LTEP.
Section 7.7.1.1 
Definitions/Adverse 
Events of Special 
Interest
Clarified that during the LTEP, pregnancies and SAEs 
will be reported to the sponsor.
Guidance on steps to 
following when 
recording safety data 
during the LTEP.
Section 7.7.1.2 
Procedures for 
Eliciting and 
Recording Adverse 
Events/Recording 
Serious Events
Added section indicating lack of efficacy as reportable 
event to Pfizer Safety only if associated with an SAE.
To support Study 
transition to Pfizer 
Pharmacovigilance 
processes and systems.
Section 7.7.1.2 
subsection
Lack of Efficacy 
Clarified that during the LTEP, pregnancy reporting 
should continue and will be collected per guideline 
outlined under EDP.
Guidance for data 
collection of 
pregnancies that occur 
during the LTEP.
Section 7.7.5 
Pregnancy Testing
Added the following text: “During the LTEP, ECG 
assessments will be performed per institutional 
guidelines and investigator-determined usual and 
customary clinical care.”
Guidance regarding 
ECG assessments 
during the LTEP.
7.7.7.2 
Electrocardiogram
Added the following text: “During the LTEP, cardiac 
assessments will be performed per institutional 
guidelines and investigator-determined usual and 
customary clinical care.”
Guidance regarding 
cardiac function 
assessments during the 
LTEP.
Section 7.7.7.1 
MUGA or ECHO
Added the following text: “During the LTEP, ECG 
assessments will be performed per institutional 
guidelines and investigator-determined usual and 
customary clinical care.”
Guidance regarding 
ECG assessments 
during the LTEP.
Section 7.7.7.2 
Electrocardiogram
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Description of Change
Brief Rationale
Section # and Name 
Added text to indicate CRFs will not be collected during 
LTEP
eCRFs will not be 
collected in the LTEP.
Section 8.2 Accuracy 
and Reliability of Data
Added text to indicate data collection needed during 
LTEP. 
Guidance for data 
collection during 
LTEP.
Section 8.3 Data 
Management 
Procedures
Added LTEP 
Column added to 
indicate assessments to 
be done during the 
LTEP.
Appendix A. Schedule 
of Events
Added footnote “v”: “During the LTEP, safety and 
efficacy assessments that include determination of 
disease progression will be performed per institutional 
guidelines and investigator-determined usual and 
customary clinical care.”
Guidance for data 
collection during 
LTEP.
Appendix A. Schedule 
of Events
Added footnote “w”: “Only SAEs and pregnancy will be 
collected by the sponsor”
Guidance for data 
collection during 
LTEP.
Appendix A. Schedule 
of Events
Non-Substantial Modification(s)
Added Pfizer sponsor’s name and logo
Alignment with Pfizer 
document format and 
requirements.
Title page
Removed Medical Monitor’s name and contact 
information
The medical monitor’s 
name and contact 
information is personal 
identifiable information
Title page
Removal of Investigator’s agreement and the 
investigator’s signature.
The investigator’s 
agreement and 
signature is personal 
identifiable 
information.
Page 2 (no Section 
number)
Pfizer Product Number added to the Seagen number. 
Throughout the rest of the protocol, Seagen product 
number replaced by Pfizer product number.
Alignment with Pfizer 
document format and 
requirements.
Title Page
Synopsis
Footer
Added ClinicalTrials.gov number 
Alignment with Pfizer 
document format and 
requirements.
Synopsis
Contraception and barrier guidance updated
To align with Pfizer’s 
Protocol Template.
Section 4.3 
Contraception
Added that the withdrawal of consent should be 
explained in detail in the medical records by the 
investigator as to whether the withdrawal is only from 
further receipt of study intervention or also from study 
procedures and/or posttreatment study follow up.
To align with Pfizer’s 
Protocol Template.
Section 4.5.1 
Discontinuation of 
Study Treatment
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Description of Change
Brief Rationale
Section # and Name 
Added: “If a participant withdraws from the study, they 
may request destruction of any remaining samples taken 
and not tested, and the investigator must document any 
such requests in the site study records and notify the 
sponsor accordingly. If the participant withdraws from 
the study and also withdraws consent for collection of 
future information, no further evaluations will be 
performed and no additional data will be collected 
except for publicly available information as 
appropriately directed in accordance with local law. The 
sponsor may retain and continue to use any data 
collected before such withdrawal of consent.”
To align with Pfizer’s 
Protocol Template
Section 4.5.2 
Participant 
Withdrawal from 
Study
Added tabular presentation of study interventions
To align with Pfizer’s 
protocol template
Section 5.1 
Treatments 
Administered
An SRSD was indicated for each IMP and NIMP/AxMP
To support study 
transition to Pfizer 
Pharmacovigilance 
processes and systems
Section 5.1 
Treatments 
Administered
Details on storage temperature recording, temperature 
excursion management, product complaint reporting, 
IMP preparation and destruction added.
To align with Pfizer’s 
Protocol Template.
Section 5.2 
Preparation, Handling, 
Storage, and 
Accountability
Added section to augment existing study intervention 
information as it relates to preparation and dispensing
To align with Pfizer’s 
Protocol Template.
Sections 5.3.8, 5.4.7 
Preparation and 
Dispensing
Added that complications that occur during 
hospitalization are AEs. Clarified that the term 
disabling/incapacitating does not include experiences of 
relatively minor medical significance.
To further define the 
definitions of 
hospitalization and 
disabling/incapacitating
Section 7.7.1.1 
Definitions
Revised language regarding exposure during pregnancy 
and added information on environmental and 
occupational exposure.
To support study 
transition to Pfizer 
Pharmacovigilance 
processes and systems.
Section 7.7.1.2 
subsections 
Environmental 
Exposure, Exposure 
During Pregnancy and 
Occupational 
Exposure
Added that if the investigator learns of any SAE, 
including a death, at any time after a participant has 
concluded study participation, and they consider the 
event to be reasonably related to the study intervention, 
the investigator must promptly report the SAE to Pfizer 
using PSSA.
Safety reporting period clarified in case a participant 
begins a new anticancer therapy.
To support study 
transition to Pfizer 
Pharmacovigilance 
processes and systems.
Section 7.7.1.3 
Reporting Period for 
Adverse Events and 
Serious Adverse 
Events
Pfizer Safety added as new destination of safety 
reporting.
PSSA added as electronic tool for reporting.
To support study 
transition to Pfizer 
Section 7.7.1.4 
Serious Adverse 
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Description of Change
Brief Rationale
Section # and Name 
Pharmacovigilance 
processes and systems.
Events Require 
Immediate Reporting
Clarified that local laboratory testing will be performed 
per institutional guidelines and investigator-determined 
usual and customary care.
Consistency with 
updates made in the 
document.
Section 7.7.3 Clinical 
Laboratory Tests
Added guidance on pregnancy testing 
To align with Pfizer’s 
Protocol Template.
Section 7.7.5 
Pregnancy Testing 
Added language requiring a protocol amendment 
incorporating any major modifications of the primary 
endpoint definitions or their analyses in the SAP.
To align with Pfizer’s 
Protocol Template.
Section 9.3 Statistical 
and Analytical Plans
Section retitled from “Informed Consent, Ethical 
Review, and Regulatory Considerations” to “Regulatory, 
Ethical, and Study Oversight Considerations” and text 
was updated with required Pfizer protocol template 
language. Numerous subsections were added 
(appropriate to this study) consistent with Pfizer 
template language and sections that were obsolete from 
prior version of this document were removed. Sections 
that were not obsolete were kept and integrated in 
appropriately.
To support study 
transition to Pfizer 
processes and to align 
with required Pfizer 
protocol template 
language.
Section 10 Regulatory, 
Ethical, and Study 
Oversight 
Considerations
Removal of Investigator’s agreement and the 
investigator’s signature.
The investigator’s 
agreement and 
signature is personal 
identifiable 
information.
Appendix J from prior 
amendment
AE definition, AE/SAE recording/reporting 
requirements and procedures
To support study 
transition to Pfizer 
Pharmacovigilance 
processes and systems.
Appendix J 
Adverse Events: 
Definitions and 
Procedures for 
Recording and 
Reporting
Replaced “package insert” with “product label”
Provide more 
informational 
terminology of product 
label.
Throughout document  
The term “subject” has been updated to “participant” 
when referring to an individual who has consented to 
participate in the clinical study. 
The term “Subject” has been updated to “patient” when 
used to describe the wider population beyond the trial.
The term “study drug” has been updated to “study 
intervention”.
Alignment with Pfizer 
document format and 
requirements.
Throughout protocol
Minor editorial modifications in the text, which are not 
provided in this summary of changes, were made for 
additional clarity.
Minor updates and 
clarifications.
Throughout protocol
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PROTOCOL SYNOPSIS
Protocol Number
C4251006/SGNTUC-025
Version
Amendment 03; 15-Oct-2024
Phase
2
Product Name
PF-07265792 (Tucatinib)
sponsor
Seagen Inc., a wholly owned subsidiary of Pfizer
21823 30th Drive SE
Bothell, WA 98021, USA
Protocol Title
A Single Arm, Open Label Phase 2 Study of Tucatinib in Combination with Trastuzumab Deruxtecan in 
Subjects with Previously Treated Unresectable Locally-Advanced or Metastatic HER2+ Breast Cancer
Regulatory Agency Identification Numbers:
US IND Number:
119421
ClinicalTrials.gov ID: 
NCT04539938
Protocol Number:
C4251006 (SGNTUC-025)
Phase:
2
Study Objectives and Endpoints
Primary Objective
Corresponding Primary Endpoint
●To determine the antitumor activity of tucatinib 
given in combination with trastuzumab deruxtecan 
(T-DXd) as measured by confirmed objective 
response rate (cORR) according to investigator 
(INV) assessment
●cORR per Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 according to INV 
assessment
Secondary Objectives
Corresponding Secondary Endpoints
●To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
progression-free survival (PFS) according to INV 
assessment
●PFS per RECIST v1.1 according to INV 
assessment
●To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
duration of response (DOR) according to INV 
assessment
●DOR per RECIST v1.1 according to INV 
assessment
●To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
disease control rate (DCR) according to INV 
assessment
●DCR per RECIST v1.1 according to INV 
assessment
●To assess overall survival (OS) in participants 
treated with tucatinib given in combination with 
T-DXd 
●OS
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●To assess the safety and tolerability of tucatinib 
given in combination with T-DXd
●Type, incidence, severity, seriousness, and 
relatedness of adverse events (AEs) and lab 
abnormalities 
●Frequency of dose modifications and treatment 
discontinuations 
●Other relevant safety variables
Exploratory Objectives
Corresponding Exploratory Endpoints
Efficacy
●To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd according to 
independent central review (ICR) assessment
●cORR per RECIST v1.1 according to ICR 
assessment 
●PFS per RECIST v1.1 according to ICR 
assessment 
●DOR per RECIST v1.1 according to ICR 
assessment 
●DCR per RECIST v1.1 according to ICR 
assessment 
Pharmacokinetic
●To evaluate the pharmacokinetics (PK) of tucatinib 
●Plasma concentrations of tucatinib
Biomarker
●To explore correlations between blood-based or 
tissue biomarkers and clinical outcomes
●Potential biomarkers of response, resistance, or 
toxicity from blood-based or tumor samples
Patient Reported Outcomes
●To assess patient-reported outcomes (PROs) 
associated with tucatinib given in combination 
with T-DXd
●Change from baseline in PRO assessments of the 
European Quality of Life 5-Dimension 5-Level 
(EQ-5D-5L)
Study Population
Participants with previously treated unresectable locally advanced/metastatic (LA/M) human epidermal growth 
factor receptor positive (HER2+) breast cancer who have received prior treatment with a taxane and 
trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant 
or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab).
Participants must meet the following criteria to be eligible for the study:
Inclusion Criteria
1.
Have confirmed HER2+ breast cancer, as defined by the current American Society of Clinical Oncology –
College of American Pathologists (ASCO/CAP) guidelines, previously determined at a Clinical Laboratory 
Improvements Amendments (CLIA)-certified or International Organization for Standardization 
(ISO)-accredited laboratory.
2.
History of prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting 
or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a 
taxane and trastuzumab (with or without pertuzumab)
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3.
Have disease progression of unresectable LA/M breast cancer after last systemic therapy (as confirmed by 
investigator), or be intolerant of last systemic therapy
4.
Have measurable disease assessable by RECIST v1.1
5.
Be at least 18 years of age at time of consent
6.
Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
7.
Have a life expectancy of at least 6 months, in the opinion of the investigator 
8.
Have adequate hepatic function as defined by the following: 
a.
Total bilirubin ≤1.5 x upper limit of normal (ULN). Exception: Participants with known history of 
Gilbert’s Syndrome who have a direct bilirubin ≤1.5 x ULN in addition to a normal AST and ALT are 
eligible.
b.
Transaminases (AST and ALT) ≤3 x ULN (≤5 x ULN if liver metastases are present) 
9.
Have adequate baseline hematologic parameters as defined by:
a.
Absolute neutrophil count (ANC) ≥1.5 x 103/µL
b.
Platelet count ≥100 x 103/µL
c.
Hemoglobin ≥9 g/dL
d.
In participants transfused before study entry, transfusion must be ≥14 days prior to start of therapy to 
establish adequate hematologic parameters independent from transfusion support
10. Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 using the Modification of Diet in Renal 
Disease (MDRD) study equation
11. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin 
time (aPTT) ≤1.5 x ULN, unless on medication known to alter INR and PTT/aPTT. 
12. Have 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 
13. For participants of childbearing potential (Section 4.4), the following stipulations apply.
a.
Must have a negative serum or urine pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent 
units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to starting study 
treatment. A participant with a false positive result and documented verification that the participant is 
not pregnant is eligible for participation.
b.
Must agree not to try to become pregnant during the study and for at least 7 months after the final dose 
of study intervention 
c.
Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing 
through 7 months after the final dose of study intervention 
d.
If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective 
methods of birth control (as defined in Appendix I) starting at the time of informed consent and 
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continuing throughout the study and for at least 7 months after the final dose of study intervention 
administration.
14. For participants who can father children, the following stipulations apply:
a.
Must agree not to donate sperm starting at time of informed consent and continuing throughout the 
study period and for at least 4 months after the final study intervention 
b.
If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must 
consistently use 2 highly effective methods of birth control (as defined in Appendix I) starting at time 
of informed consent and continuing throughout the study and for at least 4 months after the final dose 
of study intervention 
c.
If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 
2 contraception options (as defined in Appendix I) starting at time of informed consent and continuing 
throughout the study and for at least 4 months after the final dose of study intervention administration 
15. Participant must provide signed informed consent per a consent document that has been approved by an 
institutional review board or independent ethics committee (IRB/IEC) prior to initiation of any 
study-related tests or procedures that are not part of standard of care for the patient’s disease
16. Participants must be willing and able to comply with study procedures
CNS Inclusion – Based on medical history and screening contrast brain magnetic resonance imaging (MRI), 
participants with a history of brain metastases must have one of the following
17. 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 medical monitor is 
required prior to enrollment
18. 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 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 SRS is ≥7 days prior to first dose of study treatment, or time since surgical 
resection is ≥28 days 
ii.
Other sites of measurable disease 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
Participants will be excluded from the study for any of the following reasons:
1.
Have previously been treated with:
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a.
Lapatinib or neratinib within 12 months of starting study treatment (except in cases where lapatinib or 
neratinib was given for ≤21 days and was discontinued for reasons other than disease progression or 
severe toxicity)
b.
Tucatinib or enrolled on a tucatinib clinical trial
c.
Any investigational HER2/EGFR or HER2 TKI (eg, afatinib) at any time previously
d.
T-DXd or another ADC consisting of an exatecan derivative 
2.
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, Myocet) >550 mg/m2
3.
History of allergic reactions to trastuzumab or compounds chemically or biologically similar to tucatinib or 
T-DXd, except for Grade 1 or 2 infusion-related- reactions (IRRs) to trastuzumab that were successfully 
managed, or known allergy to one of the excipients in the study interventions
4.
Have received treatment with: 
a.
Any systemic anti-cancer therapy (including hormonal therapy) or experimental agent ≤21 days 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
b.
Treatment with non-CNS radiation ≤7 days prior to first dose of study treatment 
c.
Major surgery within <28 days of first dose of study treatment
5.
Have any toxicity related to prior cancer therapies that has not resolved to ≤Grade 1, with the following 
exceptions: 

Alopecia

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
6.
Have clinically significant cardiopulmonary disease such as:

Ventricular arrhythmia requiring therapy

Symptomatic hypertension or uncontrolled hypertension as determined by investigator

Any history of symptomatic CHF

Severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced malignancy
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
Hypoxia requiring supplementary oxygen therapy 

Have had a history of ILD/pneumonitis (eg, interstitial pneumonia, pneumonitis, pulmonary fibrosis, or 
radiation pneumonitis) that required systemic corticosteroids, or has current ILD/pneumonitis, or 
where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
7.
Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
8.
Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C 
infection. Participants who have been treated for hepatitis C infection are permitted if they have 
documented sustained virologic response of 12 weeks 
9.
Presence of known chronic liver disease
10. Participants known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any 
of the following criteria:

CD4+ T-cell count of <350 cells/µL

Detectable HIV viral load

History of an opportunistic infection within the past 12 months

On stable antiretroviral therapy for <4 weeks
11. Active or uncontrolled clinically serious infection 
12. Are pregnant, breastfeeding, or planning a pregnancy
13. Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate 
oral absorption of medications
14. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 elimination half-lives of the inhibitor, 
or have used a strong CYP3A4 or moderate/strong CYP2C8 inducer within 5 days prior to first dose of 
study treatment. 
15. Unable for any reason to undergo contrast MRI of the brain
16. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact 
safety or compliance with study procedures 
17. History of malignancy other than breast cancer within 2 years prior to screening, with the exception of 
those with a negligible risk of metastasis or death (eg, 5-year OS of ≥90%), such as adequately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma 
in situ, or Stage I uterine cancer.
CNS Exclusion – Based on medical history and screening contrast brain MRI, participants must not have any of 
the following (listed in criteria 18–22):
18. Any untreated brain lesions >2.0 cm in size, unless discussed with medical monitor and approval for 
enrollment is given
19. 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 
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daily dose of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical 
monitor
20. 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 (eg, 
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 18b
21. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
22. Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest neurologic 
progression due to brain metastases 
23. Have ongoing ≥ Grade 2 diarrhea of any etiology
Number of Planned Participants
Approximately 60 to 70 participants will be enrolled in the study to ensure about 60 participants will be treated 
at the Safety Monitoring Committee (SMC) recommended dose. 
Study Design
This is a single arm, open-label, multi-center phase 2 trial designed to assess the safety and efficacy of tucatinib 
in combination with T-DXd for the treatment of participants with previously treated unresectable LA/M HER2+ 
breast cancer with or without brain metastases, who have received prior treatment with a taxane and 
trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant 
or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). 
A SMC will continuously monitor participants for AEs, serious adverse events (SAEs), dose modifications, and 
laboratory abnormalities throughout the course of the study.
Safety Lead-in
Ten participants will be enrolled, irrespective of cohort, in the safety lead-in portion of the study and receive 
tucatinib 300 mg orally twice daily (PO BID) and T-DXd 5.4 mg/kg via intravenous (IV) infusion on Day 1 of 
each of 21-day cycle. The participants enrolled in the safety lead-in will undergo the same efficacy, PK, and 
biomarker analyses as all other participants with the exception of an additional PK assessment performed at 
Cycle 1 Day 12. Once 10 participants are enrolled in the safety lead-in, enrollment will be paused until all 
participants have been followed for at least 1 cycle and a comprehensive review of the safety profile by the 
SMC has occurred. The SMC will make recommendations regarding continuing with enrollment if the safety 
and tolerability of the regimen is acceptable. If clinically significant safety events are observed at any point 
during the safety lead-in, enrollment will be paused until relatedness has been determined, and review by the 
SMC has occurred. Based on the totality of the safety data, the SMC may recommend proceeding with 
enrollment, evaluation of alternative dosing, or not proceeding with further enrollment. The SMC may also 
recommend expanding the safety lead-in to enroll up to approximately 10 additional participants with continued 
monitoring for safety by the SMC.
Post-safety Lead-in
Following the safety lead-in, enrollment will continue until approximately 60 response-evaluable participants 
have been enrolled at the SMC recommended dose. There will be 2 cohorts in the study, 1 for participants 
without brain metastases (Cohort A) and 1 for participants with a history of brain metastases (Cohort B), with 
approximately 30 participants enrolled into each cohort. All participants, including those in the safety lead-in, 
treated at the SMC recommended dose, will be included in the efficacy analysis. Additional optional cohorts 
evaluating the combination of tucatinib and T-DXd in earlier treatment lines for breast cancer, such as the 
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first-line metastatic setting or neoadjuvant/adjuvant setting, may be added. Optional cohorts may also be opened 
in other malignancies, such as non-small cell lung cancer, urothelial cancer, gastric/gastroesophageal junction 
cancer, and colorectal cancer.
The incidence of diarrhea, though predominantly low grade, has resulted in dose modifications of tucatinib, and 
prophylactic antidiarrheals have been recommended by the SMC. Antidiarrheal prophylaxis will be 
administered for the first 42 days of study treatment. After this initial 42-day period, participants may continue 
on antidiarrheal prophylaxis or be switched to symptomatic treatment of diarrhea, at the investigator’s 
discretion. Symptomatic management of treatment-induced diarrhea should be based on established guidelines 
(Benson et al, 2004; Bossi et al, 2018). 
The primary endpoint of the study is confirmed ORR by investigator. Radiographic efficacy assessments will be 
made by the investigator, according to RECIST v1.1, with confirmation required ≥4 weeks from the first 
documentation of response. In addition, images will be collected by an ICR facility for possible future analysis.
Secondary efficacy endpoints include DOR, PFS, DCR, and OS.
As of Amendment 3, the objectives of the study have been achieved. Therefore, the decision has been made to 
close the study. For participants in long-term follow-up, a last visit or contact will occur prior to the 
participant’s discontinuation from participation in the study. Any participant on treatment with tucatinib with or 
without T-DXd will transition to the long-term extension phase (LTEP) of the study. The sponsor will provide 
continued access to study intervention during the LTEP for any participant who is still on tucatinib with or 
without T-DXd and receiving clinical benefit based on the investigator’s assessment. Once post-study access to 
study treatment is available, participants will have a last visit or contact prior to discontinuation from the study.
Investigational Products, Dose, and Mode of Administration
Participants will receive tucatinib and T-DXd in combination at the following doses:
●Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. 
●T-DXd 5.4 mg/kg IV on Day 1 of each 21-day cycle.
Duration of Treatment
Participants may continue on study treatment until progressive disease (PD), unacceptable toxicity, investigator 
or participant decision to discontinue, or study closure. All efforts should be made to continue treatment until 
unequivocal evidence of radiographic progression, per RECIST v1.1, occurs.
Participants assessed as having isolated progression in the CNS per RECIST v1.1, may be eligible to continue 
on study treatment for clinical benefit after undergoing local therapy to CNS disease, with approval from the 
medical monitor.
As of Amendment 3, participants still receiving clinical benefit based on the investigator’s assessment and 
remaining on treatment with tucatinib with or without T-DXd may continue receiving study intervention during 
the LTEP until post-study access to study treatment is available. 
Efficacy Assessments
Disease response per RECIST v1.1 will be assessed by the investigator. Response assessments will include 
measurement of all known sites of unresectable LA/M disease (including at a minimum the chest, abdomen, and 
pelvis), preferably by high quality spiral contrast computed tomography (CT), at baseline, every 6 weeks for the 
first 24 weeks, and every 9 weeks thereafter, irrespective of dose delays. Positron emission tomography 
(PET)/CT (if high quality CT scan included), and/or MRI scan may also be done as appropriate, as well as 
additional imaging of any other known sites of disease (eg, photography for skin lesions, nuclear bone scan 
imaging for bone lesions). For each participant, the same imaging modality as used at baseline should be used 
throughout the study.
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Contrast MRI of the brain will be required on this same schedule only in those participants with prior history of 
brain metastases or brain metastases found on screening MRI. Additional contrast MRIs of the brain may also 
be performed in participants without known brain metastases if there is clinical suspicion of new brain lesions.
Participants who discontinue study treatment for reasons other than documented PD will continue to have 
disease assessments every 9 weeks (±1 week) until the occurrence of disease progression per RECIST v1.1, 
death, withdrawal of consent or study closure.
Follow-up for survival and subsequent anti-cancer therapy will occur approximately every 3 months and 
continue until death, withdrawal of consent, lost to follow-up, or study closure.
During the LTEP, efficacy assessments will be performed per institutional guidelines and investigator-
determined usual and customary clinical care.
Pharmacokinetic Assessments
PK assessments of trough levels of tucatinib drug levels will be performed on Day 1 of Cycles 2, 3, and 6 prior 
to administration of tucatinib. On Day 1 of Cycles 2 and 3, PK assessments of peak levels of tucatinib will be 
performed 2 hours (±15 minutes) after administration of tucatinib. For safety lead-in participants only, an 
additional post-tucatinib dose pharmacokinetic assessment will be performed on Cycle 1 Day 12. 
Biomarker Assessments
Blood samples will be collected at screening, Cycle 3 Day 1 (predose), and at end of treatment (EOT) to assess 
exploratory biomarkers in relation to response, resistance, or toxicity. Biomarker assessments may include an 
exploratory assessment of HER2 mutations or other genetic alterations as potential biomarkers of response. 
Additional exploratory analyses on archival tissue including but not limited to immunohistochemistry (IHC) 
and next generation sequencing (NGS) analysis may be performed to interrogate biomarkers that are associated 
with tumor growth, survival, and resistance to targeted therapeutics. This assessment may enable the correlation 
of additional biomarkers with treatment outcome and may ultimately guide or refine participant selection 
strategies to better match tucatinib regimens with tumor phenotype/genotype in the future.
Safety Assessments
Participants will be assessed throughout the study for safety. Safety assessments including physical exam and 
collection of 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 interventions. 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 (LFTs) 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 interventions 
(unless done within 12 weeks prior to the EOT visit). 
Participants will be monitored for signs and symptoms of ILD/pneumonitis. In cases where ILD/pneumonitis is 
suspected, treatment with T-DXd will be interrupted, and the participant will undergo evaluation including 
radiographic imaging. Pulmonary consultation should also be considered. Dose modification or discontinuation 
of T-DXd for cases of ILD/pneumonitis will be made as per product label.
Only pregnancies and SAEs will be collected by the sponsor during the LTEP. All other assessments, including 
additional safety assessments, will be performed per institutional guidelines and investigator-determined usual 
and customary clinical care. Pregnancy testing will continue as outlined in the schedule of events for 
participants of child-bearing potential.
Patient-Reported Outcomes
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PROs will be explored with the EQ-5D-5L instrument. EQ-5D-5L will be administered prior to evaluation by 
study personnel (physical examination, review of AEs) and administration of study treatment at: Cycle 1 Day 1 
(C1D1), C2D1, C3D1, C4D1, every 2 cycles starting at Cycle 6 thereafter, until treatment discontinuation, PD, 
death, unacceptable toxicity, withdrawal of consent or study closure, and at the EOT visit.
Statistical Methods
Safety and efficacy will be assessed using descriptive statistics, including 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. 
The primary endpoint, cORR per investigator, is defined as the proportion of participants with confirmed 
complete response (CR) or partial response (PR), per RECIST v1.1. The 2-sided 95% exact confidence interval 
(CI) using Clopper-Pearson method will be calculated for the response rates.
For illustrative purposes, a summary of the expected 95% CIs for the overall study (N=60) and by cohort 
(N=30) is presented below, which shows reasonable precision for the estimation.
Number of participants
Number of Responses
ORR
95% exact CI
60
40
66.7%
(53.3%, 78.3%)
42
70.0%
(56.8%, 81.2%)
44
73.3%
(60.3%, 83.9%)
46
76.7%
(64.0%, 86.6%)
48
80.0%
(67.7%, 89.2%)
50
83.3%
(71.5%, 91.7%)
52
86.7%
(75.4%, 94.1%)
30
20
66.7%
(47.2%, 82.7%)
22
73.3%
(54.1%, 87.7%)
24
80.0%
(61.4%, 92.3%)
26
86.7%
(69.3%, 96.2%)
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................8
LIST OF TABLES...................................................................................................................24
APPENDICES .........................................................................................................................25
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................26
1. INTRODUCTION ...............................................................................................................30
1.1. HER2+ Breast Cancer .............................................................................................30
1.2. Treatment of HER2+ Breast Cancer .......................................................................30
1.2.1. Trastuzumab, Pertuzumab, and T-DM1 .....................................................30
1.2.2. Lapatinib and Neratinib..............................................................................31
1.2.3. Tucatinib.....................................................................................................31
1.2.4. Trastuzumab deruxtecan.............................................................................32
1.3. Brain Metastases in HER2+ Breast Cancer.............................................................33
1.4. Rationale for Combination of Tucatinib with Trastuzumab deruxtecan.................34
1.4.1. Preclinical ...................................................................................................34
1.4.2. Rationale for Study.....................................................................................34
2. OBJECTIVES......................................................................................................................35
3. INVESTIGATIONAL PLAN..............................................................................................36
3.1. Summary of Study Design ......................................................................................36
3.1.1. Clinically Significant Safety Events...........................................................38
3.1.2. Safety Monitoring Committee....................................................................38
3.1.3. Stopping Criteria.........................................................................................38
3.1.4. End of Study ...............................................................................................38
3.1.5. Method of Assigning Participants to Treatment Groups............................39
3.1.6. Rationale for Selection of Doses ................................................................39
3.1.7. Blinding and Unblinding ............................................................................39
4. STUDY POPULATION......................................................................................................39
4.1. Inclusion Criteria.....................................................................................................39
4.2. Exclusion Criteria....................................................................................................42
4.3. Contraception ..........................................................................................................44
4.4. Childbearing Potential.............................................................................................44
4.5. Removal of Participants from Therapy or Assessment...........................................45
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4.5.1. Discontinuation of Study Treatment...........................................................45
4.5.1.1. Continuing on Study for Isolated CNS Progression..................46
4.5.2. Participant Withdrawal from Study............................................................47
5. TREATMENTS...................................................................................................................47
5.1. Treatments Administered ........................................................................................47
5.2. Preparation, Handling, Storage and Accountability................................................48
5.3. Study Intervention (Tucatinib)................................................................................49
5.3.1. Description..................................................................................................49
5.3.2. Method of Procurement ..............................................................................49
5.3.3. Dose and Administration............................................................................50
5.3.4. Overdose.....................................................................................................50
5.3.5. Storage and Handling .................................................................................50
5.3.6. Packaging and Labeling..............................................................................51
5.3.7. Study intervention Accountability..............................................................51
5.3.8. Preparation and Dispensing........................................................................51
5.4. Combination Study intervention (T-DXd) ..............................................................51
5.4.1. Description..................................................................................................51
5.4.2. Method of Procurement ..............................................................................51
5.4.3. Dose, Preparation, and Administration.......................................................51
5.4.4. Overdose.....................................................................................................52
5.4.5. Storage and Handling .................................................................................52
5.4.6. Study intervention Accountability..............................................................52
5.4.7. Preparation and Dispensing........................................................................52
5.5. Dose Modifications .................................................................................................52
5.5.1. Tucatinib Dose Reductions.........................................................................53
5.5.2. Trastuzumab Deruxtecan Dose Reductions................................................53
5.5.3. Dose Modifications for Adverse Events.....................................................54
5.5.3.1. General Guidelines....................................................................54
5.5.3.2. Hepatotoxicity...........................................................................55
5.5.3.3. Interstitial Lung Disease/Pneumonitis ......................................56
5.5.3.4. Neutropenia and Febrile Neutropenia .......................................57
5.5.3.5. Left Ventricular Ejection Fraction Decrease.............................57
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5.6. Concomitant Therapy..............................................................................................58
5.6.1. Required Concomitant Therapy..................................................................58
5.6.2. Allowed Concomitant Therapy...................................................................58
5.6.3. Prohibited Concomitant Therapy................................................................59
5.7. Management of Treatment-emergent Adverse Events............................................60
5.7.1. Infusion-related Reaction and its Management ..........................................60
5.7.2. Allergic/Hypersensitivity Reaction ............................................................61
5.7.3. Anaphylaxis................................................................................................61
5.7.4. Management of Treatment-associated Diarrhea.........................................61
5.8. Treatment Compliance ............................................................................................62
6. STUDY ACTIVITIES .........................................................................................................62
6.1. Schedule of Events..................................................................................................62
6.2. Screening Visit (Days –28 to 1) ..............................................................................63
6.3. Treatment Period (21-day cycles) ...........................................................................64
6.3.1. Cycle 1 Day 1 .............................................................................................64
6.3.2. Cycle 1 Day 12 (±3 days) ...........................................................................65
6.3.3. Cycle 2 Day 1 (–1 day to +3 days) .............................................................65
6.3.4. Cycle 2 Day 12 (±3 days) ...........................................................................66
6.3.5. Cycle 3 and Beyond, Day 1 (–1 day to +3 days)........................................66
6.3.6. Every 6 Weeks (–7 days) as Determined by Cycle 1 Day 1, Through 
Week 24, then Every 9 Weeks (–7 days) Through End of Treatment.............67
6.3.7. Every 12 Weeks (–7 days) as Determined by Cycle 1 Day 1.....................67
6.4. End of Treatment Visit (30 to 37 days after last dose of study treatment)..............68
6.5. Follow-up ................................................................................................................69
6.5.1. Follow-up until Disease Progression (at least every 9 weeks 
±1 week)...........................................................................................................69
6.5.2. Long Term Follow-up (every 90 Days ±14 days) ......................................69
6.6. End of Study/End of Follow-up ..............................................................................70
6.7. Long-term Extension Phase (LTEP) .......................................................................70
7. STUDY ASSESSMENTS ...................................................................................................70
7.1. Screening/Baseline Assessments.............................................................................70
7.1.1. Treatment for Brain Metastases Prior to Study Entry ................................70
7.2. Response/Efficacy Assessments .............................................................................71
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7.2.1. Evaluation of Brain Metastases ..................................................................72
7.2.2. Isolated Progression in the Brain................................................................72
7.3. Pharmacokinetic Assessments.................................................................................73
7.4. Biomarker Studies...................................................................................................74
7.5. Biospecimen Repository .........................................................................................74
7.6. Patient-reported Outcomes......................................................................................75
7.6.1. EQ-5D-5L – Utility Measurement..............................................................75
7.7. Safety Assessments .................................................................................................75
7.7.1. Adverse Events...........................................................................................76
7.7.1.1. Definitions.................................................................................76
7.7.1.2. Procedures for Eliciting and Recording Adverse Events..........80
7.7.1.3. Reporting Periods for Adverse Events and Serious 
Adverse Events..................................................................................85
7.7.1.4. Serious Adverse Events Require Immediate Reporting............85
7.7.2. Vital Signs ..................................................................................................86
7.7.3. Clinical Laboratory Tests ...........................................................................86
7.7.4. Physical Examination .................................................................................86
7.7.5. Pregnancy Testing ......................................................................................86
7.7.6. Interstitial Lung Disease.............................................................................87
7.7.7. Cardiac Function.........................................................................................87
7.7.7.1. MUGA or ECHO ......................................................................87
7.7.7.2. Electrocardiogram .....................................................................87
7.8. Appropriateness of Measurements..........................................................................87
8. DATA QUALITY CONTROL AND QUALITY ASSURANCE.......................................88
8.1. Site Training and Monitoring Procedures ...............................................................88
8.2. Accuracy and Reliability of Data............................................................................89
8.3. Data Management Procedures.................................................................................89
9. DATA ANALYSIS METHODS .........................................................................................89
9.1. Determination of Sample Size.................................................................................89
9.2. Study Endpoint Definitions.....................................................................................90
9.2.1. Objective Response Rate............................................................................90
9.2.2. Progression-free Survival ...........................................................................90
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9.2.3. Duration of Response .................................................................................90
9.2.4. Disease Control Rate ..................................................................................90
9.2.5. Overall Survival..........................................................................................91
9.2.6. Exploratory Endpoints................................................................................91
9.2.6.1. Pharmacokinetic Analysis.........................................................91
9.2.6.2. Biomarker Analysis...................................................................91
9.2.6.3. Patient-reported Outcomes........................................................91
9.3. Statistical and Analytical Plans...............................................................................91
9.3.1. General Considerations...............................................................................91
9.3.1.1. Randomization and Blinding.....................................................91
9.3.1.2. Adjustments for Covariates.......................................................91
9.3.1.3. Handling of Dropouts and Missing Data...................................92
9.3.1.4. Multi-center Studies ..................................................................92
9.3.1.5. Multiple Comparisons and Multiplicity....................................92
9.3.1.6. Data Transformations and Derivations......................................92
9.3.1.7. Analysis Sets .............................................................................92
9.3.1.8. Examination of Subgroups........................................................92
9.3.1.9. Timing of Analyses ...................................................................92
9.3.2. Participant Disposition................................................................................93
9.3.3. Participant Characteristics ..........................................................................93
9.3.4. Exposure .....................................................................................................93
9.3.5. Efficacy Analyses .......................................................................................93
9.3.5.1. Primary Efficacy Analyses........................................................93
9.3.5.2. Secondary Efficacy Analyses....................................................93
9.3.5.3. Exploratory Efficacy Analyses..................................................94
9.3.6. Pharmacokinetic Analyses..........................................................................94
9.3.7. Biomarker Analyses....................................................................................94
9.3.8. Patient-reported Outcomes Analyses..........................................................94
9.3.9. Safety Analyses ..........................................................................................94
9.3.9.1. Adverse Events..........................................................................94
9.3.9.2. Deaths and Serious Adverse Events..........................................95
9.3.9.3. Clinical Laboratory Results.......................................................95
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9.3.9.4. Other Safety Analyses...............................................................95
9.3.10. Interim Analyses.......................................................................................95
10. REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS..........97
10.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................97
10.1.1. Informed Consent Process ........................................................................98
10.1.2. Data Protection .........................................................................................98
10.1.3. Committees Structure ...............................................................................99
10.1.4. Dissemination of Clinical Study Data ......................................................99
10.1.5. Data Quality Assurance ..........................................................................100
10.1.6. Source Documents..................................................................................101
10.1.7. Use of Medical Records..........................................................................102
10.1.8. Study and Site Start and Closure ............................................................102
10.1.9. Publication Policy...................................................................................103
10.1.10. Sponsor’s Medically Qualified Individual............................................104
10.1.11. Protocol Amendments and Study Termination.....................................104
10.2. Clinical Trial Agreement.....................................................................................104
11. REFERENCES ................................................................................................................105
SUMMARY OF CHANGES IN AMENDMENT 1....................................................129
SUMMARY OF CHANGES IN AMENDMENT 2....................................................130
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LIST OF TABLES
Table 1:
Study Objectives and corresponding endpoints........................................35
Table 2:
Study Interventions...................................................................................47
Table 3:
Recommended tucatinib dose reduction...................................................53
Table 4:
Recommended T-DXd dose reduction .....................................................54
Table 5:
Dose modifications for clinical adverse events related to either 
tucatinib or T-DXd ...................................................................................54
Table 6:
Dose modification guidelines for liver function abnormalities................55
Table 7:
Dose modification guidelines for interstitial lung 
disease/pneumonitis..................................................................................56
Table 8:
Dose modification guidelines for neutropenia and febrile 
neutropenia ...............................................................................................57
Table 9:
Dose modification guidelines for left ventricular ejection fraction 
decrease.....................................................................................................57
Table 10:
Pharmacokinetic sample collection time points .......................................74
Table 11:
Expected 95% CI for different number of responses................................89
Table 12:
Requirements for Recording AEs on the CRF and for Reporting 
SAEs via PSSA.......................................................................................127
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APPENDICES
Appendix A. SCHEDULE OF EVENTS...............................................................................109
Appendix B. CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION 
HALF-LIVES .........................................................................................115
Appendix C. CYP3A4 INDUCERS AND THEIR ELIMINATION HALF-LIVES ............116
Appendix D. EXAMPLES OF CLINICAL SUBSTRATES FOR CYP3A-MEDIATED 
METABOLISM......................................................................................117
Appendix E. ECOG PERFORMANCE STATUS SCALE...................................................118
Appendix F. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF T-
DXD INDUCED INTERSTITIAL LUNG 
DISEASE/PNEUMONITIS....................................................................119
Appendix G. POTENTIAL CONDITIONS THAT COULD TRIGGER CLINICAL 
EVALUATION FOR SUSPECTED INTERSTITIAL LUNG 
DISEASE................................................................................................121
Appendix H. EQ-5D-5L (SAMPLE QUESTIONNAIRE)....................................................122
Appendix I. GUIDANCE ON CONTRACEPTION .............................................................125
Appendix J. ADVERSE EVENTS: DEFINITIONS and PROCEDURES for 
RECORDING and REPORTING...........................................................127
Appendix K. Summary of Changes for Prior Amendments ..................................................129
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BAP
biomarker analysis plan
β-hCG
beta human chorionic gonadotropin 
BID
twice daily
CAP
College of American Pathologists
CBC
complete blood count
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CLIA
Clinical Laboratory Improvements Amendments
CNS
central nervous system
cORR
confirmed objective response rate
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DILI
drug-induced liver injury
DOR 
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic CRF
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EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EGRF
epidermal growth factor receptor
EOT
end of treatment
EQ-5D-5L
European Quality of Life 5-Dimension 5-Level 
FDA 
U.S. Food and Drug Administration
GCP
Good Clinical Practice
HER2
human epidermal growth factor receptor
HR
hazard ratio
IB
investigator’s brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICR 
independent central review
IEC
independent ethics committee
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
INR
international normalized ratio
INV 
investigator
IP
investigational product
IRB
institutional review board
IRR 
infusion-related reaction
ISO
International Organization for Standardization
IV
intravenous
LA/M
locally advanced/metastatic
LFT
liver function test
LTEP
long-term extension phase
LVEF
Left ventricular ejection fraction
MBC
metastatic breast cancer
MDRD
Modification of Diet in Renal Disease [study]
MedDRA
Medical Dictionary for Regulatory Activities
MQI
medically qualified individual
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MRI 
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
NCI 
National Cancer Institute 
NGS
Next Generation Sequencing
ORR
Objective response rate 
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetics
PO
orally
PR
partial response
PRO
patient-reported outcome
PSSA
Pfizer’s SAE submission assistant
PTT
partial thromboplastin time
QoL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SMC
Safety Monitoring Committee
SoE
schedule of events
SRS
stereotactic radiosurgery
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
T-DM1
ado-trastuzumab emtansine
T-DXd
trastuzumab deruxtecan
TEAE
treatment-emergent adverse event
T-Ex
trastuzumab conjugated with exatecan moiety
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
VAS
visual analog scale
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WBRT
whole brain radiation therapy
WOCBP
woman of childbearing potential
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1. INTRODUCTION
1.1. HER2+ Breast Cancer
Breast cancer is the most common form and leading cause of cancer-related death in women 
worldwide (Bray et al, 2018). In 2020, the estimated number of women that will be newly 
diagnosed with breast cancer in the United States is 276,480, and there will be 42,170 breast 
cancer-related deaths (Siegel et al, 2020). Approximately 15% to 20% of all breast cancers 
overexpress the human epidermal growth factor receptor 2 (HER2) (Owens et al, 2004; 
Giordano et al, 2014; American Cancer Society (ACS), 2018). HER2 is a transmembrane 
tyrosine kinase receptor that mediates cell growth, differentiation, and survival. Tumors that 
overexpress HER2 are more aggressive and historically have been associated with poorer 
overall survival (OS) compared to HER2 negative cancers (Slamon et al, 1987).
1.2. Treatment of HER2+ Breast Cancer
The introduction of HER2-targeted therapies has led to significant and meaningful 
improvements in disease-free survival, progression-free survival (PFS), and OS in both the 
neoadjuvant/adjuvant and metastatic settings (Slamon et al, 2001; Geyer et al, 2006; Baselga 
et al, 2012; Verma et al, 2012).
1.2.1. Trastuzumab, Pertuzumab, and T-DM1
Trastuzumab, a humanized anti-HER2 antibody that binds to the HER2 extracellular domain, 
was the first anti-HER2 agent approved by regulatory authorities for use in the treatment of 
HER2+ breast cancer and remains the backbone of treatment in the perioperative and 
metastatic setting, usually in combination with a taxane (Slamon et al, 2001; Vogel et al, 
2002). 
The development of trastuzumab has been followed by the approval of multiple anti-HER2 
agents for the management of HER2+ breast cancer. Pertuzumab, a monoclonal antibody that 
binds to the HER2 receptor at a site different from trastuzumab, in combination with 
trastuzumab and a taxane is the current standard of care in the first-line metastatic setting 
based on data from the CLEOPATRA study (Swain et al, 2015). In addition, pertuzumab is 
approved for the neoadjuvant treatment of patients with early stage breast cancer (either 
greater than 2 cm in diameter or node positive) and adjuvant treatment of patients with 
HER2+ early breast cancer at high risk of recurrence (Gianni et al, 2016; von Minckwitz et 
al, 2017); (PERJETA® Prescribing Information, Genentech, Inc., Dec 2018).
Ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) composed of 
trastuzumab, a thioether linker, and a derivative of the antimitotic agent maytansine, was 
approved for the treatment of patients with HER2+ metastatic breast cancer (MBC) who 
previously received trastuzumab and a taxane (prior therapy for metastatic disease, or 
development of recurrence during or within 6 months of completing adjuvant therapy), and is 
the current standard of care in the second-line metastatic setting (Verma et al, 2012)
(KADCYLA® Prescribing Information, Genentech, Inc., Dec 2018). More recently, T-DM1 
showed superior efficacy relative to trastuzumab in the adjuvant therapy management of 
participants who had less than a pathological complete remission to neoadjuvant 
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trastuzumab-based therapy in the KATHERINE study (von Minckwitz et al, 2014; von 
Minckwitz et al, 2019).
1.2.2. Lapatinib and Neratinib
Lapatinib and neratinib are HER2 targeting tyrosine kinase inhibitors (TKIs) that have also 
been approved for the treatment of HER2+ breast cancer. Lapatinib targets both the HER2 
receptor and the epidermal growth factor receptor (EGFR) and was approved in combination 
with capecitabine in patients with metastatic disease who have progressed following prior 
trastuzumab, anthracycline, and taxane therapy (Geyer et al, 2006) (TYKERB® Prescribing 
Information, Novartis Pharmaceuticals Corp., Dec 2018). Lapatinib has also been approved 
in combination with letrozole in postmenopausal patients with hormone receptor positive 
metastatic disease(Schwartzberg et al, 2010). Neratinib, a pan-Erb inhibitor, was approved 
for the extended adjuvant treatment of patients with high-risk early stage HER2+ breast 
cancer, to follow adjuvant trastuzumab-based therapy (Chan et al, 2016). Neratinib is also 
approved in combination with capecitabine for treatment in the metastatic setting in breast 
cancer patients who have received 2 or more prior anti-HER2 based regimens. However, 
lapatinib and neratinib have been associated with toxicities including diarrhea and rash that 
are likely associated with EGFR inhibition. As an example, over 40% of participants in the 
neratinib adjuvant ExteNET study experienced Grade ≥3 diarrhea, and antidiarrheal 
prophylaxis is now recommended with neratinib use (NERLYNX® Prescribing Information, 
Puma Biotechnology, Inc., Jun 2018). Despite these advances, the toxicities associated with 
lapatinib and neratinib limit their ability to combine with other HER2-directed or cytotoxic 
agents. 
1.2.3. Tucatinib
Tucatinib is an orally (PO)-available, reversible HER2 small molecule TKI. Two key 
features of tucatinib are its potency and selectivity for HER2 compared to the closely related 
kinase EGFR. Tucatinib is a potent inhibitor of HER2 in vitro, and in cellular signaling 
assays is >1000-fold more selective for HER2 compared to EGFR. The selectivity of 
tucatinib for HER2 reduces the potential for EGFR-related side effects, such as skin rash and 
gastrointestinal toxicity. This unique feature also differentiates tucatinib from other HER2 
targeting TKIs, such as lapatinib and neratinib, which inhibit both HER2 and EGFR with 
similar potency and are associated with the aforementioned side effects associated with 
EGFR inhibition. Furthermore, the limited toxicity associated with tucatinib allows for the 
potential for combination with other agents.
Recently, based on results from the HER2CLIMB study, tucatinib was approved in the US 
under the trade name TUKYSA, in combination with trastuzumab and capecitabine, for 
treatment of adult patients with advanced unresectable or metastatic HER2+ breast cancer, 
including patients with brain metastases, who have received 1 or more prior 
anti-HER2-based regimens in the metastatic setting (TUKYSA Prescribing Information, 
Seattle Genetics, Apr 2020). In HER2CLIMB, the addition of tucatinib to trastuzumab and 
capecitabine was found to be superior to trastuzumab and capecitabine alone, with a 
46% reduction in the risk of disease progression or death (hazard ratio [HR]=0.54 
[95% confidence interval {CI}: 0.42, 0.71]; p<0.00001) in participants previously treated 
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with trastuzumab, pertuzumab, and T-DM1 (Murthy et al, 2020). The trial also met the 2 key 
secondary endpoints at interim analysis. The tucatinib arm demonstrated an improvement in 
OS, with a 34% reduction in the risk of death (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048) 
compared to trastuzumab and capecitabine alone. For patients with brain metastases at 
baseline, the tucatinib arm also demonstrated superior PFS, with a 52% reduction in the risk 
of disease progression or death compared to those who received trastuzumab and 
capecitabine alone (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001). Lastly, treatment with 
tucatinib in combination with trastuzumab and capecitabine in these participants resulted in a 
significantly higher confirmed objective response rate (cORR) (40.6% [95% CI: 35.3, 46.0]) 
vs. participants treated in the control arm (22.8% [95% CI: 16.7, 29.8]; P=0.00008).
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated 
with a manageable safety profile. The most frequent adverse events (AEs) in the tucatinib 
arm included diarrhea, palmar-plantar erythrodysesthesia syndrome (PPE), nausea, fatigue, 
and vomiting. Grade 3 or greater AEs in the tucatinib arm compared to the control arm 
included diarrhea (12.9% vs. 8.6%), increased aspartate aminotransferase (AST) (4.5% vs. 
0.5%), increased alanine aminotransferase (ALT) (5.4% vs. 0.5%) and increased bilirubin 
(0.7% vs. 2.5%). There was no requirement for prophylactic antidiarrheals. AEs leading to 
discontinuations were infrequent in both the tucatinib arm and the control arm (5.7% and 
3.0%).
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 study in human participants is provided in the Investigator’s Brochure.
1.2.4. Trastuzumab deruxtecan
T-DXd is an ADC comprised of a humanized IgG1 antibody directed at HER2 
(fam-trastuzumab), the topoisomerase I inhibitor, Dxd, and a cleavable tetrapeptide linker. 
T-DXd targets HER2 at the cell surface and, upon binding to HER2, is internalized. 
Intracellularly, the tetrapeptide linker is cleaved by lysosomal cathepsins, releasing Dxd, a 
derivative of exatecan. Dxd inhibits topoisomerase I resulting in antitumor activity (Modi et 
al, 2020). 
Trastuzumab deruxtecan was granted accelerated approval in the US under the trade name 
ENHERTU for treatment of adult patients with unresectable or metastatic HER2+ breast 
cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic 
setting, based upon data from the DESTINY-Breast01 study (ENHERTU Prescribing 
Information, Daiichi Sankyo, Dec 2019). In the phase 2 single arm study, treatment with 
T-DXd resulted in a cORR of 60.9% (95% CI: 53.4, 68.0) in participants with metastatic 
HER2+ breast cancer previously treated with T-DM1 (Modi et al, 2020).  In contrast to the 
HER2CLIMB study, patients with active brain metastases were excluded; however, the study 
did enroll participants with treated brain metastases. In DESTINY-Breast03, a randomized 
phase 3 study, participants with HER2+ unresectable and/or metastatic breast cancer 
previously treated with trastuzumab and a taxane received either T-DXd or TDM1. The 
median PFS was not reached for T-DXd vs 6.8 months for T-DM1 (HR 0.28 [95% CI, 0.22, 
0.37]). The confirmed ORR for T-DXd was 79.1% (95% CI, 74.3, 84.4) (Cortés et al, 2021). 
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Common AEs for T-DXd in the DESTINY-Breast01 study were nausea, fatigue, vomiting, 
alopecia, constipation, decreased appetite, anemia, diarrhea, cough, and thrombocytopenia. 
The most common Grade ≥3 AEs were neutropenia (20.7%), anemia (8.7%), and nausea 
(7.6%) (Modi et al, 2020). The safety profile of T-DXd in the DESTINY-Breast03 study was 
consistent with what was reported in the DESTINY-Breast01 study. In DESTINY-Breast03, 
similar rates of any grade and Grade ≥3 drug-related treatment-emergent adverse events were 
reported in the two treatment arms. Treatment with T-DXd may result in severe or fatal 
interstitial lung disease (ILD), including pneumonitis. In studies of T-DXd for MBC, 9% of 
patients experienced ILD and/or pneumonitis; 2.6% of which had fatal outcomes due to ILD 
and/or pneumonitis (ENHERTU Prescribing Information, Daiichi Sankyo, Dec 2019). In 
DESTINY-Breast03, drug-related ILD and/or pneumonitis was reported in 10.5% of 
participants treated with T-DXd; none of which reported Grade 4 or Grade 5 ILD and/or 
pneumonitis events. 
1.3. Brain Metastases in HER2+ Breast Cancer
The advances over the past 2 decades in the development of novel therapeutics for HER2+ 
breast cancer have resulted in better control of systemic disease. Because of this significant 
improvement, patients live longer (as demonstrated by increases in PFS and OS) and more 
patients are developing brain metastases. Clinical trials suggest that there is an increased risk 
of first relapse occurring in the central nervous system (CNS) in participants who have 
received trastuzumab-based adjuvant therapy (Clayton et al, 2004; Olson et al, 2013a; Olson 
et al, 2013b), and up to 50% of HER2+ participants with metastatic disease will develop
CNS metastases at some point during the course of the disease (Clayton et al, 2004; 
Goldhirsch et al, 2013; Pestalozzi et al, 2013). The increasing prevalence of CNS metastases 
in participants with HER2+ breast cancer may be due to several factors (Lin et al, 2004). 
First, HER2+ breast cancer appears to display a special tropism for the CNS tissue. Second, 
with better control of non-CNS disease, participants may be living longer, allowing CNS 
metastases to become more of a critical clinical issue. Finally, the CNS may represent a 
sanctuary site for HER2+ disease, as large molecules such as trastuzumab and pertuzumab do 
not penetrate the blood-brain barrier to any meaningful extent at approved doses. The 
evidence suggests that drug blood-brain barrier permeability is most likely a function of not 
only P-glycoprotein expression but also the interplay of molecule size, charge, lipophilicity, 
tumor neovasculature anatomy, and plasma protein binding (Gerstner & Fine, 2007). 
Treatment for brain metastases usually includes either surgical resection, radiosurgery, and/or 
whole brain radiotherapy in addition to continuation of systemic anti-HER2 therapy. 
Unfortunately, these treatments often result in significant neurologic toxicities, which may 
impair quality of life (QoL). Stereotactic radiosurgery (SRS) has been increasingly used to 
avoid the neurologic toxicities of whole-brain radiotherapy, but the trade-off for this decrease 
in toxicity has been inferior control of distant brain relapse outside of the radiation fields 
(Chang et al, 2009; Brown et al, 2016; Kaidar-Person et al, 2016). 
Breast cancer patients with HER2+ brain metastases have a worse prognosis relative to those 
without CNS disease. In population-based registries of HER2+ MBC enrolled at diagnosis, 
evidence of brain metastases leads to a shortened survival relative to participants without 
brain metastases (Brufsky et al, 2011). Among the 377 participants with brain metastases, 
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median OS from the date of initial MBC diagnosis was 26.3 months (range: 1.0 to 
60.9 months) compared to 44.6 months (range: 0.5 to 59.7 months) in the 635 participants 
who did not have CNS metastases (Brufsky et al, 2011).
Taken together, HER2-targeting regimens that distribute into the brain are needed. Until the 
recent regulatory approval of tucatinib in combination with trastuzumab and capecitabine, 
which includes patients with brain metastases, no systemic agents had been shown to 
demonstrate benefit in this patient population. Moreover, breast cancer patients with brain 
metastases have historically been excluded from clinical trials. Development of novel 
combinations for this patient population remains an important medical need, and addressing 
this need will require including these participants in clinical trials.
1.4. Rationale for Combination of Tucatinib with Trastuzumab deruxtecan
Treatment failures in HER2+ breast cancer may result from primary or acquired resistance to 
HER2 blockade (Lu et al, 2001; Nahta & Esteva, 2006; Scaltriti et al, 2007; Pohlmann et al, 
2009). There is evidence that dual targeting of HER2, in particular when further combining 
with a cytotoxic agent, can lead to further improvements in efficacy in patients with MBC 
(Swain et al, 2015; Murthy et al, 2020). Therefore, the combination of tucatinib with T-DXd 
may result in further improvement on the efficacy seen with either agent, potentially through 
overcoming or delaying the development of resistance through dual HER2 blockade.
1.4.1. Preclinical
Pre-clinical data have shown that the combination of tucatinib with a HER2 directed ADC 
comprised of trastuzumab conjugated with exatecan moieties (T-Ex) results in improved 
anti-tumor activity in HER2+ breast cancer models. In HER2+ tumor-derived cell lines, 
tucatinib in combination with T-Ex can result in additive or synergistic activity (data not 
shown). In addition, the combination of tucatinib and T-Ex resulted in more effective tumor 
reduction than either drug individually in the BT-474 cell line-derived xenograft model and 
in 2 HER2+ patient-derived (PDX) breast cancer models (Kulukian et al, 2020).
1.4.2. Rationale for Study
Significant progress has been made in the management of HER2+ breast cancer over the past 
2 decades, with regulatory approval of multiple HER2-targeting agents. Recently, both 
tucatinib (in combination with trastuzumab and capecitabine) and T-DXd were approved by 
the US FDA for the treatment of patients with HER2+ MBC who have received prior 
HER2-directed therapy in the metastatic setting. However, despite these advances, metastatic 
disease remains incurable, and patients will eventually progress on currently available 
therapies. Although tucatinib (in combination with trastuzumab and capecitabine) and 
T-DXd have demonstrated clinically meaningful improvements in efficacy for patients with 
MBC, better outcomes may be achieved by combining the 2 agents. This is particularly 
important in patients with brain metastases where the prognosis remains worse when 
compared to patients without brain metastases. Gastrointestinal adverse events such as 
nausea and/or diarrhea have been observed as an overlapping toxicity with these 2 agents. 
Additionally, tucatinib is associated with increases in liver transaminases (AST and ALT), 
and T-DXd is associated with decreased blood counts (eg, neutropenia and anemia) and
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ILD/pneumonitis. Thus, the intent of this phase 2 single arm study is to assess the safety and 
preliminary efficacy of the combination of tucatinib and T-DXd in participants with HER2+ 
MBC, with and without brain metastases. 
2. OBJECTIVES
This study will evaluate the safety and efficacy of tucatinib in combination with T-DXd in 
participants with unresectable locally advanced/metastatic (LA/M) HER2+ breast cancer, 
with and without brain metastases, who have received prior treatment with a taxane and 
trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 
6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and 
trastuzumab (with or without pertuzumab). Specific objectives and corresponding endpoints 
for the study are summarized below (Table 1).
Table 1:
Study Objectives and corresponding endpoints
Primary Objective
Corresponding Primary Endpoint

To determine the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
confirmed objective response rate (cORR) 
according to investigator (INV) assessment

cORR per Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1 according 
to INV assessment
Secondary Objectives
Corresponding Secondary Endpoints

To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
progression-free survival (PFS) according to INV 
assessment

PFS per RECIST v1.1 according to INV 
assessment

To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
duration of response (DOR) according to INV 
assessment

DOR per RECIST v1.1 according to INV 
assessment

To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd as measured by 
disease control rate (DCR) according to INV 
assessment

DCR per RECIST v1.1 according to INV 
assessment

To assess overall survival (OS) in participants
treated with tucatinib given in combination with 
T-DXd 

OS

To assess the safety and tolerability of tucatinib 
given in combination with T-DXd

Type, incidence, severity, seriousness, and 
relatedness of adverse events (AEs) and lab 
abnormalities 

Frequency of dose modifications and treatment 
discontinuations 

Other relevant safety variables
Exploratory Objectives
Corresponding Exploratory Endpoints
Efficacy

To evaluate the antitumor activity of tucatinib 
given in combination with T-DXd according to 
independent central review (ICR) assessment

cORR per RECIST v1.1 according to 
ICR assessment 
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Table 1:
Study Objectives and corresponding endpoints

PFS per RECIST v1.1 according to 
ICR assessment 

DOR per RECIST v1.1 according to 
ICR assessment 

DCR per RECIST v1.1 according to 
ICR assessment 
Pharmacokinetic

To evaluate the pharmacokinetics (PK) of 
tucatinib 

Plasma concentrations of tucatinib
Biomarker

To explore correlations between blood-based or 
tissue biomarkers and clinical outcomes

Potential biomarkers of response, resistance, 
or toxicity from blood-based or tumor samples
Patient Reported Outcomes 

To assess patient-reported outcomes (PROs) 
associated with tucatinib given in combination 
with T-DXd

Change from baseline in PRO assessments of 
the European Quality of Life 5-Dimension 
5-Level (EQ-5D-5L)
3. INVESTIGATIONAL PLAN
3.1. Summary of Study Design
This is a single arm, open-label, multi-center phase 2 trial designed to assess the safety and 
efficacy of tucatinib in combination with T-DXd for the treatment of participants with 
previously treated unresectable LA/M HER2+ breast cancer with or without brain metastases 
who have received prior treatment with a taxane and trastuzumab (with or without 
pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or 
adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without 
pertuzumab). 
A Safety Monitoring Committee (SMC) will monitor participants for AEs, serious adverse 
events (SAEs), dose modifications, and laboratory abnormalities throughout the course of the 
study.
As of Amendment 3, the objectives of the study have been achieved. Therefore, the decision 
has been made to close the study. For participants in long- term follow-up, a last visit or 
contact will occur prior to the participant’s discontinuation from the study. Any participant 
on treatment with tucatinib with or without T-DXd will transition to the LTEP of the study. 
The sponsor will provide continued access to study intervention during the LTEP for any 
participant who is still on tucatinib with or without T-DXd and receiving clinical benefit 
based on the investigator’s assessment. Once post-study access to study treatment is 
available, participant will have a last visit or contact prior to discontinuation from the study. 
Safety Lead-in
Ten participants will be enrolled, irrespective of cohort, in the safety lead-in portion of the 
study and receive tucatinib 300 mg PO twice daily (BID) and T-DXd 5.4 mg/kg via 
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intravenous (IV) infusion on Day 1 of each of 21-day cycle. The participants enrolled in the 
safety lead-in will undergo the same efficacy, PK, and biomarker analyses as all other 
participants with the exception of an additional PK assessment performed at Cycle 1, Day 12. 
Once 10 participants are enrolled in the safety lead-in, enrollment will be paused until all 
participants have been followed for at least 1 cycle and a comprehensive review of the safety 
profile by the SMC has occurred. The SMC will make recommendations regarding
continuing with enrollment if the safety and tolerability of the regimen is acceptable. If 
clinically significant safety events are observed at any point during the safety lead-in, 
enrollment will be paused until relatedness has been determined, and review by the SMC has 
occurred. Based on the totality of the safety data, the SMC may recommend proceeding with 
enrollment, evaluation of alternative dosing, or not proceeding with further enrollment. The 
SMC may also recommend expanding the safety lead-in to enroll up to approximately 
10 additional participants with continued monitoring for safety by the SMC.
Post-safety Lead-in
Following the safety lead-in, enrollment will continue until approximately 
60 response-evaluable participants have been enrolled at the SMC recommended dose. There 
will be 2 cohorts in the study, 1 for participants without brain metastases (Cohort A) and 1 
for participants with a history of brain metastases (Cohort B), with approximately 
30 participants enrolled into each cohort. All participants, including those in the safety 
lead-in, treated at the SMC recommended dose, will be included in the efficacy analysis. 
Additional optional cohorts evaluating the combination of tucatinib and T-DXd in earlier 
treatment lines for breast cancer, such as the first-line metastatic setting or 
neoadjuvant/adjuvant setting, may be added. Optional cohorts may also be opened in other 
malignancies, such as non-small cell lung cancer, urothelial cancer, gastric/gastroesophageal 
junction cancer, and colorectal cancer. 
The incidence of diarrhea, though predominantly low grade, has resulted in dose 
modifications of tucatinib, and prophylactic antidiarrheals have been recommended by the 
SMC. Antidiarrheal prophylaxis will be required for all participants following protocol 
amendment 2. Antidiarrheal prophylaxis will be administered for the first 42 days of study 
treatment. Following this initial 42-day period, participants may continue on antidiarrheal 
prophylaxis or be switched to symptomatic treatment of diarrhea, at the investigator’s 
discretion. Symptomatic management of treatment-induced diarrhea should be based on 
established guidelines (Benson et al, 2004; Bossi et al, 2018).
The primary endpoint of the study is cORR by investigator. Radiographic efficacy 
assessments will be made by the investigator, according to RECIST v1.1, with confirmation 
required ≥4 weeks from the first documentation of response. In addition, images will be 
collected by an ICR facility for possible future analysis.
Secondary efficacy endpoints include DOR, PFS, DCR, and OS.
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3.1.1. Clinically Significant Safety Events
Clinically significant safety events will be AEs or laboratory abnormalities that occur during 
the safety lead-in portion that are related to tucatinib or T-DXd, and that are considered 
sufficiently important to merit a pause of enrollment during the safety lead-in for 
determination of relatedness and review by the SMC. Events for which there is an alternative 
clinical explanation (eg, clearly related to an intercurrent illness or disease progression), will 
not be considered clinically significant safety events. The severity of AEs and laboratory 
abnormalities will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The relationship of AEs to 
study interventions will be determined by the investigator. 
Occurrence of a clinically significant safety event will result in a pause in enrollment while 
the SMC evaluates the events and determines whether to proceed with the study. Participants 
who experience a clinically significant safety event may continue on study treatment if 
treatment discontinuation is not required by protocol dose modification criteria and the 
investigator believes it to be in the participant's best interest. Participants may resume 
treatment at a lower dose (eg, the next lower dose level of tucatinib and/or a reduced dose of 
T-DXd) following recovery of the AE to ≤ Grade 1 or the baseline grade. 
3.1.2. Safety Monitoring Committee
The SMC will be responsible for monitoring the safety of participants in the study at regular 
intervals. In particular, the SMC will evaluate clinically significant safety events and other 
safety data in the safety lead-in stage; PK data may also be evaluated, if available. The SMC 
will review data on deaths, study treatment and study intervention discontinuations, dose 
reductions, AEs, SAEs, laboratory abnormalities, and PK data on a regular basis. The SMC 
will make recommendations to the sponsor regarding the conduct of the study, including 
changes to dosing and administration schedule, and make recommendations concerning study 
continuation as planned, protocol amendment, or early discontinuation of the study for 
excessive toxicity. 
An SMC Charter will outline the committee’s composition, members’ roles and 
responsibilities, and describe SMC procedures. The sponsor will provide a copy of each 
SMC recommendation to the investigators.
3.1.3. Stopping Criteria
Reasons for prematurely 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 the SMC. 

Participant enrollment is unsatisfactory. 
3.1.4. End of Study
As of Amendment 3, all participants still in the study who are not entering the LTEP will 
have a last visit/contact. The study will end when the last LTEP participant has had their last 
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visit/contact. The sponsor will provide continued access to study intervention during the 
LTEP for any participant who is still on tucatinib with or without T-DXd and receiving 
clinical benefit based on the investigator’s assessment.
3.1.5. Method of Assigning Participants to Treatment Groups
This is an open-label, single arm study.
3.1.6. Rationale for Selection of Doses
Selection of the tucatinib dosing at 300 mg PO BID for the current study was based upon the 
recommended phase 2 dose (RP2D) derived from 2 phase 1b studies in HER2+ MBC that 
evaluated tucatinib in combination with T-DM1 (ONT-380-004), or capecitabine and 
trastuzumab (ONT-380-005). Moreover, in the pivotal HER2CLIMB study, the combination 
of tucatinib 300 mg PO BID with trastuzumab and capecitabine was found to be well 
tolerated with a manageable safety profile. The single-agent approved dose for T-DXd for 
HER2+ MBC is 5.4 mg/kg IV every 3 weeks. Importantly, no major overlapping toxicities 
between tucatinib and T-DXd are expected based on the individual agent safety profiles. 
Therefore, the proposed starting dose for each agent in this study is tucatinib 300 mg PO BID 
and trastuzumab 5.4 mg/kg IV every 3 weeks.
3.1.7. Blinding and Unblinding
This is an open-label, single arm study.
4. STUDY POPULATION
This study will enroll participants with previously treated unresectable LA/M HER2+ breast 
cancer who have received prior treatment with a taxane and trastuzumab (with or without 
pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or 
adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without 
pertuzumab).
Participants must meet all of the enrollment criteria outlined in Section 4.1 and Section 4.2 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
Participants must meet the following criteria to be eligible for the study:
1. Have confirmed HER2+ breast cancer, as defined by the current American Society of 
Clinical Oncology – College of American Pathologists (ASCO/CAP) guidelines, 
previously determined at a Clinical Laboratory Improvements Amendments 
(CLIA)-certified or International Organization for Standardization (ISO)-accredited 
laboratory.
2. History of prior treatment with a taxane and trastuzumab (with or without pertuzumab) in 
the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment 
involving a regimen including a taxane and trastuzumab (with or without pertuzumab)
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3. Have disease progression of unresectable LA/M breast cancer after last systemic therapy 
(as confirmed by investigator), or be intolerant of last systemic therapy
4. Have measurable disease assessable by RECIST v1.1
5. Be at least 18 years of age at time of consent
6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
7. Have a life expectancy of at least 6 months, in the opinion of the investigator 
8. Have adequate hepatic function as defined by the following: 
a.
Total bilirubin ≤1.5 x upper limit of normal (ULN). Exception: Participants with 
known history of Gilbert’s Syndrome who have a direct bilirubin ≤1.5 x ULN in 
addition to a normal AST and ALT are eligible.
b. Transaminases (AST and ALT) ≤3 x ULN (≤5 x ULN if liver metastases are present) 
9. Have adequate baseline hematologic parameters as defined by:
a.
Absolute neutrophil count (ANC) ≥1.5 x 103/µL
b. Platelet count ≥100 x 103/µL
c.
Hemoglobin ≥9 g/dL
d. In participants transfused before study entry, transfusion must be ≥14 days prior to 
start of therapy to establish adequate hematologic parameters independent from 
transfusion support
10. Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 using the Modification 
of Diet in Renal Disease (MDRD) study equation
11. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated 
partial thromboplastin time (aPTT) ≤1.5 x ULN, unless on medication known to alter 
INR and PTT/aPTT. 
12. Have 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 
13. For participants of childbearing potential (Section 4.4), the following stipulations apply.
a.
Must have a negative serum or urine pregnancy test (minimum sensitivity of 
25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result 
within 7 days prior to starting study treatment. A participant with a false positive result 
and documented verification that the participant is not pregnant is eligible for 
participation.
b. Must agree not to try to become pregnant during the study and for at least 7 months 
after the final dose of study intervention 
c.
Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 7 months after the final dose of study intervention 
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d. If sexually active in a way that could lead to pregnancy, must consistently use 2 highly 
effective methods of birth control (as defined in Appendix I) starting at the time of 
informed consent and continuing throughout the study and for at least 7 months after 
the final dose of study intervention administration.
14. For participants who can father children, the following stipulations apply:
a.
Must agree not to donate sperm starting at time of informed consent and continuing 
throughout the study period and for at least 4 months after the final study intervention 
b. If sexually active with a person of childbearing potential in a way that could lead to 
pregnancy, must consistently use 2 highly effective methods of birth control 
(as defined in Appendix I) starting at time of informed consent and continuing 
throughout the study and for at least 4 months after the final dose of study intervention 
c.
If sexually active with a person who is pregnant or breastfeeding, must consistently 
use one of 2 contraception options (as defined in Appendix I) starting at time of 
informed consent and continuing throughout the study and for at least 4 months after 
the final dose of study intervention administration 
15. Participant must provide signed informed consent per a consent document that has been 
approved by an institutional review board or independent ethics committee (IRB/IEC) 
prior to initiation of any study-related tests or procedures that are not part of standard of 
care for the patient’s disease
16. Participants must be willing and able to comply with study procedures
CNS Inclusion – Based on medical history and screening contrast brain magnetic resonance 
imaging (MRI), participants with a history of brain metastases must have one of the 
following
17. 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 medical monitor is required prior to enrollment
18. 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 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 SRS is ≥7 days prior to first dose of study 
treatment, or time since surgical resection is ≥28 days 
ii.
Other sites of measurable disease 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
Participants will be excluded from the study for any of the following reasons:
1. Have previously been treated with:
a.
Lapatinib or neratinib within 12 months of starting study treatment (except in cases 
where lapatinib or neratinib was given for ≤21 days and was discontinued for reasons 
other than disease progression or severe toxicity)
b. Tucatinib or enrolled on a tucatinib clinical trial
c.
Any investigational HER2/EGFR or HER2 TKI (eg, afatinib) at any time previously
d. T-DXd or another ADC consisting of an exatecan derivative 
2. 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, Myocet) >550 mg/m2
3. History of allergic reactions to trastuzumab or compounds chemically or biologically 
similar to tucatinib or T-DXd, except for Grade 1 or 2 infusion-related reactions (IRRs) 
to trastuzumab that were successfully managed, or known allergy to one of the excipients 
in the study interventions
4. Have received treatment with: 
a.
Any systemic anti-cancer therapy (including hormonal therapy) or experimental agent 
≤21 days 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
b. Treatment with non-CNS radiation ≤7 days prior to first dose of study treatment 
c.
Major surgery within <28 days of first dose of study treatment
5. Have any toxicity related to prior cancer therapies that has not resolved to ≤Grade 1, 
with the following exceptions: 

Alopecia

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
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
Anemia, which must have resolved to ≤ Grade 2
6. Have clinically significant cardiopulmonary disease such as:

Ventricular arrhythmia requiring therapy

Symptomatic hypertension or uncontrolled hypertension as determined by 
investigator

Any history of symptomatic CHF

Severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced 
malignancy

Hypoxia requiring supplementary oxygen therapy 

Have had a history of ILD/pneumonitis (eg, interstitial pneumonia, pneumonitis, 
pulmonary fibrosis, or radiation pneumonitis) that required systemic corticosteroids, 
or has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled 
out by imaging at screening
7. Have known myocardial infarction or unstable angina within 6 months prior to first dose 
of study treatment
8. Known to be positive for hepatitis B by surface antigen expression. Known to be positive 
for hepatitis C infection. Participants who have been treated for hepatitis C infection are 
permitted if they have documented sustained virologic response of 12 weeks 
9. Presence of known chronic liver disease
10. Participants known to be positive for human immunodeficiency virus (HIV) are excluded 
if they meet any of the following criteria:

CD4+ T-cell count of <350 cells/µL

Detectable HIV viral load

History of an opportunistic infection within the past 12 months

On stable antiretroviral therapy for <4 weeks
11. Active or uncontrolled clinically serious infection 
12. Are pregnant, breastfeeding, or planning a pregnancy
13. Have inability to swallow pills or significant gastrointestinal disease which would 
preclude the adequate oral absorption of medications
14. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 elimination half-lives 
of the inhibitor, or have used a strong CYP3A4 or moderate/strong CYP2C8 inducer 
within 5 days prior to first dose of study treatment. 
15. Unable for any reason to undergo contrast MRI of the brain
16. Have any other medical, social, or psychosocial factors that, in the opinion of the 
investigator, could impact safety or compliance with study procedures 
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17. History of malignancy other than breast cancer within 2 years prior to screening, with the 
exception of those with a negligible risk of metastasis or death (eg, 5-year OS of ≥90%), 
such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
CNS Exclusion – Based on medical history and screening contrast brain MRI, participants 
must not have any of the following (listed in criteria 18–22):
18. Any untreated brain lesions >2.0 cm in size, unless discussed with medical monitor and 
approval for enrollment is given
19. 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 dose of dexamethasone (or equivalent) may be 
eligible with discussion and approval by the medical monitor
20. 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 (eg, 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 18b
21. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
22. Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest 
neurologic progression due to brain metastases 
23. Have ongoing ≥ Grade 2 diarrhea of any etiology
4.3. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is using an appropriate method of contraception for the individual participant and 
their partner(s) from the permitted list of contraception methods (see Appendix I) and will 
confirm that the participant has been instructed in its consistent and correct use. 
At time points indicated in the SoE, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 2 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
4.4. Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
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Women in the following categories are not considered WOCBP:
Premenopausal with 1 of the following conditions: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator judgment will determine 
childbearing status and study eligibility.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
Postmenopausal female: 

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
4.5. Removal of Participants from Therapy or Assessment
Pfizer or their designee 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 electronic case report form (eCRF). For participants continuing to 
LTEP, data will only be documented in the participant’s medical record.
4.5.1. Discontinuation of Study Treatment
A participant’s study treatment may be discontinued for any of the following reasons:

Progressive disease (PD; per RECIST v1.1)

AE

Pregnancy or begins breastfeeding while on trial

Investigator decision due to clinical progression

Investigator decision, other

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 discontinue study treatment without documented radiographic progression 
will undergo follow-up disease assessments approximately every 9 weeks (±1 week) until 
disease progression is documented as per RECIST v1.1.
In the absence of progression, participants who discontinue T-DXd may continue receiving 
tucatinib alone. Participants who discontinue tucatinib may continue to receive T-DXd alone.
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent from any further 
contact with them or persons previously authorized by the participant to provide this 
information. A participant also may choose to withdraw consent from procedures and visits 
but remain on study for follow-up and further data collection through phone contact, review 
medical records, public records, or other public platforms. The withdrawal of consent should 
be explained in detail in the medical records by the investigator, as to whether the withdrawal 
is only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow up. In the event that vital status (whether the participant is alive or 
dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law.
4.5.1.1. Continuing on Study for Isolated CNS Progression
If a participant is found to have isolated progression in the CNS 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) of any progressive brain/dural metastases to allow for clinical benefit. Local 
treatment must be completed prior to the participant’s next response assessment time point. 
Participants may continue on study treatment for clinical benefit after this PFS event in the 
CNS; however, this requires discussion with and documented approval from the study 
medical monitor. Participants may continue treatment until either systemic progression or a 
second isolated CNS progression. The participant may continue on study provided the 
following criteria are met and the participant continues to receive clinical benefit:

The participant is not experiencing any worsening of cancer-related symptoms or 
signs indicating clinically significant progression of disease. Participants who are 
clinically deteriorating (eg, have a decline in ECOG PS, symptomatic rapid 
disease progression requiring urgent medical intervention) and unlikely to receive 
further benefit from continued treatment should discontinue study treatment

The participant is tolerating study intervention

Review and concurrence by the medical monitor

Participant has no evidence of unequivocal systemic progression

Participant has not had a previous isolated CNS progression while on study
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Study treatment may be held up to 6 weeks to allow local CNS therapy. Longer holds must 
be discussed and approved by the medical monitor. Interruption and re-initiation of study 
treatment is described in Section 5.5. 
4.5.2. Participant Withdrawal from Study
Reasons for discontinuation from the study may include:

Death

Participant withdrawal of consent

Lost to follow-up

Study termination by sponsor

Other
A participant may withdraw from the study at any time at their own request. If a participant 
withdraws from the study, they may request destruction of any remaining samples taken and 
not tested, and the investigator must document any such requests in the site study records and 
notify the sponsor accordingly. If the participant withdraws from the study and also 
withdraws consent for collection of future information, no further evaluations will be 
performed and no additional data will be collected except for publicly available information 
as appropriately directed in accordance with local law. The sponsor may retain and continue 
to use any data collected before such withdrawal of consent.
5. TREATMENTS
5.1. Treatments Administered
Participants will receive tucatinib and T-DXd in combination at the following doses:

Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. 

T-DXd 5.4 mg/kg IV on Day 1 of each 21-day cycle.
Study interventions are all prespecified IMPs and NIMPs intended to be administered to the 
study participants during the study conduct. 
For the purposes of this protocol, study intervention refers to tucatinib and T-DXd.
Study interventions are outlined in Table 2.
Table 2:
Study Interventions
Intervention Name
Tucatinib
T-DXd
Type
Drug
Biologic
Use
Experimental
Experimental
IMP or NIMP/AxMP
IMP
NIMP
Dose Formulation
Film-coated Tablet
Lyophilized powder for solution for 
injection
Unit Dose 
Strength(s)
50 and 150 mg
100 mg
Dosage Level(s)
300 mg BID
5.4 mg/kg
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Route of 
Administration
Oral
IV
Sourcing
Provided centrally by the sponsor or 
designee.
Locally sourced by site. 
Packaging and 
Labeling
Each bottle of tucatinib will be labeled 
in compliance with applicable 
regulatory requirements.
Each vial will be labeled as required per 
country requirement
Single Reference 
Safety Document 
(SRSD)
IB
USPI
Current/Former 
Name(s) or Alias(es)
TUKYSA; tucatinib; PF-07265792; 
ONT-380; ARRY-380
Enhertu; fam-trastuzumab deruxtecan-
nxki
5.2. Preparation, Handling, Storage and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the Pharmacy Instructions/IP 
manual.
5. Any storage conditions stated in the single reference safety document (SRSD) will be 
superseded by the storage conditions stated on the label. Site staff will instruct 
participants on the proper storage requirements for take-home study intervention. See 
the Pharmacy instructions/IP manual for storage conditions of the study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution, (where applicable) or 
authorized site staff is responsible for study intervention accountability, 
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reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records) such as the study drug accountability log. All centrally sourced 
study interventions will be accounted for using a study intervention accountability 
form/record. All unused tucatinib that is taken home by the participant must be 
returned to the investigator by the participant. Returned tucatinib must not be 
redispensed to the participants.
8. Further guidance and information for the final disposition of unused study
interventions are provided in the Pharmacy Instructions/IP manual. All destruction 
must be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
5.3. Study Intervention (Tucatinib)
Tucatinib is a kinase inhibitor that selectively inhibits HER2 and displays limited activity 
against the related kinase EGFR.
Tucatinib is supplied as coated yellow oval-shaped tablets (150 mg) or round tablets (50 mg) 
for oral administration. 
Detailed information describing the preparation, administration, and storage of tucatinib is 
located in the Pharmacy Instructions.
5.3.1. Description
Tucatinib is a potent, selective, adenosine triphosphate (ATP)-competitive small-molecule 
inhibitor of the receptor tyrosine kinase HER2. 
Chemical Name: 
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydr
ooxazol-2-yl)quinazoline-4,6-diamine.
Tucatinib drug product is supplied as both a coated yellow oval-shaped tablet in a 
150-mg dosage strength and a coated yellow round tablet in a 50 mg dosage strength. The 
tablets are manufactured from a drug product intermediate 
 of tucatinib 
in 
, which is then combined with the 
pharmaceutical excipients (copovidone, crospovidone, sodium chloride, potassium chloride, 
sodium bicarbonate, colloidal silicon dioxide, magnesium stearate, and microcrystalline 
cellulose) and compressed into tablets.
5.3.2. Method of Procurement
Tucatinib will be provided by the sponsor.
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5.3.3. Dose and Administration
Tucatinib will be administered PO BID and may be taken with or without food. Dose 
modifications of tucatinib are described in Section 5.5.1. Participants will be instructed by 
the pharmacist or investigator as to the specific number of tablets required for each dose. At 
each visit during study treatment, participants will be supplied with the appropriate number 
of tablets for the number of doses to be taken prior to the next scheduled visit. 
Participants will be instructed to take tucatinib twice each day (once in the morning, and once 
in the evening) approximately 8 to 12 hours between doses in the same calendar day. 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 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 may be taken with or without food. Tablets must be swallowed 
whole and may not be crushed, chewed or dissolved in liquid. On the day of dosing, the 
individual unit dose of the tucatinib tablet may be exposed to ambient temperature for up to 
6 hours prior to dose.
Complete dosing instructions will be provided to the pharmacist prior to the initiation of the 
study. Complete dosing instructions will also be provided to study participants and will 
include the minimum times between doses, dosing in relation to meals, and instructions for 
missed doses. Participant compliance with study intervention dosing instructions will be 
assessed with the use of study intervention accountability. Participant diaries may also be 
used to assess compliance.
5.3.4. 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 medical monitor as soon as they become aware of the overdose, to 
discuss details of the overdose (eg, exact amount of tucatinib administered, 
participant weight) and AEs, if any.
Overdose is reportable to Pfizer Safety only when associated with an SAE.
5.3.5. 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 tablets are to be stored under refrigeration at 2 to 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 
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event the tablets are broken or crushed, wash hands and exposed skin thoroughly with soap 
and water. 
Refer to the Pharmacy Instructions for more information.
5.3.6. Packaging and Labeling
Each bottle of tucatinib will be labeled in compliance with applicable regulatory 
requirements.
5.3.7. Study intervention 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. All used and unused bottles of tucatinib should be handled according to the sponsor’s 
instructions.
5.3.8. Preparation and Dispensing
Detailed drug preparation instructions are provided in the Pharmacy Binder.
A qualified staff member will dispense tucatinib in the bottles provided, in quantities 
appropriate according to the SoE. The participant/caregiver should be instructed to maintain 
the product in the bottle provided throughout the course of dosing and return the bottle to the 
site at the next study visit.
5.4. Combination Study intervention (T-DXd)
5.4.1. Description
T-DXd is an ADC consisting of a HER2-directed antibody, a topoisomerase inhibitor, and a 
tetrapeptide linker which is indicated, as a single agent, for treatment of patients with locally 
advanced unresectable or metastatic HER2+ breast cancer. 
5.4.2. Method of Procurement
T-DXd is commercially available and details regarding sourcing of T-DXd may vary by site 
and/or region as outlined in other documents such as Clinical Trial Agreements. 
5.4.3. Dose, Preparation, and Administration
T-DXd (5.4 mg/kg) will be given as an IV infusion once every 21 days (Day 1 of each 
21-day cycle). T-DXd should be prepared and administered per instructions in the 
ENHERTU product label. T-DXd will be administered IV per institutional guidelines, under 
the direction of the investigator. 
Protocol-defined visits and cycle numbering will be determined by T-DXd dosing date, 
allowing for dose holds or delays with T-DXd. Dose modifications of T-DXd are described 
in Section 5.5.2.
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5.4.4. Overdose
For this trial, an overdose will be defined as any dose at least 10% greater than the prescribed 
dose of T-DXd. In the event of an overdose, 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 T-DXd. In the event of overdose, participants should be observed, 
and appropriate supportive care should be given, if required.

Notify the medical monitor as soon as they become aware of the overdose, to 
discuss details of the overdose (eg, exact amount of T-DXd administered, 
participant weight) and AEs, if any.
Overdose is reportable to Pfizer Safety only when associated with an SAE.
5.4.5. Storage and Handling
T-DXd should be stored according to the product label.
5.4.6. Study intervention Accountability
Site will also be required to provide accountability for administration of T-DXd for entry into 
the eCRF.
5.4.7. Preparation and Dispensing
See the T-DXd product label for instructions on how to prepare T-DXd for administration. T-
DXd should be prepared and dispensed by an appropriately qualified and experienced 
member of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacy assistant/technician, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.5. Dose Modifications
Tucatinib and T-DXd dose reduction recommendations are described in Table 3 and Table 4, 
respectively.
Guidelines for dose modification recommendations (including dose holds, dose reduction, or 
discontinuation of drug) in response to potential AEs are described in the tables in 
Section 5.5.3. Dose reductions or treatment interruption/discontinuation for reasons other 
than those described in Section 5.5.3 may be made by the investigator if it is deemed in the 
best interest of participant safety. Whenever possible, these decisions should first be 
discussed with the study medical monitor.
All AEs and clinically significant laboratory abnormalities should be assessed by the 
investigator for relationship to tucatinib and T-DXd. An AE may be considered related to 
tucatinib alone, T-DXd alone, to both drugs, or to neither. In the event that the relationship is 
unclear, discussion should be held with the study medical monitor, to discuss which study 
intervention(s) should be held and/or modified.
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Doses held for toxicity will not be replaced. Tucatinib or T-DXd should be discontinued if a 
delay greater than 6 weeks is required due to treatment-related toxicity, unless a longer delay 
is approved by the study medical monitor.
In the event of isolated progression in the CNS, study treatment may be held up to 6 weeks to 
allow local CNS therapy (Section 4.5.1.1). Tucatinib and T-DXd are to be held 1 week prior 
to planned CNS-directed therapy. The potential for radiosensitization with tucatinib and 
T-DXd is unknown. Study treatment may be reinitiated ≥7 days after completion of SRS, 
≥14 days after WBRT, and ≥28 days after surgical resection. Plans for holding and 
reinitiating study interventions before and after local therapy will require discussion with, 
and documented approval from, the medical monitor.
Protocol-defined visits and cycle numbering will be determined by T-DXd dosing, allowing
for dose holds or delays with T-DXd. In the event T-DXd is discontinued but study treatment 
with tucatinib continues, protocol-defined visits and cycle numbering will proceed using a 
21-day cycle regardless of dose holds or delays for tucatinib.
5.5.1. Tucatinib Dose Reductions
Up to 3 dose reductions of tucatinib are allowed (Table 3); fewer dose reduction levels may 
be available if alternative tucatinib doses or schedules are adopted, following SMC 
recommendation. Participants who would require a dose reduction to below 150 mg BID 
should discontinue treatment with tucatinib. Dose reductions of larger intervals than those 
described in Table 3 may be made at the discretion of the investigator, but dose reductions to 
below 150 mg BID are not allowed. 
Tucatinib dose should not be re-escalated after a dose reduction is made.
Table 3:
Recommended tucatinib dose reduction
Dose Reduction Schedule
Tucatinib Dose Levela
Starting dose
300 mg PO BID
1st dose reduction
250 mg PO BID
2nd dose reduction
200 mg PO BID
3rd dose reduction
150 mg PO BID
Requirement for further dose reduction
Discontinue treatment
a Dose reductions of greater intervals than those recommended in this table (ie, 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.
5.5.2. Trastuzumab Deruxtecan Dose Reductions
Up to 2 dose reductions of T-DXd will be allowed. 
T-DXd dose should not be re-escalated after a dose reduction is made as shown in Table 4.
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Table 4:
Recommended T-DXd dose reduction
Dose Reduction Schedule
T-DXd Dose Level
Starting dose
5.4 mg/kg IV
1st dose reduction
4.4 mg/kg IV
2nd dose reduction
3.2 mg/kg IV
3rd dose reduction
Discontinue treatment
5.5.3. Dose Modifications for Adverse Events
5.5.3.1. General Guidelines
General dose modification guidelines for tucatinib and T-DXd are provided in Table 5 for 
clinical AEs.
Separate dose modification guidelines are provided for AEs of hepatotoxicity (Table 6), 
ILD/pneumonitis (Table 7), neutropenia and febrile neutropenia (Table 8), and LVEF 
decrease (Table 9).
Table 5:
Dose modifications for clinical adverse events related to either tucatinib or 
T-DXd
Tucatinib
T-DXd
Clinical adverse event
Related to tucatinib
Related to T-DXd
Grade 3 AEs other than 
Grade 3 fatigue lasting 
≤3 days; alopeciaa; nausea; 
vomiting; diarrhea; rash; 
correctable electrolyte 
abnormalities
Hold until severity ≤ Grade 1 or 
pretreatment level.
Restart at next lowest dose level.
Hold until severity ≤ Grade 1 or 
pretreatment level.
Reduce to next lowest dose level.
Grade 3 nausea and/or 
vomiting WITHOUT maximal 
use of antiemetics
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Grade 3 nausea and/or 
vomiting WITH maximal use 
of antiemetics
Hold until severity ≤ Grade 1 or 
pretreatment level.
Restart at next lowest dose level.
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level.
Grade 3 diarrhea WITHOUT 
maximal use of antidiarrheals
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Grade 3 diarrhea WITH 
maximal use of antidiarrheals
Hold until severity ≤ Grade 1 or 
pretreatment level.
Restart at next lowest dose level.
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level.
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Table 5:
Dose modifications for clinical adverse events related to either tucatinib or 
T-DXd
Tucatinib
T-DXd
Clinical adverse event
Related to tucatinib
Related to T-DXd
Grade 2 diarrhea with 
concomitant Grade 2 nausea 
and/or vomiting, both related 
to study intervention 
WITHOUT maximal use of 
antidiarrheals and/or 
antiemetics
Hold until severity ≤ Grade 1 or 
pretreatment level of either the 
Grade 2 nausea/vomiting or 
diarrhea.
Initiate appropriate therapy.
Restart without dose reduction. 
Hold until severity ≤ Grade 1 or 
pretreatment level of either the 
Grade 2 nausea/vomiting or diarrhea.
Initiate appropriate therapy.
Restart without dose reduction.
Grade 2 diarrhea with 
concomitant Grade 2 nausea 
and/or vomiting, both related 
to study intervention WITH 
maximal use of antidiarrheals 
and/or antiemetics
Hold until severity ≤ Grade 1 or 
pretreatment level of either the 
Grade 2 nausea/vomiting or 
diarrhea.
Restart at next lowest dose level. 
Hold until severity ≤ Grade 1 or 
pretreatment level of either the 
Grade 2 nausea/vomiting or diarrhea.
Restart at next lowest dose level.
Grade 3 rash WITHOUT 
maximal use of topical 
corticosteroids or 
anti-infectives
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Hold until severity ≤ Grade 1 or 
pretreatment level.
Initiate appropriate therapy.
Restart without dose reduction.
Grade 3 rash WITH maximal 
use of topical corticosteroids or 
anti-infectives 
Hold until severity ≤ Grade 1 or 
pretreatment level.
Restart at next lowest dose level. 
Hold until severity ≤ Grade 1 or 
pretreatment level.
Restart at next lowest dose level. 
Grade 4 AEs
Permanently discontinue
Permanently discontinue
Tucatinib or T-DXd should be discontinued if a delay greater than 6 weeks is required due to 
treatment-related toxicity, unless a longer delay is approved by the study medical monitor.
a.No dose modifications are required for alopecia
5.5.3.2. Hepatotoxicity
Dose modification is required in the case of liver function abnormalities, regardless of 
relationship to tucatinib and T-DXd as outlined in Table 6.
For participants with documented Gilbert’s disease, contact the medical monitor for guidance 
regarding dose modifications.
Table 6:
Dose modification guidelines for liver function abnormalities
Tucatinib
T-DXd
ALT or 
AST 
(>3 – ≤5 x ULN)
Dose modification not required.
Dose modification not required.
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Table 6:
Dose modification guidelines for liver function abnormalities
Tucatinib
T-DXd
Bilirubin 
(>1.5 – ≤3 x ULN)
Hold until recovery to (≤1.5 x ULN). 
Then resume tucatinib at the same dose 
level.
Dose modification not required.
ALT or 
AST 
(>5 – ≤20 x ULN)
Hold until recovery to (≤3 x ULN) or 
until return to pre-treatment level in 
participants with known liver metastasis.
Then resume tucatinib at the next lower 
dose level.
Hold until recovery to (≤3 x ULN) or 
until return to pre-treatment level in 
participants with known liver 
metastasis. 
Then resume at the same dose level.
Bilirubin 
(>3 – ≤10 x ULN)
Hold until recovery to (≤1.5 x ULN).
Then resume tucatinib at the next lower 
dose level.
Hold until recovery to(≤1.5 x ULN). 
Then resume T-DXd at the next lower 
dose level.
ALT or 
AST (>20 x ULN)
OR
Bilirubin (>10 x 
ULN)
Permanently discontinue. 
Permanently discontinue.
ALT or 
AST >3 x ULN
AND
Bilirubin >2 x ULN
Permanently discontinue. 
Permanently discontinue.
Source: TUKYSA Prescribing Information, Seattle Genetics, Inc., Apr, 2020; ENHERTU Prescribing 
Information Daiichi Sankyo, Inc., Dec 2019.
5.5.3.3. Interstitial Lung Disease/Pneumonitis
Dose modifications are required for ILD/pneumonitis, regardless of relationship to T-DXd 
(Table 7). 
Dose modification of tucatinib is not required for ILD/pneumonitis.
Table 7:
Dose modification guidelines for interstitial lung disease/pneumonitis
T-DXd
Asymptomatic ILD/pneumonitis 
(Grade 1)
Interrupt until resolved to Grade 0, then:
if resolved in 28 days or less from date of onset, maintain dose,
if resolved in greater than 28 days from date of onset, reduce dose 1 
level (see Table 4)
consider corticosteroid treatment as soon as ILD/pneumonitis is 
suspected
Symptomatic ILD/pneumonitis 
(Grade 2 or greater)
Permanently discontinue
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Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis 
is suspected
Source: ENHERTU Prescribing Information Daiichi Sankyo, Inc., Dec 2019
5.5.3.4. Neutropenia and Febrile Neutropenia
Dose modifications are required for neutropenia or febrile neutropenia, regardless of 
relationship to T-DXd (Table 8). 
Dose modification of tucatinib is not required for neutropenia or febrile neutropenia.
Table 8:
Dose modification guidelines for neutropenia and febrile neutropenia
T-DXd
Grade 3 neutropenia 
(less than 1.0 to 0.5 x 109/L)
Interrupt until resolved to Grade 2 or less, then 
maintain dose.
Grade 4 neutropenia 
(less than 0.5 x 109/L)
Interrupt until resolved to Grade 2 or less. Reduce 
dose by 1 level (see Table 4).
Febrile Neutropenia 
(Absolute neutrophil count of less than
1.0 x 109/L and temperature greater than 38.3°C or a 
sustained temperature of 
38°C or greater for more than 1 hour)
Interrupt until resolved. Reduced dose by 1 level 
(see Table 4). 
Source: ENHERTU Prescribing Information Daiichi Sankyo, Inc., Dec 2019.
5.5.3.5. Left Ventricular Ejection Fraction Decrease
Dose modification guidelines for LVEF decrease, regardless of relationship to T-DXd, are 
provided in Table 9. 
Dose modification of tucatinib is not required for LVEF decrease.
Table 9:
Dose modification guidelines for left ventricular ejection fraction decrease
T-DXd
LVEF greater than 45% and absolute decrease from 
baseline is 10% to 20%
Dose modification not required
LVEF 
40% to 45% 
And absolute decrease from baseline is 
less than 10%
●Dose modification not required
●Repeat LVEF assessment within 3 weeks
And absolute decrease from baseline is 
10% to 20%
●Interrupt treatment
●Repeat LVEF assessment within 3 weeks.
●If LVEF has not recovered to within 10% of 
baseline, permanently discontinue treatment
●If LVEF recovers to within 10% from 
baseline, resume treatment at the same dose.
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Table 9:
Dose modification guidelines for left ventricular ejection fraction decrease
LVEF less than 40% or absolute decrease from baseline 
is greater than 20%
●Interrupt treatment
●Repeat LVEF assessment within 3 weeks.
●If LVEF of less than 40% or absolute 
decrease from baseline of greater than 20% 
is confirmed, permanently discontinue 
treatment
Symptomatic congestive heart failure (CHF)
●Permanently discontinue treatment
Source: ENHERTU Prescribing Information Daiichi Sankyo, Inc., Dec 2019.
5.6. Concomitant Therapy
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given 
for a study protocol-related AE should be recorded from the time of informed consent 
through the safety reporting period.
Any planned surgery (major or minor) not directly related to cancer that occurs on study 
requires consultation with the sponsor medical monitor. 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 
medical monitor as soon as feasible to discuss resumption of study treatment postoperatively.
5.6.1. Required Concomitant Therapy
In participants following protocol amendment 2, loperamide 4 mg 3 times daily (Days 1 to 
14) during Cycle 1 followed by 4 mg 2 times daily (Day 15 through Day 42) is to be given.

Titrate above initial loperamide dosing schedule for a goal of 1–2 bowel 
movements per day.

Antidiarrheal prophylaxis should be held in situations where use is 
contraindicated (eg, bacterial enterocolitis), until resolution of the 
contraindication.

If either tucatinib or T-DXd is discontinued during the first 42 days of treatment, 
antidiarrheal prophylaxis is no longer required.
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, antibiotics, hematologic support, pain management, 
antacids, and laxatives.
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
Supportive care medications such as antidiarrheals and antiemetics are permitted. 
o
Antidiarrheals for symptomatic or prophylactic use are permitted at the 
discretion of the investigator. 

Participants who enroll while use of primary prophylactic 
antidiarrheals is implemented as a required concomitant therapy may 
continue on prophylactic use or be switched to symptomatic use, per 
investigator assessment, following Day 42 of therapy.

Symptomatic management of treatment-induced diarrhea should be 
based on established guidelines (Benson et al, 2004; Bossi et al, 2018).
o
Antiemetic prophylaxis prior to Day 1 infusions of T-DXd at each cycle 
should be administered per established guidelines (Hesketh et al, 2020). 
o
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 nonresectable tumor), these concomitant procedures 
are permitted for non-target non-CNS lesions only in situations where other 
disease remains assessable by RECIST v1.1. These interventions should be 
avoided if clinically feasible until after the second response assessment. The 
medical monitor should be consulted prior to the intervention occurring. 

Corticosteroids
o
Participants requiring systemic corticosteroids for control of CNS 
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 enrolled until doses <2 mg can be achieved.
o
After initiation of study treatment, corticosteroids may be initiated for 
control of CNS symptoms.
o
Systemic corticosteroids for control of other comorbidities (eg, asthma or 
auto-immune diseases) or premedication for contrast use in computed 
tomography (CT) or MRI scans are permitted.

Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.

Routine prophylaxis with vaccines (without live virus) are permitted during the 
study.
5.6.3. Prohibited Concomitant Therapy
The following therapies are prohibited during the study (unless otherwise noted):

Investigational drugs and devices
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
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 medical monitor, provided that there remain other sites of 
disease assessable by RECIST v1.1

Vaccination with live vaccines

Strong CYP2C8 inhibitors are prohibited within 5 elimination half-lives of the 
inhibitor. Moderate/strong inducers of CYP2C8 are prohibited within 5 days prior 
to the first dose of study treatment, as concomitant medications during study 
treatment, and within 1 week of discontinuation of tucatinib treatment. Moderate 
inhibitors of CYP2C8 should be used with caution. For additional information, 
including drug elimination half-lives of strong inhibitor, moderate inhibitors, and 
moderate inducers, see Appendix B

Strong inducers of CYP3A4 are prohibited within 5 days prior to first dose of 
study treatment, as concomitant medications during study treatment, and within 
1 week of discontinuation of study treatment. For additional information 
including drug elimination half-lives of strong inducers, see Appendix C

Use of sensitive CYP3A substrates should be avoided 1 week prior to first dose of 
study treatment and during study treatment (Appendix D). 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

Concomitant use of tucatinib with digoxin, a P-glycoprotein (P-gp) substrate, 
which increases digoxin concentrations and 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 dose 
adjustment recommendations due to drug interactions
5.7. Management of Treatment-emergent Adverse Events
5.7.1. Infusion-related Reaction and its Management
An IRR is characterized by an adverse reaction to the infusion of pharmacological or 
biological substances. IRRs occur within 24 hours of infusion and may manifest as a 
combination of signs or symptoms including fever, rigors, flushing, itching, various types of 
rash, urticaria, dyspnea, nausea, vomiting, back or abdominal pain, and/or hypotension (Kang 
& Saif, 2007).
IRRs with T-DXd were observed (2.6% of patients); the infusion rate should be slowed or 
interrupted if the patient develops infusion-related symptoms. T-DXd should be discontinued 
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permanently in the case of severe infusion reactions. The infusion should be administered at 
a site properly equipped and staffed to manage anaphylaxis should it occur. All supportive 
measures consistent with optimal patient care should be given throughout the study according 
to institutional standards. Supportive measures may include extending the infusion time 
and/or administering medications for IRRs. 
Any IRR related to T-DXd should be managed according to the product label and/or 
institutional standard of care. Premedication for IRRs is allowed at the investigator’s 
discretion
The severity of IRRs should be graded according to NCI CTCAE, version 5.0, guidelines.
5.7.2. Allergic/Hypersensitivity Reaction
Allergic/hypersensitivity reactions are characterized by adverse local or general responses 
from exposure to an allergen (NCI CTCAE version 5.0). For purposes of this study, 
allergic/hypersensitivity reactions are differentiated from IRRs by being defined as occurring 
>24 hours after infusion of T-DXd. Allergic/hypersensitivity reactions may manifest in the 
same manner as IRRs, ie, a combination of signs or symptoms including fever, rigors, 
flushing, itching, various types of rash, urticaria, dyspnea, nausea, vomiting, back or 
abdominal pain, and/or hypotension.
5.7.3. Anaphylaxis
Anaphylaxis is a severe, life threatening, generalized or systemic allergic/hypersensitivity 
reaction. Anaphylaxis is characterized by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing a hypersensitivity 
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, 
cyanosis, and loss of consciousness and may lead to death (NCI CTCAE, version 5.0 and 
(Rosello et al, 2017).
If anaphylaxis occurs, administration of T-DXd should be immediately and permanently 
discontinued.
5.7.4. Management of Treatment-associated Diarrhea

Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. If an 
alternate cause of diarrhea is suspected and/or identified, treat accordingly.

In participants enrolled during which primary antidiarrheal prophylaxis is implemented, 
please refer to Section 5.5.1 for dosing guidance.
o
Antidiarrheal prophylaxis should be held in situations where use is 
contraindicated (eg, bacterial enterocolitis), until resolution of the 
contraindication.

In participants receiving antidiarrheals for symptomatic control (not prophylactically) of 
treatment-associated diarrhea:
o
Early Detection: Instruct participants to report diarrhea on the first symptom/sign 
of diarrhea.
o
Early Intervention: 
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
Provide participants with prescription for loperamide and instruct them to start 
treatment as soon as first unformed stool occurs.

The recommended dose of loperamide is 4mg at first unformed stool, 
followed by 2mg every 2 to 4 hours until diarrhea free (maximum 16 mg/day).

Instruct participants to call site if diarrhea persists >48 hours or there is an 
increase of >7 stools per day over baseline (Grade 3 Diarrhea per CTCAE 
v5.0).

Instruct participants to seek medical attention if unable to maintain oral 
hydration due to diarrhea, particularly in the presence of concomitant emesis.

Instruct participants to seek medical attention if unable to maintain oral 
hydration. Intervention with IV fluids and electrolyte replacement should be 
considered as clinically indicated.
5.8. Treatment Compliance
Study intervention administration will be documented in source documents and the CRF. 
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. Tucatinib compliance may also be assessed on a participant-by-participant basis using 
participant diaries. 
Data regarding the administration and dose of T-DXd will also be collected by the site after 
each cycle. Dose modifications and interruptions of both study interventions will be 
documented in the source documents and the CRF. Following implementation of 
Amendment 3 and entry of remaining on-treatment participants into the LTEP, treatment 
administration data will no longer be collected in CRFs. Refer to Section 8.3 for further 
detail on LTEP data collection requirements.
6. STUDY ACTIVITIES
6.1. Schedule of Events
AEs and concomitant medications will be recorded from Day 1 (predose) through the safety 
reporting period (see Section 7.7.1.3). Any study protocol-related AE (defined in 
Section 7.7.1.1) as well as any concomitant medications given for treatment of the AE, 
should be recorded from the time of informed consent.
Clinical laboratory assessments (serum chemistry panel, liver function tests [LFTs], complete 
blood count [CBC] with differential [manual differential if clinically indicated, see 
Section 7.7.3], physical exam, weight, and ECOG PS) may be performed within 1 day prior 
to administration of study intervention. The results from all relevant clinical assessments 
must be reviewed prior to dosing.
The participants enrolled in the safety lead-in will undergo the same efficacy, PK, and 
biomarker analyses as all other participants enrolled in the study, with the exception of an 
additional PK assessment performed at Cycle 1 Day 12. 
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Tumor biopsies performed while the participant is on study should be made available to the 
sponsor, if feasible (see Section 7.4).
Participants still receiving clinical benefit and remaining on tucatinib with or without T-DXd 
as of Amendment 3 may continue receiving study intervention during the LTEP. During this 
phase of the study, only pregnancies and SAEs will be collected by the sponsor. All other 
assessments, including efficacy assessments, will be performed per institutional guidelines 
and investigator-determined usual and customary clinical care.
A schedule of events is provided in 11. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7.
6.2. Screening Visit (Days –28 to 1)

Informed consent*

Documentation of AEs

Study eligibility per inclusion/exclusion criteria

Documentation of concomitant medications 

Documentation of baseline medical conditions

Documentation of disease history 

Height

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight

Physical examination 

ECOG PS

Blood samples for laboratory testing (as listed in Section 7.7.3)
o
CBC with differential
o
Serum chemistry
o
LFTs
o
Coagulation panel

For participants of childbearing potential, serum or urine pregnancy test within 
7 days of first study treatment (a positive urine test must be confirmed with a 
serum pregnancy test). 

Blood samples for hepatitis screening: Hepatitis B surface antigen (HBsAg), 
antibodies to Hepatitis B core (anti-HBc), and antibodies to Hepatitis C 
(anti-HCV). (If positive, additional testing may be required after discussion with 
medical monitor.)*

Electrocardiogram (ECG)
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
ECHO or MUGA; note that whichever testing modality is chosen in screening 
should be used for all subsequent cardiac assessments throughout the study for 
comparison.*

Contrast CT (preferred), 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. Additional appropriate imaging of any other known sites of 
disease (eg, photography for skin lesions, nuclear bone scan imaging for bone 
lesions) may also be obtained at the investigator’s discretion. For each participant, 
the same assessment modalities used at screening/baseline should be used 
throughout the study. 

Contrast MRI scan 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*

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.

Blood sample for biomarker analysis*

Collection of archived tumor samples for biomarker analysis. If tumor blocks are 
not available, slides may be submitted after discussion with and approval from the 
medical monitor
*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 medical monitor approval. This 
includes the following: Informed consent, ECHO/MUGA, hepatitis screening, and biomarker 
sampling. All other safety labs and assessments will need to be repeated if outside the 28-day 
window for these participants. An additional contrast MRI brain scan 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.
6.3. Treatment Period (21-day cycles)
6.3.1. Cycle 1 Day 1

Documentation of AEs

Documentation of concomitant medications 

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight

Physical examination

ECOG PS
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
Blood samples for laboratory testing (results must be reviewed and eligibility 
confirmed prior to first dose):
o
CBC with differential
o
Serum chemistry
o
LFTs

Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to evaluation by study personnel [physical examination, review of AEs] and 
administration of study treatment)

Dispense tucatinib and administer the first dose of tucatinib‡ 

Administer T-DXd (administered IV on Day 1 of the 21-day cycle)‡ 

Beginning with the first dose of tucatinib in participants following protocol 
amendment 2, loperamide 4 mg 3 times daily (Days 1 to 14) during Cycle 1 
followed by 4 mg twice daily (Day 15 through Day 42) is to be given

Collect blood samples for PK (predose)
‡Drugs may be administered in any order and can be given simultaneously.
6.3.2. Cycle 1 Day 12 (±3 days)

Documentation of AEs

Documentation of concomitant medications 

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight

Physical examination 

ECOG PS 

Blood samples for laboratory testing:
o
CBC with differential
o
Serum chemistry
o
LFTs

Collect blood samples for PK (for safety lead-in participants only). Record time 
of tucatinib dose and blood draw 
6.3.3. Cycle 2 Day 1 (–1 day to +3 days)

Documentation of AEs

Documentation of concomitant medications, including the dosing regimen of 
antidiarrheals taken in the previous cycle

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight
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
Physical examination

ECOG PS

Blood samples for laboratory testing:
o
CBC with differential
o
Serum chemistry
o
LFTs

For participants of childbearing potential, a serum or urine pregnancy test (a 
positive urine test must be confirmed with a serum pregnancy test)

Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to evaluation by study personnel [physical examination, review of AEs] and 
administration of study treatment)

Dispense tucatinib and administer the first dose. On Day 1 of each cycle, review 
compliance from previous cycle and dispense tucatinib for next cycle.†

Administer T-DXd (administered IV on Day 1 of the 21-day cycle)† 

Collect blood samples for PK (pre-tucatinib dose and 2 hours [±15 minutes] 
post-tucatinib dose)
†At Cycle 2 Day 1, tucatinib should be administered onsite before T-DXd; participants 
should remain onsite for 2 hours (±15 minutes) after tucatinib administration to coordinate 
peak PK sampling times.
6.3.4. Cycle 2 Day 12 (±3 days)

Blood samples for LFTs
6.3.5. Cycle 3 and Beyond, Day 1 (–1 day to +3 days) 

Documentation of AEs

Documentation of concomitant medications, including the dosing regimen of 
antidiarrheals taken in the previous cycle

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight

Physical examination

ECOG PS

Blood samples for laboratory testing:
o
CBC with differential
o
Serum chemistry
o
LFTs
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
For participants of childbearing potential, a serum or urine pregnancy test 
performed at each cycle (a positive urine test must be confirmed with a serum 
pregnancy test). Pregnancy testing will be performed every 3 weeks for 
participants of child-bearing potential receiving study treatment during the LTEP 
and will follow Section 6.4 after last dose of study treatment.

Blood sample for biomarker analysis (at C3D1 only, predose)

Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to evaluation by study personnel [physical examination, review of AEs] and 
administration of study treatment for Cycle 3 and Cycle 4 and every 2 cycles 
starting at Cycle 6 through the end of treatment [EOT])

Dispense and administer the first dose of tucatinib (On Day 1 of each cycle, 
review compliance from previous cycle and dispense tucatinib for next cycle).† 

Administer T-DXd (administered IV on Day 1 of each 21-day cycle)† 

Blood samples for PK (through Cycle 6 only: Pre-tucatinib dose at Cycles 3 and 
6, and 2 hours (±15 minutes) post-tucatinib dose at Cycle 3 only)
†Tucatinib should be administered before T-DXd onsite at Cycle 3 and Cycle 6; for Cycle 3, 
participants should remain onsite for 2 hours (±15 minutes) after tucatinib administration to 
coordinate peak PK sampling times. For all other cycles, study interventions may be given in 
any order and can be given simultaneously.
6.3.6. Every 6 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 (preferred), PET/CT (if high quality CT scan included) or MRI scan 
as appropriate. The same imaging modalities used in Screening/Baseline should 
be repeated, unless otherwise clinically indicated. 

Contrast MRI of the brain (only in participants with brain metastases at baseline)
o
If cycles are delayed for any reason continue with initial scan schedule as 
determined by the date of Cycle 1 Day 1 visit.

If an interim unscheduled visit assessment is performed, scans should continue to 
be done on schedule, with scheduling determined by the date of Cycle 1 Day 1. In 
cases of medical contraindication for repeat scans, contact the medical monitor to 
discuss as, in some instances, assessments done at an unscheduled time point may 
not need to be repeated if medically contraindicated as approved by the medical 
monitor.
6.3.7. Every 12 Weeks (–7 days) as Determined by Cycle 1 Day 1

ECHO or MUGA, using the same cardiac testing modality performed in 
Screening/Baseline
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
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 treatment)

Documentation of AEs

Documentation of concomitant medications, including the dosing regimen of 
antidiarrheals taken in the previous cycle

Vital signs (blood pressure, heart rate, temperature, respiration rate, and pulse 
oximetry), including weight

Physical examination 

ECOG PS

Blood samples for laboratory testing:
o
CBC with differential
o
Serum chemistry
o
LFTs
o
Coagulation panel

For participants of childbearing potential, a serum or urine pregnancy test (if not 
done in the last 30 days) a positive urine test must be confirmed with a serum 
pregnancy test.

For persons of childbearing potential (for 7 months after the last dose of study 
treatment; see Section 7.7.5): 
o
Remind participant that monthly pregnancy tests should be performed for 
7 months after the last dose of study treatment. 
o
Testing may be performed at home. If performed at home, site staff will 
contact the participant monthly to confirm testing was performed and 
obtain pregnancy test results.

Blood sample for biomarker analysis

Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to evaluation by study personnel [physical examination, review of AEs])

Only in participants who discontinue study treatment for reasons other than 
radiographic disease progression: Contrast CT (preferred); PET/CT (if high 
quality CT scan included), and/or non-brain MRI scan may be done as 
appropriate. The same imaging modalities used in Screening/Baseline should be 
repeated, unless otherwise clinically indicated. Not required if imaging was 
performed within 30 days of discontinuing study treatment.
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
Only in participants with a history of brain metastases who discontinue study 
treatment for reasons other than radiographic disease progression: Contrast MRI 
of the brain. 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.

ECHO or MUGA, using the same cardiac testing modality performed in 
Screening/Baseline. Not required if ECHO/MUGA was done within the previous 
12 weeks (excluding the Screening/Baseline assessment).
6.5. Follow-up
Participants who discontinue study treatment will remain on study for follow-up until 
withdrawal from the study. If a participant discontinues study treatment, every attempt 
should be made to follow the participant until death or administrative study closure.
6.5.1. Follow-up until Disease Progression (at least every 9 weeks ±1 week)
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), death, withdrawal of consent, or study closure.

Contrast CT (preferred), PET/CT (if high quality CT scan included) or MRI scan 
as appropriate. The same imaging modalities used in Screening/Baseline should 
be repeated, unless otherwise clinically indicated. 

Contrast MRI of the brain (only in participants with brain metastases at baseline)
6.5.2. Long Term Follow-up (every 90 Days ±14 days)
Starting 90 days (±14 days) from the EOT Visit and continuing every 90 days (±14 days) 
until death, withdrawal of consent, lost to follow-up, or study closure, the following must be 
performed:

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 only as appropriately directed in 
accordance with local law may be used to obtain this information if reasonable 
efforts to contact the participant are unsuccessful (see 11).

For persons of childbearing potential (for 7 months after the last dose of study 
treatment; see Section 7.7.5): 
o
Remind participant that monthly pregnancy tests should be performed for 
7 months after the last dose of study treatment 
o
Testing may be performed at home. If performed at home, site staff will 
contact the participant monthly to confirm testing was performed and 
obtain pregnancy test results.
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
More frequent long-term follow-up may be conducted as needed for OS event 
tracking
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. 
6.7. Long-term Extension Phase (LTEP)
As of Amendment 3, participants still receiving clinical benefit and remaining on tucatinib 
with or without T-DXd may continue receiving study treatment during the LTEP.  During 
this phase of the study, only pregnancies and SAEs will be collected by the sponsor. All other 
assessments, including efficacy assessments, will be performed per institutional guidelines 
and investigator-determined usual and customary clinical care. Pregnancy testing will 
continue as outlined in the schedule of events for participants of child-bearing potential.
7. STUDY ASSESSMENTS
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 Section 4 will be enrolled in this study.
Participants must have confirmed HER2+ breast cancer, as determined at a CLIA-certified or 
ISO-accredited local laboratory. HER2 positivity will be defined by the current ASCO/CAP 
guidelines. Participant medical history includes a thorough review of significant past medical 
history, current conditions, any prior treatment and response to prior treatment for the 
participant’s breast cancer, and any concomitant medications.
All measurable and evaluable lesions will be assessed and documented at Screening/Baseline 
(see Section 7.2). A contrast MRI of the brain will be performed to evaluate for the presence 
of brain metastases (see Section 7.2.1). 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 7.1.1.
A physical examination including height (Section 7.7.4), vital signs and weight 
(Section 7.7.2), ECOG PS (Appendix E), clinical laboratory testing (Section 7.7.3), Contrast 
CT, PET/CT, or MRI (Section 6.3.6), ECHO/MUGA (Section 6.3.7), ECG (Section 7.7.7.2), 
hepatitis B and C screening (11), biomarker evaluation (Section 7.4), and pregnancy testing 
(Section 7.7.5) will be done at Screening/Baseline (see 11).
7.1.1. 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 
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amenable to immediate CNS-directed therapy with either surgery or radiation, they may 
undergo local therapy and then be eligible for the trial. 
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 postoperative 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
Radiographic scans and additional imaging assessments (if applicable) will be performed at 
protocol-specified time points outlined in Section 6 and 11, or if disease progression is 
suspected. Efficacy assessments will be made at each time point according to RECIST v1.1 
(Eisenhauer et al, 2009; Schwartz et al, 2016) by the investigator. 
All known sites of metastatic or locally advanced unresectable disease should be assessed by 
radiographic imaging at Screening/Baseline to document sites of disease and overall tumor 
burden. Imaging, preferably by high quality spiral contrast CT scan (with oral and/or IV 
contrast), should include the chest, abdomen, and pelvis, at a minimum; PET/CT (if high 
quality CT scan is included) and/or MRI scan may also be done as appropriate. If a CT scan 
with contrast is contraindicated (ie, in participants with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed instead, with MRI scans of 
the abdomen and pelvis (if an MRI is not feasible, a non-contrast CT scan is acceptable). At 
the investigator’s discretion, other appropriate imaging (eg, photography for skin lesions, 
nuclear bone scan imaging for bone lesions) should be used to assess additional known sites 
of measurable disease. The same imaging modalities employed in Screening/Baseline should 
be used for all subsequent response assessments during study treatment and in the follow-up 
period, unless otherwise clinically indicated. If any other radiographic or assessment exam, 
including pathology from any on-study biopsies or procedures, is conducted per standard of 
care, the assessment information will be collected in the CRF. 
In the event of equivocal progression, for example a new lesion which is small in size 
(defined as an equivocal new lesion) and no imminent threat to participant safety, all efforts 
should be made to continue the participant with study treatment until unequivocal 
progression is documented. Demonstration of an unequivocal new lesion constitutes disease 
progression.
Participants’ clinical data must be available for CRF source verification. In addition, images 
will be collected by an ICR facility for possible future analysis. Copies of tumor images must 
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be made available for review by the sponsor (or its designee) upon request. All imaging will 
be submitted or uploaded to the ICR facility as soon as reasonably possible (eg, within 
approximately 2 weeks) following the date of assessment. Refer to the Study Manual for 
instructions on collecting and submitting tumor imaging studies to the ICR facility.
During the LTEP, efficacy assessments will be performed per institutional guidelines and 
investigator-determined usual and customary clinical care.
7.2.1. Evaluation of Brain Metastases
Contrast MRI scan of the brain will be performed for all participants at Screening/Baseline to 
assess tumor burden in the brain and/or dura and identify participants with brain metastases 
at baseline. CT of the brain will not be allowed, and participants with known 
contraindications to undergoing contrast MRI imaging will be excluded from the study. 
Participants are considered to have brain metastases at baseline with any of the following:

Any history of brain metastases

Any brain metastases at baseline

Brain lesions of equivocal significance at baseline
Only participants with documented brain metastases at baseline, as defined above, will 
continue to have follow-up contrast MRIs of the brain on the same schedule as non-CNS 
response assessments (Section 6 and 11). Contrast MRIs of the brain may also be performed 
in participants without known brain metastases if there is clinical suspicion of new brain 
lesions. All participants with a history of brain metastases who discontinue study treatment 
for reasons other than radiographic disease progression will have an additional contrast MRI 
of the brain at the EOT visit, unless one has been performed within 30 days of discontinuing 
study treatment or if progression in the brain has already been documented while on the 
study.
In participants with baseline brain lesions, at least 1 brain lesion should be included in the 
baseline RECIST lesion selection as either a target or non-target lesion. As an exception,
however, when unsuspected brain metastases are discovered at screening and immediate 
CNS-directed therapy is administered, treated lesions should not be selected as target lesions 
but as non-target lesions for the purpose of disease assessment by RECIST v1.1. 
All brain imaging will be collected by an ICR facility for possible future analysis. Copies of 
brain imaging must be made available for review by the sponsor (or its designee), upon 
request. Images will be submitted or uploaded to the ICR facility as soon as reasonably 
possible (eg, within approximately 2 weeks) following the date of assessment. Refer to the 
Study Manual for instructions on collecting and submitting brain imaging studies to the ICR 
facility.
During the LTEP, brain metastases evaluations will be performed per institutional guidelines 
and investigator-determined usual and customary clinical care.
7.2.2. 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 
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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 medical monitor approval. This 
approach approximates standard clinical practice in this clinical scenario. 
Because the primary endpoint of the study is cORR, 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 and approval of the medical monitor. 
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.
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 radiographic 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
Blood samples will be collected in all participants at baseline, predose, and at 2 hours 
(±15 minutes) post-dose of tucatinib per the sample collection schedule provided in Table 10.
The steady state PK of tucatinib will be assessed through the sparse sampling of the peak and 
trough levels from Cycle 2 to Cycle 6. PK assessment of trough levels will be performed on 
all participants on Day 1 of Cycles 2, 3, and 6 prior to drug administration and peak level 
assessment will be on Day 1 of Cycles 2 and 3 at 2 hours (±15 minutes) post-tucatinib dose. 
PK samples should continue to be collected on schedule regardless of dose holds or 
interruptions. The time of tucatinib administration and PK collection will be recorded by the
site.
For safety lead-in participants only, an additional pharmacokinetic assessment will be 
performed at an unspecified time on Cycle 1 Day 12. The time of the tucatinib administration 
on the morning of the visit will be recorded by the participant. Participants will be called the 
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evening before the visit and reminded to record the time of dose. The exact time of the PK 
sample will also be recorded by the site. 
Table 10: Pharmacokinetic sample collection time points
Cycle
Day
Plasma Sample
Serum Sample
Time point
1
1
X
X
0 h (–2 h) prior to administration of tucatinib
12
X
X
For safety lead-in participants only. Record time 
of dose and blood draw.
2
1
X
X
0 h (–2 h) prior to administration of tucatinib
X
X
2 h following administration of tucatinib
3
1
X
X
0 h (–2 h) prior to administration of tucatinib
X
X
2 h following administration of tucatinib
6
1
X
X
0 h (–2 h) prior to administration of tucatinib
7.4. Biomarker Studies
When available, archival tumor blocks are to be collected at screening. If tumor blocks are 
not available, slides may be submitted after discussion with and approval from the medical 
monitor. HER2 expression may be further evaluated by multiple methods including 
immunohistochemistry (IHC), in situ hybridization (ISH), tissue-based next generation 
sequencing (NGS), and cell-free DNA. Additionally, tumor biopsies performed while the 
participant is on study should be made available to the sponsor, if feasible. For example, if a 
biopsy on residual tumor is performed at the EOT or at progression, a sample will be 
collected (if residual tumor is available). Blood samples for biomarker assay will be drawn at 
screening, Cycle 3, Day 1 (predose), and at EOT. 
Biomarker assessments may include an exploratory assessment of HER2 mutations or other 
mutations as potential biomarkers of response. Additional analyses including but not limited 
to IHC and NGS analysis may be performed to interrogate biomarkers that are associated 
with tumor growth, survival and resistance to targeted therapeutics. This assessment may 
enable the correlation of additional biomarkers with treatment outcome and may ultimately 
guide or refine participant selection strategies to better match tucatinib regimens with tumor 
phenotype/genotype in the future.
7.5. Biospecimen Repository
In the US only, for participants who provide additional consent, remaining de-identified 
unused blood and/or tissue will be retained by Pfizer and used for future research, including 
but not limited to the evaluation of targets for novel therapeutic agents, the biology of 
sensitivity and resistance mechanisms to targeted therapeutics, and the identification of 
biomarkers. Blood and tissue samples donated for future research will be retained for a 
period of up to 25 years. If additional consent is not provided, any remaining biological 
samples will be destroyed after the study has been completed and all applicable regulatory 
obligations have been met.
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7.6. Patient-reported Outcomes
Patient-reported outcome measures will be administered as specified in 11 and Section 6
using the EQ-5D-5L instrument. During study treatment, these questionnaires must be 
completed prior to evaluation by study personnel (physical examination, review of AEs) and 
administration of study treatment on treatment days.
7.6.1. EQ-5D-5L – Utility Measurement
The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a 
generic, preference-based measure of health-related quality of life (HR-QoL) outcomes that 
can be used in a wide range of health conditions and treatments (van Agt et al, 1994). The 
EQ-5D-5L consists of a descriptive system questionnaire and the EuroQoL (EQ) visual 
analog scale (VAS; Appendix H). 
The descriptive system questionnaire assesses 5 dimensions of health, including mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
comprises 5 levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems. The scores on these 5 dimensions can be presented as a health profile or 
the digits for the 5 dimensions can be converted to a 5-digit number that describes the 
participant’s health state. The recall time frame for the descriptive system is the day in which 
the questionnaire is administered. The EQ VAS records the participant’s self-rated health 
status on a vertical VAS ranging from 0 (worst imaginable health state) to 100 (best 
imaginable health state) and can be used as a quantitative measure of health outcome that 
reflects the participant’s own judgment. 
7.7. Safety Assessments
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs (including clinically significant safety events) identified during the safety 
lead-in stage and SAEs identified during the safety lead-in or study activity assessment 
phase, physical examination findings, vital signs including weight, concomitant medication, 
pregnancy testing, and laboratory tests. Participants will be monitored for signs and 
symptoms of ILD/pneumonitis. In cases where ILD/pneumonitis is suspected, treatment with 
T-DXd will be interrupted, and the participant will undergo evaluation including 
radiographic imaging. Pulmonary consultation should also be considered. Dose modification 
or discontinuation of T-DXd for cases of ILD/pneumonitis will be made as per product label. 
Assessment of cardiac ejection fraction will be performed using MUGA scan or ECHO. 
Only pregnancies and SAEs will be collected by the sponsor during the LTEP. All other 
assessments, including additional safety assessments, will be performed per institutional 
guidelines and investigator-determined usual and customary clinical care. Pregnancy testing 
will continue as outlined in the schedule of events for participants of child-bearing potential.
Safety will be monitored over the course of the study by the SMC as described in 
Sections 3.1 and 9.3.1.9.
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7.7.1. Adverse Events
7.7.1.1. Definitions
Adverse Event
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, 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 intervention, 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 intervention) should be recorded from 
study Day 1 (during and post-dose) through the end of the safety reporting period 
(see Section 7.7.1.3). Complications that occur in association with any procedure 
(eg, 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 
(eg, record “anemia” rather than “low hemoglobin”).

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF. Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
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. In general, hospitalization signifies that the 
participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 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. 
Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether 
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“hospitalization” occurred or was necessary, the AE should be 
considered serious.
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.
This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle), that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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 7.7.1.2 for the 
definition of potential DILI.)
Adverse Event Severity
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 5.0. These criteria are provided in the 
study manual.
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 or T-DXd) 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 (eg, angioedema, hepatic 
injury, Stevens-Johnson Syndrome)
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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 (eg, tendon rupture)
Unrelated:
Another cause of the AE is more plausible (eg, 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 relationship is 
considered biologically implausible
If the investigator does not know whether or not the study intervention caused the event, then 
the event will be handled as “related to study intervention” for reporting purposes, as defined 
by the sponsor. In addition, if the investigator determines that an SAE is associated with 
study procedures, the investigator must record this causal relationship in the source 
documents and CRF, and report such an assessment in the dedicated section of the PSSA and 
in accordance with the SAE reporting requirements.
Adverse Events of Special Interest
An adverse event of special interest (AESI) can be any serious or non-serious 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. 
During the LTEP, only AESIs that meet SAE criteria will be reported to the sponsor using 
the PSSA and will not be recorded within the CRF.
AESIs for this study are:

Diarrhea
o
≥Grade 3 diarrhea
o
Grade 2 diarrhea with concomitant Grade 2 nausea and/or vomiting 

Hepatotoxicity: Any of the following types of LFT elevations:
o
AST or ALT elevations that are >3 × ULN with concurrent elevation 
(within 21 days of AST and/or ALT elevations) of total bilirubin 
>2 ×ULN, except in participants with documented Gilbert’s syndrome 
o
AST or ALT elevations > 20 ×ULN
o
Bilirubin elevations > 10 ×ULN
Measurement of direct and indirect 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.
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
Interstitial lung disease (ILD)/pneumonitis
Participants should be advised to immediately report cough, dyspnea, fever, and/or 
any new or worsening respiratory symptoms. Treating physicians should monitor 
participants for signs and symptoms of ILD/pneumonitis and promptly investigate for 
any evidence of ILD/pneumonitis. The evaluation of participants with suspected 
ILD/pneumonitis should include radiographic imaging.
See Section 5.5.3.3 for dose modification guidelines and Appendix F for 
ILD/pneumonitis evaluation and treatment guidelines. See Appendix G for potential 
conditions that can trigger potential ILD. 

Left Ventricular Ejection Fraction (LVEF) decrease
The following 2 types of LVEF decrease are considered AESIs:
o
An asymptomatic decline in LVEF leading to a change in study treatment 
or discontinuation of study treatment. Use the term “ejection fraction 
decreased” and severity Grades 2 to 4 to report asymptomatic LVEF 
decrease. 
o
Symptomatic CHF. Use the term “heart failure” and severity Grades 2 to 5 
to report symptomatic CHF. 
7.7.1.2. 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 reporting through the PSSA, as 
appropriate. Refer to Appendix J for guidance on recording/reporting AEs and SAEs.
During the LTEP, pregnancies and SAEs will be reported to the sponsor using the PSSA and 
will not be recorded within the CRF.
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
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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 adverse event.
Important exceptions for this study are adverse reactions associated with the infusion of 
study intervention. 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 the CRF and  report to Pfizer Safety using the PSSA.
The following should be considered when recording SAEs:

Death is an outcome of an event. The event that resulted in the death should be 
reported to Pfizer Safety using the PSSA.

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.
Environmental Exposure, Exposure During Pregnancy, and Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. Refer to Table 12 in Appendix J for guidance on 
reporting/recording environmental exposure.
Exposure During Pregnancy
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An EDP occurs if: 

A participant is found to be pregnant while receiving or after discontinuing study 
intervention. 

A participant who is receiving or has discontinued study intervention inseminates 
a partner. 

A nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 

A family member or healthcare provider reports that they are pregnant after 
exposure to study intervention, for example, by ingestion or skin contact.

A family member or healthcare provider who has been exposed to the study 
intervention, for example, by ingestion or skin contact and then inseminates 
their partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to
termination of pregnancy). Refer to Table 12 in Appendix J for guidance on 
reporting/recording EDP.

If EDP occurs in a participant/participant’s partner after the start of study 
intervention and until 7 months after the last dose of the last study intervention, 
the investigator must report this information to Pfizer Safety via PSSA, regardless 
of whether an SAE has occurred.

If EDP occurs in the setting of environmental exposure, the investigator must 
report information to Pfizer Safety via PSSA. Since the exposure information 
does not pertain to the participant enrolled in the study, the information is not 
recorded on a CRF; however, a copy of the completed PSSA is maintained in the 
investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be 
reported as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to their partner. The investigator must document in the source documents 
that the participant was given the Pregnant Partner Release of Information Form to provide to 
their partner.
Exposure During Breastfeeding
An EDB occurs if: 

A participant is found to be breastfeeding while receiving or after discontinuing study 
intervention. 

A nonparticipant is found to be breastfeeding while being exposed or having been 
exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a family member or healthcare provider who reports 
breastfeeding after having been exposed to study intervention by ingestion or skin 
contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the PSSA. When EDB occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed PSSA is maintained in the 
investigator site file.
Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the PSSA regardless of whether there is an 
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associated SAE. Because the information about the occupational exposure does not pertain to 
a participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed PSSA must be maintained in the investigator site file.
Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE. 
Potential Drug-induced Liver Injury
Hy’s Law can be used to estimate severity and the likelihood that a study intervention may 
cause an increased incidence of severe hepatotoxicity.
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 (ie, 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 serious adverse event (SAE) and 
reported promptly to the sponsor.
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.
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Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. During this investigation, consider 
withholding study intervention.
7.7.1.3. 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.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has concluded study participation, and they 
consider the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using PSSA.
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. 
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started. SAEs occurring during the safety reporting 
period must still be reported to Pfizer Safety irrespective of any intervening treatment. Note 
that a switch to a commercially available version of the study intervention is considered as a 
new anticancer therapy for purposes of SAE reporting.
7.7.1.4. Serious Adverse Events Require Immediate Reporting
All SAEs occurring in a participant during the safety reporting period are reported to Pfizer 
Safety via the PSSA immediately upon awareness and under no circumstance should this 
exceed 24 hours. The investigator will submit any updated SAE data to the sponsor within 24 
hours of its being available.
For initial SAE reports, available case details are to be reported to Pfizer Safety using the 
PSSA. 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
An investigator who receives suspected unexpected serious adverse reactions (SUSARs) or 
other specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the SRSD(s) for the study and will notify the IRB/EC, if 
appropriate according to local requirements.
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Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.7.2. Vital Signs
Vital signs measures are to include weight, heart rate, blood pressure, temperature, 
respiratory rate, and pulse oximetry.
7.7.3. Clinical Laboratory Tests
Local laboratory testing will include institutional standard tests for evaluating safety and 
making clinical decisions. The following laboratory assessments will be performed to 
evaluate safety at scheduled time points (see 11) during the course of the study:

The serum chemistry panel is to include the following tests: bicarbonate, blood 
urea nitrogen, calcium, creatinine, chloride, glucose, magnesium, phosphorus, 
potassium, and sodium 

LFTs include albumin, alkaline phosphatase, ALT, AST, total bilirubin (and both 
direct and indirect bilirubin when total bilirubin is >ULN), and total protein

The CBC with differential is to include, but is not limited to, the following tests: 
white blood cell count with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), platelet count, hemoglobin, and 
hematocrit. 

The coagulation panel is to include the following tests: international normalized 
ratio (INR), prothrombin time (PT), and partial thromboplastin time (PTT) or 
activated partial thromboplastin time (aPTT)

The eGFR should be calculated using the MDRD equation, 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)

A serum or urine β-hCG pregnancy test for participants of childbearing potential
Following implementation of Amendment 3, local laboratory testing with the exception of 
pregnancy testing will be performed per institutional guidelines and investigator-determined 
usual and customary care. Pregnancy testing will be performed per the SoE.
7.7.4. 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.
7.7.5. Pregnancy Testing
For participants of childbearing potential, a serum or urine β-hCG pregnancy test with 
sensitivity of at least 25 mIU/mL will be performed at the times listed in the SoE. A negative 
pregnancy result is required before the subject may receive study drug. Pregnancy tests will 
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also be done whenever 1 menstrual cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at the end of the study.
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 once a month for 
7 months. Participants may do monthly home pregnancy tests and report interim results at 
long term follow-up visits. Pregnancy tests may also be repeated as requested per IRB/IEC or 
if required by local regulations.
During the LTEP, pregnancy reporting should continue per protocol and pregnancy should be 
reported to the sponsor per guideline under EDP in Section 7.7.1.2. 
7.7.6. Interstitial Lung Disease
ILD and pneumonitis, including fatal cases, have been reported with T-DXd in clinical 
studies. Evaluate participants with suspected ILD/pneumonitis by radiographic imaging. If a 
participant is suspected or diagnosed as having ILD, the investigator should consult with a 
pulmonologist as needed, and the participant will be treated appropriately. T-DXd dosing 
will be interrupted until drug induced pulmonary toxicity can be ruled out. Please see Section 
5.5.3.3 for dose modification guidelines and Appendix F for ILD/pneumonitis evaluation and 
treatment guidelines. See Appendix G for potential conditions that can trigger potential ILD. 
7.7.7. Cardiac Function
7.7.7.1. 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 (as determined by the date of Cycle 1 Day 1), and 
at the EOT visit (if not done within the previous 12 weeks). 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. During the 
LTEP, cardiac function assessments will be performed per institutional guidelines and 
investigator-determined usual and customary clinical care.
7.7.7.2. Electrocardiogram
ECGs will be performed at screening. To correct for heart rate, QT intervals should be 
calculated using the Fridericia formula (QTcF). During the LTEP, ECG assessments will be 
performed per institutional guidelines and investigator-determined usual and customary 
clinical care.
7.8. Appropriateness of Measurements
Response will be assessed according to RECIST v1.1 (Eisenhauer et al, 2009; Schwartz et al, 
2016) 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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The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. AEs and clinical laboratory 
data will be graded using standardized criteria for oncology (NCI CTCAE version 5.0). The 
EQ-5D-5L is a validated instrument for use as a measure of HR-QoL.
8. DATA QUALITY CONTROL AND QUALITY ASSURANCE
8.1. Site Training and Monitoring Procedures
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of participants at the site, Pfizer 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/product label

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

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 Pfizer 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 
comprehensive and centralized filing system of all study-related documentation that is 
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suitable for inspection by Pfizer or its designated monitors and by quality assurance auditors, 
or representatives of regulatory authorities.
8.2. 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.

During the LTEP, data will no longer be collected in CRFs.
8.3. Data Management Procedures
Following implementation of Amendment 3 and entry of remaining on-treatment participants 
into the LTEP, data will no longer be collected in CRFs. Only pregnancies and SAEs will be 
collected by the sponsor during the LTEP, using the PSSA. See Section 7.7.1.2 for further 
details on SAE and AESI reporting requirements.
9. DATA ANALYSIS METHODS
9.1. Determination of Sample Size
Approximately 60 to 70 participants will be enrolled to ensure about 60 participants will be 
treated at the SMC recommended dose, with approximately 30 per cohort 
(HER2+ MBC with or without brain metastases). Participants are considered enrolled if they 
give informed consent and meet all eligibility criteria.
For illustrative purposes, Table 11 summarizes the expected 95% CIs for the overall study 
(N=60) and by cohort (N=30), which shows reasonable precision for the estimation.
Table 11: Expected 95% CI for different number of responses
Number of 
participants
Number of Responses
ORR
95% exact CI
60
40
66.7%
(53.3%, 78.3%)
42
70.0%
(56.8%, 81.2%)
44
73.3%
(60.3%, 83.9%)
46
76.7%
(64.0%, 86.6%)
48
80.0%
(67.7%, 89.2%)
50
83.3%
(71.5%, 91.7%)
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Table 11: Expected 95% CI for different number of responses
Number of 
participants
Number of Responses
ORR
95% exact CI
52
86.7%
(75.4%, 94.1%)
30
20
66.7%
(47.2%, 82.7%)
22
73.3%
(54.1%, 87.7%)
24
80.0%
(61.4%, 92.3%)
26
86.7%
(69.3%, 96.2%)
9.2. Study Endpoint Definitions
9.2.1. Objective Response Rate
ORR is defined as the proportion of participants with confirmed complete response (CR) or 
partial response (PR), per RECIST v1.1. Participants who do not have at least 2 (initial 
response and confirmation scan) post-baseline response assessments as described in 
Section 7.2 of the protocol will be counted as non-responders. ORR per investigator and per 
ICR are based on investigator response assessments and ICR response assessments, 
respectively.
9.2.2. Progression-free Survival
PFS is defined as the time from start of study treatment to first documentation of tumor 
progression (PD per RECIST v1.1), or to death due to any cause, whichever comes first. 
Participants without documentation of progression or death at the time of analysis will be 
censored at the date of the last disease assessment with an overall response of CR, PR, stable 
disease (SD) or non-CR/non-PD. If there is no radiographic post-baseline tumor assessment, 
PFS will be censored at the date of treatment initiation. PFS per investigator and per ICR are 
based on investigator response assessments and ICR response assessments, respectively.
Detailed methodology, including handling rules for missing assessments and censoring 
approaches for the analysis of PFS, will be provided in the statistical analysis plan (SAP).
9.2.3. Duration of Response
DOR is defined as the time from first documentation of objective response (CR or PR, that is 
subsequently confirmed) to the first documentation of disease progression per RECIST v1.1 
or death from any cause, whichever occurs earlier. Only participants with an objective 
response will be included in the analysis of DOR. DOR per investigator and per ICR are 
based on investigator response assessments and ICR response assessments, respectively.
9.2.4. Disease Control Rate
DCR is defined as the proportion of participants with confirmed CR, PR or stable disease 
(SD or non-CR/non-PD) according to RECIST v1.1. DCR per investigator and per ICR are 
based on investigator response assessments and ICR response assessments, respectively.
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9.2.5. Overall Survival
OS is defined as the time from treatment initiation to death due to any cause. For a 
participant who is not known to have died by the end of study follow-up, observation of OS 
is censored on the date the participant was last known to be alive (ie, the date of last contact). 
Participants lacking data beyond the day of treatment initiation will have their survival time 
censored on the date of treatment initiation (ie, OS duration of 1 day).
9.2.6. Exploratory Endpoints
9.2.6.1. Pharmacokinetic Analysis
PK parameters for tucatinib will be evaluated.
9.2.6.2. Biomarker Analysis
Relationships of biomarker parameters (eg, baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and PK parameters may be explored. Relationships and 
associated data that are determined to be of interest will be summarized. Details will be 
described separately in the SAP or biomarker analysis plan (BAP).
9.2.6.3. Patient-reported Outcomes
Change from baseline in PRO assessments of the EQ-5D-5L.
9.3. Statistical and Analytical Plans
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP. The SAP may modify what is outlined in the protocol where appropriate; 
however, any major modifications of the primary endpoint definitions or their analyses will 
also be reflected in the protocol amendment. 
9.3.1. General Considerations
Tabular summaries will be presented by cohort, unless otherwise specified. In general, 
summary tabulations will display the number of observations, mean, standard deviation, 
median, minimum, and maximum for continuous variables, and the number and percent 
(of non-missing) per category for categorical data. 
Unless otherwise specified, CIs will be calculated at 2-sided 95% level.
The 2-sided 95% exact CI using Clopper-Pearson method (Clopper & Pearson, 1934) will be 
calculated for the response rates where applicable (eg, ORR). 
For time-to-event endpoints, the median survival time will be estimated using the 
Kaplan-Meier method; the associated 95% CI will be calculated based on the complementary 
log-log transformation (Collett, 1994).  
9.3.1.1. Randomization and Blinding
This is a single arm and open-label study. Randomization and blinding will not be performed.
9.3.1.2. Adjustments for Covariates
No adjustment for covariates is planned in the analyses.
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9.3.1.3. Handling of Dropouts and Missing Data
With the exception of time-to-event endpoints, no imputation will be conducted for missing 
data unless otherwise specified in the SAP.
9.3.1.4. Multi-center Studies
This study will be conducted at multiple study centers; however, it is not anticipated that 
site-to-site variation will be adjusted in the analyses.
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 (eg, start date and end date) will be calculated as (end date –
start date +1 [in days]) unless otherwise specified in the planned analysis section.
Baseline values used in all statistical analyses will be the most recent non-missing 
measurement prior to the first dose of study treatment unless otherwise specified in the SAP.
9.3.1.7. Analysis Sets
The all treated participants set includes all participants who receive any amount of study 
intervention. The analyses of PFS, OS, and safety will be based on this analysis set.
The response-evaluable analysis set is defined as all participants with measurable disease 
who (1) had a baseline disease assessment, (2) received study treatment, and (3) had at least 
1 post-baseline assessment or discontinued treatment due to PD, clinical progression, 
toxicity, or death. The analyses of ORR, DCR and DOR will use the response-evaluable 
analysis set.
Additional analysis sets of participants may be defined in the SAP.
9.3.1.8. Examination of Subgroups
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. The 
subgroups and detailed methodology will be provided in the SAP.
9.3.1.9. Timing of Analyses
A safety analysis will be undertaken by the SMC when the first 10 treated participants have 
been followed for at least 1 cycle (safety lead-in stage). The SMC will undertake similar 
analyses if alternative tucatinib and/or T-DXd dose levels or schedules are evaluated in 
additional safety lead-in stage(s). Once the safety lead-in stage is completed, the SMC will 
evaluate the safety of the study regimen throughout the remainder of the study. 
The primary efficacy analysis will be then undertaken when approximately 
60 response-evaluable participants have been treated at the SMC recommended dose and 
followed for at least 6 months. 
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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
The following baseline characteristics will be summarized: 

Participant demographics 

Disease history 

Prior disease-related therapies 

Baseline disease characteristics
Concomitant medications, separately for medications taken prior to enrollment and while on 
study, will be listed and summarized.
Details will be provided in the SAP.
9.3.4. Exposure
Treatment administration will be summarized for the all treated analysis sets. Summary 
statistics for duration of therapy (weeks) and the number of cycles per participant will be 
presented. The number of dose reductions, holds, cycle delays, and doses skipped and dose 
intensity for each study intervention will be summarized. 
Details will be provided in the SAP.
9.3.5. Efficacy Analyses
The efficacy analyses will be provided for all participants and by cohorts. Only participants 
who received the SMC recommended dose will be included in the main efficacy analyses. 
Efficacy from participants who did not receive the SMC recommended dose, if any, may be 
summarized separately. 
9.3.5.1. Primary Efficacy Analyses
The confirmed ORR per RECIST v1.1 according to investigator assessment will be 
summarized using the response-evaluable set. The point estimate of ORR and corresponding 
95% CIs will be presented.
9.3.5.2. Secondary Efficacy Analyses
DCR per RECIST v1.1 according to investigator assessment will be summarized using 
response-evaluable set. The point estimate of DCR and corresponding 95% CIs will be 
presented.
DOR per RECIST v1.1 according to investigator assessment will be estimated using 
response-evaluable set using Kaplan-Meier methodology, and Kaplan-Meier plots will be 
provided. Medians will be calculated, where possible. The 95% CIs may also be calculated, 
as appropriate.
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Time-to-event secondary efficacy endpoints, including PFS according to investigator 
assessment and OS will be estimated using the all treated participants set using Kaplan-Meier 
methodology, and Kaplan-Meier plots will be provided. Medians will be calculated, where 
possible. The 95% CIs may also be calculated, as appropriate. Detailed methodology will be 
provided in the SAP.
9.3.5.3. Exploratory Efficacy Analyses
cORR, PFS, DOR and DCR per RECIST v1.1 according to ICR assessment will also be 
analyzed, if the ICR assessments are available; discrepancies between the ICR and 
investigator’s assessment may be summarized descriptively. 
9.3.6. Pharmacokinetic Analyses
Individual (participant) plasma tucatinib concentrations at each sampling time will be listed; 
corresponding summary statistics at each sampling time will also be calculated. Additional 
exploratory PK analyses may be conducted. Exploratory analyses investigating the 
relationship between tucatinib exposure and efficacy and safety endpoints may be conducted. 
9.3.7. Biomarker Analyses
Relationships of biomarker parameters (eg, baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and PK parameters will be explored. Relationships and 
associated data that are determined to be of interest will be summarized. Details will be 
described separately in the SAP or BAP.
9.3.8. Patient-reported Outcomes Analyses
PRO assessments based on EQ-5D-5L will be using descriptive statistics. PRO scores will be 
analyzed descriptively. All subscales and individual item scores will be tabulated. 
Descriptive summaries of observed data at each scheduled assessment time point may be 
presented. Further investigation of missing patterns and details of imputation will be 
provided in the SAP. Additional statistical modeling for PRO measures may be performed 
separately as exploratory analyses.
9.3.9. Safety Analyses
Safety analyses will, in general, be conducted using the all treated participants set. Safety 
will be assessed through summaries of AEs, changes in laboratory test results, changes in 
vital signs, physical examination findings, changes in ECOG PS, and changes in cardiac 
ejection fraction results. AEs will be classified by System Organ Class (SOC) and preferred 
term using Medical Dictionary for Regulatory Activities (MedDRA); AE severities will be 
classified using the NCI CTCAE criteria.
If there is more than 1 dosing level/schedule, the safety summaries will be provided by each 
dosing level/schedule.
9.3.9.1. 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, deaths, and AEs leading to study treatment discontinuation. AEs will 
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be defined as treatment-emergent if they are newly occurring or worsen following study 
treatment.
AEs will be listed and summarized by MedDRA, preferred term, severity, and relationship to 
study intervention. 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. The incidence 
of AEs will be tabulated by preferred term and treatment group. AEs leading to premature 
discontinuation of study intervention will be summarized and listed in the same manner.
All collected AE data will be listed by cohort, study site, participant number, and cycle. 
Separately, all serious AEs and AESIs (see Section 7.7.1.1) will be analogously listed. 
9.3.9.2. 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. A separate listing of all on-study deaths will be presented.
9.3.9.3. Clinical Laboratory Results
For laboratory results, summary statistics for actual values and for change from baseline may 
be tabulated as appropriate by scheduled visit. Laboratory values will be listed with grade per 
NCI CTCAE version 5.0 and flagged when values are outside the normal reference range.
Changes from baseline in laboratory values (hematology, coagulation, serum chemistry, and 
liver function) will be summarized by study phase, treatment group and scheduled visit. 
Laboratory shift tables will also be provided by treatment group and scheduled visit. 
Abnormal values (relative to respective normal ranges) will be flagged in listings.
Additional analytical methods for a more thorough investigation of LFTs (including 
temporal/simultaneous summaries and figures) will be specified in the SAP.
9.3.9.4. Other Safety Analyses
Vital Signs and Physical Examinations
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
ECOG performance status will be summarized for each scheduled visit. Shifts from baseline 
to the best and worst post-baseline score may be tabulated.
Cardiac Ejection Fraction
Cardiac ejection fraction data will be summarized and listed. Shift from baseline may be 
tabulated.
9.3.10. Interim Analyses
There is no formal interim analysis planned. The SMC will review available safety and PK 
data once the first 10 participants treated in the safety lead-in stage have been followed for at 
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least 1 cycle. If alternative tucatinib and/or T-DXd dose levels or schedules are evaluated, the 
SMC will undertake similar assessments in up to the first 10 participants.
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10. REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC.

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European MDR 2017/745 for clinical device research, 
and all other applicable local regulations.
10.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP that the investigator becomes 
aware of.
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10.1.1. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH GCP guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct their personal data and to withdraw consent for the processing 
of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current IRB/EC version of the IRB/EC-
approved ICD(s) during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
10.1.2. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in a secure location with access by 
study personnel only to ensure that only authorized study staff have access. The study site 
will implement appropriate technical and organizational measures to ensure that the personal 
data can be recovered in the event of disaster. In the event of a potential personal data breach, 
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the study site will be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or datasets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.3. Committees Structure
Please see Section 3.1.2 for information on the safety monitoring committee.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
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are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.5. 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 is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password-protected or secured in a locked room to prevent access by 
unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
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requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the Data Management Plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
A Source Document Identification Log (or equivalent) should be maintained with the 
Investigator Site File on site. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
The investigator must maintain accurate documentation (source record) that supports the 
information entered on the CRF.
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The sponsor or designee will perform monitoring 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, the ICH GCP guidelines, and all applicable regulatory requirements.
10.1.7. Use of Medical Records
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, where ethically and scientifically justified and permitted by local regulations, 
to ensure participant safety.
Due to the potential for a participant to be reidentified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following: 
participant names or initials, participant dates (eg, birth date, date of hospital 
admission/discharge, date of death), participant identification numbers (eg, Social 
Security number, health insurance number, medical record number, 
hospital/institution identifier), participant location information (eg, street address, 
city, country, postal code, IP address), and participant contact information (eg, 
telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection 
of personal data (eg, Florence is the preferred system if available). 

There may be unplanned situations where the sponsor may request medical records 
(eg, sharing medical records so that the sponsor can provide study-related advice to 
the investigator). The medical records should be submitted according to the procedure 
described above.
10.1.8. Study and Site Start and Closure
The study start date is the date of the first site activation.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee if requested to do so by the responsible IRB/EC or if such termination is required 
to protect the health of study participants.
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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. When appliable, 
editorial or technical support provided by a third party and paid for by Pfizer, or provided by 
a Pfizer employee, may be a reportable transfer of value under the Sunshine Act for US 
licensed physicians or other healthcare professionals. All authors will have access to the 
relevant statistical tables, figures, and reports (in their original format) required to develop 
the publication. The results of this study may be published or presented at scientific meetings 
by the investigator after publication of the overall study results or 1 year after the end of the 
study (or study termination), whichever comes first.
10.1.10. Sponsor’s Medically Qualified Individual
The sponsor will designate a medically qualified individual (MQI, also known as the medical 
monitor) to advise the investigator on study-related medical questions. The contact 
information for the study medical monitor is documented in the Study Team Contact List 
located in the Investigator Site File or equivalent.
10.1.11. 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 subject) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling subjects 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.
10.2. 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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11. REFERENCES
American Cancer Society (ACS). Breast cancer facts & figures (2017-2018)2018 Dec 12, 
2019. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-
and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf.
Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for 
metastatic breast cancer. N Engl J Med. 2012;366(2):109-19.
Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of 
cancer treatment-induced diarrhea. J Clin Oncol. 2004;22(14):2918-26.
Bossi P, Antonuzzo A, Cherny NI, et al. Diarrhoea in adult cancer patients: ESMO Clinical 
Practice Guidelines. Ann Oncol. 2018;29(Suppl 4):iv126-42.
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J 
Clin. 2018;68(6):394-424.
Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with 
whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a 
randomized clinical trial. JAMA. 2016;316(4):401-9.
Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with 
HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from 
registHER. Clin Cancer Res. 2011;17(14):4834-43.
Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in 
patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-77.
Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated 
with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. 
Lancet Oncol. 2009;10(11):1037-44.
Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated with 
trastuzumab for metastatic breast cancer. Br J Cancer. 2004;91(4):639-43.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26(4):404-13.
Collett D. Interval-censored survival data. 8. In: Modelling survival data in medical research. 
1. Collett D, eds. London: Chapman & Hall; 1994. p 237-51.
Cortés J, Kim SB, Chung WP, et al. LBA1 Trastuzumab deruxtecan (T-DXd) vs trastuzumab 
emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of 
the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32:S1287-8.
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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.
Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in 
metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306-
12.
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. 5-year analysis of neoadjuvant pertuzumab and 
trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive 
breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet 
Oncol. 2016;17(6):791-800.
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.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant 
trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled 
trial. Lancet. 2013;382(9897):1021-8.
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.
Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 
2020;38(24):2782-97.
Kaidar-Person O, Anders CK, Zagar TM. Whole brain radiotherapy for brain metastases: is 
the debate over? JAMA. 2016;316(4):393-5.
Kang SP, Saif MW. Infusion-related and hypersensitivity reactions of monoclonal antibodies 
used to treat colorectal cancer--identification, prevention, and management. J Support Oncol. 
2007;5(9):451-7.
Kerb R, Brockmoller J, Staffeldt B, et al. Single-dose and steady-state pharmacokinetics of 
hypericin and pseudohypericin. Antimicrob Agents Chemother. 1996;40(9):2087-93.
Kulukian A, Taylor J, Olson D, et al. Tucatinib, a HER2-selective tyrosine kinase inhibitor, 
increases the anti-tumor activity of trastuzumab antibody-drug conjugates in preclinical 
models of HER2+ breast cancer. Cancer Res. 2020;80(4 Suppl):Abstract P1-18-09.
Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 
2004;22(17):3608-17.
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Lu Y, Zi X, Zhao Y, et al. Insulin-like growth factor-I receptor signaling and resistance to 
trastuzumab (Herceptin). J Natl Cancer Inst. 2001;93(24):1852-7.
Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-
positive breast cancer. N Engl J Med. 2020;382(7):610-21.
Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-
positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609.
Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast 
Cancer Res. 2006;8(6):215.
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. 2013a;24(6):1526-33.
Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of 
patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 
2013b;22(4):525-31.
Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ 
hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer 
tissues. Clin Breast Cancer. 2004;5(1):63-9.
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.
Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin 
Cancer Res. 2009;15(24):7479-91.
Rosello S, Blasco I, Garcia Fabregat L, et al. Management of infusion reactions to systemic 
anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28(Suppl 4):iv100-
18.
Scaltriti M, Rojo F, Ocana A, et al. Expression of p95HER2, a truncated form of the HER2 
receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 
2007;99(8):628-38.
Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1-update and clarification: from the 
RECIST committee. Eur J Cancer. 2016;62:132-7.
Schwartzberg LS, Franco SX, Florance A, et al. Lapatinib plus letrozole as first-line therapy 
for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122-
9.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
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Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and 
survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82.
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, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-
positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-34.
van Agt HME, Essink-Bot ML, Krabbe PFM, et al. Test-retest reliability of health state 
valuations collected with the EuroQol questionnaire. Soc Sci Med. 1994;39(11):1537-44.
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, Puglisi F, Cortes J, et al. Bevacizumab plus chemotherapy versus 
chemotherapy alone as second-line treatment for patients with HER2-negative locally 
recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus 
chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 
2014;15(11):1269-78.
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in 
early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-31.
von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive 
HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-28.
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Appendix A. SCHEDULE OF EVENTS
Study Procedure and Day
Screening
Cycle 1
Cycle 2
Days –28 to 
1
Day 1
Day 12
(±3 days)
Day 1
(–1 day to +3 days)
Day 12
(±3 days)
Assessments
Informed consent
X
Document AEs
X
X
X
X
Document study eligibility
X
Document concomitant medsa
X
X
X
X
Document baseline medical conditions
X
Document disease history
X
Height
X
Vital signs (BP, heart rate, temp, resp rate, 
pulse oximetry), including weightb
X
X
X
X
Physical examb
X
X
X
X
ECOG PSb
X
X
X
X
Labsb,c
X
X
X
X
Xd
Coagulation
X
Pregnancy teste
Xf
X
Hepatitis B and C screening
Xg
ECG
X
ECHO/MUGAh
X
CT, PET/CT, or MRIh,i
X
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Study Procedure and Day
Screening
Cycle 1
Cycle 2
Days –28 to 
1
Day 1
Day 12
(±3 days)
Day 1
(–1 day to +3 days)
Day 12
(±3 days)
Contrast MRI Brain
X
Blood sample for biomarker evaluation
X
Archived tumor sample for biomarker 
evaluation
Xj
EQ-5D-5L Questionnairek
X
X
Study 
intervention 
Tucatinibl
X
X
T-DXdm
X
Xn
PK
Blood samples
Xo
Xp
Xq
a.
Including concomitant procedures, hospitalizations, and a review of the dosing regimen of antidiarrheals taken in the previous cycle beginning with the 
first dose of tucatinib, participants following protocol amendment 2 are to receive loperamide (see Section 5.6.1). 
b.
Assessment to be done predose on days when study intervention(s) are administered. Predose assessments can be done within 1 day prior to study visit 
(with exception of vital signs). For Cycle 1 Day 1, lab results must be reviewed and eligibility confirmed prior to first dose of study treatment. 
c.
Blood samples for complete blood count with differential, serum chemistry, and liver function tests. 
d.
Only liver function tests are required at this visit.
e.
Females of childbearing potential only: serum or urine pregnancy test. Pregnancy test to be performed each cycle prior to study treatment. A positive 
urine test must be confirmed with a serum pregnancy test.
f.
Serum or urine pregnancy test within 7 days prior to treatment (required only for females of childbearing potential).
g.
Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B core (anti-HBc), and antibodies to Hepatitis C (anti-HCV). If positive, 
additional testing may be required after discussion with medical monitor.
h.
Use the same assessment modality throughout the study that was used at screening/baseline.
i.
At minimum, scans must include chest, abdomen, and pelvis. Additional appropriate imaging of any other known sites of disease such as photography for 
skin lesions or nuclear bone scan imaging for bone lesions may also be obtained at the investigator’s discretion. If bone imaging is collected, any RECIST 
appropriate imaging modality may be used.
j.
If tumor blocks are not available, slides may be submitted after discussion with and approval from the medical monitor.
k.
To be completed prior to evaluation by study personnel (physical examination, review of AEs) and administration of any study intervention .
l.
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.
m. T-DXd is administered intravenously, once every 21 days.
n.
Tucatinib should be administered prior to T-DXd on Day 1 for this cycle. 
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Study Procedure and Day
Screening
Cycle 1
Cycle 2
Days –28 to 
1
Day 1
Day 12
(±3 days)
Day 1
(–1 day to +3 days)
Day 12
(±3 days)
o.
Predose
p.
For safety lead-in participants only. After morning dose of tucatinib (record time of tucatinib dose and blood draw).
q.
Predose and 2 hour (±15 min) post-dose.
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Study Procedure and Day
Cycle 3 and Beyond
End of 
Treatment 
Visit
Follow-up
LTEP
Day 1
(–1 day to 
+3 days)
CT/MRI and 
ECHO/MUGA 
Schedule 
30 Days 
(+7 days) After 
Last Dose of 
Study 
Treatment 
90 Days (±14 days) 
Following End of 
Treatment Visit and 
Continuing Every 
90 Daysb
Assessments
Document AEs
X
X
Xv,w
Document concomitant medsa
X
X
Xv
Vital signs (BP, heart rate, temp, 
resp rate, and pulse oximetry), 
including weightc
X
X
Xv
Physical examc
X
X
Xv
ECOG PSc
X
X
Xv
Labsc,d
X
X
Xv
Coagulation
X
Xv
Pregnancy test
Xe
Xf
Xf
Xe,f
ECHO/MUGAg
Xh
Xi
Xv
CT, PET/CT, or MRIg,j
Xk
Xl
Xm
Xv
Contrast MRI Brain
Xn
Xo
Xm
Xv
Blood sample for biomarker 
evaluation
Xp
X
EQ-5D-5L Questionnaireq
X
X
Participant contact/clinic visit
X
X
Xr
Xv
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Study Procedure and Day
Cycle 3 and Beyond
End of 
Treatment 
Visit
Follow-up
LTEP
Day 1
(–1 day to 
+3 days)
CT/MRI and 
ECHO/MUGA 
Schedule 
30 Days 
(+7 days) After 
Last Dose of 
Study 
Treatment 
90 Days (±14 days) 
Following End of 
Treatment Visit and 
Continuing Every 
90 Daysb
Study 
intervention 
Tucatinibs
X
X
T-DXdt
X
X
PK 
Blood samples
Xu
a.
Including concomitant procedures, hospitalizations, and a review of the dosing regimen of antidiarrheals taken in the previous cycle. Beginning with the first dose of 
tucatinib, participants following protocol amendment 2 are to receive loperamide (see Section 5.6.1).
b.
More frequent follow-up may be requested for OS event tracking. If an End Of Treatment Visit was not done, then long term follow-up should begin every 90 days 
(±14 days) starting from the date of the last dose of study treatment.
c.
Assessment to be done predose on days when study intervention(s) are administered. Predose assessments can be done within 1 day prior to study visit (with the exception 
of vital signs).
d.
Blood samples for complete blood count with differential, serum chemistry, and liver function tests.
e.
Females of childbearing potential only: serum or urine pregnancy test. Pregnancy test to be performed each cycle prior to study treatment starting. A positive urine test must 
be confirmed with a serum pregnancy test.
f.
Females of childbearing potential only: monthly pregnancy tests should be performed for 7 months after the last dose of study treatment. Participant will be asked to 
confirm that monthly pregnancy tests have been performed and have been negative. A pregnancy test should be performed at the End of Treatment Visit if not performed 
within the last 30 days. Confirmation of correct and consistent use of contraception and assessment of whether participant has changing reproductive needs.
g.
Use the same assessment modality throughout the study that was used at screening/baseline.
h.
Every 12 weeks (–7 days) as determined by the date of C1D1. 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
i.
If not done within the previous 12 weeks (excluding screening/baseline).
j.
At minimum, scans must include chest, abdomen, and pelvis. Additional appropriate imaging of any other known sites of disease such as skin lesion photography or bone 
imaging may also be obtained at the investigator’s discretion. If bone imaging is collected, any RECIST appropriate imaging modality may be used. 
k.
Schedule determined by the C1D1 date. Contrast CT (preferred), PET/CT (if high quality CT scan included) or MRI scans should be performed every 
6 weeks (–7 days) through Week 24, then every 9 weeks (–7 days) through end of study intervention. If cycles are delayed for any reason or there is an 
interim unscheduled assessment, scans should continue to be performed according to the original C1D1 date as described in Section 6.3.6.
l.
Only in participants who discontinue study treatment for reasons other than radiographic disease progression. Not required if performed within 30 days of discontinuing 
study treatment. 
m. If study treatment is discontinued for reasons other than disease progression (per RECIST v1.1) or death, participants will continue to have follow-up for disease 
progression and scan data should be collected approximately every 9 weeks (±1 week) until the occurrence of disease progression per RECIST v1.1, death, withdrawal of 
consent, or study closure. Brain MRI only required for participants who have a history of brain metastases at baseline.
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Study Procedure and Day
Cycle 3 and Beyond
End of 
Treatment 
Visit
Follow-up
LTEP
Day 1
(–1 day to 
+3 days)
CT/MRI and 
ECHO/MUGA 
Schedule 
30 Days 
(+7 days) After 
Last Dose of 
Study 
Treatment 
90 Days (±14 days) 
Following End of 
Treatment Visit and 
Continuing Every 
90 Daysb
n.
Schedule determined by the C1D1 date. Contrast MRI of the brain (only in participants with brain metastases at baseline) should be performed every 6 weeks (–7 days) 
through Week 24, then every 9 weeks (–7 days) through end of study intervention. If cycles are delayed for any reason or there is an interim unscheduled assessment, scans 
should continue to be performed according to the original C1D1 date as described in Section 6.3.6.
o.
Only in participants who have a history of brain metastases who discontinue study treatment for reasons other than radiographic disease progression, except 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. 
p.
At C3D1 only, predose. 
q.
To be completed prior to evaluation by study personnel (physical examination, review of AEs) and administration of any study intervention for Cycle 3 and 4 and every 
2 cycles starting at Cycle 6 until treatment discontinuation, PD, death, unacceptable toxicity, withdrawal of consent or study closure, and at the End Of Treatment visit.
r.
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.
s.
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.
t.
T-DXd is administered intravenously, D1 of each 21-day cycle.
u.
PK samples will be taken at cycles 3 and 6 only. Tucatinib should be administered before T-DXd at Cycle 3 and Cycle 6; for Cycle 3, participants should remain onsite for 
2 hours (±15 minutes) after tucatinib administration to coordinate peak PK sampling times. For all other cycles, study interventions may be given in any order and can be 
given simultaneously.
v.
During the LTEP, safety and efficacy assessments that include determination of disease progression will be performed per institutional guidelines and investigator-
determined usual and customary clinical care.
w. Only SAEs and pregnancy will be collected by the sponsor
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Appendix B. 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 Inhibitor
Gemfibrozil
1–2 hours
Moderate Inhibitors
Clopidogrel
Deferasirox
Teriflunomide
6 hours
8–16 hours
18–19 days
Moderate Inducer
Rifampin
3–5 hours
Note: Any additional strong inhibitors or inducers of CYP2C8 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/DrugInteractionsLabelin
g/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/WC500129606.pdf
c Drug product label
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Appendix C. CYP3A4 INDUCERS AND THEIR ELIMINATION HALF-LIVES
Cytochrome P450 (CYP) 3A4 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, unless indicated otherwise)
Strong Inducers
Apalutamide
3 daysd
Carbamazepine
25–65 hours (single dose), 12–17 hours (repeat dose)
Enzalutamide
5.8 dayse
Mitotane
18 to 159 daysf
Phenytoin
7–42 hours
Rifampin
3–4 hours (single dose), 2–3 hours (repeat dose)
St. John’s Wort
9–43 hoursg
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/DrugInteractionsLabeli
ng/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/WC500129606.pd
f)
c Drug product label
d ERLEADA drug label 2018.
e XTANDI drug label 2018.
f LYSODREN drug label 2017.
g
(Kerb et al, 1996)
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Appendix D. EXAMPLES OF 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, 
darunavirc, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatind, midazolam, naloxegol, nisoldipine, saquinavirc, 
simvastatind, sirolimus, tacrolimus, tipranavirc, triazolam, 
vardenafil
alprazolam, aprepitant, atorvastatina, 
colchicine, eliglustatb, pimozide, rilpivirine, 
rivaroxaban, tadalafil
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, 
felodipine, indinavirc, lurasidone, maraviroc, quetiapine,
sildenafil, ticagrelor, tolvaptan
AUC=area under the concentration-time curve; CYP=cytochrome P450; DDI=drug-drug interaction; 
OATP1B1=organic anion transporting polypeptide 1B1. 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that 
demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway 
in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold 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 Listed based on pharmacogenetic studies.
b Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A.
c Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.
d Acid form is an OATP1B1 substrate
DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug 
Interaction Database (Hachad et al, 2010).
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling
/ucm093664.htm#table3-1
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Appendix E. ECOG PERFORMANCE STATUS SCALE
ECOG
Score
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature (eg, light housework, office work).
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.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair.
5
Dead.
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Appendix F. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF T-DXD INDUCED INTERSTITIAL LUNG 
DISEASE/PNEUMONITIS
Grade 1
Grade 2
Grade 3 or 4
Work-up
If a patient develops radiographic changes potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever, rule out ILD/pneumonitis

Evaluations should include:
– High resolution CT
– Pulmonologist consultation (Infectious Disease consultation as clinically indicated)
– Blood culture and CBC. Other blood tests could be considered as needed
– Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible
– Pulmonary function tests and pulse oximetry
– Arterial blood gases if clinically indicated
– One blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible

If the AE is confirmed to have an etiology other than treatment-related ILD/pneumonitis, follow routine clinical practice

If another etiology for the AE cannot be identified and it could be related to T-DXd, then follow the ILD/pneumonitis 
management guidance as outlined below

All events of ILD/pneumonitis, regardless of severity or seriousness, should be followed until resolution
Dose 
modification

The administration of T-DXd must be 
interrupted

T-DXd can be restarted only if the event is 
fully resolved:
– If resolved in ≤28 days from day of onset, 
maintain dose.
– If resolved in >28 days from day of onset, 
reduce dose by 1 level
– However, if the event Grade 1 ILD/pneumonitis 
occurs beyond cycle Day 22 and has not 
resolved within 49 days from the last infusion, 
the drug should be discontinued
Permanently discontinue patient 
from T-DXd treatment
Permanently discontinue patient 
from T-DXd treatment
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Grade 1
Grade 2
Grade 3 or 4
Toxicity 
management

Monitor and closely follow-up in 2 to 7 days 
for onset of clinical symptoms and pulse 
oximetry

Consider follow-up imaging in 1 to 2 weeks 
(or as clinically indicated)

Consider starting systemic steroids (eg, at least 
0.5 mg/kg/day prednisone or equivalent) until 
improvement, followed by gradual taper over at 
least 4 weeks

If worsening of diagnostic observations despite 
initiation of corticosteroids, then follow 
Grade 2 guidelines. (If the patient is 
asymptomatic, then they should still be 
considered as grade 1 even if steroid treatment 
is given)

Promptly start systemic 
steroids (eg, at least 
1 mg/kg/day prednisone or 
equivalent) until clinical 
improvement, followed by 
gradual taper over at least 
4 weeks.

Monitor symptoms closely 

Re-image as clinically 
indicated

If worsening or no 
improvement in clinical or 
diagnostic observations in 
5 days,
– Consider increasing dose of 
steroids (eg, 2 mg/kg/day 
prednisone or equivalent) 
and administration may be 
switched to IV (eg, 
methylprednisolone)
– Re-consider additional 
workup for alternative 
etiologies as described 
above
– Escalate care as clinically 
indicated

Hospitalization required

Promptly initiate empiric high-
dose methylprednisolone IV 
treatment (eg, 500 to 
1000 mg/day for 3 days), 
followed by at least 
1.0 mg/kg/day of prednisone 
(or equivalent) until clinical 
improvement, followed by 
gradual taper over at least 
4 weeks

Re-image as clinically 
indicated

If still no improvement within 
3 to 5 days,
– Re-consider additional 
workup for alternative 
etiologies as described 
above
– Consider other 
immunosuppressants and/or 
treat per local practice
Source: (Modi et al, 2020) (supplementary appendix Table S6).
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Appendix G. POTENTIAL CONDITIONS THAT COULD TRIGGER CLINICAL 
EVALUATION FOR SUSPECTED INTERSTITIAL LUNG DISEASE
The table below provides examples and is not intended to be an exhaustive list of conditions 
that may potentially trigger suspected ILD.

Acute interstitial pneumonitis

Allergic eosinophilia

Allergic granulomatous angiitis

Alveolar lung disease

Alveolar proteinosis

Alveolitis

Alveolitis allergic

Alveolitis necrotizing

Acute respiratory distress 
syndrome (ARDS)

Bronchiolitis

Diffuse alveolar damage

Eosinophilia myalgia syndrome

Eosinophilic pneumonia

Eosinophilic pneumonia acute

Eosinophilic pneumonia 
chronic

Granulomatous pneumonitis

Idiopathic pneumonia 
syndrome

Idiopathic pulmonary fibrosis

Interstitial lung disease

Lung infiltration

Necrotising bronchiolitis

Obliterative bronchiolitis

Organizing pneumonia

Pneumonitis

Progressive massive fibrosis

Pulmonary fibrosis

Pulmonary necrosis

Pulmonary radiation injury

Pulmonary sarcoidosis

Pulmonary toxicity

Pulmonary vasculitis

Radiation alveolitis

Radiation fibrosis - lung

Radiation pneumonitis

Restrictive pulmonary disease

Rheumatoid lung

Sarcoidosis

Transfusion-related acute lung 
injury
Source: (Modi et al, 2020) (supplemental material)
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Appendix H. EQ-5D-5L (SAMPLE QUESTIONNAIRE)
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Appendix I. GUIDANCE ON CONTRACEPTION
Acceptable methods for highly effective birth control (preventing conception)
Participants who are of childbearing potentiala or whose partners are of childbearing potentiala and 
who are sexually active in a way that could lead to pregnancy may choose any TWO of the following 
methods (please see acceptable combinations below):
●Hormonal methods of contraception (excluding progestin-only pills; method must be associated with 
inhibition of ovulation), unless contraindicated
●Intrauterine device with failure rate <1%
●Tubal ligation
●Vasectomy (at least 90 days from the date of surgery with a semen analysis documenting azoospermia)
●Barrier method (male or female condom with or without spermicide, cervical cap with or without 
spermicide, diaphragm with or without spermicide)b
a See Section 4.4 for the definition of a person of childbearing potential.  
b A barrier method should only be used with a highly effective birth control method that is not a barrier 
method. Barrier methods alone, including a double-barrier method, are not considered highly effective 
contraceptive measures (see unacceptable methods of contraception).
Acceptable combinations of contraceptive methods: 
●Hormonal method and vasectomy
●Hormonal method and barrier method
●Intrauterine device and vasectomy
●Intrauterine device and barrier method
●Tubal ligation and vasectomy
●Tubal ligation and barrier method
Acceptable methods for preventing secondary exposure to seminal fluid
Participants born male and who are sexually active with a pregnant person must use a male condom 
(even if the subject participant has had a vasectomy).
Participants born male and who are sexually active with a breastfeeding person must use a male 
condom (even if the subject participant has had a vasectomy). In addition, it is recommended that the 
breastfeeding partner use a highly effective female contraceptive method as listed in the section titled 
“Acceptable combinations of contraceptive methods”.
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Unacceptable methods of contraception
●Periodic abstinence
●Spermicide only
●No method
●Progestin-only pills
●Withdrawal
●Concomitant use of female and male condoms
●Rhythm
●Barrier methods alone, including double-barrier methods
For the purposes of this guidance, complete abstinence, if consistent with the participant’s 
preferred lifestyle, is an acceptable form of contraception. Complete abstinence is defined as 
abstinence starting from the time of informed consent and continuing throughout the study 
and until the end of systemic exposure (at least 7 months for participants of childbearing 
potential and 4 months for participants who can father children after the final dose of study 
intervention; see Section 4.1). 
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Appendix J. ADVERSE EVENTS: DEFINITIONS and PROCEDURES for 
RECORDING and REPORTING
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs via PSSA to Pfizer Safety throughout the safety reporting period. These 
requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; and (3) 
exposure to the study intervention under study during pregnancy or breastfeeding, and 
occupational exposure.
Table 12: Requirements for Recording AEs on the CRF and for Reporting SAEs via 
PSSA
Safety Event
Recorded on the CRF
Reported via PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs/SAEs associated with 
EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
on the CRF
All instances of EDP are 
reported (whether or not 
there is an associated SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated SAE) 
**
Environmental or 
occupational exposure to 
the product under study to 
a non-participant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or not 
there is an associated AE or 
SAE) must be reported***
* EDP (with or without an associated SAE) is reported to Pfizer Safety via PSSA. 
**EDB is reported to Pfizer Safety via PSSA, which would also include details of any SAE that might be 
associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure are 
reported to Pfizer Safety via PSSA.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the Report Form/AE or SAE 
CRF page.
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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to Pfizer Safety. 
SAE Reporting to Pfizer Safety via an electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
DCT (PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (PSSA) or paper form (as 
applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken off-line 
to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to 
Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the backup method to transmit 
this information to Pfizer Safety in case PSSA is unavailable for more than 24 hours.

In circumstances when the facsimile is not working, an alternative method should be 
used, eg, secured (Transport Layer Security) or password-protected email. If none of 
these methods can be used, notification by telephone is acceptable with a copy of the 
CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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Appendix K. Summary of Changes for Prior Amendments
SUMMARY OF CHANGES IN AMENDMENT 1
Section(s)
Change
Rationale
5.4.3.2
Updated first statement in section to include 
trastuzumab deruxtecan.
Updated Table 5 dose modification 
guidelines for liver function abnormalities 
for trastuzumab deruxtecan as follows: 
Bilirubin (>3 – ≤10 x ULN):
changed from “Dose modification not 
required.” to “Hold until recovery to (≤1.5 x 
ULN). Then resume trastuzumab deruxtecan 
at the next lower dose level.”
ALT or AST (>20 x ULN)
OR
Bilirubin (>10 x ULN):
Changed from “Dose modification not 
required.” to “Permanently discontinue”
ALT or AST >3 x ULN
AND
Bilirubin >2 x ULN
Changed from “Dose modification not 
required.” to “Permanently discontinue”
Modification based on FDA 
information request.
Throughout protocol
Updated Seattle Genetics, Inc. to Seagen Inc. 
in headers, body, and footers, as applicable. 
Administrative, corporate name 
change
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SUMMARY OF CHANGES IN AMENDMENT 2
Section(s)
Change
Rationale
Synopsis Study 
Population, Synopsis 
Inclusion Criteria (IC), 
Synopsis Study Design, 
Section 2, Section 3.1, 
Section 4, and Section 
4.1
Updated text to indicate subjects who have 
received prior treatment with a taxane and 
trastuzumab (with or without pertuzumab) in 
the LA/M setting or progressed within 
6 months after neoadjuvant or adjuvant 
treatment involving a regimen including a 
taxane and trastuzumab (with or without 
pertuzumab) are eligible for the study
To evaluate tucatinib in 
combination with T-DXd in earlier 
lines of therapy, given recent 
DESTINY-Breast03 data.
Synopsis IC and 
Section 4.1
Updated text to include subjects with AST 
and ALT concentrations of ≤3 x ULN rather 
than ≤2.5 x ULN 
Revised to align with CTCAE 
grading version 5.0 (Grade 1: 
>ULN - 3.0 x ULN [not 2.5 x 
ULN]) 
Synopsis IC and 
Section 4.1
Minor updates to contraception inclusion 
criteria (IC13 and IC14)
To ensure that appropriate barrier 
methods are used to avoid 
secondary exposure.
Synopsis Exclusion 
Criteria (EC) and 
Section 4.2
Adjusted EC10 to indicate subjects with 
HIV are excluded if they meet any of the 
following criteria:
●CD4+ T-cell count of <350 cells/µL
●Detectable HIV viral load
●History of an opportunistic infection 
within the past 12 months
●On stable antiretroviral therapy for 
<4 weeks
Specify criteria for subjects with 
HIV.
Synopsis EC
Updated text to exclude subjects who have 
used a strong cytochrome P450 (CYP) 2C8 
inhibitor within 5 rather than 3 elimination 
half-lives of the inhibitor
Consistency with current guidance 
Synopsis EC and 
Section 4.2
Added EC to exclude subjects with ongoing 
≥Grade 2 diarrhea of any etiology at 
screening
To exclude subjects with increased 
risk of developing significant 
treatment-related adverse events
Synopsis 
Investigational 
Products, Dose, and 
Mode of 
Administration and 
Section 5.1
Updated text related to dosing
Consistency with current guidance
Section 1.2.4
Updated introductory text to include 
information about DESTINY-BREAST03
Provide background on changes to 
subject eligibility
Synopsis Post-safety 
Lead-in, Section 3.1, 
and Section 6.3.1
Addition of text related to management of 
diarrhea and risk mitigation approaches
To provide guidelines for 
management of diarrhea 
associated with treatment
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Section(s)
Change
Rationale
Synopsis 
Patient-Reported 
Outcomes, Section 6, 
and Appendix A
Updated text on patient-reported outcomes 
that EQ-5D-5L is to be administered before 
evaluation by study personnel 
To clarify that EQ-5D-5L is to be 
administered before evaluation by 
study personnel
Section 5.4.3.1, Table 4
Updated Table 4 to include more dose 
modification information for AEs related to 
nausea and/or vomiting and diarrhea.
Additional dose modification 
guidelines for management of 
gastrointestinal adverse events
Section 5.4.3.2, Table 5
Updated to T-DXd dose modification for 
instances of ALT or AST (>5 – ≤20 x ULN)
Addition of dose modification 
guidance to ensure subject safety
Section 5.4.3.3, 
Table 6; Section 
5.4.3.4, Table 7; and 
Section 5.4.3.5, Table 8
Updated tables to remove tucatinib; since, 
no dose modifications are required
Tables updated to show that 
tucatinib dose modifications not 
required for ILD/pneumonitis or 
neutropenia and febrile 
neutropenia and for ejection 
fraction decrease
Section 5.5.1
Added text about required concomitant 
therapy for subjects who enroll during the 
time antidiarrheal prophylaxis is 
implemented.
Provide guidance on antidiarrheal 
prophylaxis for subjects who 
enroll under protocol 
amendment 2 of the protocol. 
Section 5.5.2
Updated text about antidiarrheal and 
antiemetic supportive care medications
Updated text on premedication for contrast 
use in CT or MRI scans
Provide additional guidance for 
antidiarrheal and antiemetic 
prophylaxis
Provide additional guidance for 
allowed concomitant therapy in 
CT or MRI scans
Section 5.5.3
Updated Prohibited Concomitant Therapy 
text
Provide additional guidance for 
prohibited concomitant use of 
CYP agents and digoxin 
Section 5.6.4
Added text for Management of 
Treatment-associated Diarrhea
Provide additional guidance for 
management of 
treatment-associated diarrhea
Section 6.3.1
Added required concomitant antidiarrheal 
medication
Provide additional guidance for 
antidiarrheal medication
Section 6.3.3, Section 
6.3.5, and Section 6.4
Added text about reviewing the dosing 
regimen of antidiarrheals taken in the 
previous cycle 
Consistency with updates to the 
schedule of events (SoE)
Section 7.2
Added text allowing non-contrast CT scan if 
MRI is not feasible
Consistency with updates to other 
sections of the protocol
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Section(s)
Change
Rationale
Section 7.7.1.1
Added section on Overdose, Medication 
Error, and Abuse
Added Diarrhea as an AESI
Adverse Events of Special Interest text was 
updated 
Define and provide guidance on 
overdose, medication error, and 
abuse
Consistency with risk mitigation 
strategies implemented in the 
protocol and stringent collection of 
diarrhea events in the database
Differentiate information around 
AST or ALT elevations and 
Bilirubin elevations. 
Section 7.7.1.2, 
Pregnancy, Notification 
to Drug Safety
Update notification from 48 to 24 hours
Consistency with current guidance 
Section 7.7.3
Updated text for tests included in the CBC 
with differential
Clarify guidance 
Appendix A
Updated footnote “a” to indicate that a 
review of the dosing regimen of 
antidiarrheals taken in the previous cycle 
should be done
Consistency with updates to SoE
and Section 6 
Appendix B
List of CYP2C8 inhibitors updated
Clarify strong inhibitors and 
include moderate inhibitors
Appendix C
List of CYP3A4 inducers updated
List strong inducers 
Appendix D
Minor wording changes
Clarify examples of substrates for 
CYP3A-mediated metabolism
Appendix I
Updated text on contraception: Modified the 
methods for preventing secondary exposure 
to seminal fluid to specify that they apply 
even if the subject has had a vasectomy and 
recommended that the breastfeeding partner 
use a highly effective female contraceptive 
method as listed in the appendix.
To ensure that appropriate barrier 
methods are used to avoid 
secondary exposure.
Throughout protocol
Editorial and Administrative Changes 
(formatting, updates to footers, etc.)
Administrative
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