A Phase 2 Basket Study of Tucatinib in Combination With Trastuzumab in Subjects With Previously Treated, Locally Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations
Phase: PHASE2
Conditions: Uterine Neoplasms, Uterine Cervical Neoplasms, Biliary Tract Neoplasms, Urologic Neoplasms, Carcinoma, Non-Small-Cell Lung, HER2 Mutations Breast Neoplasms
Sponsor: Seagen, a wholly owned subsidiary of Pfizer

 
 
 
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handled using the disclosure procedure described above. 
 
Protocol Number: 
SGNTUC-019 
Version: 
Amendment A05; 24-Apr-2024 
Protocol Title: 
A Phase 2 Basket Study of Tucatinib in Combination with 
Trastuzumab in Subjects with Previously Treated, 
Locally-Advanced Unresectable or Metastatic Solid Tumors 
Driven by HER2 Alterations 
Investigational 
Product: 
Tucatinib 
Brief Title: 
Basket study of tucatinib and trastuzumab in solid tumors with 
HER2 alterations 
Phase: 
2 
IND Number: 
152278  
EudraCT Number: 
2020-004873-29 
EU Trial Number 
2024-511481-37 
Sponsor: 
Seagen Inc*. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
, DO 
Pfizer Inc. 
Tel: 
 
E-mail:
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 
* Please note that as of 14 December 2023, Seagen Inc. became a part of Pfizer Inc. 
 
 
PPD
PPD
PPD

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PROTOCOL SYNOPSIS 
Protocol Number 
SGNTUC-019 
Version 
Amendment A05; 24-Apr-2024  
Phase 
2 
Product Name 
Tucatinib 
Sponsor 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Protocol Title 
A Phase 2 Basket Study of Tucatinib in Combination with Trastuzumab in Subjects with Previously Treated, 
Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations 
 
Study Objectives and Endpoints 
Primary Objective 
Corresponding Endpoints 
Primary Endpoint: 
To evaluate the antitumor activity of 
tucatinib given in combination with 
trastuzumab in subjects with previously 
treated, locally-advanced unresectable or 
metastatic human epidermal growth factor 
receptor 2 (HER2) 
overexpressing/amplified or mutated solid 
tumors 
Confirmed objective response rate (ORR; confirmed complete 
response [CR] or partial response [PR]) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 per 
investigator assessment 
Secondary Endpoints: 
• 
Disease control rate (DCR; confirmed CR or PR, or stable 
disease) per investigator assessment 
• 
Duration of response (DOR; confirmed CR or PR) per 
investigator assessment 
• 
Progression-free survival (PFS) per investigator assessment 
• 
Overall survival (OS) 
Secondary Objectives 
Corresponding Endpoints 
• 
To evaluate the safety and tolerability 
of tucatinib given in combination 
with trastuzumab with or without 
fulvestrant 
• 
Type, incidence, severity, seriousness, and relatedness of 
adverse events (AEs) 
• 
Type, incidence, and severity of laboratory abnormalities 
• 
Frequency of treatment interruptions, dose reductions, and 
treatment discontinuations due to AEs 
• 
Other relevant safety variables including AEs of special 
interest (AESIs) 
• 
To evaluate the pharmacokinetics 
(PK) of tucatinib 
• 
Plasma concentrations of tucatinib 
Exploratory Objectives 
Corresponding Endpoints 
• 
To determine the concordance of 
HER2 alterations as detected by 
tissue and blood-based HER2 testing 
methodologies  
• 
Concordance of HER2 alterations as detected by different 
testing methodologies 
• 
Identify tumor-specific alterations 
that are associated with resistance to 
tucatinib 
• 
Identify tumor-specific alterations that are associated with 
resistance to tucatinib 
 
 
 
 

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• 
To evaluate patient-reported 
outcomes (PROs) 
• 
Change from baseline in health-related quality of life 
(HRQoL), as assessed by the European Quality of Life 
5-Dimension 5-Level (EQ-5D-5L) 
 
Study Design 
This multi-cohort, open label, multicenter, international Phase 2 clinical study is designed to assess the activity, 
safety, and tolerability of tucatinib in combination with trastuzumab for the treatment of selected solid tumors 
with HER2 alterations. Subjects will be enrolled into separate cohorts based on tumor histology and HER2 
alteration status (see Table 1). 
There are 5 tumor specific cohorts with HER2 overexpression/amplification (cervical cancer [Cohort 1], uterine 
cancer [Cohort 2], biliary tract cancer [Cohort 3], urothelial cancer [Cohort 4], and non-squamous non-small 
cell lung cancer [NSCLC] [Cohort 5]), 2 tumor specific cohorts with HER2 mutations (non-squamous NSCLC 
and [Cohort 7] breast cancer [Cohort 8]), and 2 cohorts which will enroll all other HER2 
amplified/overexpressed solid tumor types (except breast, gastric or gastroesophageal junction adenocarcinoma 
[GEC], and colorectal cancer [CRC]) or HER2-mutated solid tumor types (Cohorts 6 and 9 respectively). 
If a sufficient number of subjects with a particular tumor type are enrolled in Cohorts 6 or 9, the sponsor 
may evaluate that tumor type in a separate cohort, drawn from optional Cohorts 10 to 15. If any optional cohort 
is opened, all subjects enrolled in Cohorts 6 or 9 with the applicable tumor type will be reassigned to the new 
tumor-specific cohort; these subjects will be replaced in Cohorts 6 and 9. 
In Stage 1, up to approximately 12 response-evaluable subjects may be enrolled in each of Cohorts 1 to 5, 
and 7. If sufficient activity is observed in Stage 1 for a particular cohort (see Statistical Methods), up to a total 
of 30 response-evaluable subjects will be enrolled in the cohort (Stage 2 expansion) to further characterize the 
activity and safety of the study regimen in the given disease and HER2 alteration type. Cohorts 6, 8, and 9 will 
enroll up to 30 response-evaluable subjects without undergoing the Stage 1 assessment in 12 subjects. Subjects 
who are not response-evaluable will be replaced. 
Table 1: Definition of cohorts according to disease type and HER2 alterations, and number of subjects 
 
HER2 alteration 
N subjects per cohort 
 
Overexpression/ 
amplification 
Mutations Stage 1 Stage 1 and 
Stage 2 
Cervical cancer 
Cohort 1 
 
12 
30 
Uterine cancer 
Cohort 2 
 
12 
30 
Biliary tract cancer  
Cohort 3 
 
12 
30 
Urothelial cancer 
Cohort 4 
 
12 
30 
Non-squamous NSCLC 
Cohort 5 
Cohort 7 
12 
30 
Other solid tumors (except breast cancer, GEC, and CRC) 
Cohort 6 
 
30 
 
Breast cancer 
 
Cohort 8 
30 
 
All solid tumors (except breast and non-squamous NSCLC) 
 
Cohort 9 
30 
 
Optional tumor specific Cohorts  
 
 
 
 
Cervical cancer 
 
Cohort 10 
12 
30 
Uterine cancer 
 
Cohort 11 
12 
30 
Biliary tract cancer 
 
Cohort 12 
12 
30 
Urothelial cancer 
 
Cohort 13 
12 
30 
Additional tumor specific 
Cohort 14 
Cohort 15 
12 
30 
 
Study treatment is composed of tucatinib 300 mg BID PO combined with trastuzumab 8 mg/kg intravenously 
(IV) on Cycle 1 Day 1 and then 6 mg/kg every 21 days starting on Cycle 2 Day 1. Subjects with hormone 
receptor (HR) positive (HR+), HER2-mutated breast cancer will also receive, in combination with tucatinib and 
trastuzumab, fulvestrant 500 mg intramuscular (IM) once every 4 weeks starting from Cycle 1 Day 1, as well as 
on Cycle 1 Day 15. A Safety Monitoring Committee (SMC) will be responsible for monitoring the safety of 
subjects in the study at regular intervals. Subjects will continue study treatment until the occurrence of 

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radiographic or clinical progression, unacceptable toxicity, withdrawal of consent, death, or study closure. 
Following treatment discontinuation, disease progression (in subjects without progression at treatment 
discontinuation), further anti-cancer therapy, and survival status will be monitored from EOT until withdrawal 
of consent, death, or study closure.  
As of Amendment 5, the objectives of the study have been achieved. Therefore, the decision has been made to 
close the study. For subjects in long-term follow-up, a last visit or contact will occur prior to the subject’s 
discontinuation from participation in the study. Any subject on study treatment will transition to the long-term 
extension phase (LTEP) of the study. Once post-study access to study treatment is available, subjects will have 
a last visit or contact prior to discontinuation from the study. The Sponsor will provide continued access to 
study treatment for any subject who is still on treatment and receiving clinical benefit based on the 
investigator’s assessment.  
Study Population 
Inclusion criteria 
All subjects must meet the following eligibility criteria for enrollment: 
1. Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid 
tumor, including primary brain tumors 
2. Prior therapy:  
a. 
Subjects with non-squamous NSCLC: Must have progressed during or after standard treatment or for 
which no standard treatment is available  
b. Subjects with other disease types: Must have progressed during or after ≥1 prior line of systemic 
therapy for locally-advanced unresectable or metastatic disease  
i. 
Subjects with metastatic HR+ HER2-mutated breast cancer must have received a prior 
CDK4/6 inhibitor in the metastatic setting  
ii. 
Subjects with metastatic cervical cancer must have received platinum-based chemotherapy 
with or without bevacizumab in the metastatic setting  
3. Progression during or after, or intolerance of, the most recent line of systemic therapy  
4. Disease demonstrating HER2 alterations (overexpression/amplification or HER2 activating mutations), as 
determined by local or central testing processed in a Clinical Laboratory Improvement Amendments 
(CLIA)- or International Organization for Standardization (ISO)-accredited laboratory, according to one of 
the following: 
a. 
HER2 overexpression/amplification from fresh or archival tumor tissue or blood utilizing one of the 
following tests, in subjects with tumor types other than breast cancer, GEC, or CRC: 
i. 
HER2 overexpression by immunohistochemistry (IHC): 3+ by breast or gastric algorithms 
ii. 
HER2 amplification by in situ hybridization (ISH) assay: fluorescence in situ hybridization 
(FISH) or chromogenic in situ hybridization (CISH) signal ratio ≥2.0 or gene copy number >6 
iii. 
HER2 amplification in tissue by next generation sequencing (NGS) assay 
iv. 
HER2 amplification in circulating tumor DNA (ctDNA) by blood-based NGS assay 

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b. Known activating HER2 mutations detected in fresh or archival tumor tissue or blood by NGS assay, 
including: 
● Extracellular domain: G309A/E; S310F/Y; C311R/S; C334S 
● Kinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; V777L/M; 
G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896C, other exon 20 insertions 
● Transmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; V697. 
● Subjects with HER2 activating mutations not listed above may be eligible, if supported by scientific 
literature and approved by the medical monitor 
5. Have measurable disease per RECIST v1.1 criteria according to investigator assessment 
6. Be at least 18 years of age at time of consent, or considered an adult by local regulations 
7. Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
8. Have a life expectancy of at least 3 months, in the opinion of the investigator 
9. Have adequate hepatic function as defined by the following: 
a. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal 
(ULN) (≤5 × ULN if liver metastases are present) 
b. Total bilirubin ≤1.5 × ULN. Exception: subjects with known history of Gilbert’s syndrome with direct 
bilirubin ≤1.5 × ULN and normal AST and ALT are eligible 
10. Have adequate baseline hematologic parameters as defined by: 
a. 
Absolute neutrophil count (ANC) ≥1.0 × 109/L 
b. Platelet count ≥100 × 109/L; subjects with stable platelet count from 75 to 100 × 109/L may be 
included with approval from Medical Monitor 
c. 
Hemoglobin ≥9.0 g/dL; subjects with hemoglobin ≥8 and <9 g/dL may be included with approval from 
the Medical Monitor 
d. In subjects transfused before study entry, transfusion must be ≥14 days prior to start of therapy to 
establish adequate hematologic parameters independent from transfusion support 
11. Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m² using the Modification of Diet in Renal 
Disease (MDRD) study equation 
12. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or multiple-gated 
acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment 

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13. For subjects of childbearing potential, 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 the first dose of 
study treatment. A subject with a false positive result and documented verification that the subject 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 any study drug, and, if applicable, for at least 2 years after the final dose of fulvestrant. 
c. 
Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing 
through at least 7 months after the final dose of any study drug, and, if applicable, at least 2 years after 
the final dose of fulvestrant. 
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 B, starting at the time of informed consent and 
continuing throughout the study and for at least 7 months after the final dose of any study drug, and, if 
applicable, for at least 2 years after the final dose of fulvestrant. 
14. For subjects 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 7 months after the final dose of any study drug, and, if applicable, for at 
least 2 years after the final dose of fulvestrant. 
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, starting at time of informed consent and 
continuing throughout the study and for at least 7 months after the final dose of any study drug, and, if 
applicable, for at least 2 years after the final dose of fulvestrant. 
c. 
If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 
2 methods of birth control, as defined in Appendix B, starting at time of informed consent and 
continuing throughout the study and for at least 7 months after the final dose of any study drug, and, if 
applicable, for at least 2 years after the final dose of fulvestrant. 
15. Subject must provide signed informed consent that has been approved by an institutional review 
board/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 subject’s disease 
16. Subject must be willing and able to comply with study procedures 
Exclusion criteria 
1. Subjects with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or CRC whose disease 
shows HER2 amplification/overexpression. 

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2. Previous treatment with HER2-directed therapy; subjects with uterine serous carcinoma or HER2-mutated 
gastric or gastroesophageal junction adenocarcinoma without HER2-overexpression/amplification may 
have received prior trastuzumab 
3. Known hypersensitivity to any component of the drug formulation of tucatinib or trastuzumab (drug 
substance, excipients, murine proteins), or any component of the drug formulation of fulvestrant in subjects 
with HR+ HER2-mutated breast cancer 
4. History of exposure to a >360 mg/m² doxorubicin-equivalent or >720 mg/m² epirubicin-equivalent 
cumulative dose of anthracyclines 
5. Treatment with any systemic anti-cancer therapy, radiation therapy, major surgery, or experimental agent 
within ≤3 weeks of first dose of study treatment or are currently participating in another interventional 
clinical trial. 
6. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following 
exceptions: 
a. 
Alopecia 
b. Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, 
and must have resolved completely 
c. 
Anemia, which must have resolved to ≤ Grade 2 
7. Have clinically significant cardiopulmonary disease such as: 
a. 
Ventricular arrhythmia requiring therapy 
b. Symptomatic hypertension or uncontrolled hypertension as determined by investigator 
c. 
Any history of symptomatic CHF 
d. Severe dyspnea at rest (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Grade 3 or above) due to complications of advanced malignancy 
e. 
Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for 
obstructive sleep apnea 
8. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment 
9. Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C 
infection (positive by polymerase chain reaction). Subjects who have been treated for hepatitis C infection 
are permitted if they have documented sustained virologic response of 12 weeks 
10. Presence of known chronic liver disease 

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11. Subjects 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 
12. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after 
the final dose of any study drug, and, if applicable, for at least 2 years after the final dose of fulvestrant 
13. Have inability to swallow pills 
14. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 half-lives of the inhibitor, or have used 
a strong CYP3A4 or CYP2C8 inducer within 5 days prior to start of treatment 
15. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact 
safety or compliance with study procedures 
16. History of another malignancy 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 
17. Subjects with known central nervous system (CNS) lesions must not have any of the following: 
a. 
Any untreated brain lesions >2.0 cm in size, unless approved by the medical monitor 
b. Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose 
of >2 mg of dexamethasone (or equivalent). However, subjects on a chronic stable dose of ≤2 mg total 
daily of dexamethasone (or equivalent) may be eligible, following approval by the medical monitor 
c. 
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 subject 
(eg, brain stem lesions). Subjects who undergo local treatment for such lesions identified by screening 
brain magnetic resonance imaging (MRI) may still be eligible for the study 
d. Known or suspected leptomeningeal disease as documented by the investigator 
e. 
Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest neurologic 
progression due to brain lesions notwithstanding CNS-directed therapy 
Number of Planned Subjects 
Approximately 162 to 270 subjects may be enrolled in the study. This is comprised of up to approximately 12 to 
30 subjects in each of Cohorts 1 to 5 and Cohort 7, and up to approximately 30 subjects in each of Cohorts 6, 8, 
and 9. Additional subjects may be enrolled if any of the optional Cohorts 10 to 15 are opened. Subjects initially 
enrolled in Cohorts 6 or 9 who are reassigned to an optional cohort will be replaced. 

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Investigational Product, Dose, and Mode of Administration 
Tucatinib 300 mg will be administered PO BID continuously starting from Cycle 1 Day 1 onwards. 
Trastuzumab 8 mg/kg will be administered IV on Cycle 1 Day 1 and then will be administered at 6 mg/kg every 
21 days starting on Cycle 2 Day 1. However, if trastuzumab IV was administered within the 4 weeks prior to 
treatment initiation, trastuzumab 6 mg/kg IV should be administered on Cycle 1 Day 1. 
Fulvestrant 500 mg will be administered IM once every 4 weeks starting from Cycle 1 Day 1, as well as on 
Cycle 1 Day 15. 
Duration of Treatment 
Study treatment will continue until unacceptable toxicity, occurrence of radiographic progression or clinical 
progression, withdrawal of consent, death, or study closure. If a study drug (tucatinib, trastuzumab, or 
fulvestrant) is discontinued, study treatment can continue with remaining study drug(s). 
Subjects still receiving clinical benefit and remaining on study treatment as of Amendment 5 may continue 
receiving study drug during the LTEP. During this phase of the study, only pregnancies, SAEs, and adverse 
events of special interest (AESIs) will be collected by the Sponsor. Pregnancy testing will continue as outlined 
in the schedule of events for subjects of child-bearing potential. All other assessments, including efficacy 
assessments, will be performed per institutional guidelines and investigator-determined usual and customary 
clinical care.  
Efficacy Assessments 
Disease response will be assessed by the investigator according to RECIST v1.1. Treatment decisions will be 
made based upon local assessment of radiologic scans. Radiographic disease assessments will evaluate all 
known sites of disease, preferably using high quality spiral contrast computed tomography (CT) (with oral 
and/or IV contrast), and covering, at a minimum, the chest, abdomen, and pelvis. Positron emission 
tomography-CT scans (if high quality CT scan is included) and/or MRI scans may also be used as appropriate, 
as well as additional imaging of any other known sites of disease. In subjects with breast or lung cancer, a 
contrast MRI scan of the brain should be performed at screening. Subjects with known or suspected brain 
lesions should undergo brain MRIs during treatment and follow-up according to the same assessment schedule 
as for other disease assessments. If contrast is contraindicated (ie, in subjects 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). For each subject, the same imaging 
modality as used at screening/baseline should be used throughout the study, unless otherwise clinically 
indicated. In subjects with lung cancer, scans of the pelvis do not need to be undertaken after the screening 
assessment unless lesions were detected at screening, or as clinically indicated. Images will be collected by an 
independent central review (ICR) facility for possible future analysis. Disease assessments will be done at 
screening/baseline, and every 6 weeks for first 24 weeks then every 12 weeks, irrespective of dose interruptions. 
Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks after first documentation of 
response. The schedule for response assessments should not be adjusted after the confirmatory scan (eg, CR at 
Week 6, confirmatory scans at Week 10–12, next assessment due at Week 12). Tumor imaging should also be 
performed whenever disease progression is suspected. 
Subjects will be considered evaluable for response if they (1) had a baseline disease assessment with 
measurable disease (ie, at least one target lesion at baseline), (2) received study treatment, and (3) had a 
post-baseline disease assessment or discontinued treatment due to documented disease progression or clinical 
progression. 
Subjects that discontinue study treatment for reasons other than documented progressive disease or death will 
continue to have disease assessments every 6 weeks (±1 week) until 24 weeks after treatment initiation, then 
every 12 weeks (±1 week), until the occurrence of documented disease progression per RECIST v1.1, death, 
withdrawal of consent, lost to follow-up, or study closure. 
Follow-up for survival and subsequent anti-cancer therapy will occur approximately every 12 weeks (±14 days) 
from EOT and continue until death, withdrawal of consent, lost to follow-up, or study closure. 

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During the LTEP, efficacy assessments will be performed per institutional guidelines and investigator-
determined usual and customary clinical care. 
Pharmacokinetic Assessments 
Blood samples for PK assessment of trough tucatinib drug levels will be collected in all subjects on Day 1 of 
Cycles 2 to 6, prior to administration of tucatinib. On Day 1 of Cycle 3, PK assessments of peak levels of 
tucatinib will be performed 1 to 4 hours after administration of tucatinib. Plasma concentrations of tucatinib will 
be determined using validated liquid chromatography (LC)-mass spectrometry (MS)/MS methods. PK 
parameters will be summarized using descriptive statistics. 
HER2 Testing for Eligibility and Biomarker Assessments 
Study eligibility requirements for HER2 overexpressing/amplified disease and HER2-mutated disease are to be 
met by assays performed pre-study (assessments undertaken prior to any study-related activities) or in 
prescreening, as follows: 
• 
Previously established HER2 alterations: HER2 eligibility can be demonstrated via HER2 overexpression 
or amplification in an IHC/ISH assay of tumor tissue or HER2 amplification or activating mutations in an 
NGS assay of ctDNA or tumor tissue, processed locally in a CLIA- or ISO-accredited laboratory before 
enrollment in the study.  
• 
Pre-screening for HER2 alterations: if HER2 alterations have not been detected in pre-study assessments, 
HER2 eligibility may alternatively be established during pre-screening, up to 3 months prior to the 
Screening visit, via an NGS assay of ctDNA evaluating the presence of HER2 amplification or mutations. 
Additional biomarker analyses: For the evaluation of the exploratory biomarker objectives, all subjects will 
provide a blood sample for NGS assay of ctDNA and archival tumor tissue or a fresh tumor biopsy, if available. 
The blood sample will be collected during pre-screening or on Cycle 1 Day 1, if not collected during 
pre-screening. However, the blood sample does not need to be drawn if a pre-study NGS assay of ctDNA has 
previously been performed by the sponsor since the end of prior therapy. The tumor tissue sample will be 
collected during screening, once the subject has been approved for enrollment by the medical monitor.  
The list of acceptable known activating mutations are detailed in the inclusion criteria. As specified, subjects 
with HER2 exon 20 insertions are eligible. Subjects with HER2 activating mutations not listed in the inclusion 
criteria may be eligible, if supported by scientific literature and approved by the medical monitor. Archival 
tumor tissue samples should be the most recent tissue sample available. If an archival sample is not available, a 
fresh biopsy will be undertaken during screening, if the subject has an available tumor lesion and consents to 
the biopsy. Subjects with no archival tissue and whose tumors are considered not accessible or appropriate for 
biopsy are eligible for enrollment, following approval by the medical monitor. 
Safety Assessments 
Safety assessments will include the surveillance and recording of AEs, including serious adverse events (SAEs) 
and AESI, physical examination findings, vital signs, 12-lead electrocardiograms, concomitant medications, 
pregnancy testing, and laboratory tests. Assessment of cardiac ejection fraction will be performed using 
multigated acquisition scan (MUGA) scan or echocardiogram. An ongoing, real-time review of subject safety 
and SAEs will be conducted by the sponsor’s Drug Safety Department. The SMC will be responsible for 
monitoring the safety of subjects in the study at regular intervals. AE and laboratory abnormality severity will 
be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5. 
Only pregnancies, SAEs, and AESIs 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 subjects of child-bearing potential. 

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Patient-Reported Outcomes Assessments 
The EQ-5D-5L questionnaire will be administered to assess subject HRQoL. Administration will occur at 
Cycle 1 Day 1 prior to the start of study drug treatment and then on Day 1 of every second cycle, starting from 
Cycle 2. Additionally, a post-treatment assessment will be undertaken 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. Confirmed ORR per investigator is defined as the 
proportion of subjects with confirmed CR or PR, per RECIST v1.1. The 2-sided 90% exact confidence interval 
(CI) using Clopper-Pearson method will be calculated for the response rates. 
The primary analysis of the study will be performed when 30 response-evaluable subjects in each cohort have 
been followed for at least 12 weeks or have documented disease progression. The primary efficacy endpoint of 
confirmed ORR per RECIST v1.1 will be estimated for each cohort based on the response-evaluable set, 
comprising all subjects who received any amount of study treatment who are considered evaluable for response. 
The 90% exact CIs using the Clopper-Pearson method will be provided. The confirmed ORR may also be 
summarized combining cohorts with same disease type. 
Interim futility analyses will be performed separately for Cohorts 1 to 5 and 7 after approximately 12 subjects of 
a given cohort (Stage 1) have been treated and had at least two response assessments post-baseline or had 
disease progression. 
The Bayesian predictive probability approach will be used to determine the futility criteria. At the time of each 
interim analysis, the predictive probability of success (PPoS) will be calculated. A PPoS <20% indicates that it 
is unlikely the ORR will be better than the response rate of current standard of care at the end of the study given 
the interim result. Based on activity and safety data, together with the PPoS, a cohort may be stopped early by 
the sponsor. Cohorts that successfully pass the interim analysis for futility may, at the sponsor’s decision, 
continue to enroll up to an additional 18 response-evaluable subjects, totaling up to 30 response-evaluable 
subjects for each tumor cohort. A cohort may be expanded to Stage 2 earlier if the futility rule is cleared before 
12 subjects, in other words, if the minimal required responses are observed in fewer than 12 subjects. 
Safety measurements will be summarized by descriptive statistics based on the safety analysis set. The safety 
analysis set will include all subjects who received any amount of study treatment. 
For those cohorts that are expanded to Stage 2, a total of 30 subjects (combining two stages) will be treated in 
each cohort. For a sample size of 30 subjects, assuming confirmed ORR is between 10% and 30%, the 2-sided 
90% exact CIs are summarized below: 
Confirmed ORR 
90% Exact CI (N=30) 
10% 
(3%, 24%) 
20% 
(9%, 36%) 
30% 
(17%, 47%) 
 

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SCHEDULE OF EVENTS 
 
 
Pre- 
Screening/  
Treatment 
EOT 
Follow-up 
LTEP 
 
 
screening 
Baseline 
Cycles 1 and 2 
Cycles >1 
Every  Every  
Every  Within 30–37  
Until  
Every 12  
- 
 
 
up to 3 months 
prior to Screening 
Days  
–28 to 1 
Days  
–7 to 1 
Predose 
Day 1 
Day  
12 
Predose  
Day 1 
4 
weeks 
6 weeksA 
12 
weeks 
days of last 
doseB 
disease 
progressionC 
weeks from 
EOTD 
 
 
Visit window (days) 
 
 
 
 
-1,+3 
-1,+3 
±3 
+7 
±14 
 
±7 
±14 
 
HER2 
HER2 testing informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
alterations 
testing 
Blood sample for NGS assay of 
ctDNA  
 X 
 
 
XE 
 
 
 
 
 
 
 
 
 
 
Submission of archived tumor 
specimen F 
  
X 
 
 
 
 
 
 
 
 
 
 
 
Screening/  
Study informed consent G 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Inclusion/Exclusion 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Assessments 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for hepatitis B and C H 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug  
Tucatinib I 
 
 
 
BID, from Cycle 1 Day 1 
 
 
 
 
 
 
X 
Treatment 
Trastuzumab J 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Fulvestrant K 
 
 
 
X 
Cycle 1 
Day 15 
 
X 
 
 
 
 
 
X 
Safety 
Physical exam L 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
XAA 
Assessments Vital signs and weight L,M 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
XAA 
 
ECOG performance status L 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
XAA 
 
CBC with differential N,L 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
XAA 
 
Serum or plasma chemistry 
panel O L 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
XAA 
 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
X 
 
 
XAA 
 
Echocardiogram or MUGA scan  
 
X 
 
 
 
 
 
 
XP 
XP  
 
XQ 
XAA 
 
Serum or urine β-hCG 
pregnancy test for FOCBP 
 
 
X 
XR 
 
XR 
 
 
 
XS 
 
XS 
X 
 
Concomitant medications 
 
Related to  
Collect from Day 1 predose through safety reporting period of study  
 
 
XAA 
 
Adverse event collection 
 
study procedures 
drug(s)T 
 
 
XAA, BB  
Disease  
CT scan, PET-CT, MRI U 
 
X 
 
 
 
 
 
XV 
XV 
X 
XW 
 
XAA 
Evaluation 
Brain MRI 
 
XX 
 
 
 
 
 
XV,Y 
XV,Y 
X 
XW 
 
XAA 
 
Survival and further therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
XAA 
PK and 
Biomarker 
Blood/tissue sample collection 
 
 
See Pharmacokinetic and biomarker sample collection time points, 
Table 10  
 
 
 
PRO 
EQ-5D-5L 
 
 
 
X 
 
XZ 
 
 
 
X 
 
 
 
FOCBP=females of child-bearing potential.; LTEP=long-term extension phase 
 

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A. 
Scheduling determined by date of Cycle 1, Day 1 visit, irrespective of dose holds or 
interruptions. 
B. 
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT 
evaluations are completed before 30 days following the last study treatment, conduct a 
phone screen 30-37 days following the subject’s last study treatment to ensure that no 
changes in AE profile have occurred. For subjects who have received fulvestrant, the EOT 
visit should be undertaken no sooner than 8 weeks after the last dose of fulvestrant. 
C. 
Scheduling determined by date of the last imaging scan. To be performed every 6 weeks 
until 24 weeks after treatment initiation, then every 12 weeks until the occurrence of 
documented disease progression, withdrawal of consent, death, or study closure 
D. 
Every 12 weeks (±2 weeks) from the EOT visit, until withdrawal of consent, death, or 
study closure. May be either an in-person assessment, contact by telephone, or review of 
publicly available information (if reasonable efforts to contact the subject are 
unsuccessful). 
E. 
Blood sample for NGS assay of ctDNA to be drawn predose on Cycle 1 Day 1, if not 
already done in pre-screening. However, the blood sample does not need to be drawn if a 
pre-study NGS assay of ctDNA has previously been performed by the sponsor since the 
end of prior therapy. 
F. 
Tumor tissue samples are to be collected once the subject has been approved for 
enrollment by the medical monitor. The archival sample should be the most recent tissue 
sample available. If an archival sample is not available, a fresh biopsy will be undertaken 
at screening, if the subject has an available tumor lesion and consents to the biopsy. 
Subjects with no archival tissue and whose tumors are considered not accessible or 
appropriate for biopsy are eligible for enrollment, following approval by the medical 
monitor. 
G. 
All subjects must sign informed consent for the study before Screening/Baseline 
procedures are conducted. 
H. 
Hepatitis B surface antigen, antibodies to hepatitis B core, and antibodies to hepatitis C are 
to be assessed. If hepatitis C serology is positive, hepatitis C virus RNA test by polymerase 
chain reaction is required to confirm. If hepatitis B core antibody is positive, and there is 
no evidence of long-term immunity, a hepatitis B virus DNA test by polymerase chain 
reaction is required to confirm.  
I. 
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. 
J. 
Trastuzumab is administered IV, once every 21 days 
K. 
For subjects with HR+ HER2-mutated breast cancer, administer fulvestrant 500 mg IM 
once every 4 weeks starting from Cycle 1 Day 1, as well as on Cycle 1 Day 15. 
L. 
Assessment to be done predose on days when study drug(s) are administered. Predose 
assessments can be done within 1 day prior to study visit. Confirm assessments results 
prior to administering any study drug. 
M. 
Vital signs to be collected are heart rate, systolic and diastolic blood pressure, respiratory 
rate, and temperature. 
N. 
Hemoglobin, hematocrit, platelet count, red blood cell count, and white blood cell count 
with differential (lymphocytes, and neutrophils). 
O. 
ALT, AST, alkaline phosphatase, total bilirubin (and direct bilirubin when total bilirubin is 
> ULN), albumin, bicarbonate (if available), blood urea nitrogen, magnesium, phosphorus, 
calcium, chloride, glucose, potassium, sodium, total protein, creatinine, calculated GFR 
using the MDRD equation (at baseline and as clinically indicated). In subjects with 
baseline GFR <50 mL/min/1.73 m², cystatin C will be evaluated at baseline and whenever 
serum or plasma creatinine is evaluated. 
P. 
Scheduling is determined by date of most recent screening or on-treatment 
echocardiogram/MUGA. Not required at EOT visit if an echocardiogram or MUGA scan 
was done within the previous 12 weeks (excluding the Screening/Baseline assessment). 
Q. 
Echocardiogram/MUGA assessments should be undertaken every 6 months for at least 
2 years following trastuzumab discontinuation. 
R. 
FOCBP only: Pregnancy test must be performed at baseline, at Cycle 1 Day 1 (within 
24 hours predose for urine pregnancy tests or 72 hours for serum tests), within 7 days prior 
to Day 1 of each treatment cycle starting from Cycle 2, and at the EOT visit. 
S. 
FOCBP only: After the last dose of study treatment, pregnancy tests will be performed 
once a month for 7 months, and for 2 years after the last dose of fulvestrant, if applicable. 
Subjects may do monthly home pregnancy tests and report interim results at long term 
follow up visits. Subjects will be asked to confirm that monthly pregnancy tests have been 
performed and have been negative. 
T. 
SAEs and non-serious AESIs will be followed until significant changes return to baseline, 
the event stabilizes or is no longer considered clinically significant by the investigator, or 
the subject dies or withdraws consent. All treatment-related SAEs that occur after the 
safety reporting period should be reported (see Section 7.6.1.2). 
U. 
At minimum, disease assessments, preferably using CT-scans (with oral and/or IV 
contrast), must include the chest, abdomen, and pelvis, as well as appropriate imaging of 
any other known sites of disease such as bone imaging. If bone imaging is collected, any 
RECIST-appropriate imaging modality may be used. If contrast is contraindicated (ie, in 
subjects 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). 
V. 
During treatment, scans will be performed every 6 weeks (based on Cycle 1 Day 1) 
through Week 24 then every 12 weeks through end of study treatment. If cycles are 
delayed for any reason or there is an interim unscheduled assessment, scans should 
continue to be performed according to the original schedule. The same imaging modality 
as used at screening/baseline should be used throughout the study. In subjects with lung 
cancer, scans of the pelvis do not need to be undertaken after the screening assessment 
unless lesions were detected at screening, or as clinically indicated. Responses (CR or PR) 
will be confirmed with repeat scans at least 4 weeks after first documentation of response. 
The schedule for response assessments should not be adjusted after the confirmatory scan. 
Tumor imaging should also be performed whenever disease progression is suspected. 
W. 
In subjects without disease progression at study treatment discontinuation, disease 
assessments should be undertaken every 6 weeks through Week 24 from treatment 
initiation then every 12 weeks until the occurrence of documented disease progression, 
withdrawal of consent, death, or study closure. 
X. 
Contrast brain MRIs are to be performed at screening in all subjects with breast or lung 
cancer. 
Y. 
Subjects with known or suspected brain lesions should undergo contrast brain MRIs 
during treatment and follow-up according to the same assessment schedule as for other 
disease assessments. 
Z. 
Day 1 of every second cycle from Cycle 2. 
AA. 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. Pregnancy testing will continue every 3 weeks for 
subjects of child-bearing potential. 
BB. Only SAEs, AESIs, and pregnancy collected by the Sponsor. 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
SCHEDULE OF EVENTS ................................................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................................... 18 
1 
INTRODUCTION ......................................................................................................................................... 21 
1.1 
HER2 in Cancer .................................................................................................................................. 21 
1.2 
Tucatinib ............................................................................................................................................. 21 
1.3 
Trastuzumab ....................................................................................................................................... 22 
1.4 
Fulvestrant .......................................................................................................................................... 22 
2 
OBJECTIVES ............................................................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 24 
3.1 
Summary of Study Design .................................................................................................................. 24 
3.1.1 
Safety Monitoring Committee .............................................................................................. 28 
3.1.2 
Stopping Criteria .................................................................................................................. 28 
3.1.3 
End of Study ......................................................................................................................... 28 
3.1.4 
Retreatment .......................................................................................................................... 28 
3.1.5 
Method of Assigning Subjects to Treatment Groups ........................................................... 28 
3.2 
Discussion and Rationale for Study Design ........................................................................................ 28 
3.2.1 
Rationale for Combination of Tucatinib and Trastuzumab .................................................. 28 
3.2.2 
Rationale for Evaluation of Tucatinib and Trastuzumab in Solid Tumors ........................... 30 
3.2.3 
Rationale for Evaluation of Tucatinib, Trastuzumab and Fulvestrant in HR+ HER2-mutant 
breast cancer ......................................................................................................................... 32 
3.2.4 
Rationale for Selection of Doses .......................................................................................... 33 
3.2.5 
Blinding and Unblinding ...................................................................................................... 35 
4 
STUDY POPULATION ................................................................................................................................ 35 
4.1 
Inclusion Criteria ................................................................................................................................ 35 
4.2 
Exclusion Criteria ............................................................................................................................... 38 
4.3 
Childbearing Potential ........................................................................................................................ 40 
4.4 
Removal of Subjects From Therapy or Assessment ........................................................................... 40 
4.4.1 
Discontinuation of Study Treatment..................................................................................... 40 
4.4.2 
Subject Withdrawal From Study .......................................................................................... 41 
4.4.3 
Tucatinib Treatment After Study Closure ............................................................................ 41 
5 
TREATMENTS ............................................................................................................................................ 42 
5.1 
Treatments Administered .................................................................................................................... 42 
5.2 
Investigational Products...................................................................................................................... 42 
5.2.1 
Tucatinib............................................................................................................................... 42 
5.2.2 
Trastuzumab ......................................................................................................................... 44 
5.2.3 
Fulvestrant ............................................................................................................................ 45 
5.3 
Dose Modifications ............................................................................................................................. 46 
5.3.1 
Tucatinib Dose Modifications .............................................................................................. 46 
5.3.2 
Trastuzumab Dose Modifications ......................................................................................... 48 
5.3.3 
Fulvestrant Dose Modification ............................................................................................. 49 
5.4 
Required Premedication and Postmedication ..................................................................................... 49 
5.5 
Concomitant Therapy ......................................................................................................................... 50 
5.5.1 
Allowed Concomitant Therapy ............................................................................................ 50 
5.5.2 
Prohibited Concomitant Therapy ......................................................................................... 50 
5.6 
Management of Treatment-Emergent Adverse Events ....................................................................... 51 
5.6.1 
Management of Overdose .................................................................................................... 51 
5.7 
Treatment Compliance........................................................................................................................ 52 
6 
STUDY ACTIVITIES ................................................................................................................................... 53 
6.1 
Schedule of Events ............................................................................................................................. 53 
6.2 
Screening Period ................................................................................................................................. 53 

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6.2.1 
Pre-screening (Up to 3 Months Before Screening Visit) ...................................................... 53 
6.2.2 
Screening Visit (Days –28 to 1) ........................................................................................... 53 
6.2.3 
Baseline Visit (Days –7 to Day 1) ........................................................................................ 54 
6.3 
Tucatinib and Trastuzumab Treatment Period (21-day cycles) .......................................................... 54 
6.3.1 
Cycle 1 Day 1 ....................................................................................................................... 54 
6.3.2 
Cycles 1 and 2 Day 12 (-1 to +3 days) ................................................................................. 55 
6.3.3 
Cycles >1 Day 1 (-1 to +3 days) ........................................................................................... 55 
6.3.4 
Every 6 Weeks as Determined by Cycle 1 Day 1, through Week 24, then Every 12 Weeks 
(±7 days) ............................................................................................................................... 56 
6.3.5 
Every 12 Weeks (±14 days) ................................................................................................. 56 
6.4 
Fulvestrant Treatment Period (if applicable) ...................................................................................... 56 
6.4.1 
Cycle 1 Day 1 ....................................................................................................................... 56 
6.4.2 
Cycle1 Day 15 (±1 day) ....................................................................................................... 57 
6.4.3 
Every 4 weeks after Cycle 1 Day 1 (±3 days) ...................................................................... 57 
6.5 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................. 57 
6.6 
Follow-up ........................................................................................................................................... 58 
6.6.1 
Disease Progression Follow-up (Every 6 Weeks as Determined by Cycle 1 Day 1, through 
Week 24, then Every 12 Weeks [±7 days]) .......................................................................... 58 
6.6.2 
Survival Follow-up (Every 12 Weeks from EOT [±14 days]) ............................................. 58 
6.6.3 
Long-term Extension Phase (LTEP)..................................................................................... 59 
6.7 
Subject End of Study/End of Follow-up ............................................................................................. 59 
7 
STUDY ASSESSMENTS ............................................................................................................................. 60 
7.1 
Screening/Baseline Assessments ........................................................................................................ 60 
7.2 
Response/Efficacy Assessments ......................................................................................................... 60 
7.3 
Pharmacokinetic Assessments ............................................................................................................ 61 
7.4 
Biomarker Studies .............................................................................................................................. 62 
7.4.1 
Evaluation of HER2 Status ................................................................................................... 62 
7.4.2 
Other Biomarker Assessments ............................................................................................. 64 
7.4.3 
Biospecimen Repository ....................................................................................................... 64 
7.5 
Patient-Reported Outcomes ................................................................................................................ 64 
7.5.1 
EQ-5D-5L – Utility Measurement ........................................................................................ 64 
7.6 
Safety Assessments ............................................................................................................................. 65 
7.6.1 
Adverse Events ..................................................................................................................... 65 
7.6.2 
Vital Signs ............................................................................................................................ 71 
7.6.3 
Clinical Laboratory Tests ..................................................................................................... 72 
7.6.4 
Physical Examination ........................................................................................................... 72 
7.6.5 
Pregnancy Testing ................................................................................................................ 72 
7.6.6 
Cardiac Function .................................................................................................................. 73 
7.7 
Appropriateness of Measurements ...................................................................................................... 73 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE................................................................. 74 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 74 
8.2 
Data Management Procedures ............................................................................................................ 74 
8.3 
Access to Source Data ........................................................................................................................ 75 
8.4 
Accuracy and Reliability of Data ........................................................................................................ 75 
8.5 
Quality Assurance Procedures ............................................................................................................ 75 
8.6 
Data Handling and Record Keeping ................................................................................................... 75 
8.6.1 
Data Handling ...................................................................................................................... 75 
8.6.2 
Investigator Record Retention .............................................................................................. 76 
9 
DATA ANALYSIS METHODS ................................................................................................................... 77 
9.1 
Determination of Sample Size ............................................................................................................ 77 
9.2 
Study Endpoint Definitions ................................................................................................................ 77 
9.2.1 
Objective Response Rate ...................................................................................................... 77 
9.2.2 
Duration of Response ........................................................................................................... 77 
9.2.3 
Disease Control Rate ............................................................................................................ 78 

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9.2.4 
Progression-free Survival ..................................................................................................... 78 
9.2.5 
Overall Survival ................................................................................................................... 78 
9.2.6 
Pharmacokinetic Analysis .................................................................................................... 78 
9.2.7 
Exploratory Endpoints .......................................................................................................... 78 
9.3 
Statistical and Analytical Plans........................................................................................................... 78 
9.3.1 
General Considerations ........................................................................................................ 79 
9.3.2 
Subject Disposition............................................................................................................... 80 
9.3.3 
Subject Characteristics ......................................................................................................... 80 
9.3.4 
Concomitant, and Further Therapy ....................................................................................... 81 
9.3.5 
Exposure ............................................................................................................................... 81 
9.3.6 
Efficacy Analyses ................................................................................................................. 81 
9.3.7 
Pharmacokinetic Analyses.................................................................................................... 81 
9.3.8 
Biomarker Analyses ............................................................................................................. 81 
9.3.9 
Patient Reported Outcomes Analyses................................................................................... 81 
9.3.10 
Safety Analyses .................................................................................................................... 82 
9.3.11 
Interim Analyses .................................................................................................................. 83 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 84 
10.1 Informed Consent ............................................................................................................................... 84 
10.2 Ethical Review .................................................................................................................................... 84 
10.3 Regulatory Considerations .................................................................................................................. 84 
10.3.1 
Investigator Information ....................................................................................................... 85 
10.3.2 
Protocol Amendments and Study Termination..................................................................... 85 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 85 
10.5 Data Protection ................................................................................................................................... 85 
10.6 Clinical Trial Agreement .................................................................................................................... 86 
11 REFERENCES .............................................................................................................................................. 87 
APPENDIX A: PERFORMANCE STATUS SCALES CONVERSION ............................................................. 92 
APPENDIX B: GUIDANCE ON CONTRACEPTION ....................................................................................... 93 
APPENDIX C: RESPONSE EVALUATION CRITERIA FOR SOLID TUMORS V1.1 ................................... 94 
APPENDIX D: CYP3A INDUCERS AND THEIR ELIMINATION HALF-LIVES ......................................... 95 
APPENDIX E: CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION HALF-LIVES ................. 96 
APPENDIX F: CLINICAL SUBSTRATES FOR CYP3A-MEDIATED METABOLISM ................................. 97 
APPENDIX G: EQ-5D-5L ................................................................................................................................... 98 
APPENDIX H: INVESTIGATOR SIGNATURE PAGE .................................................................................. 101 
APPENDIX I: DOCUMENT HISTORY ........................................................................................................... 102 
SUMMARY OF CHANGES IN AMENDMENT 1 ........................................................................................... 103 
SUMMARY OF CHANGES IN AMENDMENT 2 ........................................................................................... 105 
SUMMARY OF CHANGES IN AMENDMENT 3 ........................................................................................... 106 
SUMMARY OF CHANGES IN AMENDMENT 4 ........................................................................................... 110 
SUMMARY OF CHANGES IN AMENDMENT 5 ........................................................................................... 111 
 

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LIST OF IN-TEXT TABLES 
Table 1: 
Objectives and corresponding endpoints ....................................................................................... 23 
Table 2: 
Definition of cohorts according to disease type and HER2 alterations, and number of subjects ... 24 
Table 3: 
In vivo efficacy of tucatinib as monotherapy or in combination with trastuzumab in various tumor 
models............................................................................................................................................ 29 
Table 4: 
Reported frequency of HER2 amplification, overexpression, and mutation, by disease type ....... 31 
Table 5: 
Treatment schedule ........................................................................................................................ 42 
Table 6: 
Tucatinib: Recommended dose reduction schedule for AEs ......................................................... 47 
Table 7: 
Dose modifications for clinical AEs related to tucatinib ............................................................... 47 
Table 8: 
Dose modifications of tucatinib for LFT abnormalities, regardless of relationship to tucatinib* .. 47 
Table 9: 
Trastuzumab dose modification guidelines for left ventricular dysfunction .................................. 48 
Table 10: 
Pharmacokinetic and biomarker sample collection timepoints ...................................................... 62 
Table 11: 
Timing of prospective assays used to determine HER2 status for eligibility ................................ 63 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study visits .................................................................................................................................... 27 
Figure 2: 
Study design .................................................................................................................................. 27 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
%TGI 
percent tumor growth inhibition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin  
BID 
twice daily 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CDX 
cell line-derived xenograft 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic CRF 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level 
ER 
estrogen receptor 
FISH 
fluorescence in situ hybridization 
GDPR 
General Data Protection Regulation  
GEC 
gastric or gastroesophageal junction adenocarcinoma 
GFR 
glomerular filtration rate 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
HER2-positive 

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HIV 
human immunodeficiency virus 
HR 
hormone receptor 
HR+ 
hormone receptor positive 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation  
ICR 
independent central review 
IEC 
independent ethics committee 
IgG1 
immunoglobulin G1 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
investigational new drug 
IRB 
institutional review board 
IRR 
infusion-related reaction 
ISO 
International Organization for Standardization 
IV 
Intravenous 
LC 
liquid chromatography 
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 
MRI 
magnetic resonance imaging 
MS 
mass spectrometry 
MUGA 
multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
next generation sequencing 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PDX 
patient-derived xenograft 
PET 
positron emission tomography  
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PO 
Orally 
PPE 
palmar-plantar erythrodysesthesia 
PPoS 
predictive probability of success 
PR 
partial response 
PRO 
patient-reported outcomes 

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QTc 
corrected QT intervals 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SmPC 
Summary of Product Characteristics 
T-DM1 
Trastuzumab emtansine 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 

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1 
INTRODUCTION 
1.1 HER2 in Cancer 
Encoded by the ERBB2 gene, human epidermal growth factor receptor 2 (HER2) is part of a 
family of 4 related receptor tyrosine kinases, which include HER1 (also known as epidermal 
growth factor receptor [EGFR]), HER2, HER3, and HER4. HER1-4 are single-pass 
transmembrane glycoprotein receptors containing an extracellular ligand binding region and 
an intracellular signaling domain. HER2 has no known ligand, but it is the preferred 
dimerization partner for the other HER family receptors. When overexpressed in tumors, 
HER2 forms ligand-independent homodimeric complexes that autophosphorylate. HER2 
homo- or heterodimerization results in the activation of multiple signaling cascades, 
including the Ras/Raf/MEK/MAPK, PI3K/AKT, Src, and STAT pathways. These signaling 
pathways lead to cell proliferation, inhibition of apoptosis, and metastasis (Riese 1998; 
Olayioye 2000; Yarden 2001; Schlessinger 2002; Holbro 2004; Hynes 2005). 
HER2 is a validated target in multiple solid tumors, with anti-HER2 biologics and small 
molecule-drugs approved for patients with HER2 overexpressing/amplified (hereafter 
HER2+) breast and gastric cancers. Amplification of the HER2 gene or overexpression of its 
protein occurs in approximately 15% to 20% of breast cancers (Haque 2012; 
American Cancer Society (ACS) 2018) and 6% to 30% of gastric and esophageal cancers 
(Kelly 2016). Recently, interest has grown in HER2-targeting strategies for patients with 
refractory metastatic colorectal cancer (CRC), where overexpression of HER2 has been 
found to occur in approximately 3% to 5% of patients (Valtorta 2015; Takegawa 2017). 
HER2 can also be overexpressed in other gastrointestinal cancers, such as 
cholangiocarcinoma and gallbladder carcinoma, where studies suggest ERBB2 amplification 
ranges from 1% to 6% (Weinberg 2019; Albrecht 2020). 
Increasing attention has been given to the impact of oncogenic HER2 activation through 
somatic gene mutation. The majority of these HER2-mutant cancers have not been associated 
with concurrent HER2 gene amplification (Connell 2017), with the result that an important 
subgroup of HER2-altered cancers are not detected by immunohistochemistry (IHC) or in 
situ hybridization (ISH) methods. The role of HER2-directed therapy in these HER2-mutated 
cancers is the subject of active exploration. 
1.2 Tucatinib 
Tucatinib ((N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-
4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine) (TUKYSA®; formerly known as 
ARRY-380 and ONT-380) is an orally (PO) administered, potent, highly selective, 
small-molecule tyrosine kinase inhibitor (TKI) of HER2. Tucatinib is a potent inhibitor of 
HER2 in vitro, and in cellular signaling assays is >1000-fold more selective for HER2 
compared to the closely related kinase EGFR. The selectivity of tucatinib for HER2 reduces 
the potential for EGFR-related toxicities that can be seen with dual HER2/EGFR inhibitors. 
Tucatinib inhibits the HER2-driven mitogen-activated protein and PI3 kinase signaling 
pathways, resulting in inhibition of tumor cell proliferation, survival, and metastasis. 

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Tucatinib, combined with trastuzumab and capecitabine, is approved for use in previously 
treated patients with advanced unresectable or metastatic HER2+ breast cancer in multiple 
regions of the world. It is being developed as a treatment for patients with advanced cancers 
that demonstrate HER2 overexpression, and is currently being evaluated in other breast 
cancer indications and in other combinations, and in CRC, gastric or gastroesophageal 
junction adenocarcinoma (GEC), cholangiocarcinoma, and gallbladder cancer. 
A complete summary of the clinical and nonclinical data relevant to tucatinib and its study in 
human subjects is provided in the Investigator’s Brochure. 
1.3 Trastuzumab 
Trastuzumab, a humanized anti-HER2 antibody that binds to the HER2 extracellular domain, 
is approved 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 2001; Vogel 2002). Trastuzumab is also approved for the treatment of HER2+ 
metastatic GEC and is being evaluated in a variety of disease types, as a single agent and in 
combination therapy (Oh 2020). 
1.4 Fulvestrant 
Fulvestrant is an estrogen receptor (ER) antagonist approved for use in treatment of hormone 
receptor (HR) positive (HR+) metastatic breast cancer (mBC) in postmenopausal women 
with disease progression following antiestrogen therapy. Fulvestrant is administered via 
intramuscular (IM) injection. 
For patients with tumors simultaneously expressing HR and HER2, guidelines support the 
combination of anti-HER2-targeted agents and endocrine therapy based on superior efficacy 
demonstrated in clinical studies (Rimawi 2018). Administration of fulvestrant will be 
required in subjects with HR+ HER2-mutant breast cancer. 

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2 
OBJECTIVES 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of tucatinib in 
combination with trastuzumab in subjects with solid tumors displaying HER2 alterations. 
Specific objectives and corresponding endpoints for the study are summarized below 
(Table 1). 
Table 1: 
Objectives and corresponding endpoints 
Primary Objective 
Corresponding Endpoints: 
To evaluate the antitumor activity of 
tucatinib given in combination with 
trastuzumab in subjects with previously 
treated, locally-advanced unresectable or 
metastatic HER2 overexpressing/amplified 
or mutated solid tumors 
Primary endpoint: 
Confirmed objective response rate (ORR; confirmed complete 
response [CR] or partial response [PR]) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 per 
investigator assessment 
 
Secondary endpoints: 
• 
Disease control rate (DCR; confirmed CR or PR, or stable 
disease) per investigator assessment 
• 
Duration of response (DOR; confirmed CR or PR) per 
investigator assessment 
• 
Progression-free survival (PFS) per investigator assessment 
• 
Overall survival (OS) 
Secondary Objectives 
Corresponding Endpoints 
• 
To evaluate the safety and tolerability 
of tucatinib given in combination with 
trastuzumab with or without fulvestrant 
• 
Type, incidence, severity, seriousness, and relatedness of 
adverse events (AEs) 
• 
Type, incidence, and severity of laboratory abnormalities 
• 
Frequency of treatment interruptions, dose reductions, and 
treatment discontinuations due to AEs 
• 
Other relevant safety variables including AEs of special 
interest (AESIs) 
• 
To evaluate the PK of tucatinib 
• 
Plasma concentrations of tucatinib 
Exploratory Objectives 
Corresponding Endpoints 
• 
To determine the concordance of HER2 
alterations as detected by tissue and 
blood-based HER2 testing 
methodologies 
• 
Concordance of HER2 alterations as detected by different 
testing methodologies  
• 
Identify tumor-specific alterations that 
are associated with resistance to 
tucatinib 
• 
Identify tumor-specific alterations that are associated with 
resistance to tucatinib 
• 
To evaluate patient-reported outcomes 
(PROs) 
• 
Change from baseline in health-related quality of life 
(HRQoL), as assessed by the European Quality of Life 
5-Dimension 5-Level (EQ-5D-5L) 
 

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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
SGNTUC-019 is a multi-cohort, multicenter, international, open-label Phase 2 study 
designed to assess the activity, safety, and tolerability of tucatinib in combination with 
trastuzumab for the treatment of subjects with previously treated solid tumors whose disease 
displays HER2 overexpression/amplification or activating mutations. 
Subjects will be enrolled into separate cohorts based on tumor histology and HER2 alteration 
status (see Table 2, Figure 1). There are 5 tumor specific cohorts with HER2 
overexpression/amplification (cervical cancer [Cohort 1], uterine cancer [Cohort 2], biliary 
tract cancer [Cohort 3], urothelial cancer [Cohort 4], and non-squamous non-small cell lung 
cancer [NSCLC] [Cohort 5]), 2 tumor specific cohorts with HER2 mutations (non-squamous 
NSCLC [Cohort 7] and breast cancer [Cohort 8]), and 2 cohorts which will enroll all other 
HER2 amplified/overexpressed solid tumor types (except breast cancer, GEC, and CRC) or 
HER2-mutated solid tumor types (Cohorts 6 and 9, respectively). If a subject has both HER2 
overexpressed/amplified and HER2-mutated disease, and thus qualifies for enrollment in 
2 different cohorts, the subject will be enrolled in the HER2 overexpressed/amplified cohort. 
If a sufficient number of subjects with a particular tumor type are enrolled in Cohorts 6 or 9, 
the sponsor may evaluate that tumor type in a separate cohort, drawn from optional 
Cohorts 10 to 15 (Table 2). If any optional cohort is opened, all subjects enrolled in Cohorts 
6 or 9 with the applicable tumor type will be reassigned to the new tumor-specific cohort; 
these subjects will be replaced in Cohorts 6 and 9. 
Table 2: 
Definition of cohorts according to disease type and HER2 alterations, and 
number of subjects 
 
HER2 alteration 
N subjects per 
cohort 
 
Overexpression/ 
amplification 
Mutations Stage 
1 
Stage 1 and 
Stage 2 
Cervical cancer 
Cohort 1 
 
12 
30 
Uterine cancer 
Cohort 2 
 
12 
30 
Biliary tract cancer  
Cohort 3 
 
12 
30 
Urothelial cancer 
Cohort 4 
 
12 
30 
Non-squamous NSCLC 
Cohort 5 
Cohort 7 
12 
30 
Other solid tumors (except breast cancer, GEC, and CRC) 
Cohort 6 
 
30 
 
Breast cancer 
 
Cohort 8 
30 
 
All solid tumors (except breast cancer and non-squamous NSCLC) 
 
Cohort 9 
30 
 
Optional tumor-specific cohorts 
 
 
 
 
Cervical cancer 
 
Cohort 10 
12 
30 
Uterine cancer 
 
Cohort 11 
12 
30 
Biliary tract cancer 
 
Cohort 12 
12 
30 
Urothelial cancer 
 
Cohort 13 
12 
30 
Additional tumor specific 
Cohort 14 
Cohort 15 
12 
30 

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Once up to approximately 12 response-evaluable subjects have been enrolled in Stage 1 of 
each of Cohorts 1 to 5 and Cohort 7, enrollment to the cohort will be halted for an interim 
analysis of activity (see Section 9.3.11). If sufficient activity is observed in Stage 1 for a 
particular cohort, up to a total of 30 response-evaluable subjects will be enrolled in the cohort 
(Stage 2 expansion) in order to further characterize the activity and safety of the study 
regimen in the given disease and HER2 alteration type. Cohorts 6, 8, and 9 will each enroll 
up to 30 response-evaluable subjects without an interim analysis. Subjects who are not 
response-evaluable (see Section 9.3.1.7) will be replaced. Approximately 162 to 
270 response-evaluable subjects may be enrolled in the study. Additional subjects may be 
enrolled if optional cohorts are opened. 
Adult subjects with any type of locally-advanced unresectable or metastatic solid tumor that 
shows HER2 overexpression/amplification or activating mutations will be enrolled (except 
subjects with HER2 overexpressing/amplified breast cancer, CRC, or GEC). In general, 
subjects will have progressed during or after ≥1 prior line of systemic therapy for 
locally-advanced unresectable or metastatic disease and will have progressed on or after, or 
be intolerant of, the most recent line of systemic therapy. Subjects must have measurable 
disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, and 
adequate baseline hepatic, renal, and hematologic function. Subjects must not have received 
prior HER2-directed therapy (except for subjects with uterine serous carcinoma or 
HER2-mutated GEC without HER2-overexpression/amplification, who may have received 
prior trastuzumab), or have clinically significant cardiopulmonary disease, chronic liver 
disease, or uncontrolled central nervous system (CNS) metastases. 
Study treatment is composed of tucatinib 300 mg twice daily (BID) PO combined with 
trastuzumab 8 mg/kg intravenously (IV) on Cycle 1 Day 1 and then 6 mg/kg every 21 days 
starting on Cycle 2 Day 1. Subjects with HR+ HER2-mutant breast cancer will also receive, 
in combination with tucatinib and trastuzumab, fulvestrant 500 mg IM once every 4 weeks 
starting from Cycle 1 Day 1, as well as on Cycle 1 Day 15. 
A Safety Monitoring Committee (SMC) will be responsible for monitoring the safety of 
subjects in the study at regular intervals. Subjects will continue study treatment until the 
occurrence of radiographic or clinical progression, unacceptable toxicity, withdrawal of 
consent, death, or study closure. Following treatment discontinuation, disease progression (in 
subjects without progression at treatment discontinuation), further anti-cancer therapy, and 
survival status will be monitored from EOT until withdrawal of consent, death, or study 
closure.  
As of Amendment 5, the objectives of the study have been achieved. Therefore, the decision 
has been made to close the study. For subjects in long term follow-up, a last visit or contact 
will occur prior to the subject’s discontinuation from participation in the study. Any subject 
on study treatment will transition to the long-term extension phase (LTEP) of the study.  
Once post-study access to study treatment is available, subjects will have a last visit or 
contact prior to discontinuation from the study. The Sponsor will provide continued access to 

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study treatment for any subject who is still on treatment and receiving clinical benefit based 
on the investigator’s assessment.  
 

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Figure 1: 
Study visits 
 
a 
For subjects who have received fulvestrant, the EOT visit should be undertaken no sooner than 8 weeks after the last dose of fulvestrant. 
Figure 2: 
Study design 
 
a 
If a sufficient number of subjects with a particular tumor type are enrolled in Cohorts 6 or 9, the sponsor may evaluate that tumor type in a separate cohort, drawn from 
optional Cohorts 10 to 15 (See Section 3.1). 
Screening 
28 days 
Study treatment 
21-day cycles 
EOT visit 
30-37 days after last dosea 
Disease assessments: q6 weeks until 24 weeks after treatment initiation, then q12 weeks 
Progression follow-up 
Survival  
follow-up 
q12 weeks from EOT 

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3.1.1 Safety Monitoring Committee 
The SMC will be responsible for monitoring the safety of subjects in the study at regular 
intervals. The SMC will review data on deaths, study treatment and study drug 
discontinuations, dose reductions, AEs, serious adverse events (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 cohort or study continuation as planned, 
protocol amendment, or early discontinuation of a cohort or 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. 
3.1.2 Stopping Criteria 
Reasons for prematurely terminating the study may include but are not limited to: 
● 
The incidence or severity of AEs in this or other studies indicate a potential health 
hazard to subjects, either through a safety review by the sponsor or the SMC. 
● 
Subject enrollment is unsatisfactory. 
3.1.3 End of Study 
As of Amendment 5, all subjects still on study who are not entering the LTEP will have a last 
visit/contact. The study will end when the last LTEP subject has had their last visit/contact. 
The sponsor will provide continued access to study treatment for any subject who is still on 
treatment receiving clinical benefit based on the investigator’s assessment.  
3.1.4 Retreatment 
Retreatment with study treatment is not permitted during the duration of the subject's 
participation in the study. 
3.1.5 Method of Assigning Subjects to Treatment Groups 
Following informed consent and screening assessments, eligible subjects will be assigned to 
currently enrolling cohorts on the basis of the subjects' disease type and the observed HER2 
alterations (overexpression/amplification or mutation). If any disease-specific optional cohort 
is opened, all subjects enrolled in Cohorts 6 or 9 with the applicable tumor type will be 
reassigned to the new tumor-specific cohort. 
3.2 Discussion and Rationale for Study Design 
3.2.1 Rationale for Combination of Tucatinib and Trastuzumab 
Trastuzumab binds to the extracellular domain of HER2, resulting in the inhibition of HER2 
homodimerization and heterodimerization, inhibition of downstream signaling through the 
PI3K–AKT pathway, and suppression of tumor cell proliferation. Tucatinib prevents 
phosphorylation of the tyrosine kinase domain of the HER2 receptor, preventing activation of 

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MAPK and PI3K-AKT signal transduction pathways, thereby inhibiting tumor cell 
proliferation, survival, and metastasis. 
The combination of tucatinib and trastuzumab is being evaluated in this study based on 
preclinical data in various tumor types that demonstrates  superior activity of dual targeting 
of HER2 with tucatinib and trastuzumab compared with either single-agent alone. This is 
further supported by clinical data in breast cancer and CRC showing enhanced activity with 
tucatinib and trastuzumab. 
Preclinical models examining single-agent tucatinib activity in HER2+ patient-derived 
xenograft (PDX) and cell line-derived xenograft (CDX) models have demonstrated tucatinib 
activity  in gastric, esophageal, colorectal, cholangiocarcinoma, and breast tumors. These 
models have also suggested a more robust anti-neoplastic response when tucatinib is 
administered in combination with trastuzumab, compared to monotherapy (Table 3) 
(Peterson 2017). Across 12 PDX models and 2 CDX models of breast, gastric, colorectal, and 
esophageal cancers and cholangiocarcinoma, a nominal dose of tucatinib 50 mg/kg BID 
resulted in percent tumor growth inhibition (%TGI) of 48% to 117%, while trastuzumab 
20 mg/kg every 3 days resulted in %TGIs of -34% to 109%. The combination of tucatinib 
and trastuzumab resulted in %TGIs of 85% to 137%. Additionally, the frequency of PR and 
CR was higher for the combination than either single agent alone, indicating that the activity 
of the combined anti-HER2 agents was superior to either agent alone. Based on these data, 
several clinical studies are actively investigating the use of dual HER2 blockade with 
tucatinib and trastuzumab. 
Table 3: 
In vivo efficacy of tucatinib as monotherapy or in combination with 
trastuzumab in various tumor models 
Tumor 
Cancer type 
%TGI 
 Response rate (CR or PR) (%) 
name 
Tuc 
Tras Tuc+tras  
Tuc 
Tras 
Tuc+tras 
BT-474 
Breast carcinoma CDX 
86 
68 
133 
 
0 
0 
92 
CTG-0708 
Breast carcinoma PDX 
88 
66 
98 
 
0 
0 
0 
CTG-0717 
Breast carcinoma PDX 
79 
21 
99 
 
13 
0 
38 
CTG-0807 
Breast carcinoma PDX 
98 
63 
120 
 
25 
0 
75 
NCI-N87 
Gastric carcinoma CDX 
101 
87 
130 
 
40 
0 
90 
GXA-3038 
Gastric carcinoma PDX 
110 
50 
116 
 
90 
0 
100 
GXA-3039 
Gastric carcinoma PDX 
48 
38 
103 
 
0 
0 
43 
GXA-3054 
Gastric carcinoma PDX 
65 
93 
136 
 
10 
70 
100 
CTG-0121 
Colorectal carcinoma PDX 
104 
109 
124 
 
60 
80 
100 
CTG-0383 
Colorectal carcinoma PDX 
117 
80 
137 
 
60 
40 
100 
CTG-0784 
Colorectal carcinoma PDX 
50 
36 
103 
 
10 
0 
0 
CTG-0137 
Esophageal carcinoma PDX 
49 
55 
85 
 
0 
0 
0 
CTG-0138 
Esophageal carcinoma PDX 
69 
−34 
120 
 
20 
0 
90 
CTG-0927 
Cholangiocarcinoma PDX 
48 
63 
86 
 
0 
0 
10 
Tras=trastuzumab; Tuc=tucatinib. 
 

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Clinical data from the pivotal HER2CLIMB study (ONT-380-206) clearly demonstrated the 
benefit of adding tucatinib to trastuzumab and capecitabine in HER2+ mBC (Murthy 2020). 
In this global, randomized, double-blind study, 612 subjects who were required to have been 
treated with 3 prior HER2-directed agents (trastuzumab, pertuzumab, and trastuzumab 
emtansine) were randomized in a 2:1 ratio to receive tucatinib (300 mg BID) or placebo in 
combination with trastuzumab (8 mg/kg IV followed by 6 mg/kg every 3 weeks) and 
capecitabine (1000 mg/m² BID for 14 days of each 3 week cycle). The primary endpoint, 
PFS, was statistically significant and clinically meaningful in favor of the tucatinib 
combination, with a hazard ratio of 0.54 (95% confidence interval |CI]: 0.42-0.71; 
P<0.00001). Additionally, all multiplicity-adjusted secondary endpoints supported the 
primary endpoint and demonstrated benefit with tucatinib, including OS (hazard ratio 0.66; 
95% CI: 0.50-0.88; P= 0.005), PFS in subjects with brain metastases (hazard ratio 0.48; 
95% CI: 0.34-0.69; P<0.00001) and confirmed ORR (40.6% [95% CI: 35.3-46.0] in the 
tucatinib arm vs 22.8% [95% CI: 16.7-29.8] for placebo, P<0.001). 
In addition to demonstrating benefit in HER2+ mBC, the combination of tucatinib and 
trastuzumab has shown promising activity in HER2+ metastatic CRC, based on initial results 
reported from the single-arm, Phase 2 MOUNTAINEER trial (Strickler 2019). In this study, 
subjects with HER2+, RAS-wildtype metastatic CRC who had been previously treated with 
fluorouracil, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) 
antibody received tucatinib (300 mg BID) in combination with trastuzumab (8 mg/kg IV 
followed by 6 mg/kg every 3 weeks). The primary endpoint is ORR, with the study 
comparing an ORR of 20% (null hypothesis) vs 40% (alternative hypothesis). Among 
23 evaluable subjects, an ORR of 52.2% was observed, with a median PFS of 8.1 months 
(95% CI: 3.8 months-not evaluable) and a median OS of 18.7 months (95% CI: 12.3 months-
not evaluable). 
The results from the HER2CLIMB and MOUNTAINEER studies demonstrate a clear benefit 
of dual targeted HER2 inhibition with tucatinib + trastuzumab in HER2+ malignancies. Both 
the preclinical and clinical data summarized above support the proposed evaluation of 
tucatinib and trastuzumab in solid tumors showing HER2 alterations. 
3.2.2 Rationale for Evaluation of Tucatinib and Trastuzumab in Solid Tumors 
This "basket" study will provide the opportunity to evaluate the activity of targeted therapy 
with tucatinib and trastuzumab across a wide variety of solid tumors, in populations defined 
according to HER2 alterations, and, for a selected group of tumor types that display higher 
rates of HER2 alterations or that represent larger patient populations, in disease-specific 
cohorts. In this study, tucatinib combined with trastuzumab will be explored in solid tumors 
with HER2 overexpression/amplification or HER2 activating mutations. It has been found 
that most tumors have either HER2 amplification/overexpression or mutations, rather than 
both (Arcila 2012; Mazieres 2013), supporting the need to explore both within a clinical 
study to understand the impact of the type of HER2 alteration and disease on efficacy. 

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HER2 overexpressing/amplified solid tumors 
While various HER2-directed agents have been evaluated in HER2-amplified and 
HER2-overexpressing tumors, there are no approved HER2 therapies outside of breast and 
gastric cancers, despite HER2 overexpression/amplification being present in >10% of 
patients for various disease types, and rising to >50% in certain types (Table 4). Current 
National Comprehensive Cancer Network (NCCN) guidelines recommend pertuzumab or 
lapatinib combined with trastuzumab in patients with HER2+ CRC unable to receive 
intensive therapy or following chemotherapy (NCCN, Colon Cancer, 15 June 2020). NCCN 
guidelines also recommend HER2 testing in uterine cancer, pancreatic cancer, and salivary 
gland cancer. 
Based on the preclinical evidence for the activity of tucatinib across a variety of HER2 
overexpressing/amplified xenograft models (Section 3.2.1), in particular when combined 
with trastuzumab, the proven efficacy of tucatinib in combination with trastuzumab and 
capecitabine in metastatic HER2 overexpressing/amplified breast cancer, and the preliminary 
activity observed for dual HER2 inhibition with tucatinib and trastuzumab in metastatic 
HER2 overexpressing/amplified CRC, this study will evaluate tucatinib and trastuzumab in 
disease-specific cohorts of HER2 overexpressing/amplified cervical cancer, uterine cancer, 
biliary tract cancer, urothelial cancer, and non-squamous NSCLC, and in a cohort of all other 
solid tumors. 
Table 4: 
Reported frequency of HER2 amplification, overexpression, and mutation, by 
disease type  
 
HER2 amplification (%) 
HER2 overexpression (%) 
HER2 mutation (%) 
Salivary 
12-52 
17-44 
1 
Breast 
20 
15-20 
2 
Stomach 
11-16 
20 
3 
Ovary 
7 
27 
1 
Uterus 
4-59 
18-80 
2 
Cervix 
0.5-14 
21 
3 
Lung 
2-3 
2.5 
1-3 
Biliary tract 
5-15 
20 
2 
Pancreas 
2 
26 
<1 
Colorectum 
5.8 
5 
2 
Bladder 
8.6 
12.4 
9 
Prostate 
5.8-6 
10 
<1 
Source: (Oh 2020) 
 
HER2-mutant solid tumors 
Mutations are found across all exons of ERBB2, the gene encoding for HER2, with 
significant heterogeneity both between and within human cancer types (Connell 2017). 
Mutations typically occur in the absence of gene amplification, can lead to enhanced HER2 
kinase activity or receptor dimerization, and, unlike other mutant oncogenes, no single 
mutant allele predominates (Hyman 2018). The proportion of subjects with disease showing 
HER2 mutations varies with tumor type, not exceeding 10% in any type, and the distribution 
of mutations varies by tumor type. 

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HER2-directed agents are being evaluated in patients with HER2-mutated NSCLC, breast 
cancer, CRC, urothelial tract carcinoma, and solid tumors (Cocco 2019), and promising 
initial assessments of activity have been reported. Current NCCN guidelines recommend 
trastuzumab emtansine (T-DM1) for HER2-mutant lung cancer (NCCN, NSCLC, 15 June 
2020). In HER2-mutated NSCLC, single agent trastuzumab deruxtecan achieved an ORR of 
56% to 62% but only 5% ORR in HER2-mutated CRC (Smit 2020; Tsurutani 2020). Single 
agent pyrotinib achieved an ORR of 32% in patients with NSCLC showing HER2 exon 20 
mutations (Gao 2019). In the SUMMIT basket study of neratinib in HER2-mutated solid 
tumors, an ORR of 24% was reported in breast cancer for single agent neratinib, with 
responses also observed in lung and cervical cancers (Hyman 2018). In HR+ HER2-mutated 
breast cancer, ORR was 30% for neratinib plus fulvestrant and 53% when trastuzumab was 
added (Smyth 2019; Wildiers 2020). 
Tucatinib is a potent inhibitor of mutant HER2 signaling in vitro. In cell signaling assays, 
tucatinib exhibits potent inhibition of HER2 phosphorylation in exon20 insertion mutants 
without measurable effects on EGFR phosphorylation. In the exon 20 G776 InsV_G/C 
mutation background, tucatinib potently blocked downstream signal transduction and 
inhibited cell proliferation in vitro. In the HER2 L755S and V777L mutants tucatinib 
potently blocked HER2 phosphorylation (Peterson 2020). 
Tucatinib is active in multiple HER2-mutant driven tumor models, including models 
containing the L755S mutation which has been associated with lapatinib resistance 
preclinically and trastuzumab resistance clinically. Tucatinib significantly inhibited tumor 
growth in 5 of 6 HER2 point mutant PDX models, compared to 1 of 6 for trastuzumab alone. 
The combination of the 2 drugs was significantly active in all HER2 mutant models (Peterson 
2020). 
Tucatinib has demonstrated selective inhibition of HER2-mutants, resulting in the regression 
or inhibition of tumor growth in patient derived xenograft models and supporting the 
evaluation of tucatinib in clinical studies in HER2-mutant driven cancers. Tucatinib's HER2 
selective inhibition could potentially provide clinical benefit in patients with cancers with 
activating HER2 mutations by blocking oncogenic signaling elicited by mutant HER2. 
3.2.3 Rationale for Evaluation of Tucatinib, Trastuzumab and Fulvestrant in 
HR+ HER2-mutant breast cancer 
Somatic HER2 mutations occur in 7-8% of HR+ mBC (Bose 2013). Preclinical data suggests 
that resistance to anti-HER2-targeted therapies via upregulation of ER pathways can be 
suppressed by the addition of endocrine therapy (Giuliano 2013). For patients with tumors 
simultaneously expressing HR and HER2, guidelines support the combination of 
anti-HER2-targeted agents and endocrine therapy based on superior efficacy demonstrated in 
clinical trials (Rimawi 2018). It is hypothesized that if ER signaling is left uninhibited, it can 
become an alternative driver of cell growth and survival in ER+/HER2+ tumors in the 
presence of HER2 inhibition (Giuliano 2015). 

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Fulvestrant is an injectable pure steroidal ER antagonist and has a high ER-binding affinity to 
produce complete receptor blockade. Fulvestrant’s lack of estrogen agonist activity is 
associated with reduced risk of endometrial abnormalities seen with tamoxifen (Bissett 1994; 
Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 2005). Furthermore, 
fulvestrant uniquely impairs dimerization and the bound receptor is rapidly degraded 
(Steger 2005), blocking the nuclear ER as well as cytoplasmic and membrane-bound ER, 
which may limit the potential for cross-talk between EGFR/HER2-mediated pathways and 
delay the time to development of resistance to endocrine therapy (Wright 1992; Pietras 1995; 
Rusz 2018). Fulvestrant has clinical activity in patients previously treated with antiestrogen 
therapies, including aromatase inhibitors (Ingle 2006; Perey 2007) and in patients with 
ER+/HER2+ breast cancer (Steger 2005; Robertson 2010). 
The results from the SUMMIT trial demonstrated that dual HER2-targeted therapy (neratinib 
and trastuzumab) with fulvestrant improved clinical benefit in patients with HR+ 
HER2-mutated mBC compared to neratinib combined with fulvestrant or neratinib 
monotherapy. The cohort who received neratinib + fulvestrant + trastuzumab demonstrated 
an ORR of 53% and median PFS of 9.8 months (Wildiers 2020) versus ORR of 30% in 
cohorts who received neratinib combined with fulvestrant (Smyth 2019 ) or neratinib 
monotherapy (Hyman 2018). 
3.2.4 Rationale for Selection of Doses 
3.2.4.1 Tucatinib 
The tucatinib 300 mg PO BID dose regimen is approved in multiple regions of the world.  
In the pivotal HER2CLIMB study (ONT-380-206) in subjects with HER2+ mBC, the 
combination of tucatinib 300 mg PO BID with trastuzumab and capecitabine was found to be 
well tolerated, with a manageable safety profile. The most frequent AEs included diarrhea 
(80.9% in the tucatinib, trastuzumab, and capecitabine arm versus 53.3% in the placebo, 
trastuzumab, and capecitabine arm), palmar-plantar erythrodysesthesia (PPE) syndrome 
(63.4% versus 52.8%), nausea (58.4% versus 43.7%), fatigue (45.0% versus 43.1%), and 
vomiting (35.9% versus 25.4%). Elevated liver function test (LFT) AEs were observed, with 
all grade aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin 
elevations reported in 21.3%, 20.0% and 18.6% of subjects in the experimental arm, 
respectively, and 11.2%, 6.6%, and 10.2% in the control arm. Grade ≥3 AEs included PPE 
syndrome (13.1% versus 9.1%), diarrhea (12.9% versus 8.6%), increased AST (4.5% versus 
0.5%), increased ALT (5.4% versus 0.5%), and increased bilirubin (0.7% versus 2.5%). 
The Phase 1b studies ONT-380-004 and ONT-380-005 evaluated the safety of tucatinib 
300 and 350 mg PO BID in combination with T-DM1 and trastuzumab/capecitabine, 
respectively, in subjects with HER2+ mBC. Both studies determined the recommended 
tucatinib clinical dose to be 300 mg PO BID. 
In the 18 subjects in ONT-380-005 who received tucatinib 300 mg plus trastuzumab, the 
most frequent AEs were diarrhea (56% of 18 subjects), nausea (33%), constipation (28%), 

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and arthralgia, vomiting, and dizziness (22% each). No Grade ≥3 AEs occurred in more than 
1 subject. All grade AST, ALT and bilirubin laboratory abnormalities reported in 67%, 44%, 
and 22%, respectively. There were no Grade ≥3 LFT laboratory abnormalities. 
In the tucatinib plus trastuzumab and capecitabine cohort, the most frequent AEs were 
diarrhea (74% of 27 subjects), nausea (78%), PPE syndrome (67%), vomiting (52%), and 
fatigue (44%). Grade ≥3 AEs occurring in >10% of subjects were fatigue (15%), and diarrhea 
and PPE syndrome (11% each). All grade AST, ALT and bilirubin laboratory abnormalities 
reported in 89%, 78%, and 52%, respectively. Grade ≥3 LFT laboratory abnormalities were 
reported in 2 subjects (7%) each. 
Interim data were reported from 26 subjects with HER2+ metastatic CRC enrolled in the 
MOUNTAINEER study (SGNTUC-017) evaluating tucatinib 300 mg PO BID and 
trastuzumab (Strickler 2019). Combination treatment with tucatinib + trastuzumab appeared 
to be efficacious and well-tolerated. The most frequent AEs were AST increased (38.5%), 
ALT increased and diarrhea (23.1% each), fatigue (19.2%), and infusion-related reactions 
(IRRs; 11.5%); only 2 Grade 3 AEs were reported, for diarrhea and hypertension (3.8% 
each). 
In ONT-380-004, the most frequent AEs at the tucatinib 300 mg dose level combined with 
T-DM1 were nausea (72% of 50 subjects), diarrhea (60%), fatigue (58%), vomiting (46%). 
All grade AST, ALT, and bilirubin laboratory abnormalities were reported in 92%, 88%, and 
36% of subjects, respectively. Grade ≥3 AEs included thrombocytopenia 28%, 
hypokalemia 16%, increased AST 16%, increased ALT 14%, and increased bilirubin 4%. 
Based on these studies, the proposed starting dose of tucatinib combined with trastuzumab is 
300 mg BID. 
3.2.4.2 Trastuzumab 
Trastuzumab will be administered IV in accordance with the every 3-week dosing schedule 
specified in the trastuzumab label for neoadjuvant treatment of subjects with breast cancer 
and for subjects with metastatic gastric cancer. The combination of this trastuzumab regimen 
with tucatinib 300 mg BID PO was found to be safe and tolerable in the HER2CLIMB, 
MOUNTAINEER, and ONT-380-005 studies described above. 
3.2.4.3 Fulvestrant 
Fulvestrant will be administered in accordance with the dosing schedule specified in the 
fulvestrant label for treatment of subjects with HR+ mBC. Fulvestrant 500 mg IM will be 
administered once every 4 weeks starting from Cycle 1 Day 1, as well as on Cycle 1 Day 15. 

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3.2.5 Blinding and Unblinding 
Not applicable, as this is an open-label study. 
4 
STUDY POPULATION 
This study will enroll adult subjects with any type of locally-advanced unresectable or 
metastatic solid tumor that shows HER2 overexpression/amplification or mutations (except 
subjects with HER2 overexpressing/amplified breast cancer, CRC, or GEC). 
Subjects must meet all of the enrollment criteria to be eligible for this study. Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of a 
good clinical practice audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or 
metastatic solid tumor, including primary brain tumors 
2. Prior therapy:  
a. Subjects with non-squamous NSCLC: Must have progressed during or after standard 
treatment or for which no standard treatment is available 
b. Subjects with other disease types: Must have progressed during or after ≥1 prior line 
of systemic therapy for locally-advanced unresectable or metastatic disease  
i. 
Subjects with metastatic HR+ HER2-mutated breast cancer must have received a 
prior CDK4/6 inhibitor in the metastatic setting  
ii. 
Subjects with metastatic cervical cancer must have received platinum-based 
chemotherapy with or without bevacizumab in the metastatic setting  
3. Progression during or after, or intolerance of, the most recent line of systemic therapy  
4. Disease demonstrating HER2 alterations (overexpression/amplification or HER2 
activating mutations), as determined by local or central testing processed in a Clinical 
Laboratory Improvement Amendments (CLIA)- or International Organization for 
Standardization (ISO)-accredited laboratory, according to one of the following: 
a. HER2 overexpression/amplification from fresh or archival tumor tissue or blood 
utilizing one of the following tests, in subjects with tumor types other than breast 
cancer, GEC, or CRC: 
i. 
HER2 overexpression (3+ IHC) (breast or gastric algorithms) 
ii. 
HER2 amplification by in situ hybridization assay (fluorescence in situ 
hybridization [FISH] or chromogenic in situ hybridization [CISH] signal ratio 
≥2.0 or gene copy number >6) 
iii. 
HER2 amplification in tissue by next generation sequencing (NGS) assay 
iv. 
HER2 amplification in circulating tumor DNA (ctDNA) by blood-based NGS 
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b. Known activating HER2 mutations detected in fresh or archival tumor tissue or blood 
by NGS assay, including: 
● 
Extracellular domain: G309A/E; S310F/Y; C311R/S; C334S 
● 
Kinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; 
V777L/M; G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896C, 
other exon 20 insertions 
● 
Transmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; 
V697. 
● 
Subjects with HER2 activating mutations not listed above may be eligible, if 
supported by scientific literature and approved by the medical monitor. 
5. Have measurable disease per RECIST v1.1 criteria according to investigator assessment 
6. Be at least 18 years of age at time of consent, or considered an adult by local regulations 
7. Have ECOG performance status 0 or 1 
8. Have a life expectancy of at least 3 months, in the opinion of the investigator 
9. Have adequate hepatic function as defined by the following: 
a. AST and ALT ≤3 × upper limit of normal (ULN) (≤5 × ULN if liver metastases are 
present) 
b. Total bilirubin ≤1.5 × ULN. Exception: subjects with known history of Gilbert’s 
syndrome with direct bilirubin ≤1.5 × ULN and normal AST and ALT are eligible 
10. Have adequate baseline hematologic parameters as defined by: 
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L 
b. Platelet count ≥100 × 109/L; subjects with stable platelet count from 75 to 
100 × 109/L may be included with approval from Medical Monitor 
c. Hemoglobin ≥9.0 g/dL; subjects with hemoglobin ≥8 and <9 g/dL may be included 
with approval from the Medical Monitor 
d. In subjects transfused before study entry, transfusion must be ≥14 days prior to start 
of therapy to establish adequate hematologic parameters independent from 
transfusion support 
11. Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m² using the Modification 
of Diet in Renal Disease (MDRD) study equation 
12. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or 
multigated acquisition scan (MUGA) documented within ≤28 days prior to first dose of 
study treatment 

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13. For subjects of childbearing potential (as defined in Section 4.3), 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 the first dose of study treatment. A subject with a false positive 
result and documented verification that the subject 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 any study drug, and, if applicable, for at least 2 years after the 
final dose of fulvestrant 
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through at least 7 months after the final dose of any study drug, and, if 
applicable, at least 2 years after the final dose of fulvestrant 
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 B, starting at the 
time of informed consent and continuing throughout the study and for at least 
7 months after the final dose of any study drug, and, if applicable, for at least 2 years 
after the final dose of fulvestrant 
14. For subjects 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 7 months after the final dose of any study 
drug, and, if applicable, for at least 2 years after the final dose of fulvestrant 
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 B, starting at time of informed consent and continuing 
throughout the study and for at least 7 months after the final dose of any study drug, 
and, if applicable, for at least 2 years after the final dose of fulvestrant 
c. If sexually active with a person who is pregnant or breastfeeding, must consistently 
use one of 2 highly effective methods of birth control, as defined in Appendix B, 
starting at time of informed consent and continuing throughout the study and for at 
least 7 months after the final dose of any study drug, and, if applicable, for at least 
2 years after the final dose of fulvestrant 
15. Subject must provide signed informed consent that has been approved by an institutional 
review board/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 subject’s 
disease 
16. Subject must be willing and able to comply with study procedures 

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4.2 Exclusion Criteria 
1. Subjects with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or 
CRC whose disease shows HER2 amplification/overexpression. 
2. Previous treatment with HER2-directed therapy; subjects with uterine serous carcinoma 
or HER2-mutated gastric or gastroesophageal junction adenocarcinoma without 
HER2-overexpression/amplification may have received prior trastuzumab 
3. Known hypersensitivity to any component of the drug formulation of tucatinib or 
trastuzumab (drug substance, excipients, murine proteins), or any component of the drug 
formulation of fulvestrant in subjects with HR+ HER2-mutated breast cancer 
4. History of exposure to a >360 mg/m² doxorubicin-equivalent or >720 mg/m² 
epirubicin-equivalent cumulative dose of anthracyclines 
5. Treatment with any systemic anti-cancer therapy, radiation therapy, major surgery, or 
experimental agent within ≤3 weeks of first dose of study treatment or are currently 
participating in another interventional clinical trial. 
6. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, 
with the following exceptions: 
a. Alopecia 
b. Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the 
time of occurrence, and must have resolved completely 
c. Anemia, which must have resolved to ≤ Grade 2 
7. Have clinically significant cardiopulmonary disease such as: 
a. Ventricular arrhythmia requiring therapy 
b. Symptomatic hypertension or uncontrolled hypertension as determined by 
investigator 
c. Any history of symptomatic CHF 
d. Severe dyspnea at rest (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] Grade 3 or above) due to complications of advanced 
malignancy 
e. Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is 
needed only for obstructive sleep apnea 
8. Have known myocardial infarction or unstable angina within 6 months prior to first dose 
of study treatment 

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9. Known to be positive for hepatitis B by surface antigen expression. Known to be positive 
for hepatitis C infection (positive by polymerase chain reaction). Subjects who have been 
treated for hepatitis C infection are permitted if they have documented sustained virologic 
response of 12 weeks 
10. Presence of known chronic liver disease 
11. Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if 
they meet any of the following criteria: 
a. CD4+ T-cell count of <350 cells/µL 
b. Detectable HIV viral load 
c. History of an opportunistic infection within the past 12 months 
d. On stable antiretroviral therapy for <4 weeks 
12. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 
7 months following the last dose of study drug and, if applicable, until 2 years after the 
final dose of fulvestrant 
13. Have inability to swallow pills 
14. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 half-lives of the 
inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to start 
of treatment 
15. Have any other medical, social, or psychosocial factors that, in the opinion of the 
investigator, could impact safety or compliance with study procedures 
16. History of another malignancy 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 
17. Subjects with known CNS lesions must not have any of the following: 
a. Any untreated brain lesions >2.0 cm in size, unless approved by the medical monitor 
b. Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a 
total daily dose of >2 mg of dexamethasone (or equivalent). However, subjects on a 
chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) may be 
eligible, following approval by the medical monitor 
c. 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 subject (eg, brain stem lesions). Subjects 
who undergo local treatment for such lesions identified by screening brain magnetic 
resonance imaging (MRI) may still be eligible for the study 
d. Known or suspected leptomeningeal disease as documented by the investigator 
e. Have poorly controlled (>1/week) generalized or complex partial seizures, or 
manifest neurologic progression due to brain lesions notwithstanding CNS-directed 
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4.3 Childbearing Potential 
A person of childbearing potential is anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 
12 months of amenorrhea in a person over age 45 in the absence of other biological, 
physiological, or pharmacological causes. 
A person who can father children is anyone born male who has testes and who has not 
undergone surgical sterilization (eg, vasectomy followed by a clinical test proving that the 
procedure was effective). 
4.4 Removal of Subjects From Therapy or Assessment 
Seagen or their designee must be notified if a subject is withdrawn from study treatment or 
from the study. The reason(s) for withdrawal must be documented in the subject’s medical 
records and case report form (CRF). For subjects continuing to LTEP, data will only be 
documented in the subject’s medical record. 
4.4.1 Discontinuation of Study Treatment 
A subject’s study treatment may be discontinued for any of the following reasons: 
● 
Progressive disease 
● 
AE 
● 
Pregnancy or begins breastfeeding while on study 
● 
Investigator decision, due to clinical progression 
● 
Investigator decision, other 
● 
Subject decision, non-AE  
Note: Ensure that subjects who decide to stop treatment because of an AE are not 
included in this rationale. 
● 
Study termination by sponsor 
● 
Other, non-AE 
 
If a study drug (tucatinib, trastuzumab, or fulvestrant) is discontinued, study treatment can 
continue with remaining study drug(s). Subjects who discontinue study treatment for reasons 
other than documented progressive disease or death will continue to have disease 
assessments every 6 weeks (±1 week) until 24 weeks after treatment initiation, then every 
12 weeks (±1 week), until the occurrence of disease progression per RECIST v1.1, death, 
withdrawal of consent, lost to follow-up, or study closure. 
Follow-up for survival and subsequent anti-cancer therapy will occur approximately every 
12 weeks (±14 days) from EOT and continue until death, withdrawal of consent, lost to 
follow-up, or study closure. (Section 4.4.2). 
Every effort should be made to confirm disease progression (per RECIST v1.1) whenever 
possible. However, in instances where subjects appear to have progressive symptoms for 

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whom it is not possible or feasible to undergo radiologic assessment, investigators may 
remove the subject from study treatment due to "physician decision due to clinical 
progression." Use of this reason for removing such subjects from study treatment should be 
restricted to those cases in which it is not clinically appropriate for the subject to undergo 
further radiologic assessment and where there is clinical confidence for cancer progression in 
the absence of radiographic confirmation. Special consideration should be given to ensure 
that other possible reasons, particularly AEs, are not a more accurate description of the 
reason for study drug discontinuation in these cases. 
4.4.2 Subject Withdrawal From Study 
Any subject may be discontinued from the study for any of the following reasons: 
● 
Subject withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
4.4.3 Tucatinib Treatment After Study Closure 
The sponsor commits to continue providing tucatinib in accordance with local regulations to 
subjects on tucatinib who are continuing to demonstrate clinical benefit upon study closure. 

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5 
TREATMENTS 
5.1 Treatments Administered 
Subjects will receive combination therapy of the investigational medicinal products tucatinib 
and trastuzumab. Study treatment will be given on a 21-day cycle, with tucatinib every day 
and trastuzumab on Day 1 (Table 5). Subjects who have HR+ HER2-mutant breast cancer 
will also receive fulvestrant once every 4 weeks starting from Cycle 1 Day 1, as well as on 
Cycle 1 Day 15. In this study, subjects are considered to be on study treatment if they are 
receiving any of the study drugs (tucatinib, trastuzumab, or fulvestrant). Cycles are defined 
by trastuzumab administration, with a new cycle starting whenever the Day 1 infusion of 
trastuzumab is administered. If trastuzumab is discontinued, cycles will be defined as 
occurring every 21 days from the last Day 1 administration of trastuzumab. 
Table 5: 
Treatment schedule 
Agent 
Dose  
Route 
Period 
Daily frequency 
Dosing Schedule 
Tucatinib 
300 mg  
PO 
All cycles 
BID 
Every day, from Cycle 1 Day 1 
Trastuzumab  
8 mg/kg  
IV 
Cycle 1 
Once 
Day 1 
 
6 mg/kg 
IV 
Cycles >1 
Once 
Day 1 
Fulvestrant 
500 mg 
IM 
Every 4 weeks 
Once 
Starting from Cycle 1 Day 1 
(if applicable) 
 
 
Cycle 1 
Once 
Day 15 
 
5.2 Investigational Products 
5.2.1 Tucatinib 
Tucatinib, an investigational agent under study in this protocol, is a kinase inhibitor that 
selectively inhibits HER2, and displays limited activity against the related kinase EGFR. 
Tucatinib will be supplied in an open-label manner, by the sponsor. 
Detailed information describing the preparation, administration, and storage of tucatinib is 
located in the Pharmacy Instructions. 
5.2.1.1 Description 
Tucatinib drug product is supplied as both a coated yellow oval-shaped tablet in a 150 mg 
dosage strength and a coated yellow round convex tablet in a 50 mg dosage strength. The 
tablets are manufactured from a drug product intermediate 
 of tucatinib 
in polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the 
pharmaceutical excipients (microcrystalline cellulose, sodium chloride, potassium chloride, 
sodium bicarbonate, silicon dioxide, crospovidone, and magnesium stearate), and 
compressed into tablets. 
CCI

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5.2.1.2 Dose and Administration 
Tucatinib will be administered according to the following: 
● 
Route of administration: PO 
● 
Dose: Tucatinib 300 mg will be administered PO BID from Cycle 1 Day 1 onwards. 
● 
Dosing schedule: BID on each day of study treatment. Tucatinib should be taken once 
in the morning and once in the evening, with approximately 8 to 12 hours between 
doses in the same calendar day. 
 
Dose modifications of tucatinib are described in Section 5.3.1. Subjects 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, subjects will be supplied with the appropriate number of 
tablets for the number of doses to be taken prior to the next scheduled visit. 
It is recommended that if a subject misses a scheduled dose of tucatinib and less than 6 hours 
have passed since the scheduled dosing time, the dose should be taken immediately. It is 
recommended that if more than 6 hours have passed since the scheduled dosing time, the 
subject should not take the missed dose but should wait and take the next regularly scheduled 
dose. Tablets may be taken with or without food. Tablets must be swallowed whole and may 
not be crushed, chewed, cut or dissolved in liquid.  
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 subjects and will include 
the minimum times between doses, dosing in relation to meals, and instructions for missed 
doses. Subject compliance with investigational study drug instructions will be assessed with 
the use of subject diaries and confirmed with pill counts. Study drug accountability will be 
assessed using pill counts. 
5.2.1.3 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 
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. 
5.2.1.4 Packaging and Labeling 
Each bottle of investigational study drug will be labeled in compliance with applicable 
regulatory requirements. Refer to the Pharmacy Instructions for more information. 

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5.2.1.5 Preparation 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
5.2.2 Trastuzumab 
5.2.2.1 Description 
Trastuzumab is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody which 
binds to the extracellular domain of HER2; it mediates antibody-dependent cellular 
cytotoxicity by inhibiting proliferation of cells which over express the HER2 protein. 
Trastuzumab is indicated for adjuvant treatment of HER2-overexpressing node positive or 
node negative breast cancer, in combination with paclitaxel or docetaxel for first-line 
treatment of HER2-overexpressing mBC and in combination with an aromatase inhibitor for 
HR+ mBC, as a single agent for treatment of HER2-overexpressing breast cancer in patients 
who have received one or more chemotherapy regimens for metastatic disease, and in 
combination with a platinum agent and capecitabine or 5-fluorouracil, for the treatment of 
patients with HER2-overexpressing metastatic GEC who have not received prior treatment 
for metastatic disease. 
5.2.2.2 Method of Procurement 
Trastuzumab will be supplied in an open-label manner, by the sponsor. 
5.2.2.3 Dose and Administration 
Trastuzumab will be administered on Day 1 of every 21-day cycle. A loading dose of 
8 mg/kg in a 90-minute IV infusion will be administered on Cycle 1 Day 1 followed by 
6 mg/kg in a 30-minute IV infusion for each subsequent dose. However, if trastuzumab IV 
was administered within the 4 weeks prior to treatment initiation, trastuzumab 6 mg/kg IV 
should be administered on Cycle 1 Day 1. If the Day 1 dosing of trastuzumab is delayed by 
>1 week, the IV loading dose of 8 mg/kg should be given per approved dosing instructions. If 
dosing of trastuzumab is held for >6 weeks due to treatment-related AEs, medical monitor 
approval is required before restarting trastuzumab. 
It is recommended to observe subjects from the start of the infusion for fever, chills and other 
infusion-related symptoms. Interruption or slowing of the infusion may help control such 
symptoms and may be resumed when symptoms abate. All infusion-related symptoms must 
have resolved before the subject is discharged unless deemed clinically not significant by the 
investigator. See Section 5.3.2.2 for recommended treatment of IRRs and premedication for 
subsequent administrations. 
5.2.2.4 Storage and Handling 
Refrigeration should be set at 2 to 8°C for storage of vials containing trastuzumab. Follow 
the package insert for more information. 

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5.2.2.5 Packaging and Labeling 
Each vial of trastuzumab will be labeled in compliance with applicable regulatory 
requirements. 
5.2.2.6 Preparation 
Single-dose vial (150 mg/vial) as a lyophilized sterile powder for reconstitution is 
commercially available and should be prepared and administered per instructions in the 
trastuzumab package insert for administration instructions. Trastuzumab will be administered 
IV under the direction of the investigator. 
5.2.3 Fulvestrant 
5.2.3.1 Description 
Fulvestrant is an ER antagonist approved for use in treatment of HR+ mBC in 
postmenopausal women with disease progression following antiestrogen therapy. 
Administration of fulvestrant will be required in subjects with HR+ HER2-mutant breast 
cancer. 
5.2.3.2 Method of Procurement 
Fulvestrant is commercially available. Details regarding its sourcing may vary by site and/or 
region as outlined in other documents such as Clinical Trial Agreements. 
5.2.3.3 Dose and Administration 
Fulvestrant will be administered once every 4 weeks starting from Cycle 1 Day 1, as well as 
on Cycle 1 Day 15. The recommended dose is 500 mg to be administered intramuscularly 
into the buttocks slowly (1-2 minutes per injection) as two 5 mL injections; one in each 
buttock. 
Because fulvestrant is administered intramuscularly, it should be used with caution in 
subjects with bleeding diatheses, thrombocytopenia, or anticoagulant use. 
Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral 
neuropathy have been reported with fulvestrant injections. Caution should be taken while 
administering fulvestrant at the dorsogluteal injection site due to the proximity of the 
underlying sciatic nerve. 
5.2.3.4 Storage and Handling 
Consult the package insert for storage and handling. 
5.2.3.5 Packaging and Labeling 
Each syringe of fulvestrant will be labeled in compliance with applicable regulatory 
requirements. 

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5.2.3.6 Preparation 
Fulvestrant should be prepared and administered per instructions in the fulvestrant package 
insert. Fulvestrant will be administered IM under the direction of the investigator. 
5.3 Dose Modifications 
Dose modification recommendations (including dose holds, dose reduction, or 
discontinuation of drugs) in response to AEs are described in Section 5.3.1 for tucatinib, 
Section 5.3.2 for trastuzumab, and Section 5.3.3 for fulvestrant. Dose reductions or treatment 
interruption/discontinuation for reasons other than those described in the following sections 
may be made at the discretion of the investigator if it is deemed in the best interest of subject 
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 trastuzumab. An AE may be considered related 
to any single study drug, any combination of study drugs, or to none of them. In the event 
that the relationship is unclear, discussion should be held with the study medical monitor, to 
determine which study drug(s) should be held and/or modified. 
The beginning of each cycle is defined by the administration of the Day 1 infusion of 
trastuzumab. If trastuzumab is discontinued, protocol-defined visits will proceed using a 
21-day cycle starting from the last trastuzumab Day 1, regardless of tucatinib dose holds or 
delays. 
Doses held for toxicity will not be replaced. Once reduced, the dose of a study drug should 
not be re-escalated. Any study drug that requires a delay >6 weeks due to a treatment-related 
AE should be discontinued, unless a longer delay is approved by the study medical monitor. 
If one of the study drugs is discontinued, study treatment can continue with the remaining 
study drug. 
5.3.1 Tucatinib Dose Modifications 
Up to 3 dose reductions of tucatinib are allowed (Table 6). Subjects 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 6 may be made at the discretion 
of the investigator, with approval by the medical monitor. 

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Table 6: 
Tucatinib: Recommended dose reduction schedule for AEs 
Dose Reduction Schedule 
Tucatinib Dose Level 
Starting dose 
300 mg PO BIDa 
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 tucatinib 
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 and approved by the medical monitor. However, 
tucatinib may not be dose reduced below 150 mg BID. 
General dose modification guidelines for tucatinib are provided in Table 7 and Table 8. For 
subjects with documented Gilbert’s disease, contact the medical monitor for guidance 
regarding dose modifications for LFT abnormalities. 
Table 7: 
Dose modifications for clinical AEs related to tucatinib  
Adverse Reactions 
Tucatinib Dose Modification 
Diarrhea 
 
 
Grade 3 without anti-diarrheal treatment 
Initiate or intensify appropriate medical therapy. 
Hold tucatinib until recovery to ≤ Grade 1 or baseline 
Resume tucatinib at same dose 
 
Grade 3 with anti-diarrheal treatment 
Initiate or intensify appropriate medical therapy. 
Hold tucatinib until recovery to ≤ Grade 1 or baseline 
Reduce tucatinib dose. 
 
Grade 4 (life-threatening consequences; 
 
urgent intervention indicated) 
Permanently discontinue tucatinib. 
Other adverse reactions 
 
 
Grade 3 
Hold tucatinib until recovery to ≤ Grade 1 or baseline 
Reduce tucatinib dose 
 
Grade 4 
Permanently discontinue tucatinib. 
 
Table 8: 
Dose modifications of tucatinib for LFT abnormalities, regardless of 
relationship to tucatinib* 
Laboratory Abnormality 
Tucatinib Dose Modification 
Bilirubin elevation >1.5–3 × ULN 
Hold tucatinib until recovery to ≤1.5 × ULN 
Resume tucatinib at same dose 
Bilirubin elevation >3–10 × ULN 
Hold tucatinib until recovery to ≤1.5 × ULN 
Reduce tucatinib dose. 
Bilirubin elevation >10 × ULN 
Permanently discontinue tucatinib. 
ALT or AST elevation >5–20 × ULN 
Hold tucatinib until recovery to ≤3 × ULN or return to 
baseline level in subjects with known liver metastasis 
Reduce tucatinib dose. 
ALT or AST elevation >20 × ULN 
Permanently discontinue tucatinib. 
ALT or AST elevation >3 × ULN AND  
bilirubin elevation >2 × ULN 
Permanently discontinue tucatinib. 
*If the LFT abnormalities are determined to be exclusively related to biliary obstruction, subjects may be 
allowed to continue on tucatinib following resolution of the obstruction and approval by the medical monitor.  
 

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5.3.2 Trastuzumab Dose Modifications 
In the event of Grade ≥3 trastuzumab-related AEs, hold trastuzumab until the AE has 
resolved to Grade ≤1 or pretreatment levels. Resume trastuzumab at the same dose; the 
trastuzumab dose may not be reduced. If the Day 1 dosing of trastuzumab is delayed by 
>1 week, the IV loading dose of 8 mg/kg should be given per approved dosing instructions. If 
dosing of trastuzumab is held for >6 weeks due to a treatment-related AE, medical monitor 
approval is required before restarting trastuzumab. 
Trastuzumab dose modification guidelines for left ventricular dysfunction and 
cardiomyopathy are presented in Section 5.3.2.1, for IRR in Section 5.3.2.2, and for 
hypersensitivity reactions in Section 5.3.2.3. 
5.3.2.1 Left Ventricular Dysfunction and Cardiomyopathy 
Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, 
disabling cardiac failure, cardiomyopathy, and cardiac death. Trastuzumab can also cause 
asymptomatic decline in LVEF. 
Trastuzumab dose modification guidelines for left ventricular dysfunction, regardless of 
relationship to study drug, are provided in Table 9. 
Table 9: 
Trastuzumab dose modification guidelines for left ventricular dysfunction 
LVEF at assessment 
Action 
Symptomatic CHF 
Discontinue trastuzumab  
LVEF ≥50%  
Continue treatment with trastuzumab  
LVEF 45% to <50% with <10% decrease from baseline  
Continue treatment with trastuzumab  
LVEF <45% or 45% to <50% with ≥10% decrease from baseline  Hold trastuzumab, repeat LVEF in 3 weeks 
 
Repeat LVEF at 3 weeks:  
 
 
 
- LVEF ≥50% 
Resume treatment with trastuzumab  
 
 
- LVEF 45% to 49% 
 
 
 
 
<10% decrease from baseline 
Resume treatment with trastuzumab  
 
 
 
≥10% decrease from baseline 
Discontinue trastuzumab  
 
 
- LVEF <45% 
Discontinue trastuzumab  
 
5.3.2.2 Infusion-related Reactions 
Symptoms of IRR occurring after trastuzumab administration include fever and chills, and on 
occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, 
dyspnea, hypotension, rash, and asthenia. In severe cases, symptoms have included 
bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, usually reported 
during or immediately following the initial infusion. However, the onset and clinical course 
are variable, including progressive worsening, initial improvement followed by clinical 
deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal 
events, death occurred within hours to days following a serious IRR. 

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Decrease the rate of infusion for mild or moderate infusion reactions. Interrupt trastuzumab 
infusion in all subjects experiencing dyspnea or clinically significant hypotension, and 
administer supportive therapy (which may include epinephrine, corticosteroids, 
diphenhydramine, bronchodilators, paracetamol, and oxygen). Subjects should be evaluated 
and carefully monitored until complete resolution of signs and symptoms. Subjects who 
experience infusion-related or injection-related symptoms may be pre-medicated with 
paracetamol and antihistamines for subsequent infusions/injections. 
Discontinue trastuzumab in subjects with severe or life-threatening IRRs. 
5.3.2.3 Hypersensitivity Reactions 
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 trastuzumab. 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. 
Any allergic/hypersensitivity reaction related to trastuzumab should be managed according to 
the product label and/or institutional standard of care. 
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 2017). 
If anaphylaxis occurs, administration of trastuzumab should be immediately and permanently 
discontinued. 
5.3.3 Fulvestrant Dose Modification 
For subjects who develop moderate hepatic impairment (Child-Pugh class B) on study, a 
discussion with the medical monitor is required. If the subject is approved by the medical 
monitor to continue on study, a dose reduction to fulvestrant 250 mg is required. 
5.4 Required Premedication and Postmedication 
Subjects who experience infusion-related or injection-related symptoms may be 
premedicated with paracetamol and antihistamines for subsequent infusions/injections. 

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5.5 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Cycle 1 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. 
5.5.1 Allowed Concomitant Therapy 
Subjects 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. All blood products and 
concomitant medications received from the first day of study treatment administration until 
30 days after the final dose of tucatinib and trastuzumab, whichever is later, or 8 weeks after 
the last dose of fulvestrant, if applicable, are to be recorded in the CRF. 
● 
During study treatment, subjects may receive supportive care, including 
bisphosphonates, hematologic and anti-infectious support, pain management, 
antacids, laxatives, and treatment of other newly diagnosed or concurrent medical 
conditions 
● 
Supportive care medications such as antidiarrheals and antiemetics are permitted. 
Prophylactic use of anti-diarrheals are permitted at the discretion of the investigator. 
Prophylactic and symptomatic treatment of nausea and vomiting may be used per 
standard-of-care 
● 
Thoracentesis or paracentesis may be performed, if needed for comfort 
● 
If surgical intervention or localized radiation become indicated (either for palliation 
or down-staging of previously nonresectable tumor). These concomitant procedures 
are permitted for non-target lesions only, in situations where other disease sites 
remain assessable per 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. 
● 
Blood products and growth factors should be utilized as clinically indicated. 
● 
Concomitant prednisone (or equivalent) may be used at a dose of ≤20 mg/day. 
● 
Routine prophylaxis with vaccines is permitted 
5.5.2 Prohibited Concomitant Therapy 
The following therapies are prohibited during the study (unless otherwise noted): 
● 
Investigational drugs and devices 
● 
Anticancer therapy, including but not limited to chemotherapy (fulvestrant is allowed 
for subjects with HR+ HER2-mutant breast cancer) 
● 
Radiation therapy, except for palliative radiotherapy at focal sites which are not 
considered target lesions per RECIST version 1.1, which may be given after 
consultation with the medical monitor. Radiation therapy directed at target lesions per 

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RECIST version 1.1 requires prior approval by the medical monitor. Tucatinib must 
be held 7 days prior to and 7 days after radiation therapy. 
● 
Strong inducers of CYP3A4 are prohibited as concomitant medications during study 
treatment and within 1 week of discontinuation of tucatinib (see APPENDIX D) 
● 
Strong inhibitors or inducers of CYP2C8 are prohibited as concomitant medications 
during study treatment; Strong inhibitors of CYP2C8 are also prohibited within one 
week of discontinuation of tucatinib (see APPENDIX E). Moderate inhibitors of 
CYP2C8 should be used with caution 
● 
Use of sensitive CYP3A substrates should be avoided 1 week prior to first dose of 
study treatment and during study treatment (see APPENDIX F). 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, 
increases digoxin concentrations, which may increase the risk for digoxin related 
adverse reactions. Concomitant use of tucatinib with digoxin or P-gp substrates with a 
narrow therapeutic index (such as, but not limited to, dabigatran, fexofenadine, and 
cyclosporine) should be used with caution. Refer to the prescribing information of 
digoxin or other P-gp substrates for dosage adjustment recommendations due to drug 
interactions. 
5.6 Management of Treatment-Emergent Adverse Events 
For management of IRRs, allergic/hypersensitivity reactions, and anaphylaxis, see 
Section 5.3.2.2 and Section 5.3.2.3. 
5.6.1 Management of Overdose 
In the event of an overdose of tucatinib, defined as any dose greater than the prescribed dose, 
study personnel should: 
● 
Care for and medically stabilize the subject 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, subject weight) 
and AEs, if any. 
Any AE associated with an overdose of study drug should be recorded on the AE electronic 
Case Report Form (eCRF) with the diagnosis of the AE. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Refer to the package insert for overdose information for trastuzumab and fulvestrant. 

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5.7 Treatment Compliance 
Study drug administration will be documented in source documents and the CRF. 
Tucatinib compliance will be assessed on a subject-by-subject basis using subject diaries and 
confirmed by pill counts. The pharmacist or designee will record the number of tucatinib 
tablets dispensed to each individual subject, and the number of tablets returned to the clinic at 
the end of each cycle. 
Data regarding the administration and dose of trastuzumab will also be collected by the site 
after each cycle. Data regarding the administration and dose of fulvestrant will also be 
collected by the site. Dose modifications and interruptions of any study drug will be 
documented in the source documents and the CRF. Following implementation of 
Amendment 5 and entry of remaining on-treatment subjects into the LTEP, treatment 
administration data will no longer be collected in CRFs. Refer to Section 8.2 for further 
details on LTEP data collection requirements. 
 

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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 7.6.1.2). Any study protocol-related AE (defined in 
Section 7.6.1.1) 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 or plasma chemistry panel and complete blood count 
[CBC] with differential), physical exam, weight, and performance status may be performed 
within 1 day prior to administration of study drug. The results from all relevant clinical 
laboratory assessments must be reviewed prior to dosing. 
Tumor biopsies performed during the study should be made available to the Sponsor if 
feasible (see Section 7.4). 
Subjects still receiving clinical benefit and remaining on study treatment as of Amendment 5 
may continue receiving study treatment during the LTEP. During this phase of the study, 
only pregnancies, SAEs, and AESIs 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. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. 
6.2 Screening Period 
6.2.1 Pre-screening (Up to 3 Months Before Screening Visit) 
If HER2 alterations have not been detected in pre-study assessments, subjects may consent to 
submit a blood sample for central assessment of HER2 alterations by NGS assay of ctDNA 
up to 3 months before the Screening visit (Pre-screening period). Subjects must be informed 
that HER2 testing consent is not informed consent for the study and participation in HER2 
testing does not guarantee study eligibility. 
● 
HER2 alterations testing consent 
● 
Submission of sample for HER2 testing: Blood sample for NGS assay of HER2 
amplification and mutations in ctDNA 
6.2.2 Screening Visit (Days –28 to 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
Height 
● 
Collection of archived tissue. If tumor blocks are not available, 20 freshly-cut slides 
may be submitted following approval by the medical monitor. The archival sample 
should be the most recent available 

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● 
Tumor lesion biopsy, if no archival tissue sample is available, a tumor lesion is 
available for biopsy, and the subject consents, once the subject has been approved for 
enrollment by the medical monitor 
● 
Blood sample for hepatitis B and C serology 
● 
12-lead electrocardiogram (ECG) 
● 
Echocardiogram or MUGA scan 
● 
Radiographic disease assessments will evaluate all known sites of disease, preferably 
using high quality spiral contrast computed tomography (CT) (with oral and/or IV 
contrast), and covering, at a minimum, the chest, abdomen, and pelvis. Positron 
emission tomography (PET)-CT scans (if high quality CT scan is included) and/or 
MRI scans may also be used as appropriate, as well as additional imaging of any 
other known sites of disease, but the same imaging modality as used at 
screening/baseline should be used throughout the study, unless otherwise clinically 
indicated. Subjects with breast or lung cancer will undergo contrast brain MRI. 
6.2.3 Baseline Visit (Days –7 to Day 1) 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Serum or urine β-hCG pregnancy test for subjects of childbearing potential (see 
Section 4.3) 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiratory rate) and weight 
● 
Physical exam 
● 
ECOG performance status 
● 
Blood samples for laboratory testing (as listed in Section 7.6.3): 
○ 
CBC with differential 
○ 
Serum or plasma chemistry panel 
6.3 Tucatinib and Trastuzumab Treatment Period (21-day cycles) 
6.3.1 Cycle 1 Day 1 
● 
EQ-5D-5L questionnaire (Section 7.5.1; to be completed prior to evaluation by study 
personnel [physical examination, review of AEs] and administration of study 
treatment) 
● 
Documentation of AEs 
● 
Documentation of concomitant medications 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiratory rate) and weight * 
● 
Physical exam * 
● 
ECOG performance status * 
● 
Blood samples for laboratory testing (as listed in Section 7.6.3; Results must be 
reviewed and eligibility confirmed prior to first dose): 
○ 
CBC with differential * 
○ 
Serum or plasma chemistry panel * 

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● 
Serum or urine β-hCG pregnancy test for subjects of childbearing potential (see 
Section 4.3); to be done within 24 hours predose for urine pregnancy tests or 72 hours 
for serum tests 
● 
Blood sample (predose) for NGS assay of ctDNA, if the subject did not undergo 
pre-screening. However, the blood sample does not need to be drawn if a pre-study 
NGS assay of cDNA has previously been obtained by the sponsor since the end of 
prior therapy 
● 
Dispense tucatinib and provide dosing diary to subject. Administer the first dose of 
tucatinib. (Subject will self-administer the remainder of doses during the treatment 
cycle and document in the diary) 
● 
Administer trastuzumab 8 mg/kg IV loading dose, unless trastuzumab IV was 
administered within the previous 4 weeks, in which case administer trastuzumab 
6 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.3.2 Cycles 1 and 2 Day 12 (-1 to +3 days) 
● 
Blood samples for laboratory testing (as listed in Section 7.6.3): 
○ 
CBC with differential * 
○ 
Serum or plasma chemistry panel * 
○ 
Documentation of AEs 
○ 
Documentation of concomitant medications 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.3.3 Cycles >1 Day 1 (-1 to +3 days) 
● 
Day 1 of every second cycle from Cycle 2: EQ-5D-5L questionnaires (Section 7.5.1); 
to be completed prior to evaluation by study personnel (physical examination, review 
of AEs) and administration of study treatment 
● 
Documentation of AEs 
● 
Documentation of concomitant medications 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiratory rate) and weight * 
● 
Physical exam * 
● 
ECOG performance status * 
● 
Blood for laboratory testing (as listed in Section 7.6.3): 
○ 
CBC with differential * 
○ 
Serum or plasma chemistry panel * 
○ 
Serum or urine β-hCG pregnancy test for subjects of childbearing potential (see 
Section 4.3); to be done within 7 days prior to study drug dosing. Pregnancy 
testing will continue every 3 weeks for subjects of child-bearing potential during 
the LTEP. 

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● 
Cycles 2 to Cycle 6: Tucatinib predose PK samples (see Section 7.3) 
● 
Cycle 3: Tucatinib PK sample 1 to 4 hours after the tucatinib dose 
● 
Review subject diary and pill count for tucatinib drug compliance from previous 
cycle, dispense tucatinib, and administer the first dose. (Subject will self-administer 
the remainder of doses during the treatment cycle and may document 
self-administration in the diary.) 
● 
Administer trastuzumab 6 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.3.4 Every 6 Weeks as Determined by Cycle 1 Day 1, through Week 24, then 
Every 12 Weeks (±7 days) 
● 
High-quality spiral contrast CT (preferred); PET/CT (if high quality CT scan is 
included), and/or MRI scan, as appropriate (see Section 7.2). The same imaging 
modality as used at screening/baseline should be used throughout the study. In 
subjects with lung cancer, scans of the pelvis do not need to be undertaken after the 
screening assessment unless lesions were detected at screening, or as clinically 
indicated. Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks 
after first documentation of response. The schedule for response assessments should 
not be adjusted after the confirmatory scan (eg, CR at Week 6, confirmatory scans at 
Weeks 10–12, next assessment due at Week 12). Tumor imaging should also be 
performed whenever disease progression is suspected. 
● 
Subjects with known or suspected brain lesions should undergo contrast brain MRIs 
during treatment and follow-up according to the same assessment schedule as for 
other disease assessments. 
● 
If an interim unscheduled 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 timepoint may not need to be 
repeated if medically contraindicated, as approved by the medical monitor 
6.3.5 Every 12 Weeks (±14 days) 
● 
Echocardiogram or MUGA scan, using the same cardiac testing modality performed 
in Screening/Baseline. Scheduling is determined by date of most recent screening or 
on treatment echocardiogram/MUGA. 
6.4 Fulvestrant Treatment Period (if applicable) 
● 
For subjects with HR+ HER2-mutant breast cancer, administer fulvestrant 500 mg IM 
once every 4 weeks starting from Cycle 1 Day 1, as well as on Cycle 1 Day 15. 
6.4.1 Cycle 1 Day 1 
● 
Administer fulvestrant 500 mg IM. 

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6.4.2 Cycle1 Day 15 (±1 day) 
● 
Administer fulvestrant 500 mg IM. 
6.4.3 Every 4 weeks after Cycle 1 Day 1 (±3 days) 
● 
Administer fulvestrant 500 mg IM. 
6.5 End of Treatment Visit (30 to 37 days after last dose of study drug) 
● 
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of study 
drug unless delayed due to an AE. Note: The time to EOT visit may be longer than 
37 days, but in no case should it be <30 days. However, EOT evaluations must be 
performed before initiation of a new therapy. If EOT evaluations are completed 
before 30 days after the last study treatment, the subject will be contacted 30 to 
37 days following the last treatment to assess for AEs. For subjects who have 
received fulvestrant, the EOT visit should be undertaken no sooner than 8 weeks after 
the last dose of fulvestrant. 
● 
EQ-5D-5L questionnaire (Section 7.5.1); to be completed prior to evaluation by study 
personnel (physical examination, review of AEs) and administration of study 
treatment 
● 
Documentation of AEs 
● 
Documentation of concomitant medications 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiratory rate) and weight 
● 
Physical exam 
● 
ECOG performance status 
● 
Blood samples for laboratory testing (as listed in Section 7.6.3): 
○ 
CBC with differential 
○ 
Serum or plasma chemistry panel 
● 
12-lead ECG 
● 
Echocardiogram or MUGA scan, using the same cardiac testing modality performed 
in Screening/Baseline. Not required if an echocardiogram or MUGA scan was done 
within the previous 12 weeks (excluding the Screening/Baseline assessment). 
● 
Serum or urine β-hCG pregnancy test for subjects of childbearing potential (see 
Section 4.3) 
● 
Blood sample for biomarker analysis 
● 
Only in subjects who discontinue study treatment for reasons other than radiographic 
disease progression per RECIST version 1.1: High-quality spiral contrast CT 
(preferred); PET/CT (if high quality CT scan is included), and/or MRI scan, as 
appropriate (see Section 7.2). The same imaging modality as used at 
screening/baseline should be used throughout the study, unless otherwise clinically 
indicated. Not required if imaging was performed within 30 days of discontinuing 
study treatment. 

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● 
Review subject diary and pill count for tucatinib drug compliance from previous 
cycle, if tucatinib was administered in the last cycle 
● 
For persons of childbearing potential: Remind subject that monthly pregnancy tests 
should be performed for 7 months after the last dose of trastuzumab and, if 
applicable, for 2 years after the last dose of fulvestrant. Testing may be performed at 
home. If performed at home, site staff will contact the subject monthly to confirm 
testing was performed and obtain pregnancy test results. 
6.6 Follow-up 
Subjects who discontinue study treatment will remain on study for follow-up until 
withdrawal from the study. A subject may discontinue study treatment without withdrawing 
from the study (Section 4.4). If a subject discontinues study treatment, every attempt should 
be made to follow the subject until death or administrative study closure. 
6.6.1 Disease Progression Follow-up (Every 6 Weeks as Determined by 
Cycle 1 Day 1, through Week 24, then Every 12 Weeks [±7 days]) 
For subjects who discontinue study treatment prior to disease progression (per RECIST 
version 1.1), the following assessments must be undertaken at least every 6 weeks (±7 days) 
until 24 weeks from treatment initiation then every 12 weeks, until investigator-assessed 
disease progression (per RECIST version 1.1), death, withdrawal of consent, lost to 
follow-up, or study closure: 
● 
High-quality spiral contrast CT (preferred); PET/CT (if high quality CT scan is 
included), and/or MRI scan, as appropriate (see Section 7.2). The same imaging 
modality as used at screening/baseline should be used throughout the study, unless 
otherwise clinically indicated. 
6.6.2 Survival Follow-up (Every 12 Weeks from EOT [±14 days]) 
Once subjects have discontinued study treatment, they will undergo long-term survival 
follow-up every 12 weeks (±14 days) from the EOT visit, until death, withdrawal of consent, 
or study closure. The following information is to be collected: 
● 
Subject contact or in-person assessment of OS and/or disease recurrence, as well as 
collection of information regarding any additional anticancer therapies administered 
after completion of study treatment. Review of medical records, public records, or 
other public platforms may be used to obtain this information if reasonable efforts to 
contact the subject are unsuccessful. 
● 
Echocardiogram/MUGA assessments should be undertaken every 6 months for at 
least 2 years following trastuzumab discontinuation. 
● 
For persons of childbearing potential (for 7 months after the last dose of 
trastuzumab): 
○ 
Confirm with the subject that monthly pregnancy tests have been performed and 
have been negative 

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○ 
Remind subject that monthly pregnancy tests should be performed for 7 months 
after the last dose of trastuzumab 
More frequent long-term follow-up may be conducted as needed for OS event tracking. 
6.6.3 Long-term Extension Phase (LTEP) 
As of Amendment 5, subjects still receiving clinical benefit and remaining on treatment may 
continue receiving study drug during the LTEP. During this phase of the study, only 
pregnancies, SAEs, and AESIs 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 subjects of child-bearing potential. 
6.7 Subject End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 

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7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Screening/Baseline assessments will be conducted to establish study baseline status and 
determine study eligibility. Only subjects who meet all inclusion and exclusion criteria 
specified in Section 4 will be enrolled in this study. 
Subject medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications. 
The following assessments are required for all subjects at screening and/or baseline as 
described in Section 6.2.2, and the Schedule of Events: physical exam, height, vital signs, 
weight, ECOG performance status, CT with contrast/PET-CT/MRI scan for baseline disease 
assessment, CBC with differential, serum or plasma chemistry panel, 12-lead ECG, 
echocardiogram or MUGA, hepatitis B and C screening, and serum or urine β-hCG 
pregnancy test (for females of childbearing potential). 
Blood and tissue samples will be collected for biomarker assessments (see Table 10). 
7.2 Response/Efficacy Assessments 
Disease response to study treatment and the occurrence of disease progression will be 
determined according to RECIST version 1.1 (Eisenhauer 2009) (Appendix C), as assessed 
by the investigator. Radiographic scans and additional imaging assessments (if applicable) 
will be performed at protocol-specified time points outlined in Section 6 and Schedule of 
Events. Clinical management decisions will be based on local investigator assessment. 
Images will be collected by an independent central review (ICR) facility for possible future 
analysis. Copies of tumor images must 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. 
Disease assessments will be performed at screening/baseline, and every 6 weeks for the first 
24 weeks then every 12 weeks, irrespective of dose holds or interruptions. Subjects that 
discontinue study treatment for reasons other than documented progressive disease or death, 
will continue to have disease assessments at least every 6 weeks until 24 weeks after 
treatment initiation then every 12 weeks, until the occurrence of documented disease 
progression per RECIST version 1.1, death, withdrawal of consent, lost to follow-up, or 
study closure. 
Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks after first 
documentation of response. The schedule for response assessments should not be adjusted 
after the confirmatory scan (eg, CR at Week 6, confirmatory scans at Weeks 10–12, next 
assessment due at Week 12). Tumor imaging should also be performed whenever disease 
progression is suspected. 

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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 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 contrast is 
contraindicated (ie, in subjects 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 should be used to assess additional 
known sites of disease. The same imaging modality as used at screening/baseline should be 
used throughout the study, unless otherwise clinically indicated. In subjects with lung cancer, 
scans of the pelvis do not need to be undertaken after the screening assessment unless lesions 
were detected at screening, or as 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. Tumor lesions 
situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, 
are not considered measurable unless there has been demonstrated progression of the lesion. 
In subjects with breast or lung cancer, a contrast MRI scan of the brain should be performed 
at screening. Subjects with known or suspected brain lesions should undergo contrast brain 
MRIs during treatment and follow-up according to the same assessment schedule as for other 
disease assessments. 
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 subject safety, all efforts 
should be made to continue the subject until unequivocal radiologic progression is 
documented or the investigator determines clinical progression has occurred. Demonstration 
of an unequivocal new lesion constitutes disease progression. 
Subjects’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee) upon request. Refer to the 
Study Manual for instructions on collecting and submitting tumor imaging studies to the ICR. 
During the LTEP, efficacy assessments will be performed per institutional guidelines and 
investigator-determined usual and customary clinical care. 
7.3 Pharmacokinetic Assessments 
In all subjects, blood samples will be collected for assessment of trough tucatinib 
concentrations on Day 1 of Cycles 2 to 6 prior to administration of tucatinib. On Day 1 of 
Cycle 3, a blood sample will be collected 1 to 4 hours after administration of tucatinib for 
assessment of peak levels of tucatinib concentrations (Table 10). 
Trough PK samples should continue to be collected on schedule regardless of dose holds or 
interruptions. The Day 1 Cycle 3 post-dose sample should not be collected during dose hold 

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or interruptions. Plasma concentrations of tucatinib will be determined using validated liquid 
chromatography (LC)-mass spectrometry (MS)/MS methods. 
Table 10: 
Pharmacokinetic and biomarker sample collection timepoints 
Visit 
Study day  
Time 
Window Relative Time 
Blood Samples 
FFPE Tumor  
PK 
NGS assay 
of ctDNA  
Specimen 
Pre-screening -3 months to 
-29 days 
N/A 
N/A 
N/A 
 
X 
 
Screening/ 
baseline 
-28 to 1 
N/A 
N/A 
N/A 
 
 
Xa 
Cycle 1 
Day 1 
Predose 
N/A 
Time of administration 
of tucatinib 
 
Xb 
 
Cycle 2 
Day 1  
Predose 
Within  
2 hours 
Time of administration 
of tucatinib 
X 
 
 
Cycle 3  
Day 1 
Predose 
Within  
2 hours 
Time of administration 
of tucatinib 
X 
 
 
Post-dose Within  
1-4 hours 
Post-dose of tucatinib 
X 
 
 
Cycles 4, 5, 
and 6 
Day 1 
Predose 
Within  
2 hours 
Time of administration 
of tucatinib 
X 
 
 
End of Treatment 
 
X 
 
FFPE=formalin-fixed paraffin-embedded. 
a 
Tumor tissue sample is to be collected once the subject has been approved for enrollment by the medical monitor. If 
archived tissue is not available, a new biopsy of a tumor lesion should be obtained, if there is a lesion available for 
biopsy and the subject consents. Subjects with no archival tissue, and whose tumors are considered not accessible or 
appropriate for biopsy are eligible for enrollment, following approval by the medical monitor. 
b 
If not obtained during pre-screening, and if a pre-study NGS assay of ctDNA has not previously been performed by the 
sponsor since the end of prior therapy. 
 
7.4 Biomarker Studies 
See Table 10 for the schedule of biomarker assessments. 
7.4.1 Evaluation of HER2 Status 
Study eligibility requirements for HER2 overexpressing/amplified disease and 
HER2-mutated disease are to be met by assays performed pre-study (assessments undertaken 
prior to any study-related activities) or in pre-screening (Table 11), as follows: 
• Previously established HER2 alterations: HER2 eligibility can be demonstrated via HER2 
overexpression or amplification in an IHC/ISH assay of tumor tissue or HER2 
amplification or activating mutations in an NGS assay of ctDNA or tumor tissue, 
processed locally in a CLIA- or ISO-accredited laboratory before enrollment in the study.  
• Pre-screening for HER2 alterations: if HER2 alterations have not been detected in 
pre-study assessments, HER2 eligibility may alternatively be established during 
pre-screening, up to 3 months prior to the Screening visit, via an NGS assay of ctDNA 
evaluating the presence of HER2 amplification or mutations. 

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Additional biomarker analyses: For the evaluation of the exploratory biomarker objectives, 
all subjects will provide a blood sample for NGS assay of ctDNA and archival tumor tissue 
or a fresh tumor biopsy, if available. The blood sample will be collected during pre-screening 
or on Cycle 1 Day 1, if not collected during pre-screening. However, the blood sample does 
not need to be drawn if a pre-study NGS assay of ctDNA has previously been performed by 
the sponsor since the end of prior therapy. The tumor tissue sample will be collected during 
screening, once the subject has been approved for enrollment by the medical monitor.  
If eligibility is determined by local testing, information concerning the local test, such as the 
test name, methodology/technology used, device description, specimen type used, will be 
collected in the eCRF. Other available characteristics should be retained and made available 
to the sponsor on request. 
Table 11: 
Timing of prospective assays used to determine HER2 status for eligibility 
HER2 assay 
 
Visit 
 
 
Pre-study 
Pre-screening 
Screening 
NGS assay showing HER2 
alterations in ctDNA 
If done pre-study and  
test is positive 
If not done pre-study 
Not done 
IHC/ISH assay showing HER2 
overexpression in tissue 
If done pre-study and  
test is positive 
Not done 
Not done 
NGS assay showing HER2 
alterations in tissue 
If done pre-study and  
test is positive 
Not done 
Not done 
Pre-study refers to all HER2 assessments undertaken prior to any study-related activities. 
 
Testing of HER2 amplification and mutation in ctDNA will be done using a CLIA-certified 
liquid blood-based NGS assay. HER2 expression in tissue will be evaluated using IHC and 
FISH, according to either the American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) 2018 guideline “HER2 Testing in Breast Cancer” or the 
ASCO/CAP 2016 guideline “HER2 Testing and Clinical Decision Making in 
Gastroesophageal Adenocarcinoma”, using an FDA-approved test for breast cancer or GEC 
(Bartley 2017; Wolff 2018). Testing of HER2 amplification and mutation in tissue will be 
done using an FDA-approved tissue-based NGS assay for HER2 in breast cancer. The list of 
acceptable known activating mutations are detailed in the inclusion criteria (Section 4.1). As 
specified, subjects with exon 20 insertions in HER2 are eligible. Subjects with HER2 
activating mutations not listed in the inclusion criteria may be eligible, if supported by 
scientific literature and approved by the medical monitor. 
In all subjects, the most recent archival tumor block is to be collected during the screening 
visit, once the subject has been approved for enrollment by the medical monitor. If tumor 
blocks are not available, 20 freshly-cut slides may be submitted, following approval by the 
medical monitor (if 20 slides are not available, consultation with the medical monitor is 
required). If archival samples are not available, a fresh biopsy from a lesion that has not been 
previously irradiated should be undertaken, if the subject consents. Subjects are still eligible 
if archival or fresh tumor tissue samples cannot be obtained, following approval by the 
medical monitor. Additionally, tumor biopsies performed while the subject is on study should 

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be made available to the Sponsor if feasible. For example, if a biopsy on residual tumor is 
performed at the end of treatment or at progression, a sample will be collected (if available). 
Tissue samples obtained via resection, excision, punch (skin lesions only), or core needle 
from a tumor site are suitable for testing. Fine needle aspiration, brushing, cell pellets from 
pleural effusion, forceps, and lavage samples are not acceptable. Tumor tissue should be of 
good quality based on total and viable tumor content; eg, samples should contain a minimum 
of 100 tumor cells that preserve cellular context and tissue architecture, regardless of the 
needle gauge used to collect the sample or the retrieval method. See the Laboratory Manual 
for details concerning tissue samples. 
See the Central Laboratory Manual for more details. 
7.4.2 Other Biomarker Assessments 
Biomarker assessments will be performed in peripheral blood and tumor tissue as specified in 
this section and Table 10. The assessments will be used to determine the concordance of 
HER2 alterations as detected by tissue and blood-based HER2 testing methodologies. In 
addition, they are to be used to identify tumor-specific alterations that are associated with 
resistance to tucatinib. Assays may include NGS, IHC, and ISH. These assessments may 
provide insights into treatment-related changes associated with tucatinib. 
7.4.3 Biospecimen Repository 
In the US only, for subjects who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seagen and used for future research, including but not 
limited to the evaluation of targets for novel therapeutic agents. 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. 
7.5 Patient-Reported Outcomes 
The EQ-5D-5L questionnaires will be administered according to the schedule specified in 
Schedule of Events and Section 6.3, until the EOT visit. The questionnaire will be 
administered to subjects in their local language, if available. The objective is to evaluate 
improvements, deteriorations, and stabilization in HRQoL by cohort. 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. 
7.5.1 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 HRQoL outcomes that can be used in a wide range of 
health conditions and treatments (van Agt 1994). The EQ-5D-5L consists of a descriptive 
system questionnaire and the EuroQol visual analog scale (VAS; APPENDIX G). 

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The descriptive system questionnaire assesses 5 dimensions of health, including mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. The scores on these 
5 dimensions can be presented as a health profile or can be converted to a single summary 
index number (utility) reflecting preference compared to other health profiles. The EQ VAS 
records the subject’s self-rated health status on a vertical VAS ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state). The recall period is the day in 
which the questionnaire is administered. 
7.6 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication, and measurements 
of protocol-specified physical examination findings and laboratory tests. 
Only pregnancies, SAEs, and AESIs 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 subjects of child-
bearing potential. 
7.6.1 Adverse Events 
7.6.1.1 Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, 
Investigational New Drug (IND) Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject 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 Cycle 1 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 Cycle 1 Day 1 that 
increase in NCI CTCAE grade should be recorded. 
● 
Medical conditions present or ongoing predose on study Cycle 1 Day 1 that worsen in 
severity, increase in frequency, become related to study drug, or worsen in any other 
way but do not meet the threshold for increase in NCI CTCAE grade should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Cycle 1 Day 1 (during and post-dose) through the end of the safety reporting period 

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(see Section 7.6.1.2). 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”). 
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 subject at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study or routine 
check-ups are not SAEs by this criterion. Admission to a palliative unit or hospice 
care facility is not considered to be a hospitalization. Hospitalizations or prolonged 
hospitalizations for scheduled therapy of the underlying cancer or study target 
disease need not be captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or substantial 
disruption of the subject’s ability to conduct normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a subject 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 
subject 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 below for the definition of potential 
DILI.) 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 5. 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 drug (tucatinib and trastuzumab) should be 
evaluated by the investigator using the following criteria: 

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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) 
● 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 
Overdose, Medication Error, Misuse, and Abuse  
Overdose is defined as the administration of a quantity of study treatment given per 
administration or cumulatively which is above the maximum dose, according to the protocol. 
Medication error refers to an unintentional error in dispensing or administration of the study 
treatment not in accordance with the protocol.  
Misuse is defined as any situation where the study treatment is intentionally and 
inappropriately used not in accordance with the protocol.  
Abuse is defined as the persistent or sporadic intentional excessive use of the study 
treatment, which is accompanied by harmful physical or psychological effects.  
Overdoses, medication errors, abuse, or misuse will be collected as part of study treatment 
dosing information and/or as a protocol violation, as required. Any AE associated with an 
overdose, medication error, misuse, or abuse of study drug should be recorded on the AE 
CRF with the diagnosis of the AE. Overdose per se will not be reported as an AE/SAE, 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. Such 
overdoses should be reported regardless of sequelae. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during 
subject questioning, discovered during physical examination, laboratory testing and/or other 
means by recording them on the CRF and/or SAE form, as appropriate.  
During the LTEP, pregnancies, SAEs, and AESIs will be reported to the sponsor using 
SAE/pregnancy report forms 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: 

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● 
Description including onset and resolution dates 
● 
Whether it met SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug. Record each sign or symptom as an individual AE in addition to the IRR term. If 
multiple signs or symptoms occur with a given infusion-related event, each sign or symptom 
should be recorded separately with its level of severity. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
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. 
● 
During the LTEP, SAEs will be reported to the Sponsor solely on the SAE form and 
will not be recorded within the CRF, following the same reporting guidelines as 
outlined in this section. 
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. 

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Pregnancy 
Notification to Drug Safety 
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 7 months after the last dose of tucatinib and trastuzumab, whichever is later, 
or 2 years after the last dose of fulvestrant, if applicable, including any pregnancies that 
occur in the partner of a study subject who is able to father a child. Only report pregnancies 
that occur in a subject’s partner if the estimated date of conception is after the subject’s first 
study drug dose. Email or fax to the sponsor’s Drug Safety Department within 48 hours of 
becoming aware of a pregnancy. All pregnancies will be monitored for the full duration; all 
perinatal and neonatal outcomes should be reported. Infants should be followed for a 
minimum of 8 weeks. 
Collection of data on the CRF 
All pregnancies (as described above) that occur within 30 days of the last dose of study 
drug(s), or, if applicable, within 8 weeks of last dose of fulvestrant, will also be recorded on 
the Adverse Events CRF. Pregnancies that occur during the LTEP will be reported using the 
Pregnancy Report Form and will not be recorded within the CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.6.1.1) should be reported as SAEs. 
Potential Drug-Induced Liver Injury 
Hy’s Law can be used to estimate severity and the likelihood that a study drug may cause an 
increased incidence of severe hepatotoxicity. 
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 × ULN 
AND 
2. Total bilirubin >2 × ULN, without initial findings of cholestasis (ie, elevated serum or 
plasma 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. 

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Reporting Requirements 
Any potential Hy’s Law case should be handled as an 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 or plasma ALT or AST to >3 × ULN should be followed by 
repeat testing within 48 to 72 hours of serum or plasma ALT, AST, alkaline phosphatase, and 
total bilirubin, to confirm the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. During this investigation, consider 
withholding study drug. 
Left Ventricular Ejection Fraction Decreased 
For asymptomatic declines in LVEF leading to a change in study treatment or 
discontinuation of study treatment, the term “ejection fraction decreased” should be used, and 
severity Grades 2 to 4 used to report asymptomatic LVEF decrease. 
For symptomatic CHF, the term “heart failure” should be used, and severity Grades 2 to 5 
used to report symptomatic CHF. 
7.6.1.2 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Cycle 1 Day 1 (predose) 
through 30 days after the last dose of tucatinib or trastuzumab, whichever is later, or 8 weeks 
after the last injection of fulvestrant, if applicable. However, all study protocol-related AEs 
are to be recorded from the time of informed consent. All SAEs that occur after the safety 
reporting period and are considered study treatment-related in the opinion of the investigator 
should also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the subject dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure. 
7.6.1.3 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 

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● 
Subject number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
● 
Investigator causality assessment 
 
The completed SAE form is to be emailed or faxed to the sponsor’s Drug Safety Department 
within 24 hours (see email or fax number specified on the SAE report form), unless 
otherwise instructed on the Sponsor’s SAE form. 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.6.1.4 Adverse Events of Special Interest 
An AESI can be any serious or nonserious AE that is of scientific or medical concern as 
defined by the sponsor and specific to the program, for which ongoing monitoring and rapid 
communication to the sponsor may be appropriate. 
AESIs need to be reported to the sponsor irrespective of regulatory seriousness criteria or 
causality within 24 hours (Section 7.6.1.3).  
During the LTEP, AESIs will be reported to the sponsor using an SAE form only and will not 
be recorded within the CRF. 
AESIs for this study are: 
● 
Hepatotoxicity: either of the following types of LFT elevation: 
○ 
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 
subjects with documented Gilbert’s syndrome 
○ 
AST or ALT elevations >20 × ULN 
○ 
Bilirubin elevations >10 × ULN 
Measurement of conjugated and unconjugated bilirubin should be considered in cases of 
hyperbilirubinemia to assist in determination of its etiology. The sponsor will subsequently 
determine whether the elevations are associated with other possible causes of 
aminotransferase elevation and hyperbilirubinemia, such as viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
7.6.2 Vital Signs 
Vital signs measures are to include heart rate, systolic and diastolic blood pressure, 
respiratory rate, and temperature. 

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7.6.3 Clinical Laboratory Tests 
Samples will be drawn for local labs. Local laboratory testing will include the following 
institutional standard tests for evaluating safety and making clinical decisions: 
● 
The chemistry panel is to include the following tests: ALT, AST, alkaline 
phosphatase, total bilirubin (and direct bilirubin when total bilirubin is > ULN), 
albumin, bicarbonate (if available), blood urea nitrogen, magnesium, phosphorus, 
calcium, chloride, glucose, potassium, sodium, total protein, creatinine 
● 
The CBC with differential is to include the following tests: hemoglobin, hematocrit, 
platelet count, red blood cell count, and white blood cell count with differential 
(lymphocytes, and neutrophils) 
● 
The estimated GFR should be calculated using the MDRD equation as applicable, 
with serum or plasma creatinine reported in mg/dL.  
GFR (mL/min/1.73 m²) = 175 x (Serum or plasma creatinine)-1.154 x (Age)-0.203 x  
 
 
 
      (0.742 if female) x (1.212 if African American) 
● 
In subjects with baseline GFR <50 mL/min/1.73 m², cystatin C will be evaluated at 
baseline and whenever serum or plasma creatinine is evaluated 
● 
Hepatitis B surface antigen, antibodies to hepatitis B core, and antibodies to hepatitis 
C are to be assessed. If hepatitis C serology is positive, hepatitis C virus RNA test by 
polymerase chain reaction is required to confirm. If the hepatitis B core antibody is 
positive, and there is no evidence of long-term immunity, a hepatitis B virus DNA 
test by polymerase chain reaction is required to confirm.     
● 
Serum or urine β-hCG pregnancy tests for subjects of childbearing potential 
 
Following implementation of Amendment 5, 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 continue every 3 weeks for subjects of 
child-bearing potential. 
7.6.4 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. For adult subjects only, 
measurements of height obtained within the prior 12 months may be utilized. 
7.6.5 Pregnancy Testing 
For subjects of childbearing potential, a serum or urine β-hCG pregnancy test with sensitivity 
of at least 25 mIU/mL will be performed at baseline, at Cycle 1 Day 1 (within 24 hours 
predose for urine pregnancy tests or 72 hours for serum tests), within 7 days prior to Day 1 of 
each treatment cycle starting from Cycle 2, and at the EOT visit. A negative pregnancy result 
is required before the subject may receive study drug. Pregnancy tests will be performed 
once a month for 7 months after the last dose of any study drug, and for 2 years after the last 
dose of fulvestrant, if applicable. Subjects may do monthly home pregnancy tests and report 

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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 and will be collected by the Sponsor 
using the Pregnancy Report Form. See Section 7.6.1.1 for further details on pregnancy 
reporting requirements. 
7.6.6 Cardiac Function 
7.6.6.1 MUGA or Echocardiogram 
Assessment of cardiac ejection fraction will be performed by MUGA scan or echocardiogram 
at screening and at least once every 12 weeks thereafter until treatment discontinuation, and 
at the EOT visit (unless done within 12 weeks prior to the EOT Visit, excluding 
screening/baseline assessment). If there is an interim assessment, subsequent echocardiogram 
or MUGA should be performed every 12 weeks as determined by the date of the most recent 
interim assessment. Echocardiogram/MUGA assessments should also be undertaken every 
6 months for at least 2 years following trastuzumab discontinuation. 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. 
7.6.6.2 Electrocardiogram 
ECGs (12-lead) will be performed at baseline and at the EOT visit. To correct for heart rate, 
corrected QT intervals (QTc) should be calculated using the Fridericia formula. 
During the LTEP, ECG assessments will be performed per institutional guidelines and 
investigator-determined usual and customary clinical care. 
7.7 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Response will be assessed according to RECIST version 1.1 (Eisenhauer 2009), which are 
standardized criteria for evaluating response in solid tumors. The intervals of evaluation in 
this protocol are considered appropriate for disease management. 
The EQ-5D-5L is a validated instrument for use as a measure of HRQoL (Janssen 2013). 
This PRO has been incorporated into previous clinical trials that seek to quantify the HRQoL 
in subjects. 

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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 subjects at the site, Seagen or its designated clinical and 
medical personnel will review the following items with the investigator and clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/package insert 
● 
Recording and reporting AEs and SAEs 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
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 
● 
Subject coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seagen 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 subjects, 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 suitable for inspection 
by Seagen or its designated monitors and by quality assurance auditors, or representatives of 
regulatory authorities. 
8.2 Data Management Procedures 
Seagen will provide CRF Completion Guidelines for eCRF data entry. Study specific data 
management procedures will be maintained in the data management plan. Queries resulting 
from edit checks and/or data verification procedures will be posted electronically in the 
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Following implementation of Amendment 5 and entry of remaining on-treatment subjects 
into the LTEP, data will no longer be collected in CRFs. Only pregnancies, SAEs, and AESIs 
will be collected by the Sponsor during the LTEP, utilizing the Pregnancy Report Form and 
SAE form (for both SAEs and AESIs). See Section 7.6.1.1 for further details on pregnancy, 
SAE, and AESI reporting requirements. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect subject confidentiality are to be employed 
during monitoring. The CRFs and related source documents will typically be reviewed in 
detail by the monitor at each site visit. Original source documents or certified copies are 
needed for review. This review includes inspection of data acquired as a requirement for 
participation in this study and other medical records as required to confirm that the 
information collected is correct. Other study records, such as correspondence with the 
sponsor and the IRB/IEC and screening and drug accountability logs will also be inspected. 
All source data and study records must also be available for inspection by representatives of 
regulatory authorities and the IRB/IEC. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
● 
During the LTEP, CRFs will not be collected. 
8.5 Quality Assurance Procedures 
The Research and Development Quality group or its designee may conduct audits at the 
clinical site or other study-related facilities and organizations. Audit reports will be retained 
by the Research and Development Quality group of Seagen as part of the written record. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 

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Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
Electronic patient-reported outcomes (ePRO) instruments and/or electronic patient diaries 
(eDiary) may be utilized. If any of these instruments are utilized, the data will be transmitted 
to the eCRF from those instruments. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by Seagen, whichever is longer. The investigator must 
contact Seagen prior to destroying any records associated with the study. If the investigator 
withdraws from the study (due to relocation, retirement, etc.), the records shall be transferred 
to a mutually agreed upon designee, such as another investigator or IRB/IEC. Notice of such 
transfer will be provided in writing to Seagen. 

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9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
For cohorts that will have interim futility analysis (Cohorts 1 to 5 and 7), up to 
12 response-evaluable subjects will be enrolled in Stage 1. Cohorts that successfully pass the 
interim analysis for futility (see Section 9.3.11) may, at the sponsor’s decision, continue to 
enroll up to an additional 18 response-evaluable subjects, totaling up to 
30 response-evaluable subjects for each tumor cohort. 
Cohorts 6, 8, and 9 will each enroll 30 response-evaluable subjects without an interim 
analysis. 
Approximately 162 to 270 subjects may be enrolled in the study. This is comprised of up to 
approximately 12 to 30 subjects in each of Cohorts 1 to 5 and Cohort 7, and up to 
approximately 30 subjects in each of Cohorts 6, 8, and 9. Additional subjects may be enrolled 
if optional cohorts are opened. 
If a sufficient number of subjects with a particular tumor type are enrolled in Cohorts 6 or 9, 
the sponsor may evaluate that tumor type in a separate cohort, drawn from optional 
Cohorts 10 to 15. If any optional cohort is opened, all subjects enrolled in Cohorts 6 or 9 with 
the applicable tumor type will be reassigned to the new tumor-specific cohort and will not 
count towards the sample size of Cohorts 6 and 9. 
For a sample size of 30 subjects, assuming confirmed ORR is between 10% and 30%, the 
2-sided 90% exact CIs are summarized below: 
Confirmed ORR 
90% Exact CI (N=30) 
10% 
(3%, 24%) 
20% 
(9%, 36%) 
30% 
(17%, 47%) 
 
9.2 Study Endpoint Definitions 
9.2.1 Objective Response Rate 
ORR is defined as the proportion of subjects with best overall response of confirmed CR or 
confirmed PR per investigator assessment according to RECIST version 1.1. Only response 
assessments before first documented disease progression or new anticancer therapies will be 
considered. ORR per ICR may be evaluated in selected cohorts. 
9.2.2 Duration of Response 
DOR is defined as the time from first documentation of objective response of confirmed CR 
or confirmed PR to the first documentation of disease progression per RECIST version 1.1 or 
death from any cause, whichever occurs first. Only subjects with an objective response will 
be included in the analysis of DOR. DOR per ICR may be evaluated in selected cohorts. 

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9.2.3 Disease Control Rate 
DCR is defined as the proportion of subjects with confirmed CR, confirmed PR, or stable 
disease (SD or non-CR/non-progressive disease) according to RECIST version 1.1. DCR per 
ICR may be evaluated in selected cohorts. 
9.2.4 Progression-free Survival 
PFS is defined as the time from the date of treatment initiation to the date of disease 
progression according to RECIST version 1.1 or death from any cause, whichever occurs 
first. Subjects 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, SD, or 
non-CR/non-progressive disease. If there is no radiographic post-baseline tumor assessment, 
PFS will be censored at the date of treatment initiation. PFS per ICR may be evaluated in 
selected cohorts. 
Detailed methodology, including handling rules for missing assessments and censoring 
approaches for the analysis of PFS, is provided in the statistical analysis plan (SAP). 
9.2.5 Overall Survival 
OS is defined as the time from treatment initiation to death due to any cause. For a subject 
who is not known to have died by the end of study follow-up, observation of OS is censored 
on the date the subject was last known to be alive (ie, the date of last contact). Subjects 
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 Pharmacokinetic Analysis 
PK parameters will be calculated using non-compartmental analysis for tucatinib. 
9.2.7 Exploratory Endpoints 
9.2.7.1 Biomarker Analysis 
Relationships of biomarkers to antitumor activity may be evaluated. 
9.2.7.2 Patient-Reported Outcomes 
Changes in HRQoL will be measured based on PROs according to 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. A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters site conduct (eg, adding baseline assessments 
to define a subgroup). The SAP will be finalized prior to the first interim analysis. Any 
changes to the methods described in the final SAP will be described and justified in the 
clinical study report. 

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9.3.1 General Considerations 
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, by cohort. 
Unless otherwise specified, CIs will be calculated at 2-sided 90% level. 
The 2-sided 90% exact CI using Clopper-Pearson method (Clopper 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 90% CI will be calculated based on the complementary 
log-log transformation (Collett 1994). 
9.3.1.1 Randomization and Blinding 
Blinding will not be performed. 
9.3.1.2 Adjustments for Covariates 
There will be no adjustment for covariates. 
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 Multicenter Studies 
This study will be conducted at multiple study centers; however, it is not anticipated that any 
center will accrue enough subjects to warrant an analysis by center. 
9.3.1.5 Multiple Comparisons and Multiplicity 
There are no formal comparisons. 
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 
analysis plan. 

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9.3.1.7 Analysis Sets 
The Safety Analysis set includes all subjects who receive any amount of study drug. 
The Response-Evaluable analysis set includes all subjects with measurable disease who meet 
the following 3 criteria: (1) had a baseline disease assessment with measurable disease (ie, at 
least one target lesion at baseline), (2) received study treatment, and (3) had post-baseline 
disease assessment or discontinued treatment due to documented disease progression or 
clinical progression. 
Additional analysis sets of subjects may be defined in the SAP. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
Interim efficacy and safety analyses will be undertaken in Cohorts 1 to 5 and 7 when the first 
12 response-evaluable subjects in each cohort have been followed for at least 12 weeks or 
have documented disease progression. 
Final efficacy analyses will be undertaken separately for each cohort when 
30 response-evaluable subjects in each cohort have been followed for at least 12 weeks or 
have documented disease progression. 
Supplementary analyses may be undertaken after the final analysis to evaluate PFS and OS. 
9.3.2 Subject Disposition 
An accounting of study subjects by disposition will be tabulated and the number of subjects 
in each analysis set will be summarized. Subjects who discontinue study treatment and 
subjects who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal. 
9.3.3 Subject Characteristics 
The following baseline characteristics will be summarized by treatment group: 
● 
Subject demographics 
● 
Disease history 
● 
Prior disease-related therapies 
● 
Baseline disease characteristics 
 
Details will be provided in the SAP. 

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9.3.4 Concomitant, and Further Therapy 
Concomitant medications, separately for medications taken prior to enrollment and while on 
study, will be listed and summarized by treatment group. 
The frequency and types of further anticancer therapies started after study treatment 
discontinuation will be summarized. 
9.3.5 Exposure 
Treatment administration will be summarized by study drug. Summary statistics for duration 
of therapy (weeks) and the number of cycles per subject will be presented. The number of 
dose reductions, holds, cycle delays, and doses skipped and dose intensity for each study 
drug will be summarized. Details will be provided in the SAP. 
9.3.6 Efficacy Analyses 
Confirmed ORR, DOR, and DCR per RECIST version 1.1 per investigator assessment will 
be evaluated by cohort in response-evaluable subjects. In addition, the same disease type 
from different cohorts might be combined for efficacy analysis. The point estimate of 
confirmed ORR, and DCR and their corresponding 90% CIs will be presented by treatment 
group. 
PFS and DOR will be estimated using the using Kaplan-Meier methodology, and 
Kaplan-Meier plots will be provided. Medians and 90% CIs will be calculated by treatment 
group, as appropriate. Detailed methodology will be provided in the SAP. 
Sensitivity efficacy analyses may be conducted per ICR if deemed necessary. 
9.3.7 Pharmacokinetic Analyses 
Individual (subject) plasma concentrations at each sampling time will be listed for tucatinib; 
corresponding summary statistics at each sampling time will also be calculated. 
Exploratory analyses investigating the relationship between tucatinib exposure and efficacy 
and safety endpoints may be conducted. Additional exploratory PK analyses may be 
conducted. 
Details will be described separately in the SAP. 
9.3.8 Biomarker Analyses 
Relationships of biomarkers to antitumor activity and associated data that are determined to 
be of interest may be summarized. Details will be described separately in the SAP or 
biomarker analysis plan. 
9.3.9 Patient Reported Outcomes Analyses 
Descriptive summaries of observed data will be provided at each scheduled assessment 
timepoint. Time to deterioration in HRQoL will be assessed utilizing the EQ-5D-5L VAS 

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item and defined as a change of ≥7 points. Further investigation of missing patterns and 
details of imputation may be provided in the SAP. 
9.3.10 Safety Analyses 
Safety analysis will be conducted in the safety analysis set, separately for each cohort. 
9.3.10.1 
Extent of Exposure 
Duration of treatment will be summarized and listed. 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized by 
cohort. Dose modifications will also be summarized. Details will be provided in the SAP. 
9.3.10.2 
Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all AEs, 
treatment-emergent AEs, treatment-related AEs, Grade 3 and higher AEs, SAEs, 
treatment-related SAEs, deaths, and AEs leading to study treatment discontinuation. Adverse 
events will be defined as treatment emergent if they are newly occurring or worsen following 
study treatment. 
AEs will be listed and summarized by Medical Dictionary for Regulatory Activities 
(MedDRA), preferred term, severity, and relationship to study drug. In the event of multiple 
occurrences of the same AE with the same preferred term in 1 subject, 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 drug will be 
summarized and listed in the same manner. 
All collected AE data will be listed with cohort, stage, study site, subject number, and cycle. 
All serious AEs and AESIs (see Section 7.6.1.4) will be analogously listed, separately. 
9.3.10.3 
Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. All deaths will be summarized and listed. 
9.3.10.4 
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, chemistry, and liver function) will 
be summarized by cohort and scheduled visit. Laboratory shift tables will also be provided 
by cohort 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. 

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9.3.10.5 
Other Safety Analyses 
Vital Signs 
The frequency and percentage of subjects with post-baseline clinically significant vital signs 
will be summarized. Abnormal physical examination findings may be collected as AEs. 
ECOG Status 
ECOG shifts from baseline to the best and worst postbaseline score may be tabulated. 
ECG 
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
may be summarized for each scheduled 12-lead ECG, and shifts from baseline may be 
tabulated. 
LVEF 
The minimal post baseline ejection fraction and the maximum decrease from baseline will be 
summarized for each cohort. 
9.3.11 Interim Analyses 
Interim futility analyses will be performed separately for Cohorts 1 to 5 and 7 after 
approximately 12 subjects of a given cohort (Stage 1) have been treated and had at least two 
response assessments post-baseline or had disease progression. 
The Bayesian predictive probability approach will be used to determine the futility criteria. 
At the time of each interim analysis, the predictive probability of success (PPoS) will be 
calculated (Lee 2008). PPoS is the probability of achieving “success” should the cohort be 
continued to the maximum sample size of 30, given the data observed at the interim analysis. 
A cohort is considered a “success” if the posterior probability is >80% that the ORR exceeds 
the response rate of current standard of care, which is 10% for biliary tract and urothelial 
cancer, and 15% for cervical, uterine and non-small cell lung cancer (Bregar 2014; 
Garon 2014; Lamarca 2014; Raggi 2016; Borcoman 2017). If at least 2 responders are 
observed in 12 subjects at the interim analysis in any cohort, then the PPoS for that cohort 
will be greater than 20%. A PPoS <20% indicates that it is unlikely the ORR will be better 
than the response rate of current standard of care at the end of the study given the interim 
result. Based on activity and safety data, together with the PPoS, a cohort may be stopped 
early by the sponsor. 
Cohorts that successfully pass the interim analysis for futility may, at the sponsor’s decision, 
continue to enroll up to an additional 18 response-evaluable subjects, totaling up to 
30 response-evaluable subjects for each tumor cohort. A cohort may be expanded to Stage 2 
earlier if the futility rule is cleared before 12 subjects, ie, if the minimal required responses 
are observed in fewer than 12 subjects. 
Interim data from the study may be presented at scientific meetings such as the annual 
meetings of ASCO and the European Society of Medical Oncology. 

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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements. For studies 
conducted in the European Union (EU)/European Economic Area (EEA) countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC) or 
applicable European local regulations. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring subjects are re-consented when the informed consent document is updated during 
the study, if required. The investigator will ensure that written informed consent is obtained 
from each subject, by obtaining the signature and date on the informed consent document 
prior to the performance of protocol evaluations or procedures. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (eg, quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 

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10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study 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. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and subject 
medical records in the subject files as original source documents for the study. If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing subject medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the subject 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of subject identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 
10.5 Data Protection 
For clinical sites covered by the General Data Protection Regulation (GDPR), personal data 
in this study will be protected in accordance with the General Data Protection Regulation 
(EU) 2016/679 (GDPR) including those which govern the transfer of data and the 
management of any potential personal data breaches. The sponsor will ensure equivalent 
guarantees regarding personal data protection standards before transferring the encoded data 
to non-EU countries by the use of standard contractual clauses which are included in data 
protection agreements.  
For all other clinical sites, in the event of a potential personal data breach, the study site will 
be responsible for determining whether a personal data breach has in fact occurred and, if so, 
providing breach notification as required by law. 
 

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10.6 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 
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Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat 
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Ingle JN, Suman VJ, Rowland KM, et al. Fulvestrant in women with advanced breast cancer 
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Kerb R, Brockmoller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady-state 
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Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 
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Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: 
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Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-
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aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor 

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receptor 2-positive and hormone receptor-positive metastatic or locally advanced 
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Strickler JH, Zemla T, Ou FS, et al. Trastuzumab and tucatinib for the treatment of HER2 
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Takegawa N, Yonesaka K. HER2 as an emerging oncotarget for colorectal cancer treatment 
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Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-
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Valtorta E, Martino C, Sartore-Bianchi A, et al. Assessment of a HER2 scoring system for 
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Wildiers H, Boni V, Saura C, et al. Neratinib + trastuzumab + fulvestrant for HER2-mutant, 
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2001;2(2):127-37. 
 

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

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APPENDIX B: GUIDANCE ON CONTRACEPTION 
For the purposes of this guidance, complete abstinence, if consistent with the subject’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 
after the final dose of any study drug, and, if applicable, at least 2 years after the final dose of fulvestrant; see 
Section 4.1). 
Acceptable methods for highly effective birth control (preventing conception) 
Subjects 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 
A person of childbearing potential is defined as anyone born female who has experienced menarche and who has not 
undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not 
completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person born female over 
age 45 in the absence of other biological, physiological, or pharmacological causes. 
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 
Subjects born male and who are sexually active with a pregnant or breastfeeding person must use a male 
condom (even if the subject 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”. 
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 
 

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APPENDIX C: RESPONSE EVALUATION CRITERIA FOR SOLID TUMORS V1.1 
Response Evaluation Criteria for Solid Tumors (RECIST) Version 1.1 (Eisenhauer 2009) 
Term 
Definition 
Complete response (CR) 
● Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm 
● Cannot have previously met criteria for progressive disease 
● Confirmation required only for non-randomised studies 
Partial response (PR) 
● A ≥30% decrease in the sum of diameters of target lesions (longest for 
non-nodal target lesions and the short axes for nodal target lesions), 
taking as reference the baseline sum diameters 
● Cannot have previously met criteria for progressive disease 
● Confirmation required only for non-randomised studies 
Stable disease (SD) 
● Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, taking as reference the smallest sum 
diameters while on study 
● Cannot have previously met criteria for progressive disease 
● Confirmation is not required 
Progressive disease (PD) 
● A ≥20% relative increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (including baseline sum 
if that is the smallest on study). In addition, the sum must also 
demonstrate an absolute increase ≥5 mm 
● The appearance of 1 or more new lesions is also considered 
progression 
● Confirmation is not required unless equivocal. 
New measurable or 
non-measurable lesions 
● Always represent progressive disease 
Non-target lesions 
● Changes contribute to defining CR, PR, SD, and PD 
 

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APPENDIX D: CYP3A INDUCERS AND THEIR ELIMINATION HALF-LIVES 
CYP3A4 inducers include but are not limited to the following. There could also be additional 
new drugs and marketed drugs that could be identified as inhibitors/inducers with continued 
research. 
Druga,b 
Elimination Half-lifec (hours) 
Strong Inducers 
 
Barbiturates 
Variable 
 
Carbamazepine 
25–65 hours (single dose), 12–17 hours (repeat dose) 
 
Phenytoin 
7–42 hours 
 
Rifampin 
3–4 hours (single dose), 2–3 hours (repeat dose) 
 
St. John’s Wort 
9–43 hoursd 
Note: Any additional CYP3A4 inducers that are identified or become commercially available while the clinical trial is 
ongoing are also prohibited. 
a. 
FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.htm#potency) 
b. 
European Medicines Agency (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 package insert 
d. 
(Kerb 1996) 
 

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APPENDIX E: 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 
Strong Inhibitors 
 
Gemfibrozil 
1–2 hours 
Moderate Inhibitors 
 
 
Clopidogrel 
6 hours 
 
Deferasirox 
8-16 hours 
 
Teriflunomide 
18-19 days 
Moderate Inducer 
 
Rifampin 
3–5 hours 
Note: Any additional CYP2C8 inhibitors/inducers that are identified or become commercially available while the clinical 
trial is ongoing are also prohibited. 
a 
FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.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 package insert 
 

 
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APPENDIX F: 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, 
darunavira, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatinb, midazolam, naloxegol, nisoldipine, 
saquinavira, simvastatinb, sirolimus, tacrolimus, 
tipranavira, triazolam, vardenafil 
alprazolam, aprepitant, atorvastatinc, colchicine, 
eliglustatd, pimozide, rilpivirine, rivaroxaban, 
tadalafil 
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavira, lurasidone, 
maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 
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 drug-drug interaction (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. 
AUC=area under the concentration-time curve. 
a 
Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
b 
Acid form is an organic anion transporting polypeptide 1B1 (OATP1B1) substrate. 
c 
Listed based on pharmacogenetic studies. 
d 
Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction 
Database (Hachad 2010). 
Source : 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.h
tm#table3-1) 
 

 
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APPENDIX G : EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the UK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 

 
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CCI

 
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CCI

 
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APPENDIX H: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled 
A Phase 2 Basket Study of Tucatinib in Combination with Trastuzumab in Subjects with 
Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by 
HER2 Alterations 
I understand and agree to the provisions of the protocol, and I accept the responsibilities 
listed above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator Name, Printed 
 
 
 

 
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APPENDIX I: DOCUMENT HISTORY 
Version 
Date 
Original 
08-Sep-2020 
Amendment A01 
27-Oct-2020 
Amendment A02 
03-Nov-2020 
Amendment A03 
16-Aug-2021 
Amendment A04 
02-Dec-2022 
Amendment A05 
24-Apr-2024 
 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 1 
Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Title page 
Added EudraCT number. 
The study will be conducted in the 
EU.  
Synopsis 
In the pharmacokinetics (PK) section, changed 
“Day 1 of Cycles 3 to 6” to “Day 1 of Cycles 2 
to 6”. 
Consistency with the PK schedule. 
Sections 6.6.1, 6.6.2, 
7.6.6.1, Schedule of 
Events 
Specified that echocardiogram/ multigated 
acquisition scan (MUGA) assessments of left 
ventricular ejection fraction (LVEF) should be 
performed every 6 months for at least 2 years 
after the discontinuation of trastuzumab. 
Conformity with Herceptin 
(trastuzumab) EU product 
information. 
Section 4.1, Synopsis 
It was specified that subjects with cervical 
cancer are not subject to the provisions in 
inclusion criterion #2 regarding required prior 
therapy. 
A specific inclusion criterion (#6) 
has been created for pretreatment 
of subjects with cervical cancer 
and per health authority request. 
Section 4.1, Synopsis 
Inclusion criterion #3 was modified to specify 
that subjects with metastatic hormone 
receptor-positive (HR+) human epidermal 
growth factor receptor 2 (HER2)-mutated 
disease must have received a prior CDK4/6 
inhibitor in the metastatic setting 
In order to ensure that subjects 
with HR+ breast cancer have 
received standard prior therapy 
and per health authority request. 
Section 4.1, Synopsis 
Inclusion criteria #3b and #4 were modified to 
say that subjects must have progressed on or 
after ≥1 prior line of treatment, rather than 
have completed. 
To ensure that subjects have failed 
prior therapy.  
Section 4.1, Synopsis 
Inclusion criterion #6 was added to specify 
required prior therapy for subjects with 
metastatic or with locally-advanced 
unresectable cervical cancer. 
In order to ensure that subjects 
with cervical cancer have received 
standard prior therapy and per 
health authority request. 
Section 4.1, Synopsis 
The last bullet of inclusion criterion #7b 
(formerly #6b in the A00 version) was 
modified to specify that HER2 mutations 
which are not listed in criterion #7b will 
require support by the scientific literature to 
serve as evidence of the presence of HER2 
activating mutations. 
In order to implement a more 
rigorous selection process for 
mutations that are not listed in 
criterion #7b and per health 
authority request. 
Section 4.2, Synopsis 
Exclusion criterion #4 was modified to specify 
that an unacceptable prior cumulative 
anthracycline dose is >360 mg/m² 
doxorubicin-equivalent, and to also specify a 
limit in terms of cumulative 
epirubicin-equivalent dose. 
Clarification of text concerning the 
change to “>360”. 
The limit for epirubicin-equivalent 
dose was added in order to provide 
more guidance concerning patients 
who have received other 
anthracyclines. 
Section 4.2, Synopsis 
Removed “based on criteria described under 
central nervous system (CNS) inclusion 
criteria b” from exclusion criterion #17c. 
Correction, as there is no inclusion 
criterion b referring to CNS 
disease. 
Section 5.2.2.1 
Updated the indications for which trastuzumab 
is approved. 
To include indications cited in 
SmPC.  

 
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Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Section 5.2.2.3 
Specified infusion durations for trastuzumab 
and added instructions for surveillance of 
IRRs during trastuzumab infusions. 
Conformity with EU product 
information. 
Section 5.3.2.1 
Revised trastuzumab dose modification 
criteria in the event of LVEF dysfunction. 
New dose modification guideline 
for LVEF dysfunction to 
accommodate decreases of LVEF 
between 45-50% 
Sections 5.3.2.2, 5.4 
Revised treatment of infusion-related reactions 
(IRRs) to include paracetamol, and changed 
premedication in the event of IRRs to be 
paracetamol and antihistamines. 
Conformity with EU product 
information. 
Section 7.4.1 
Specified that information concerning local 
tests used for eligibility, such as the test name, 
methodology/technology used, device 
description, specimen type used, are to be 
collected in electronic Case Report Form 
(eCRF), and that other information on the test 
is to be made available to the sponsor on 
request.  
In order to ensure that pertinent 
information regarding subject 
eligibility is collected. 
Section 7.6.1.2 
Changed “Adverse Events and Pre-Existing 
Conditions CRF” to “Adverse Events CRF”. 
Consistency with other mentions 
of this Case Report Form (CRF) 
page. 
Throughout the 
document 
Changed the sponsor name, Seattle Genetics, 
Inc., to Seagen Inc. 
Company name change. 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 2 
 
 
 
Section(s) 
Change 
Rationale 
Sections 6.2.2, 6.3.1, 
7.3, 7.4.1, Synopsis, 
Schedule of Events 
Moved the NGS assay of ctDNA from the 
Screening visit to predose on Cycle 1 Day 1. 
To ensure that this NGS assay is 
only done in eligible subjects. 
Sections 6.2.2, 6.3.1, 
7.4.1, Synopsis, 
Schedule of Events 
Clarified the conditions under which a blood 
sample for the NGS assay does not have to be 
obtained on Cycle 1 Day 1. 
Clarification. 
Section 7.3 Table 10 
Added line for pre-screening biomarker 
samples. 
Correction. 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 3 
Amendment A03 
 
 
Section(s) 
Change 
Rationale 
Section 2, Synopsis 
Moved the objective to evaluate the PK of 
tucatinib from exploratory to secondary. 
Reevaluation of the importance of 
the assessment of PK in this study. 
Section 2, Synopsis 
Modified the exploratory biomarker objective 
to be: “To determine the concordance of 
HER2 alterations as detected by tissue and 
blood-based HER2 testing methodologies”. 
Modified the corresponding endpoint to be: 
“Concordance of HER2 alterations as detected 
by different testing methodologies”. 
Clarification of planned biomarker 
assessments. 
Section 2, Synopsis 
Added an exploratory biomarker objective to 
identify tumor-specific alterations that are 
associated with resistance to tucatinib and 
corresponding objective. 
Clarification of planned biomarker 
assessments. 
Section 3.1, Synopsis 
Removed “(gallbladder cancer and 
cholangiocarcinoma)” from the line 
concerning biliary tract cancer. 
Consistency. 
Sections 3.1, 6.1, 
6.2.3, 6.5, 7.1, 7.6.3, 
Schedule of Events 
Removed the assessments of coagulation 
function. 
The study regimen has been 
determined not to affect 
coagulation. 
Sections 3.1, 4.4.1, 
6.6.2, Schedule of 
Events 
Specified that the Survival Follow-up visits 
are to be undertaken following EOT, rather 
than following disease progression. 
To ensure that information on 
survival and further anticancer 
therapies is collected from the 
time of treatment discontinuation. 
Sections 3.1, 4.1, 
Synopsis 
Replaced inclusion criteria #2 to #6 with a 
single inclusion criterion #2 pertaining to prior 
therapy. The following changes were made, 
with respect to inclusion criteria #2 to #6: 
• 
For disease types other than breast cancer, 
biliary tract cancer, non-squamous 
NSCLC, and cervical cancer changed from 
“Disease progression on or after the most 
recent systemic therapy “ to “progressed 
during or after ≥1 prior line of systemic 
therapy” 
• 
Created a single criteria #2.b covering all 
disease types except non-squamous 
NSCLC  
• 
Removed specifications of types of 
systemic therapy applicable from criteria 
#3.b and #4  
To simplify and harmonize the 
specification of prior therapy 
requirements. 
Section 4.1, Synopsis 
Modified inclusion criterion #2.a (formerly 
#5) concerning subjects with non-squamous 
NSCLC: to require that subjects must have 
progressed on or after standard treatment 
rather than relapsed from or be refractory to 
standard treatment. 
Clarification.  

 
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Amendment A03 
 
 
Section(s) 
Change 
Rationale 
Sections 3.1, 4.1, 
Synopsis 
Added new inclusion criterion #3: Progression 
during or after, or intolerance of, the most 
recent line of systemic therapy. 
To ensure that all subjects had 
failed the last line of prior therapy. 
Sections 4.1, 7.4.1, 
Synopsis 
Inclusion criterion #4.b (formerly #7.b): 
Specified that subjects with HER2 exon 20 
insertion mutations are eligible. 
To extend the range of HER2 
activating mutations that can 
support enrollment. 
Section 4.1, Synopsis 
Modified inclusion criterion #9.b (formerly 
#12.b) to allow subjects with known history of 
Gilbert’s syndrome to have direct bilirubin 
≤1.5 × ULN rather than normal, if AST, and 
ALT are eligible. 
In subjects with Gilbert’s 
syndrome, direct bilirubin direct 
bilirubin ≤1.5 × ULN provides 
sufficient assurance of adequate 
hepatic function. 
Section 4.1, Synopsis 
Removed former inclusion criterion #15, 
concerning limits on coagulation parameters. 
The study regimen has been 
determined not to affect 
coagulation. 
Section 4.2, Synopsis 
Exclusion criterion #1: replaced “GEC” with 
“gastric or gastroesophageal junction 
adenocarcinoma” 
Clarification 
Sections 3.1, 4.2, 
Synopsis 
Exclusion criterion #2 regarding the exclusion 
of subjects who have received prior 
HER2-directed therapy: added that subjects 
with HER2-mutated gastric or 
gastroesophageal junction adenocarcinoma 
without HER2-overexpression/amplification 
are allowed to have received prior 
trastuzumab. 
It is anticipated that subjects with 
HER2-negative, HER2-mutated 
GEC may benefit from the study 
regimen despite prior 
administration of trastuzumab. 
Section 4.2, Synopsis 
Added “major surgery” to exclusion criterion 
#5 regarding limitations on prior treatment 
modalities within 3 weeks of treatment 
initiation. 
To ensure that recent major 
surgery does not impact the safety 
of study subjects. 
Sections 5.2.2.3, 5.3, 
5.3.2 
Specified that subjects are to discontinue 
trastuzumab in the event of treatment delay 
>6 weeks due to a treatment-related AE, rather 
than for any delay >3 weeks. 
To allow subjects who may 
potentially benefit from study 
treatment to resume treatment 
despite a prolonged delay, if the 
nature of and severity of the 
adverse event (AE) allow for 
re-initiation. 
Section 5.3.2.1 
Added trastuzumab dose modification 
guidelines for symptomatic CHF. 
Conformity with product label. 
Section 5.3.2.2 
Modified the criteria for discontinuation of 
trastuzumab in the event of IRRs from 
“Grade 3 to 4” to “severe or life-threatening”. 
Conformity with product label. 
Section 5.5.1 
Added specification that supportive care 
medications such as antidiarrheals and 
antiemetics are permitted and removed 
requirement to consult the medical monitor 
prior to performing thoracentesis or 
paracentesis. 
To allow symptomatic treatment 
with antidiarrheals and 
antiemetics. 
Sections 5.5.1, 5.5.2 
Removed the prohibition on live vaccines. 
Live vaccines are not considered 
to pose a threat when administered 
during study treatment. 

 
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Amendment A03 
 
 
Section(s) 
Change 
Rationale 
Section 5.6.1 
Revised the specific that overdose should be 
reported as an AE on the eCRF, to state that 
AEs associated with overdose should be 
reported. Revied the specification that 
overdose should be reported according to the 
procedures used for SAEs, to say it should not 
be reported as an AE/SAE, unless it is an 
intentional overdose taken with possible 
suicidal/self-harming intent 
Revision to Seagen reporting 
procedures. 
Sections 6.1, 6.2.3, 
7.1, 7.6.3, Schedule 
of Events 
Removed urinalysis. 
Renal toxicity has not been 
observed with the study regimen. 
Sections 6.2.1, 
6.2.2, 7.1, 7.3, 7.4.1, 
Synopsis, Schedule 
of Events 
Removed collection of tumor tissue samples 
during pre-screening. 
Given the timeframe within which 
tissue samples must be assayed for 
HER2 alterations once they have 
been collected, the assays would 
often have to be done prior to 
patient enrollment, leading to a 
significant number of assays done 
in patients who are not eventually 
enrolled. 
Sections 6.2.2, 7.3, 
7.4.1, Synopsis, 
Schedule of Events 
Specified that tumor tissue samples are to be 
collected once the subject has been approved 
for enrollment by the medical monitor. 
To avoid assay of tissue in 
subjects who are screen failures. 
Sections 6.3.1, 6.3.3, 
7.6.1.1, 7.6.5, 
Schedule of Events 
Changed the window for pregnancy tests on 
Cycle 1 Day 1 from within 7 days predose to 
24 hours predose for urine pregnancy tests or 
72 hours for serum tests. 
To ensure a shorter window for 
pregnancy assessment prior to first 
administration. 
Section 6.3.2, 
Schedule of Events 
Changed the Cycle 1 Day 8 and 15 visits to 
Cycles 1 and 2 Day 12, changed the window 
of the visit from ±1 day to -1 to +3 days, and 
added documentation of AEs and concomitant 
medications. 
To ensure that mid-cycle 
laboratory function is evaluated in 
first 2 cycles. 
Sections 6.3.4, 7.2, 
Synopsis, Schedule 
of Events 
Specified that in subjects with lung cancer, 
scans of the pelvis do not need to be 
undertaken after the screening assessment 
unless lesions were detected at screening, or as 
clinically indicated. 
Lesions involving the pelvis are 
uncommon in subjects with lung 
cancer. 
Section 6.6.1, 
Schedule of Events 
Removed echocardiogram/MUGA-scan and 
pregnancy test assessments from the 
Progression Follow-up visits. 
Survival Follow-up visits now 
begin at EOT rather than after 
disease progression and these 
assessments are already 
undertaken in the survival 
follow-up. 
Section 7.2, 
Synopsis, Schedule 
of Events 
Added specification that in subjects for who 
contrast is contraindicated, can have a CT-scan 
of abdomen and pelvis if an MRI is not 
feasible. 
To allow for non-feasibility of 
MRI scans in this situation. 
Section 7.4.1, 
Synopsis 
Specified the nature of assessments undertaken 
for exploratory biomarker objectives. 
Clarification of planned biomarker 
assessments. 

 
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Amendment A03 
 
 
Section(s) 
Change 
Rationale 
Sections 6.2.2, 7.4.1 
Concerning the supply of an archival tumor 
tissue sample, specified that medical monitor 
approval, not consultation, is required to 
supply slides rather than blocks and added that 
at least 20 freshly-cut slides would be 
required. 
To control the use of slides in the 
place of blocks 
Section 7.4.2 
Changed blood draw for biomarker from 
screening to Cycle 1 Day 1. 
Consistency. 
Section 7.4.2, 
Synopsis 
Revised the description of additional 
biomarker assessments to be undertaken. 
Clarification of planned biomarker 
assessments. 
Section 7.6.1.1 
Added a section with definitions of overdose, 
medication error, misuse, and abuse to section 
on AE definitions, moving an existing section 
on dosing errors to the new section.  
Revision to Seagen reporting 
procedures. 
Section 7.6.1.4 
Changed one part of the criteria for a 
hepatotoxicity AESI from Grade 4 AST, ALT, 
or bilirubin elevation to AST or ALT elevation 
>20 × ULN or bilirubin elevation >10 x ULN. 
Consistency with formulation of 
other hepatotoxicity AESI 
criterion. 
Section 7.6.3, 
Schedule of Events 
Indicated that in laboratory tests bicarbonate 
should be evaluated only if the test is available 
in the laboratory.  
To allow for site laboratories that 
do not evaluate bicarbonate. 
Section 7.6.3, 
Schedule of Events 
Removed lactase dehydrogenase from the 
chemistry panel laboratory assessments.  
This test is not expected to be 
useful for the evaluation of subject 
safety. 
Section 9.2.7.1 
Removed the specification “Biomarkers 
assessments in blood may include 
measurements of HER2 amplification, and 
genetic polymorphisms in order to assess 
potential response and resistance biomarkers. 
Methods of analysis may include, but are not 
limited to, NGS of RNA and DNA” and 
specified that relationships of biomarkers to 
antitumor activity may be evaluated. 
Revised analysis plan. 
Section 9.3.8 
Revised biomarker analysis methods to 
remove specification that relationships of 
biomarker parameters with safety and PK 
parameters will be evaluated. 
Revised analysis plan. 
Appendix B 
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 the 
protocol 
Administrative changes. 
 
 
 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 4  
Amendment A04 
Section(s) 
Change 
Rationale 
Synopsis and Title 
Page  
Changed version A03 to A04 and changed 
date from 16-Aug-2021 to 02-Dec-2022 
Administrative change to update 
version. 
Schedule of Events 
footnote text  
& Section 7.6.3  
Added language related to hepatitis B 
screening  
Clarification on follow-up testing 
required to assess hepatitis B 
status 
Schedule of Events 
table  
Updated schedule of events table to align with 
section 6.3.3, visit window for Cycles >1, 
Predose day 1 is now -1, +3 
Updated to align with Section 
6.3.3. 
Section 3.2.4  
Updated regions where tucatinib is currently 
approved 
Updated to align with most recent 
approvals  
Section 5.2.1.2 
Deleted “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.” 
Removed for consistency with 
tucatinib pharmacy instructions 
Section 5.3.1 
Added footnote to Table 8 liver function test 
abnormality table to clarify dose modification 
requirements. 
In subjects where biliary 
obstruction was clearly the cause 
of the LFT abnormality, those 
subjects may potentially continue 
on treatment once the obstruction 
and LFT abnormalities resolve and 
with medical monitor approval as 
this etiology is not related to 
tucatinib treatment. 
Section 6.3.1  
Updated language to include that blood 
samples for laboratory testing must be 
reviewed and eligibility must be confirmed 
prior to first dose.  
To clarify that subject eligibility 
should be confirmed prior to first 
dose. 
Section 9.3.1.7  
Added language to describe response-
evaluable analysis set  
To clarify the definition of 
response-evaluable dataset, as only 
subjects with measurable disease 
can have a response per RECIST 
v1.1. 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 5  
 
 
Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Cover page 
Indicated that Seagen Inc. has been 
acquired by Pfizer Inc. 
 
Seagen is part of Pfizer as of 14 Dec 2023 
No 
Throughout 
Added an LTEP for subjects who are 
still receiving treatment. 
 
All study objectives have been met. LTEP 
being added to allow subjects still receiving 
clinical benefit to remain on study 
treatment. 
No 
Synopsis, HER2 Testing 
for Eligibility and 
Biomarker Assessments 
• Added: “Pre-screening for HER2 
alterations: if HER2 alterations 
have not been detected in 
pre-study assessments, HER2 
eligibility may alternatively be 
established during pre-screening, 
up to 3 months prior to the 
Screening visit, via an NGS assay 
of ctDNA evaluating the presence 
of HER2 amplification or 
mutations.” 
Bullet point restored to align with Section 
7.4.1 
No 

 
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Synopsis, Study Design, 
Section 3.1 Summary of 
Study Design 
Added that subjects still receiving 
clinical benefit and remaining on 
study treatment as of Amendment 5 
may continue to receive study drug 
during the LTEP. 
 
To allow subjects who are still receiving 
clinical benefit to remain on treatment. 
No 
Synopsis, Efficacy 
Assessments 
Section 9.3.1.7 Analysis 
Sets 
Defined measurable disease as at least 
one target lesion at baseline 
Clarification to align with SAP.  
No 
Synopsis, Duration of 
Treatment, Section 6.1 
Schedule of Events 
Added: “Subjects still receiving 
clinical benefit and remaining on 
study treatment as of Amendment 5 
may continue receiving study drug 
during the LTEP. During this phase 
of the study, only pregnancies, SAEs, 
and AESIs 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.” 
LTEP added to allow subjects still receiving 
clinical benefit to remain on study treatment 
and clarification of data collection during 
the LTEP.  
No 

 
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Synopsis, Efficacy 
Assessments and Section 
7.2 Response/Efficacy 
Assessments 
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.  
No 
Synopsis, Safety 
Assessments, Section 7.6 
Safety Assessments 
Clarified that only pregnancies, 
SAEs, and AESIs 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 subjects of 
child-bearing potential. 
Clarification of data collection during 
LTEP. 
No 
Schedule of Events 
Added LTEP  
Column added to indicate assessments to be 
done during the LTEP. 
No 

 
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Section 3.1.3 End of Study 
Added: “As of Amendment 5, all 
subjects still on study who are not 
entering the LTEP will have a last 
visit/contact. The study will end when 
the last LTEP subject has had their 
last visit/contact. The sponsor will 
provide continued access to study 
treatment for any subject who is still 
on treatment receiving clinical benefit 
based on the investigator’s 
assessment.” 
Defined end of study for subjects entering 
LTEP. 
No 
Section 4.4 Removal of 
Subjects From Therapy or 
Assessment 
Added that for subjects continuing to 
LTEP, data will only be documented 
in the subject’s medical record. 
Clarification of data collection during 
LTEP. 
No 
Section 5.7 Treatment 
Compliance 
Added that treatment administration 
data will no longer be collected 
during the LTEP. 
Clarification of data collection during 
LTEP. 
No 
Section 6.3.3 Cycles >1 
Day 1 (-1 to +3 days) 
Added that pregnancy testing will 
continue every 3 weeks for subjects 
of child-bearing potential during the 
LTEP 
To clarify that pregnancy testing per 
protocol specified frequency will continue 
during the LTEP. 
No 

 
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Section 6.6.3 Long-term 
Extension Phase (LTEP) 
Added long-term extension phase for 
subjects still receiving clinical benefit 
and remaining on treatment. During 
this phase of the study, only 
pregnancies, SAEs, and AESIs 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 subjects of 
child-bearing potential. 
Clarification of safety data collection during 
LTEP. 
No 
Section 7.6.1 Adverse 
Events 
Identified that SAEs should be 
reported to the Sponsor solely on the 
SAE form. 
Clarification of data collection during 
LTEP. 
No 
Section 7.6.1.1 
Definitions/Procedures for 
Eliciting and Recording 
Adverse Events/Recording 
Serious Adverse 
Events/Pregnancy 
Clarified that during the LTEP, 
pregnancies, SAEs, and AESIs will 
be reported to the Sponsor on the 
SAE/pregnancy forms and will not be 
recorded within the CRF. 
Guidance on steps to follow when recording 
safety data during the LTEP. 
No 

 
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Section 7.6.1.4 Adverse 
Events of Special Interest 
Clarified that during the LTEP, 
AESIs will be reported to the sponsor 
using an SAE form only and will not 
be recorded within the CRF. 
Clarification of data collection during 
LTEP. 
No 
Section 7.6.3 Clinical 
Laboratory Tests 
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. 
No 
Section 7.6.5 Pregnancy 
Testing 
Clarified that during the LTEP, 
pregnancy reporting should continue 
and will be collected by the Sponsor 
using the Pregnancy Report Form. 
Guidance for data collection of pregnancies 
that occur during the LTEP. 
No 
Section 7.6.6.1 MUGA or 
Echocardiogram 
Added the following text: “During the 
LTEP, cardiac function assessments 
will be performed per institutional 
guidelines and investigator-
determined usual and customary 
clinical care.” 
Guidance regarding cardiac function 
assessments during the LTEP. 
No 
Section 7.6.6.2 
Electrocardiogram 
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. 
No 

 
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Clinical Protocol  
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Tucatinib  
Seagen Inc. – Confidential  
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Section(s) 
Change 
Rationale 
Substantial (Yes/No) 
Section 8.2 Data 
Management Procedures 
Added text to indicate data collection 
needed during LTEP.  
Guidance for data collection during the 
LTEP. 
No 
Section 8.4 Accuracy and 
Reliability of Data 
Added text to indicate CRFs will not 
be collected during LTEP 
eCRFs will not be collected during the 
LTEP. 
No 
Section 10 Informed 
Consent, Ethical Review, 
and Regulatory 
Considerations 
Added: “For studies conducted in the 
European Union (EU)/European 
Economic Area (EEA) countries, the 
investigator will ensure compliance 
with the EU Clinical Trial Directive 
(2001/20/EC) or applicable European 
local regulations.” 
To ensure compliance with EU regulations. 
No 
Section 10.3.2 Protocol 
Amendments and Study 
Termination 
Deleted: “The sponsor may terminate 
the study at any time. The IRB/IEC 
must be advised in writing of study 
completion or early termination.” 
 
The study is being terminated 
No 
Section 10.5 Data 
Protection  
Added new section to describe data 
protection features and steps to take 
in the event of a data breach. 
To clarify data protection policy. 
No