Clinical trial NCT04499924
Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Esophageal Adenocarcinoma
Keywords: HER2+ HER2-positive GEA GEC GEJ Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2021-03-22; Completion date: 2024-04-17
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to see if tucatinib with trastuzumab, ramucirumab and paclitaxel works better than ramucirumab and paclitaxel to treat HER2-positive (HER2+) cancer of the gut (stomach or gastroesophageal cancer). This study will also look at what side effects happen when participants take this combination of drugs. A side effect is anything the drug does other than treating cancer.

Study treatment will be given in 28-day cycles.

In the Phase 2 part of the trial, participants and their doctors will know what drugs are being given (open-label). In the Phase 3 part, the study is "blinded." This means that participants, their doctor, and the study sponsor will not know which drugs are being given.

Detailed description:

Arms: arm 1: Tucatinib + trastuzumab + ramucirumab + paclitaxel arm 2: Tucatinib + trastuzumab + ramucirumab + paclitaxel arm 3: Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo arm 4: Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
Interventions: intervention 1: tucatinib intervention 2: trastuzumab intervention 3: ramucirumab intervention 4: paclitaxel intervention 5: tucatinib placebo intervention 6: trastuzumab placebo
Intervention descriptions: intervention 1: 300 mg given twice daily orally intervention 2: 6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter intervention 3: 8 mg/kg will be administered IV on Days 1 and 15 of each cycle intervention 4: 60 or 80 mg/m\^2 IV on Days 1, 8, and 15 of each cycle intervention 5: Given twice daily orally intervention 6: IV on Days 1 and 15 of each cycle

Protocol documents:
Prot_000.pdf: 
 
This document contains information proprietary to Seagen Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Seagen Inc. You may disclose the contents of this document to study 
personnel under your supervision and to your Institutional Review Board (IRB) or Ethics Committee (EC) for 
the same purpose. You may not disclose the contents of this document to any other party, unless government 
regulations or laws require such disclosure, without prior written permission from Seagen Inc. Any 
supplemental information that may be added to this document is proprietary to Seagen Inc. and should be 
handled using the disclosure procedure described above. 
 
 
 
Protocol Number: 
SGNTUC-022 
Version: 
Amendment 2, 02-Apr-2021 
Protocol Title: 
MOUNTAINEER-02: A randomized, double-blind, 
placebo-controlled, active comparator Phase 2/3 study of 
tucatinib in combination with trastuzumab, ramucirumab, and 
paclitaxel in subjects with previously treated, locally-advanced 
unresectable or metastatic HER2+ gastric or gastroesophageal 
junction adenocarcinoma (GEC)  
Investigational 
Product: 
Tucatinib 
Brief Title: 
Tucatinib, trastuzumab, ramucirumab, and paclitaxel versus 
paclitaxel and ramucirumab in previously treated HER2+ 
gastroesophageal cancer 
Phase: 
2/3 
IND Number: 
134840  
EudraCT Number 
2020-003249-12 
Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 PharmD, BCOP 
Tel: 
 
E-mail: 
  
 
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 
 
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PPD
PPD
PPD


 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGNTUC-022  
Version 
Amendment 2, 02-Apr-2021  
Phase 
2/3 
Product Name 
Tucatinib 
Sponsor 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Protocol Title 
MOUNTAINEER-02: A randomized, double-blind, placebo-controlled, active comparator Phase 2/3 study of 
tucatinib in combination with trastuzumab, ramucirumab, and paclitaxel in subjects with previously treated, 
locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma 
(GEC) 
Study Objectives 
Phase 2 
 
Primary Objectives 
Corresponding Endpoints 
● To determine the recommended 
dose of paclitaxel when 
administered in combination with 
tucatinib, trastuzumab, and 
ramucirumab 
● Frequency of dose-limiting toxicities (DLTs) during the first cycle of 
treatment with tucatinib, trastuzumab, ramucirumab, and paclitaxel 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with trastuzumab, 
ramucirumab, and paclitaxel  
● Type, incidence, severity, seriousness, and relatedness of adverse 
events (AEs) and laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations of 
tucatinib, paclitaxel, trastuzumab, and ramucirumab 
Secondary Objectives 
Corresponding Endpoints 
● To evaluate the preliminary activity 
of tucatinib in combination with 
trastuzumab, ramucirumab, and 
paclitaxel in subjects with 
previously treated locally-advanced 
unresectable or metastatic GEC that 
is HER2+ according to blood-based 
next generation sequencing (NGS) 
assay of circulating tumor DNA 
(ctDNA)  
● Objective response rate (ORR; complete response [CR] or partial 
response [PR]) per Response evaluation criteria in solid tumors 
(RECIST) version 1.1 according to investigator assessment 
● Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
● Progression-free survival (PFS) per RECIST version 1.1 according to 
investigator assessment  
● Duration of response (DOR; CR or PR) per RECIST version 1.1 
according to investigator assessment  
● Disease control rate (DCR; CR or PR or stable disease/non-CR, non-
progressive disease as best objective response) per RECIST version 
1.1 according to investigator assessment 
● To evaluate the pharmacokinetics 
(PK) of tucatinib and the tucatinib 
metabolite ONT-993 
● To evaluate the PK of paclitaxel 
and its metabolites in the presence 
and absence of tucatinib 
● The PK parameters to be calculated for tucatinib, paclitaxel, and their 
respective metabolites (if applicable) may include but are not limited 
to: area under the plasma concentration-time curve (AUC) to the time 
of the last quantifiable concentration (AUClast), maximum observed 
concentration (Cmax), time of Cmax (Tmax), trough concentration 
(Ctrough), and metabolic ratio based on AUC (MRAUC) 
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Exploratory Objectives 
Corresponding Endpoints 
● To evaluate the preliminary 
activity of tucatinib in 
combination with trastuzumab, 
ramucirumab, and paclitaxel in 
subjects with disease that is 
HER2-negative according to 
blood-based NGS assay but 
HER2+ according to 
immunohistochemistry (IHC)/in 
situ hybridization (ISH) assay of 
a tumor tissue sample 
● ORR per RECIST version 1.1 according to investigator assessment 
● Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
● PFS per RECIST version 1.1 according to investigator assessment  
● DOR per RECIST version 1.1 according to investigator assessment  
● DCR per RECIST version 1.1 according to investigator assessment 
● To evaluate the correlation 
between HER2 alterations as 
detected by blood-based NGS 
assays and standard tissue-based 
assays  
● Frequency of HER2 alterations according to blood-based NGS 
assay and according to assays on tumor tissue samples obtained 
after progression on the most recent line of therapy  
● To explore correlations between 
blood-based biomarkers and 
clinical outcomes 
● Potential biomarkers of response, resistance, or toxicity may be 
evaluated in blood 
● To evaluate the PK of tucatinib 
and ONT-993 in subjects with 
and without a gastrectomy 
● The PK parameters of tucatinib and ONT-993 in subjects with and 
without a gastrectomy (without maintenance of the pylorus) may 
include but are not limited to: AUClast, Cmax, Tmax, Ctrough, and 
MRAUC 
 
Phase 3 
Primary Objective 
Corresponding Endpoints 
● To compare the efficacy of 
tucatinib and trastuzumab 
versus placebo, in 
combination with 
ramucirumab and paclitaxel 
in subjects with previously 
treated, locally-advanced 
unresectable or metastatic 
HER2+ GEC 
Dual primary endpoints 
● Overall survival (OS)  
● PFS per RECIST version 1.1 according to investigator assessment 
Key secondary endpoints 
Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
Other secondary endpoints 
● PFS per RECIST version 1.1 according to blinded independent central 
review (BICR) assessment  
● Confirmed ORR per RECIST version 1.1 according to BICR 
assessment  
● ORR per RECIST version 1.1 according to investigator assessment 
● ORR per RECIST version 1.1 according to BICR assessment 
● DOR per RECIST version 1.1 according to investigator assessment 
● DOR per RECIST version 1.1 according to BICR assessment  
● DCR per RECIST version 1.1 according to investigator assessment  
● DCR per RECIST version 1.1 according to BICR assessment 
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Secondary Objectives 
Corresponding Endpoints 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with 
trastuzumab, ramucirumab, 
and paclitaxel 
● Type, incidence, severity, seriousness, and relatedness of AEs and 
laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations of 
tucatinib, trastuzumab, ramucirumab, and paclitaxel  
● To evaluate the anti-tumor 
activity of tucatinib in 
combination with 
ramucirumab and paclitaxel 
Secondary Endpoints 
● Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
● DOR per RECIST version 1.1 according to investigator assessment 
Exploratory Endpoints 
● OS  
● PFS per RECIST version 1.1 according to investigator assessment 
● PFS per RECIST version 1.1 according to BICR assessment 
● Confirmed ORR per RECIST version 1.1 according to BICR 
assessment 
● ORR per RECIST version 1.1 according to investigator assessment 
● ORR per RECIST version 1.1 according to BICR assessment 
● DOR per RECIST version 1.1 according to BICR assessment 
● DCR per RECIST version 1.1 according to investigator assessment  
● DCR per RECIST version 1.1 according to BICR assessment 
● To assess PROs by treatment 
arm 
● Time to deterioration of GEC symptoms as assessed by the European 
Organisation for Research and Treatment of Cancer (EORTC) quality 
of life questionnaire (QLQ)-C30 and EORTC QLQ-OG25 
questionnaires 
●  Change from baseline in health-related quality of life (HRQoL) 
● Utility index values as assessed by the EQ-5D-5L 
Exploratory Objectives 
Corresponding Endpoints 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with 
ramucirumab, and paclitaxel 
● Type, incidence, severity, seriousness, and relatedness of AEs and 
laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations of 
tucatinib, ramucirumab, and paclitaxel 
● To evaluate the PK of 
tucatinib 
● The PK parameter to be calculated for tucatinib (if applicable) 
includes: Ctrough 
● To explore correlations 
between blood-based 
biomarkers and clinical 
outcomes 
● Potential biomarkers of response, resistance, or toxicity may be 
evaluated in blood 
● To assess HCRU by treatment 
arm 
● Cumulative incidence of healthcare resource utilization, including 
length of stay, hospitalizations, and emergency department visits 
 
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Study Population 
Inclusion Criteria  
1. Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ 
gastric or gastroesophageal junction adenocarcinoma 
2. HER2+ disease documented since progression of the most recent line of systemic therapy, as follows: 
a. 
Phase 2 paclitaxel dose optimization stage:  
• HER2 amplification in a blood-based NGS assay performed at a central laboratory, or 
• HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue 
sample, processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International 
Organization for Standardization (ISO)‑accredited laboratory 
b. Phase 2 dose expansion stage: 
i. 
Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory 
ii. 
Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 
overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue 
sample, processed in a CLIA- or ISO‑accredited laboratory 
c. 
Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory 
3. Can supply archival tumor tissue for central review; if an archival sample is not available, the subject may 
be eligible, following approval by the medical monitor.  
4. History of prior treatment with a HER2-directed antibody 
5. Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC 
6. Phase 2: Measurable disease according to RECIST version 1.1 
Phase 3: Measurable or non-measurable disease according to RECIST version 1.1 
7. Age ≥18 years, or considered an adult by local regulations, at time of consent 
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 
9. Life expectancy of at least 3 months, in the opinion of the investigator 
10. Adequate hepatic function as defined by the following: 
a. 
Total bilirubin ≤1.5 × upper limit of normal (ULN), except for subjects with known Gilbert’s disease, 
who may enroll if the conjugated bilirubin is ≤1.5 × ULN 
b. Transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤2.5 × ULN 
(≤5 × ULN if liver metastases are present) 
11. Adequate baseline hematologic parameters as defined by: 
a. 
Absolute neutrophil count ≥1.5 × 109/L  
b. Platelet count ≥100 × 109/L; subjects with stable platelet count from 75-100 × 109/L may be included 
with approval from the Medical Monitor 
c. 
Hemoglobin ≥9 g/dL; subjects with hemoglobin ≥8-9 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 
12. Estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m² using the Modification of Diet in Renal 
Disease (MDRD) study equation as applicable.  
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13. International normalized ratio (INR) ≤1.5, and prothrombin time (PT) and partial thromboplastin time 
(PTT)/activated partial thromboplastin time (aPTT) ≤1.5 × ULN if not receiving anticoagulation therapy. 
Subjects on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular 
weight heparin. If on warfarin, the subject must have an INR of ≤3 and have no active bleeding (within 
≤14 days prior to enrollment or randomization, excluding trace hematuria) or pathological condition that 
carries a high risk of bleeding (i.e., tumor involving major vessels or known varices). Refer to Section 5.4.2 
Prohibited Concomitant Therapy for potential drug interactions with tucatinib and oral anticoagulants. 
14. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or multi-gated acquisition 
(MUGA) scan documented within 4 weeks prior to first dose of study treatment  
15. Urinary protein of ≤1+ on dipstick or routine urinalysis. If dipstick or routine analysis indicates proteinuria 
≥2+, then either a 24-hour urine must be collected and must demonstrate <1000 mg of protein in 24 hours 
or the urine protein/creatinine (UPC) ratio must be <1 to allow participation in study 
16. 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  
c. 
Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing 
through 7 months after the final dose of any study drug  
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 C, 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.  
17. 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  
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 C, 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  
c. 
If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 
2 contraception options (as defined in APPENDIX C), 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  
18. The subject must provide written informed consent 
19. Subject must be willing and able to comply with study procedures, laboratory tests, and other requirements 
of the study  
Exclusion Criteria 
1. Subjects with squamous cell or undifferentiated GEC 
2. Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic 
disease 
3. Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior 
treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or 
anti-EGFR tyrosine kinase inhibitor, or with trastuzumab emtansine (T-DM1), trastuzumab deruxtecan 
(T-DXd), or any other HER2-directed antibody-drug conjugate 
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4. History of exposure to the following cumulative doses of anthracyclines: 
• 
Doxorubicin >360 mg/m² 
• 
Epirubicin >720 mg/m² 
• 
Mitoxantrone >120 mg/m² 
• 
Idarubicin >90 mg/m² 
• 
Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) >550 mg/m² 
5. History of allergic reactions to paclitaxel, trastuzumab, ramucirumab, or compounds chemically or 
biologically similar to tucatinib, except for Grade 1 or 2 infusion-related reactions to trastuzumab or 
ramucirumab that were successfully managed, or known allergy to any of the excipients in the study drugs 
or placebos 
6. Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy 
7. Treatment with any systemic anti-cancer therapy (including hormonal and biologic therapy), radiation, or 
an experimental agent, or participation in another interventional clinical trial ≤3 weeks prior to first dose of 
study treatment.  
8. Major surgery within 28 days prior to enrollment or randomization, central venous access device placement 
within 7 days prior to enrollment or randomization, or planned major surgery following initiation of study 
treatment  
9. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following 
exceptions: 
• 
Anemia 
• 
Alopecia 
• 
Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, 
and must have resolved completely 
10. Clinically significant cardiopulmonary disease such as: 
• 
Ventricular arrhythmia requiring therapy 
• 
Symptomatic hypertension or uncontrolled asymptomatic hypertension ≥150/≥90 mmHg despite 
standard medical management, as determined by the investigator 
• 
Any symptomatic history of CHF, left ventricular systolic dysfunction or decrease in ejection fraction 
• 
Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or 
above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen 
therapy, except when therapy is needed for obstructive sleep apnea 
11. 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 
12. Presence of known chronic liver disease 
13. Phase 2: Known to be positive for human immunodeficiency virus (HIV) 
 Phase 3: Subjects known to be positive for HIV are excluded if they meet any of the following criteria: 
• 
CD4+ T-cell count of <350 cells/uL 
• 
Detectable HIV viral load 
• 
History of an opportunistic infection within the past 12 months 
• 
On stable antiretroviral therapy for <4 weeks 
14. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent 
until 7 months following the last dose of study drug 
15. Unable to swallow pills  
16. Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or have used 
a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment.  
17. Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or 
compliance with study procedures 
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18. History of malignancy other than GEC within 2 years prior to screening, with the exception of those with a 
negligible risk of metastasis or death (e.g., 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. 
19. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during 
the 3 months prior to enrollment or randomization.  
20. Chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, 
naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, 
anagrelide). Aspirin use at doses up to 325 mg/day is permitted.  
21. Significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal 
tract within 3 months prior to study entry.  
22. History of any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular 
accident, or transient ischemic attack, within 6 months prior to enrollment or randomization.  
23. History of gastrointestinal perforation and/or fistulae within 6 months prior to enrollment or randomization.  
24. Serious non-healing wound or peptic ulcer or bone fracture within 28 days prior to enrollment or 
randomization 
25. History of bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal 
resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn’s disease, 
ulcerative colitis or chronic diarrhea 
26. Active or uncontrolled clinically serious infection 
27. Known active central nervous system metastases. Irradiated or resected lesions are permitted, provided the 
lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for 
at least 30 days. 
Number of Planned Subjects 
Phase 2: Up to approximately 78 subjects will be enrolled and treated 
Phase 3: Approximately 500 subjects will be randomized to 3 arms  
 Study Design 
This is an international, multicenter Phase 2/3 study in subjects with locally-advanced unresectable or 
metastatic HER2+ GEC who have received prior treatment with a HER2-directed antibody, and have received 
1 prior line of therapy in the advanced disease setting.  
The 2-stage, 2-cohort, open-label Phase 2 portion will include a paclitaxel dose optimization stage, in which 
paclitaxel dose escalation will be used to determine the recommended dose of paclitaxel to be given in 
combination with tucatinib, trastuzumab, and ramucirumab. Subsequently, enrollment will continue, to further 
evaluate the safety and activity of the regimen in a total of approximately 30 response-evaluable subjects in 
each of 2 cohorts, once the recommended paclitaxel dose is determined.  
The randomized, double-blind, placebo-controlled Phase 3 portion is designed to compare the efficacy and 
evaluate the safety of tucatinib and trastuzumab versus placebo, in combination with ramucirumab and 
paclitaxel. The efficacy and safety of tucatinib combined with ramucirumab and paclitaxel will also be 
evaluated. 
Phase 2 - Paclitaxel dose optimization stage 
Six subjects will initially be enrolled and treated at paclitaxel 60 mg/m². Subjects can have HER2+ disease 
according to blood-based NGS assay or IHC/ISH assay of a tumor tissue sample (IHC3+ or IHC2+/ISH+). 
Once 6 subjects are evaluable for DLT, enrollment will be paused and the Safety Monitoring Committee (SMC) 
will undertake an evaluation of safety and PK. If necessary, additional subjects will be enrolled to replace 
subjects who are not evaluable for DLT.  
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In the 6 DLT-evaluable subjects receiving 60 mg/m²: 
● If ≤1 DLT are observed in 6 subjects, the paclitaxel dose will be escalated to 80 mg/m² and evaluated in a 
further 6 subjects. 
● If 2 DLTs are observed in 6 subjects, an additional 3 subjects will be treated at 60 mg/m², for a total of 
9 subjects:  
◦ If ≤2 DLT are observed in 9 subjects, the paclitaxel dose will be escalated to 80 mg/m² and evaluated in a 
further 6 subjects.  
◦ If >2 DLT are observed in 9 subjects, the evaluation of the regimen will be halted, or an alternative dose 
level/schedule may be recommended by the SMC. 
● If >2 DLTs are observed in 6 subjects, the evaluation of the regimen will be halted, or an alternative dose 
level/schedule may be recommended by the SMC. 
In the 6 DLT-evaluable subjects receiving 80 mg/m²: 
● If ≤1 DLT are observed in 6 subjects, 80 mg/m² will be the recommended dose. 
● If 2 DLTs are observed in 6 subjects, an additional 3 subjects will be treated at 80 mg/m², for a total of 
9 subjects:  
◦ If ≤2 DLT are observed in 9 subjects, 80 mg/m² will be the recommended dose.  
◦ If >2 DLT are observed in 9 subjects, the 60 mg/m² paclitaxel dose will be declared the recommended dose, 
and evaluation of the regimen will continue in the Dose Expansion stage. 
● If >2 DLTs are observed in 6 subjects, the 60 mg/m² paclitaxel dose will be declared the recommended dose, 
and evaluation of the regimen will continue in the Dose Expansion stage. 
The SMC may also recommend the inclusion of additional subjects in any dose level or the evaluation of an 
alternative dose level/schedule, if necessary. The SMC will continuously monitor subjects for AEs, deaths, 
other serious adverse events (SAEs), dose modifications, and laboratory abnormalities, with a specific focus on 
DLTs.  
Phase 2 – Dose Expansion stage  
Following the paclitaxel dose optimization stage, two cohorts will be opened to further evaluate the safety of the 
study regimen and undertake an initial assessment of anti-tumor activity. Cohort 2A will enroll subjects with 
HER2+ disease as determined by HER2 amplification in a blood-based NGS assay of ctDNA performed at a 
central laboratory at screening. The exploratory Cohort 2B will enroll subjects whose disease did not show 
HER2 amplification in the blood-based NGS assay, but did show HER2 overexpression/amplification by IHC 
and ISH assay of a tumor tissue sample, processed in a CLIA- or ISO‑accredited laboratory. 
For each type of HER2-positivity evaluated (blood-based NGS assay or IHC/ISH assay of a tumor tissue 
sample), approximately 30 response-evaluable subjects who have been treated at the recommended paclitaxel 
dose will be included in Cohort 2A or 2B, in order to further evaluate the safety of the study regimen and 
undertake an initial assessment of anti-tumor activity. Subjects who are not evaluable for response will be 
replaced. Subjects in the dose optimization stage will be counted towards the sample size for these cohorts, if 
they received the recommended dose and are response -evaluable. 
The SMC will evaluate the safety of the study regimen throughout the remainder of Phase 2, in the 2 cohorts. At 
least 6 subjects with a history of prior gastrectomy (without maintenance of the pylorus) will be enrolled in 
either cohort to evaluate the PK of tucatinib and ONT-993 in this population; alternative dose levels/schedules 
may be explored depending on the PK of tucatinib in subjects with gastrectomy.  
After approximately 30 response-evaluable subjects who are HER2+ according to the blood-based NGS assay 
have been treated at the recommended paclitaxel dose in the dose optimization stage or in Cohort 2A, and have 
been followed for at least 6 weeks, a formal analysis of the activity of the regimen will be undertaken. If the 
ORR per RECIST v1.1 according to investigator assessment is 36%, the SMC may recommend that the 
Phase 3 evaluation of the regimen will be initiated, given that it is safe and tolerable.  
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Phase 3 
Approximately 500 subjects will be randomized ~8:8:1 to either Arm 3A (tucatinib + trastuzumab + 
ramucirumab + paclitaxel; 235 subjects), Arm 3B (tucatinib placebo + trastuzumab placebo + ramucirumab + 
paclitaxel; 235 subjects), or Arm 3C (tucatinib + trastuzumab placebo + ramucirumab + paclitaxel; 30 subjects). 
Randomization will be stratified by region (Asia vs Rest of World), time to progression on first-line therapy for 
locally-advanced unresectable or metastatic disease (<6 months vs ≥6 months), and history of prior gastrectomy 
(yes vs no). Subjects, investigators, and staff, and the sponsor study team will be blinded to study arm 
allocation.  
In the Phase 3 portion of the study, an Independent Data Monitoring Committee (IDMC) will periodically 
review relevant aggregate safety data and will make recommendations to the sponsor on the conduct of the 
study. Safety will also be monitored in an ongoing basis by the sponsor throughout the study.  
Investigational Product, Dose, and Mode of Administration 
In subjects in the Phase 2 undergoing PK assessment on Cycle 1 Day 8 and Cycle 2 Day 1, tucatinib should be 
dosed at approximately the same time as the start of the paclitaxel infusion. The administration order of 
intravenous (IV) study drugs is paclitaxel first, followed by trastuzumab and ramucirumab, or according to 
institutional standard of care.  
Study treatment will be administered in 28-day cycles. 
Phase 2  
Tucatinib 300 mg will be administered orally (PO) twice-daily (BID) from Cycle 1 Day 1 onwards. In subjects 
undergoing Cycle 1 PK assessment, tucatinib will not be administered in the morning; the first dose will be in 
the evening, after all PK samples have been collected.  
A trastuzumab 6 mg/kg IV loading dose will be administered on Cycle 1 Day 1, followed by trastuzumab 
4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter. Trastuzumab is not to be 
administered subcutaneously.  
Ramucirumab 8 mg/kg will be administered IV on Days 1 and 15 of each cycle. 
Paclitaxel will be administered on Days 1, 8, and 15 of each cycle. The paclitaxel dose will be as follows: 
• Paclitaxel dose optimization stage: Planned paclitaxel dose levels are 60 and 80 mg/m² IV 
• Dose Expansion stage: recommended dose determined in the dose optimization stage  
Alternative dose levels/schedules may be evaluated, as recommended by the SMC. 
Phase 3 
 Arm 3A 
Tucatinib 300 mg PO BID starting on Day 1 of Cycle 1. 
A trastuzumab 6 mg/kg IV loading dose will be administered on Cycle 1 Day 1, followed by trastuzumab 
4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter. Trastuzumab is not to be 
administered subcutaneously.  
Ramucirumab 8 mg/kg will be administered IV on Days 1 and 15 of each cycle. 
Paclitaxel will be administered on Days 1, 8, and 15 of each cycle at the recommended dose determined in the 
Phase 2. 
 Arm 3B 
Tucatinib placebo PO BID from Cycle 1 Day 1 onwards 
Trastuzumab placebo in an IV loading dose on Cycle 1 Day 1, followed by trastuzumab placebo IV on Cycle 1 
Day 15 and then Days 1 and 15 of each cycle thereafter 
Ramucirumab 8 mg/kg IV on Days 1 and 15 of each cycle. 
Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of each cycle  
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Seagen Inc. - Confidential 
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Arm 3C 
Tucatinib 300 mg PO BID from Cycle 1 Day 1 onwards 
Trastuzumab placebo in an IV loading dose on Cycle 1 Day 1, followed by trastuzumab placebo IV on Cycle 1 
Day 15 and then Days 1 and 15 of each cycle thereafter 
Ramucirumab 8 mg/kg IV on Days 1 and 15 of each cycle. 
Paclitaxel on Days 1, 8, and 15 of each cycle at the recommended dose determined in the Phase 2 
Duration of Treatment 
Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, death, or 
study closure. If a study drug (tucatinib/placebo, trastuzumab/placebo, ramucirumab, or paclitaxel) is 
discontinued, study treatment can continue with remaining study drug(s). 
In the absence of clear evidence of radiographic progression per RECIST version 1.1, all efforts should be made 
to continue treatment until unequivocal evidence of radiologic progression per RECIST version 1.1 occurs. No 
crossover will be allowed.  
Efficacy Assessments 
Disease response will be assessed by the investigator (in the Phase 2 and 3 portions) and the BICR (in the 
Phase 3 portion only) according to RECIST version 1.1. 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), 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 magnetic resonance imaging (MRI) scans may also be used as appropriate, as well as additional imaging 
of any other known sites of disease (e.g., nuclear bone scan imaging for bone lesions). For each subject, the 
same imaging modality as used at baseline should be used throughout the study. Disease assessments will be 
done at screening, and every 6 weeks for the first 36 weeks then every 9 weeks, irrespective of dose holds or 
interruptions. Subjects that discontinue study treatment for reasons other than documented progressive disease 
will continue to have disease assessments every 9 weeks until the occurrence of documented progression per 
RECIST version 1.1, death, withdrawal of consent, or study closure. After disease progression is documented, 
subjects will be followed every 12 weeks for survival and further anti-cancer therapy.  
Pharmacokinetic Assessments  
Blood samples for tucatinib, ONT-993, paclitaxel, and paclitaxel metabolite PK assessments will be collected at 
protocol-defined timepoints (see PK Sampling Schedule). Tucatinib and ONT-993 concentrations will be 
sampled on Cycle 1 Day 8 and Cycle 2 Day 1, and concentrations of paclitaxel and its metabolites will be 
sampled on Cycle 1 Days 1 and 8 and Cycle 2 Day 1, in all subjects in the paclitaxel dose optimization stage 
and in the first 6 subjects in the Phase 2 dose expansion stage with gastrectomy. Subjects with a gastrectomy 
can come from either Cohort 2A or Cohort 2B. In all subjects in the Phase 2 and Phase 3 portions of the study, 
tucatinib trough drug concentrations will be sampled predose on Day 1 of Cycles 2 to 6. Plasma concentrations 
of tucatinib, paclitaxel, and their metabolites will be determined using validated liquid 
chromatography (LC)-mass spectrometry (MS)/MS methods. PK parameters of tucatinib, paclitaxel, and their 
respective metabolites will be calculated using standard noncompartmental methods. PK parameters to be 
estimated may include, but are not limited to: AUClast, Cmax, Ctrough, Tmax, and MRAUC. 
PRO and HCRU Assessments 
The EORTC QLQ-C30, EORTC QLQ- OG25, and EQ-5D-5L patient-reported outcome measures will be 
administered to assess GEC symptoms and HRQoL/health status information. PROs will be assessed, in the 
Phase 3 portion, predose on Cycle 1 Day 1, predose on Day 1 of every second cycle (Cycles 2, 4, 6, etc.) until 
discontinuation of all study treatment, at the end-of-treatment (EOT) visit, and at each follow-up visit until the 
occurrence of documented progression, death, withdrawal of consent, or study closure. HCRU data will also be 
collected during treatment and follow-up, including procedures that occur on study, length of stay, 
hospitalizations, ED visits, planned/unplanned provider visits, medication use, radiology, and other treatments 
or procedures. 
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Biomarker Assessments  
HER2 status will be determined by blood-based NGS assay or IHC/ISH assay of a tumor tissue sample (IHC3+ 
or IHC2+/ISH+) at screening. Additional biomarker assessments may include HER2 status by tissue-based 
NGS as well as an exploratory assessment of HER2 mutations or other mutations as potential biomarkers of 
response. Additional exploratory analyses including but not limited to IHC and NGS analysis may be performed 
to interrogate biomarkers that are associated with tumor growth, survival, and resistance to targeted 
therapeutics. This assessment may enable the correlation of additional biomarkers with treatment outcome and 
may ultimately guide or refine patient selection strategies to better match tucatinib regimens with tumor 
phenotype/genotype in the future.  
Safety Assessments 
Safety assessments will include the surveillance and recording of AEs and SAEs, physical examination 
findings, vital signs including weight, electrocardiograms (ECGs), concomitant medications, pregnancy testing, 
and laboratory tests. Assessment of cardiac ejection fraction will be performed using MUGA scan or 
echocardiogram. 
Statistical Methods 
Sample Size Considerations 
Phase 2: 
The preliminary activity of the study regimen will be formally evaluated in approximately 
30 response-evaluable subjects from the dose optimization stage or the dose expansion stage (Cohort 2A) who 
are HER2+ by the blood-based NGS assay and who were treated at the paclitaxel recommended dose. 
The Phase 3 may be initiated if the observed ORR per investigator is 36%. With the sample size of 30, it is 
expected that at least 11 responders will be observed if the underlying ORR is 36%. The point estimate and 
95% CI for ORR under different underlying ORR for the sample size of 30 is as follows: 
ORR 
Number of responses in 30 subjects 
Lower bound of 95% CI 
Upper bound of 95% CI 
30% 
9 
14.7% 
49.4% 
36% 
11 
19.4% 
55.5% 
40% 
12 
22.7% 
59.4% 
47% 
14 
28.6% 
66.0% 
50% 
15 
31.3% 
68.7% 
 
Response-evaluable subjects in the Phase 2 include all subjects who meet all following criteria: (1) had baseline 
disease assessment, and (2) received study treatment, and (3) had post baseline assessment or discontinued 
treatment due to documented disease progression, clinical progression, treatment-related AEs, or death.  
Phase 3: 
The sample size for this portion of study was calculated based on maintaining 90% power for the dual primary 
endpoint of PFS with an alpha of 0.02 and 88% power for the dual primary endpoint of OS with an alpha of 
0.03. For PFS, 317 events from Arm 3A or 3B are required with 90% power to detect a hazard ratio of 0.67 
(4.5 months median PFS in Arm 3B versus 6.75 months in Arm 3A) using a 2-sided log-rank test and alpha 
of 0.02. For OS, 354 events from Arm 3A or 3B are required with 88% power to detect a hazard ratio of 0.70 
(10 months median OS in Arm 3B versus 14.3 months in Arm 3A) using a 2-sided log-rank test and alpha 
of 0.03. The 2 primary endpoints will be evaluated using parallel testing, with alpha recycling if only one of 
them meets statistical significance.  
 
Approximately 500 subjects will be randomized in approximately an 8:8:1 ratio to Arm 3A, Arm 3B, or 
Arm 3C. Approximately 470 subjects are expected to be randomized to the formal comparison of Arm 3A and 
Arm 3B. Assuming an accrual period of 30 months and a 5% yearly drop-out rate, it is expected that 317 PFS 
events and 354 OS events out of the 470 subjects will be observed approximately 25 and 39 months after first 
subject randomized, respectively. 
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Interim Analyses 
The SMC will undertake safety and PK analyses once the first 6 subjects evaluable for DLT in each dose level 
in the paclitaxel dose optimization stage have been followed for at least 1 cycle. The SMC will conduct 
additional analyses of safety and PK should a dose level be expanded to include a total of 9 subjects. If 
alternative paclitaxel dose levels/schedule are evaluated, the SMC will undertake similar assessments. 
In the Phase 3, there is no formal interim analysis planned for PFS. An interim efficacy analysis for OS is 
planned at the time of final analysis for PFS. Approximately 61% of the total OS events are expected to have 
occurred by the time of the interim analysis. The stopping boundary will be determined using Lan-DeMets 
spending functions with O'Brien and Fleming boundaries.  
Analysis Methods 
For Phase 2, "treatment group" will designate each dose level evaluated in the Phase 2 for analyses done in the 
All-Treated analysis set. For analyses using the Recommended Dose analysis set, 2 treatment groups will be 
presented: 1) subjects with HER2+ disease according to blood-based NGS assay treated at the paclitaxel 
recommended dose in the dose optimization stage or Cohort 2A, and 2) subjects who have HER2-negative 
disease according to blood-based NGS but HER2+ disease according to IHC/ISH assay of a tumor tissue sample 
treated at the paclitaxel recommended dose in the dose optimization stage or Cohort 2B.  
For Phase 3, Arms 3A and 3B will be compared in the ITT analysis set and the Safety Analysis set; Arm 3C 
will be separately evaluated in these analysis sets. 
In the Phase 2, efficacy will be summarized by treatment group in the Recommended Dose analysis set; safety 
will be summarized by treatment group in the All-Treated analysis set. In the Phase 3, efficacy and PROs will 
be summarized by treatment group in the ITT analysis set; safety will be summarized by treatment group in the 
Safety Analysis set. 
In the Phase 2, ORR, confirmed ORR, DOR, DCR and PFS per investigator will be summarized by treatment 
group. In the Phase 3, for the primary endpoints of PFS per investigator and OS, Arm 3A and Arm 3B will be 
compared using a 2-sided stratified log-rank test. Estimation of the hazard ratio will be based upon the stratified 
Cox regression model. PFS per investigator and OS will also be summarized using the Kaplan-Meier method, 
which will be used to estimate the time to event curves, including the median and milestone estimates. All 
subjects randomized to Arms 3A and 3B in the Phase 3 portion of the study will be included in the primary 
analysis of PFS and OS.  
If only one of the two primary endpoints are statistically significant, the unused alpha can be passed to the other 
one. If both PFS per investigator and OS are statistically significant, then confirmed ORR per investigator 
among subjects with measurable disease in the Phase 3 portion will be formally compared between two 
treatment arms at the two-sided alpha level of 0.05, using a stratified Cochran-Mantel-Haenszel test. 
The other secondary efficacy endpoints for the Phase 3 portion, including PFS, ORR per investigator, confirmed 
ORR per BICR, and DOR and DCR per BICR and per investigator, will be summarized by treatment arm. The 
PFS per investigator, OS, and confirmed ORR per investigator will be summarized separately for Arm 3C.  
In the Phase 3, assessments based on the EORTC-QLQ-C30, EORTC QLQ OG25, EQ 5D 5L and HCRU data 
will summarized using descriptive statistics by treatment group for Arms 3A and 3B of the ITT set. PRO scores 
will be analyzed using longitudinal models. All subscales and individual item scores will be tabulated. 
Descriptive summaries of observed data at each scheduled assessment timepoint may be presented. Time to 
deterioration will be assessed in specific pre-specified single items from either the EORTC QLQ-C30 or 
EORTC QLQ OG25; deterioration is defined as a 10-point increase from baseline in the symptom scales and a 
10-point decrease from baseline for overall HRQoL. 
Safety will be assessed through summaries of AEs, changes in laboratory test results, and changes in cardiac 
ejection fraction results. AEs will be classified by system organ class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA); AE severities will be classified using the CTCAE 
version 5.0 criteria. All collected AE data will be listed.  
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Worst post-baseline laboratory values (hematology, coagulation, chemistry, and liver enzyme tests) and change 
from baseline will be summarized. Abnormal laboratory values (relative to respective normal ranges) will be 
flagged in listings. The frequency and percentage of subjects with post-baseline clinically significant vital signs 
will be summarized. Cardiac ejection fraction data will be summarized for the all-treated subjects in Phase 2, by 
initial dose level, and for the Phase 3 by treatment group. 
Extent of exposure for study drugs including frequency of dose holding, dose reductions, and dose 
discontinuations, as well as treatment compliance (percent of actual to planned dosing) will be summarized. 
Statistical analysis methods for PK will include descriptive statistics on plasma concentrations and PK 
parameters, as well as exploratory analysis of the geometric mean ratios and 90% CIs of AUClast and Cmax for 
paclitaxel and its metabolites between Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1, and exploratory 
analysis of the geometric mean ratios and 90% CIs of tucatinib and ONT-993 between Cycle 1 Day 8 and 
Cycle 2 Day 1, and between subjects with and without gastrectomy. 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................................... 19 
1 
INTRODUCTION ......................................................................................................................................... 22 
1.1 
HER2+ Gastroesophageal Cancers ..................................................................................................... 22 
1.2 
Tucatinib ............................................................................................................................................. 23 
2 
OBJECTIVES ............................................................................................................................................... 24 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 27 
3.1 
Summary of Study Design .................................................................................................................. 27 
3.1.1 
Phase 2 ................................................................................................................................. 28 
3.1.2 
Phase 3 ................................................................................................................................. 32 
3.1.3 
Dose-Limiting Toxicity ........................................................................................................ 33 
3.1.4 
Safety Monitoring Committee .............................................................................................. 34 
3.1.5 
Independent Data Monitoring Committee ............................................................................ 34 
3.1.6 
Stopping Criteria .................................................................................................................. 34 
3.1.7 
End of Study ......................................................................................................................... 35 
3.1.8 
Method of Assigning Subjects to Treatment Groups ........................................................... 35 
3.1.9 
Blinding and Unblinding ...................................................................................................... 35 
3.2 
Discussion and Rationale .................................................................................................................... 36 
3.2.1 
Rationale for Study Design .................................................................................................. 36 
3.2.2 
Rationale for Combination of Tucatinib and Trastuzumab .................................................. 37 
3.2.3 
Rationale for Selection of Doses .......................................................................................... 38 
4 
STUDY POPULATION................................................................................................................................ 42 
4.1 
Inclusion Criteria ................................................................................................................................ 42 
4.2 
Exclusion Criteria ............................................................................................................................... 44 
4.3 
Childbearing Potential ........................................................................................................................ 47 
4.4 
Removal of Subjects from Therapy or Assessment ............................................................................ 47 
4.4.1 
Discontinuation of Study Treatment .................................................................................... 47 
4.4.2 
Subject Withdrawal from Study ........................................................................................... 48 
5 
TREATMENTS ............................................................................................................................................ 48 
5.1 
Treatments Administered.................................................................................................................... 48 
5.1.1 
Investigational Products ....................................................................................................... 49 
5.1.2 
Standard of Care ................................................................................................................... 52 
5.2 
Dose Modifications............................................................................................................................. 54 
5.2.1 
Tucatinib/placebo Dose Modifications ................................................................................. 55 
5.2.2 
Trastuzumab/placebo Dose Modifications ........................................................................... 56 
5.2.3 
Ramucirumab Dose Modifications ....................................................................................... 58 
5.2.4 
Paclitaxel Dose Modifications .............................................................................................. 60 
5.3 
Required Premedication and Postmedication ..................................................................................... 62 
5.4 
Concomitant Therapy ......................................................................................................................... 62 
5.4.1 
Allowed Concomitant Therapy ............................................................................................ 62 
5.4.2 
Prohibited Concomitant Therapy ......................................................................................... 63 
5.4.3 
Management of Overdose .................................................................................................... 64 
5.5 
Treatment Compliance ....................................................................................................................... 64 
6 
STUDY ACTIVITIES ................................................................................................................................... 65 
6.1 
Schedule of Events ............................................................................................................................. 65 
6.2 
Screening Visit (Days –28 to -1) ........................................................................................................ 65 
6.2.1 
Baseline Visit (Days –7 to 1) ............................................................................................... 66 
6.3 
Randomization (Days –5 to 1) ............................................................................................................ 66 
6.4 
Treatment Period (28-day cycles) ....................................................................................................... 66 
6.4.1 
Cycle 1 Day 1 ....................................................................................................................... 66 
6.4.2 
Cycle 1 Day 8 (±1 day) ........................................................................................................ 67 
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6.4.3 
Cycle 1 Day 15 (±1 day) ...................................................................................................... 68 
6.4.4 
Cycle 1 Day 22 (±1 day) ...................................................................................................... 68 
6.4.5 
Cycles >1 Day 1 (-1 to +3 days) ........................................................................................... 68 
6.4.6 
Cycles >1 Day 8 (±1 day) ..................................................................................................... 69 
6.4.7 
Cycles >1 Day 15 (±1 day) ................................................................................................... 69 
6.4.8 
Every 6 Weeks as Determined by Cycle 1 Day 1, through Week 36, then Every 9 Weeks 
(±7 days) ............................................................................................................................... 70 
6.4.9 
Every 12 Weeks (±14 days) ................................................................................................. 70 
6.5 
End of Treatment Visit (30 to 37 days after last dose of any study drug) .......................................... 70 
6.6 
Follow-up ........................................................................................................................................... 71 
6.6.1 
Follow-up Until Disease Progression (At Least Every 9 Weeks ±1 week) .......................... 71 
6.6.2 
Survival Follow-up (Every 12 Weeks After Disease Progression ±2 weeks) ...................... 72 
6.7 
End of Study/End of Follow-up .......................................................................................................... 72 
7 
STUDY ASSESSMENTS ............................................................................................................................. 73 
7.1 
Screening/Baseline Assessments ........................................................................................................ 73 
7.1.1 
Evaluation of HER2 Status at Screening .............................................................................. 73 
7.2 
Response/Efficacy Assessments ......................................................................................................... 74 
7.3 
Pharmacokinetic Assessments ............................................................................................................ 75 
7.4 
Biomarker Studies .............................................................................................................................. 77 
7.5 
Biospecimen Repository ..................................................................................................................... 77 
7.6 
Healthcare Resource Utilization ......................................................................................................... 77 
7.7 
Patient-Reported Outcomes ................................................................................................................ 77 
7.7.1 
EORTC QLQ-C30 ................................................................................................................ 78 
7.7.2 
EORTC QLQ-OG25 ............................................................................................................ 78 
7.7.3 
EQ-5D-5L – Utility Measurement........................................................................................ 78 
7.8 
Safety Assessments............................................................................................................................. 79 
7.8.1 
Adverse Events ..................................................................................................................... 79 
7.8.2 
Vital Signs ............................................................................................................................ 85 
7.8.3 
Clinical Laboratory Tests ..................................................................................................... 85 
7.8.4 
Physical Examination ........................................................................................................... 86 
7.8.5 
Pregnancy Testing ................................................................................................................ 86 
7.8.6 
Cardiac Function .................................................................................................................. 86 
7.9 
Appropriateness of Measurements...................................................................................................... 87 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 88 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 88 
8.2 
Data Management Procedures ............................................................................................................ 88 
8.3 
Access to Source Data ........................................................................................................................ 89 
8.4 
Accuracy and Reliability of Data........................................................................................................ 89 
8.5 
Quality Assurance Procedures ............................................................................................................ 89 
8.6 
Data Handling and Record Keeping ................................................................................................... 89 
8.6.1 
Data Handling ...................................................................................................................... 89 
8.6.2 
Investigator Record Retention .............................................................................................. 90 
9 
DATA ANALYSIS METHODS ................................................................................................................... 91 
9.1 
Determination of Sample Size ............................................................................................................ 91 
9.1.1 
Phase 2 ................................................................................................................................. 91 
9.1.2 
Phase 3 ................................................................................................................................. 91 
9.2 
Study Endpoint Definitions ................................................................................................................ 92 
9.2.1 
PFS ....................................................................................................................................... 92 
9.2.2 
Overall Survival ................................................................................................................... 92 
9.2.3 
Objective Response Rate ...................................................................................................... 92 
9.2.4 
Duration of Response ........................................................................................................... 92 
9.2.5 
Disease Control Rate ............................................................................................................ 93 
9.2.6 
Exploratory Endpoints .......................................................................................................... 93 
9.3 
Statistical and Analytical Plans .......................................................................................................... 93 
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9.3.1 
General Considerations ........................................................................................................ 94 
9.3.2 
Subject Disposition .............................................................................................................. 97 
9.3.3 
Subject Characteristics ......................................................................................................... 97 
9.3.4 
Concomitant, and Further Therapy ....................................................................................... 97 
9.3.5 
Exposure ............................................................................................................................... 97 
9.3.6 
Efficacy Analyses ................................................................................................................. 98 
9.3.7 
Pharmacokinetic Analyses ................................................................................................... 99 
9.3.8 
Biomarker Analyses ............................................................................................................. 99 
9.3.9 
Patient Reported Outcomes and HCRU Analyses ................................................................ 99 
9.3.10 
Safety Analyses .................................................................................................................. 100 
9.3.11 
Interim Analyses ................................................................................................................ 101 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ............... 102 
10.1 Informed Consent ............................................................................................................................. 102 
10.2 Ethical Review .................................................................................................................................. 102 
10.3 Regulatory Considerations................................................................................................................ 103 
10.3.1 
Investigator Information ..................................................................................................... 103 
10.3.2 
Protocol Amendments and Study Termination .................................................................. 103 
10.4 Study Documentation, Privacy and Records Retention .................................................................... 103 
10.5 Clinical Trial Agreement .................................................................................................................. 103 
11 REFERENCES ............................................................................................................................................ 104 
APPENDIX A: 
SCHEDULE OF EVENTS ................................................................................................. 109 
APPENDIX B: 
PERFORMANCE STATUS SCALES CONVERSION .................................................... 111 
APPENDIX C: 
GUIDANCE ON CONTRACEPTION .............................................................................. 112 
APPENDIX D: 
CYP3A INDUCERS AND THEIR ELIMINATION HALF-LIVES ................................. 113 
APPENDIX E: 
CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION HALF-LIVES........ 114 
APPENDIX F: 
CLINICAL SUBSTRATES FOR CYP3A-MEDIATED METABOLISM ........................ 115 
APPENDIX G: 
EORTC QLQ-C30 .............................................................................................................. 116 
APPENDIX H: 
EORTC QLQ-OG25 .......................................................................................................... 118 
APPENDIX I: 
EQ-5D-5L .......................................................................................................................... 120 
APPENDIX J: 
INVESTIGATOR SIGNATURE PAGE ............................................................................ 123 
APPENDIX K: 
DOCUMENT HISTORY ................................................................................................... 124 
SUMMARY OF CHANGES IN AMENDMENT 1 ........................................................................................... 125 
SUMMARY OF CHANGES IN AMENDMENT 2 ........................................................................................... 130 
 
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LIST OF IN-TEXT TABLES 
Table 1: 
Objectives and corresponding endpoints (Phase 2) ....................................................................... 24 
Table 2: 
Objectives and corresponding endpoints (Phase 3) ....................................................................... 25 
Table 3: 
Treatment schedule ........................................................................................................................ 49 
Table 4: 
Criteria for paclitaxel treatment on Day 1, 8, and 15 of each cycle ............................................... 54 
Table 5: 
Tucatinib/placebo: Recommended dose reduction schedule for adverse events ........................... 55 
Table 6: 
Dose modifications for clinical adverse events related to tucatinib/placebo ................................. 56 
Table 7: 
Dose modifications of tucatinib/placebo for liver enzyme abnormalities, regardless of relationship 
to tucatinib/placebo........................................................................................................................ 56 
Table 8: 
Trastuzumab and trastuzumab placebo dose modification guidelines for left ventricular 
dysfunction .................................................................................................................................... 57 
Table 9: 
Ramucirumab: Recommended dose reduction schedule for adverse events .................................. 58 
Table 10: 
Dose modifications for clinical adverse events ............................................................................. 59 
Table 11: 
Paclitaxel dose modifications for clinical adverse events related to paclitaxel ............................. 61 
Table 12: 
Paclitaxel dose modifications for hematological abnormalities, regardless of relationship to 
paclitaxel........................................................................................................................................ 61 
Table 13: 
Paclitaxel dose modification guidelines for liver enzyme abnormalities, regardless of relationship 
to paclitaxel ................................................................................................................................... 61 
Table 14: 
Paclitaxel premedication ................................................................................................................ 62 
Table 15: 
PK and biomarker sample collection timepoints: All subjects in Phase 2 and Phase 3 ................. 76 
Table 16: 
PK sample collection timepoints: Phase 2 paclitaxel dose optimization stage and first 6 subjects 
with a gastrectomy in Phase 2 dose expansion stage ..................................................................... 76 
Table 17: 
Expected 95% CI under different underlying true ORRs for a sample size of 30 ......................... 91 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study visits and overall study design ............................................................................................. 28 
Figure 2: 
Phase 2 design ............................................................................................................................... 31 
Figure 3: 
Phase 3 design ............................................................................................................................... 32 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUClast 
AUC to the time of the last quantifiable concentration 
β-hCG 
beta human chorionic gonadotropin  
BAP 
biomarker analysis plan  
BICR 
blinded independent central review 
BID 
twice daily 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CDX 
cell line-derived xenograft 
CHF 
congestive heart failure 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum observed concentration 
CR 
complete response 
mCRC 
metastatic colorectal cancer 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
Ctrough 
trough concentration 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic CRF 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of treatment 
GEC 
gastric or gastroesophageal junction adenocarcinoma 
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GFR 
glomerular filtration rate 
HCRU 
health care resource utilization 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
HER2-positive 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee  
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB/IEC 
Institutional review board/independent ethics committee 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ISO 
International Organization for Standardization 
ITT 
intent-to-treat 
IV 
intravenous 
LC 
liquid chromatography 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
mBC 
metastatic breast cancer 
MDRD 
Modification of Diet in Renal Disease [study] 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
metabolic ratio based on AUC 
MRI 
magnetic resonance imaging 
MS 
mass spectrometry 
MSI 
microsatellite instability 
MUGA 
multi-gated acquisition 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSAID 
nonsteroidal anti-inflammatory agents 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PCR 
polymerase chain reaction 
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PD-1 
programmed death receptor-1 
PDX 
patient-derived xenograft 
PET 
positron emission tomography  
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
orally 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
PRO 
patient-reported outcomes 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QLQ 
quality of life questionnaire 
RECIST 
Response evaluation criteria in solid tumors 
RPLS 
reversible posterior leukoencephalopathy syndrome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Scr 
serum creatinine 
SMC 
Safety Monitoring Committee 
SUSAR 
suspected unexpected serious adverse reactions 
T-DM1 
trastuzumab emtansine 
T-DXd 
trastuzumab deruxtecan 
TGI 
tumor growth inhibition 
TKI 
tyrosine kinase inhibitor 
Tmax 
time of the maximum observed concentration 
ToGA 
Trastuzumab for Gastric Cancer 
ULN 
upper limit of normal 
UPC 
urine protein/creatinine 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 
VEGFR-2 
vascular endothelial growth factor receptor-2 
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1 
INTRODUCTION  
1.1 HER2+ Gastroesophageal Cancers 
Gastric cancer is the 6th most common cancer and the 2nd leading cause of cancer-related 
death worldwide (Bray 2018). Incidence rates for gastric cancer vary based on geographic 
region, with the highest rates reported in Eastern Asia, Eastern Europe, and South America, 
and lower rates reported in Northern Europe, North America, and Africa. The vast majority 
of gastric cancers are adenocarcinomas, and when combined with gastroesophageal junction 
adenocarcinomas, are often referred to as gastroesophageal cancers. The prognosis for early 
stage gastric or gastroesophageal junction adenocarcinomas (GEC) is favorable, with 5-year 
survival rates exceeding 90% following surgery and chemotherapy. Unfortunately, the 
majority of cases are diagnosed at an advanced stage, where the median overall survival (OS) 
is less than 12 months (Digklia 2016; Song 2017). 
Approximately 12%-23% of GEC overexpresses the human epidermal growth factor 
receptor 2 (HER2) (Tanner 2005; Yan 2010; Chua 2012; Gomez-Martin 2012; 
Janjigian 2012; Kunz 2012). Encoded by the ERBB2 gene, 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. HER2 homo- or heterodimerization results in the activation 
of multiple signaling pathways, 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).  
While the prognostic value of HER2 status in GEC is not clear, patients with advanced stage 
disease who are HER2-positive (HER2+) may benefit from the addition of trastuzumab (a 
HER2-directed monoclonal antibody [mAb]) to chemotherapy as first-line treatment 
(Bang 2010). In the Phase 3 Trastuzumab for Gastric Cancer (ToGA) study, 594 subjects 
were randomized 1:1 to receive chemotherapy (cisplatin with either capecitabine or 
fluorouracil) alone or in combination with trastuzumab. A statistically significant 
improvement in median OS was observed in subjects who received trastuzumab with 
chemotherapy (13.8 months) versus chemotherapy alone (11.1 months) (hazard ratio [HR] 
0.74; 95% CI 0.60-0.91, p=0.0046). Based on these results, the use of trastuzumab in 
combination with a platinum-agent and fluoropyrimidine is globally recognized as standard 
first-line therapy in patients with HER2+ advanced GEC. 
In second-line GEC, the vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) 
inhibitor ramucirumab in combination with paclitaxel has become a standard of care 
(Lopez 2018). The Phase 3 RAINBOW study evaluated ramucirumab plus paclitaxel versus 
paclitaxel in subjects progressing on or soon after first-line treatment with a platinum agent 
and a fluoropyrimidine, with or without an anthracycline (Wilke 2014). Significant benefits 
were reported for the combination therapy in terms of OS (median 9.6 months 
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[95% CI: 8.5-10.8 months] for the combination versus 7.4 months [95% CI: 6.3–8.4 months] 
for paclitaxel alone), progression-free survival (PFS; median 4.4 months 
[95% CI: 4.2-5.3 months] versus 2.9 months [95% CI: 2.8–3.0]), and objective response rate 
(ORR; 28% [95% CI: 23%–33%] versus 16% [95% CI: 13%–20%]). The programmed death 
receptor-1 (PD-1) inhibitor pembrolizumab (in microsatellite instability (MSI)-high or 
mismatch repair-deficient disease) and chemotherapy (either as single-agent [paclitaxel, 
docetaxel, or irinotecan], or combination therapy [fluorouracil and irinotecan (FOLFIRI)]) 
are also recognized treatment options in this line of therapy. Response rates for these 
treatments range from 20% to 30%, with median OS ranging from 6 to 9 months. 
(Wesolowski 2009; Shitara 2018).  
While several randomized studies have evaluated targeted HER2 therapies in the second-line 
setting, none have demonstrated an OS benefit over standard-of-care chemotherapy 
(Satoh 2014; Thuss-Patience 2017; Makiyama 2020). A potential explanation for the failure 
of anti-HER2 therapies in this setting may lie with the higher incidence of intratumoral 
heterogeneity of HER2 in gastric cancer than in breast cancer (Ruschoff 2012; Zhao 2019). 
Of particular note is the high frequency (approximately 30 to 60%) of conversion from 
HER2+ to HER2-negative disease following trastuzumab-based first-line therapy 
(Janjigian 2015; Pietrantonio 2016; Kashiwada 2018). However, in the third-line setting, the 
DESTINY-Gastric01 study has demonstrated an OS benefit for trastuzumab deruxtecan 
(T-DXd) over physician's choice of paclitaxel or irinotecan monotherapy (Shitara 2020), 
leading to approval in trastuzumab-pretreated patients. 
To improve clinical outcomes, newer strategies are needed for patients with advanced 
HER2+ GEC in the second-line setting. 
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) (formerly known as ARRY-380 and 
ONT-380) is an orally 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. The frequent overexpression 
of HER2 in breast, colorectal, and gastric cancer and the tumor dependence on HER2 
supports the use of tucatinib in these diseases. Tucatinib is being developed as a treatment for 
patients with advanced cancers that demonstrate HER2 overexpression. 
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. 
MOUNTAINEER-02 is an international, multicenter Phase 2/3 study in subjects with 
locally-advanced unresectable or metastatic HER2+ GEC who have received prior treatment 
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with a HER2-directed antibody, and have received at least 1 prior line of therapy in the 
advanced disease setting. See Section 3.2 for the rationale for the study design, treatment 
regimen, and selection of doses. 
2 
OBJECTIVES 
The Phase 2 portion of this study will determine the recommended dose of paclitaxel when 
administered in combination with tucatinib, trastuzumab, and ramucirumab, evaluate the 
safety and tolerability of tucatinib in combination with trastuzumab, ramucirumab, and 
paclitaxel, and evaluate the activity, and pharmacokinetics (PK) of the regimen in subjects 
with locally-advanced unresectable or metastatic HER2+ GEC who have received prior 
treatment with a HER2-directed antibody in the locally-advanced unresectable or metastatic 
disease setting. Specific objectives and corresponding endpoints for the study are 
summarized below (Table 1). 
Table 1: 
Objectives and corresponding endpoints (Phase 2) 
Primary Objectives 
Corresponding Endpoints 
● To determine the recommended dose 
of paclitaxel when administered in 
combination with tucatinib, 
trastuzumab, and ramucirumab 
● Frequency of dose-limiting toxicities (DLT) during the first 
cycle of treatment with tucatinib, trastuzumab, ramucirumab, 
and paclitaxel 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with trastuzumab, 
ramucirumab, and paclitaxel  
● Type, incidence, severity, seriousness, and relatedness of 
adverse events (AEs) and laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations 
of tucatinib, paclitaxel, trastuzumab, and ramucirumab 
Secondary Objectives 
Corresponding Endpoints 
● To evaluate the preliminary activity 
of tucatinib in combination with 
trastuzumab, ramucirumab, and 
paclitaxel in subjects with previously 
treated locally-advanced 
unresectable or metastatic GEC that 
is HER2+ according to blood-based 
next generation sequencing (NGS) 
assay of circulating tumor DNA 
(ctDNA) 
● ORR (complete response [CR] or partial response [PR]) per 
Response evaluation criteria in solid tumors (RECIST) version 
1.1 according to investigator assessment 
● Confirmed ORR per RECIST version 1.1 according to 
investigator assessment 
● PFS per RECIST version 1.1 according to investigator 
assessment  
● Duration of response (DOR; CR or PR) per RECIST version 1.1 
according to investigator assessment  
● Disease control rate (DCR; CR or PR or stable disease/non-CR, 
non-progressive disease as best objective response) per RECIST 
version 1.1 according to investigator assessment 
● To evaluate the PK of tucatinib and 
the tucatinib metabolite ONT-993 
● To evaluate the PK of paclitaxel and 
its metabolites in the presence and 
absence of tucatinib 
 
● The PK parameters to be calculated for tucatinib, paclitaxel, and 
their respective metabolites (if applicable) may include but are 
not limited to: area under the plasma concentration-time curve 
(AUC) to the time of the last quantifiable concentration 
(AUClast), maximum observed concentration (Cmax), time of Cmax 
(Tmax), trough concentration (Ctrough), and metabolic ratio based 
on AUC (MRAUC) 
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Exploratory Objectives 
Corresponding Endpoints 
● To evaluate the preliminary activity 
of tucatinib in combination with 
trastuzumab, ramucirumab, and 
paclitaxel in subjects with disease 
that is HER2-negative according to 
blood-based NGS assay but HER2+ 
according to IHC/ISH assay of a 
tumor tissue sample 
● ORR per RECIST version 1.1 according to investigator 
assessment 
● Confirmed ORR per RECIST version 1.1 according to 
investigator assessment 
● PFS per RECIST version 1.1 according to investigator 
assessment  
● Duration of response per RECIST version 1.1 according to 
investigator assessment  
● Disease control rate per RECIST version 1.1 according to 
investigator assessment 
● To evaluate the correlation between 
HER2 alterations as detected by 
blood-based NGS assays and 
standard tissue-based assays 
● Frequency of HER2 alterations according to blood-based NGS 
assay and according to assays on tumor tissue samples obtained 
after progression on the most recent line of therapy  
● To explore correlations between 
blood-based biomarkers and clinical 
outcomes 
● Potential biomarkers of response, resistance, or toxicity may be 
evaluated in blood 
● To evaluate the PK of tucatinib and 
ONT-993 in subjects with and 
without gastrectomy 
● The PK parameters of tucatinib and ONT-993 in subjects with 
and without a gastrectomy may include but are not limited to: 
AUClast, Cmax, Tmax, Ctrough, and MRAUC 
 
The Phase 3 portion will compare the efficacy, safety, patient-reported outcomes (PRO), and 
health care resource utilization (HCRU) of tucatinib and trastuzumab versus placebo in 
combination with ramucirumab and paclitaxel. It will also evaluate the activity of tucatinib 
combined with ramucirumab and paclitaxel. Specific objectives and corresponding endpoints 
for the study are summarized below (Table 2). 
Table 2: 
Objectives and corresponding endpoints (Phase 3) 
Primary Objective 
Corresponding Endpoints 
To compare the efficacy of 
tucatinib and trastuzumab versus 
placebo, in combination with 
ramucirumab and paclitaxel in 
subjects with previously treated, 
locally-advanced unresectable or 
metastatic HER2+ GEC 
Dual primary endpoints 
● OS  
● PFS per RECIST version 1.1 according to investigator assessment 
Key secondary endpoints 
● Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
Other secondary endpoints 
● PFS per RECIST version 1.1 according to blinded independent 
central review (BICR) assessment  
● Confirmed ORR per RECIST version 1.1 according to BICR 
assessment  
● ORR per RECIST version 1.1 according to investigator assessment 
●  ORR per RECIST version 1.1 according to BICR assessment  
● DOR per RECIST version 1.1 according to investigator assessment 
● DOR per RECIST version 1.1 according to BICR assessment  
● DCR per RECIST version 1.1 according to investigator assessment  
● DCR per RECIST version 1.1 according to BICR assessment 
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Secondary Objectives 
Corresponding Endpoints 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with trastuzumab, 
ramucirumab, and paclitaxel 
● Type, incidence, severity, seriousness, and relatedness of AEs and 
laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations of 
tucatinib, trastuzumab, ramucirumab, and paclitaxel  
● To evaluate the anti-tumor 
activity of tucatinib in 
combination with ramucirumab 
and paclitaxel 
Secondary Endpoints 
● Confirmed ORR per RECIST version 1.1 according to investigator 
assessment 
● DOR per RECIST version 1.1 according to investigator assessment 
Exploratory Endpoints 
● OS  
● PFS per RECIST version 1.1 according to investigator assessment 
● PFS per RECIST version 1.1 according to BICR assessment 
● Confirmed ORR per RECIST version 1.1 according to BICR 
assessment 
● ORR per RECIST version 1.1 according to investigator assessment 
● ORR per RECIST version 1.1 according to BICR assessment 
● DOR per RECIST version 1.1 according to BICR assessment 
● DCR per RECIST version 1.1 according to investigator assessment  
● DCR per RECIST version 1.1 according to BICR assessment 
● To assess PROs by treatment arm 
● Time to deterioration of GEC symptoms as assessed by the 
European Organisation for Research and Treatment of Cancer 
(EORTC) quality of life questionnaire (QLQ)-C30 and 
EORTC QLQ-OG25 questionnaires 
●  Change from baseline in health-related quality of life (HRQoL) 
● Utility index values as assessed by the EQ-5D-5L 
Exploratory Objectives 
Corresponding Endpoints 
● To evaluate the safety and 
tolerability of tucatinib in 
combination with ramucirumab, 
and paclitaxel 
● Type, incidence, severity, seriousness, and relatedness of AEs and 
laboratory abnormalities 
● Vital signs and other relevant safety variables 
● Frequency of dose holds, dose reductions, and discontinuations of 
tucatinib, ramucirumab, and paclitaxel 
● To evaluate the PK of tucatinib 
● The PK parameter to be calculated for tucatinib (if applicable) 
includes: Ctrough 
● To explore correlations between 
blood-based biomarkers and 
clinical outcomes 
● Potential biomarkers of response, resistance, or toxicity may be 
evaluated in blood 
● To assess HCRU by treatment 
arm 
● Cumulative incidence of healthcare resource utilization, including 
length of stay, hospitalizations, and emergency department visits 
 
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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is an international, multicenter Phase 2/3 study in subjects with locally-advanced 
unresectable or metastatic HER2+ GEC who have received prior treatment with a 
HER2-directed antibody, and have received 1 prior line of therapy in the advanced disease 
setting.  
The study is composed of the following parts: 
• Open-label Phase 2 portion: 
o 
Paclitaxel dose optimization stage: this single-arm stage will determine the 
recommended dose of paclitaxel when combined with tucatinib, trastuzumab, and 
ramucirumab (see Section 3.1.1.1 for details).  
o 
Dose expansion stage: this 2-cohort stage will enroll subjects to further evaluate the 
safety and activity of the regimen in a total of approximately 30 response-evaluable 
subjects in each cohort, once the recommended paclitaxel dose is determined (see 
Section 3.1.1.2 for details).  
• Randomized, double-blind, placebo-controlled Phase 3 portion: will compare the efficacy 
and evaluate the safety of tucatinib and trastuzumab versus placebo, in combination with 
ramucirumab and paclitaxel, and evaluate the efficacy and safety of tucatinib combined 
with ramucirumab and paclitaxel (see Section 3.1.2 for details). 
 
Dose reductions of tucatinib (or placebo), ramucirumab, and paclitaxel will be allowed. Dose 
reductions of trastuzumab (or placebo) will not be allowed; if trastuzumab cannot be 
restarted after being held for an AE, it must be discontinued. If any study drug is 
discontinued, the subject can continue to receive study treatment with the remaining agents. 
Study treatment (defined as the administration of any of the 4 study drugs, without initiation 
of new anti-cancer treatment) will continue until unacceptable toxicity, disease progression, 
withdrawal of consent, death, or study closure. Disease response and progression will be 
assessed using RECIST version 1.1.  
While on study treatment, radiographic disease evaluations will be done every 6 weeks for 
the first 36 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions 
(Figure 1). All efforts should be made to continue treatment until unequivocal evidence of 
radiologic progression occurs according to RECIST version 1.1. If study treatment is 
discontinued before documentation of disease progression, radiographic evaluations will be 
performed at least every 9 weeks until the occurrence of progression, withdrawal of consent, 
or study closure. After occurrence of disease progression, subjects will continue to be 
followed for survival every 12 weeks, until death, consent withdrawal, or study closure. 
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Figure 1: 
Study visits and overall study design 
 
 
Pac=paclitaxel; plbo=placebo; Ramu=ramucirumab; Tuc=tucatinib; Trast=trastuzumab. 
a 
Subjects in the dose optimization stage will be counted towards the sample size for these cohorts, if they received the 
recommended dose and are response-evaluable. 
 
3.1.1 Phase 2  
3.1.1.1 Paclitaxel Dose Optimization Stage 
In the paclitaxel dose optimization stage of the study, the initial paclitaxel dose will be 
60 mg/m² intravenous (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with 
tucatinib 300 mg orally (PO) twice daily (BID), trastuzumab (6 mg/kg IV loading dose on 
Cycle 1 Day 1, 4 mg/kg IV on Cycle 1 Day 15 and Days 1 and 15 of each cycle thereafter), 
and ramucirumab (8 mg/kg IV on Days 1 and 15).  
Six subjects will initially be enrolled and treated at paclitaxel 60 mg/m² (Figure 2). Subjects 
can have HER2+ disease according to a blood-based NGS assay of ctDNA done at screening 
or immunohistochemistry (IHC)/in situ hybridization (ISH) assay of a tumor tissue sample 
obtained after progression on the most recent line of systemic therapy. Once 6 subjects are 
evaluable for DLT, enrollment will be paused and the Safety Monitoring Committee (SMC) 
will undertake an evaluation of safety and PK (see Section 3.1.4 for details concerning the 
Screening 
28 days 
Enrollment  
(Phase 2) or 
Randomization  
(Phase 3) 
Study treatment 
28-day cycles 
EOT visit 
30-37 days 
after last dose 
Disease assessments 
q6 weeks until 36 weeks, then q9 weeks 
Progression 
follow-up 
q9 weeks until 
progression 
Survival  
follow-up 
q12 weeks after 
progression 
Phase 2 Portion 
Evaluating Tuc + Trast + Ramu + Pac 
Phase 3 Portion 
Paclitaxel dose optimization stage 
Determine Pac recommended dose in 6-18 subjects 
Dose expansion stage 
To evaluate safety and activity of regimen 
Cohort 2A 
30 subjectsa 
HER2+ by blood-based 
NGS assay 
Exploratory Cohort 2B 
30 subjectsa 
HER2-negative by  
blood-based NGS assay, but 
HER2+ by assay of a tumor 
tissue sample 
Randomize subjects who are HER2-positive by  
blood-based NGS assay ~8:8:1 to: 
Arm 3A: Tuc + Trast + Ramu + Pac 
235 subjects 
Arm 3B: Tuc plbo + Trast plbo + Ramu + Pac 
235 subjects 
Arm 3C: Tuc + Trast plbo + Ramu + Pac 
30 subjects 
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SMC). If necessary, additional subjects will be enrolled to replace subjects who are not 
evaluable for DLT (see Section 3.1.3 for the definition of evaluable for DLT).  
In the 6 DLT-evaluable subjects receiving 60 mg/m²: 
● 
If ≤1 DLT are observed in 6 subjects, the paclitaxel dose will be escalated to 
80 mg/m² and evaluated in a further 6 subjects. 
● 
If 2 DLTs are observed in 6 subjects, an additional 3 subjects will be treated at 
60 mg/m², for a total of 9 subjects:  
○ 
If ≤2 DLT are observed in 9 subjects, the paclitaxel dose will be escalated to 
80 mg/m² and evaluated in a further 6 subjects.  
○ 
If >2 DLT are observed in 9 subjects, the evaluation of the regimen will be halted, 
or an alternative dose level/schedule may be recommended by the SMC. 
● 
If >2 DLTs are observed in 6 subjects, the evaluation of the regimen will be halted, or 
an alternative dose level/schedule may be recommended by the SMC. 
In the 6 DLT-evaluable subjects receiving 80 mg/m²: 
● 
If ≤1 DLT are observed in 6 subjects, 80 mg/m² will be the recommended dose. 
● 
If 2 DLTs are observed in 6 subjects, an additional 3 subjects will be treated at 
80 mg/m², for a total of 9 subjects:  
○ 
If ≤2 DLT are observed in 9 subjects, 80 mg/m² will be the recommended dose.  
○ 
If >2 DLT are observed in 9 subjects, the 60 mg/m² paclitaxel dose will be 
declared the recommended dose, and evaluation of the regimen will continue in 
the Dose Expansion stage. 
● 
If >2 DLTs are observed in 6 subjects, the 60 mg/m² paclitaxel dose will be declared 
the recommended dose, and evaluation of the regimen will continue in the Dose 
Expansion stage. 
The SMC may also recommend the inclusion of additional subjects in any dose level or the 
evaluation of an alternative dose level/schedule, if necessary. The SMC will continuously 
monitor subjects for AEs, deaths, other serious adverse events (SAEs), dose modifications, 
and laboratory abnormalities, with a specific focus on DLTs (see Section 3.1.3).  
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3.1.1.2  Dose Expansion Stage 
Following the paclitaxel dose optimization stage, two cohorts will be opened to enroll further 
subjects. Cohort 2A will enroll subjects with HER2+ disease as determined by HER2 
amplification in a blood-based NGS assay of ctDNA performed at a central laboratory at 
screening. The exploratory Cohort 2B will enroll subjects whose disease did not show HER2 
amplification in the blood-based NGS assay, but did show HER2 
overexpression/amplification by IHC and ISH assay of a tumor tissue sample obtained after 
progression on the most recent line of systemic therapy, processed in a Clinical Laboratory 
Improvement Amendments (CLIA)- or International Organization for Standardization 
(ISO)‑accredited laboratory, according to the American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) 2016 guideline for gastroesophageal 
adenocarcinoma (IHC3+ or IHC2+/ISH+).  
For each type of HER2 positivity evaluated (blood-based NGS assay or IHC/ISH assay of a 
tumor tissue sample), approximately 30 response-evaluable subjects who have been treated at 
the recommended paclitaxel dose will be included in Cohort 2A or 2B, in order to further 
evaluate the safety of the study regimen and undertake an initial assessment of anti-tumor 
activity. Subjects who are not evaluable for response will be replaced. See Section 7.2 for the 
definition of response-evaluable in the Phase 2. Subjects in the dose optimization stage will 
be counted towards the sample size for these cohorts, if they received the recommended dose 
and are response evaluable. 
The SMC will evaluate the safety of the study regimen throughout the remainder of the 
Phase 2, in the 2 cohorts. At least 6 subjects with a history of prior gastrectomy (without 
maintenance of the pylorus) will be enrolled in either cohort to evaluate the PK of tucatinib 
and ONT-993 in this population; alternative dose levels/schedules may be explored 
depending on the PK of tucatinib in subjects with gastrectomy.  
A formal efficacy analysis will be undertaken when 30 subjects with HER2+ disease 
according to blood-based NGS assay from either Cohort 2A or the dose optimization stage 
have been treated at the recommended paclitaxel dose, are evaluable for response, and have 
been followed for at least 6 weeks. If the ORR per RECIST v1.1 according to investigator 
assessment is 36%, the SMC may recommend that the Phase 3 evaluation of the regimen be 
initiated in subjects with HER2 amplification in a blood-based NGS assay, given that it is 
safe and tolerable. See Section 9.1.1 for details concerning the formal end-of-Phase 2 
analysis. Enrollment in Cohort 2B can continue after the initiation of the Phase 3. 
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Figure 2: 
Phase 2 design 
 
a. 
Tucatinib 300 mg BID PO; trastuzumab 6 mg/kg on Cycle 1 Day 1, then 4 mg/kg in subsequent infusions; 
ramucirumab 8 mg/kg per infusion; paclitaxel 60 or 80 mg/m² per infusion, or an alternate dose/schedule upon 
recommendation of the SMC. 
b. 
HER2+ disease documented since progression of the most recent line of systemic therapy. 
c. 
Subjects in the dose optimization stage will be counted towards the sample size for these cohorts, if they received the 
recommended dose and are response-evaluable. 
d. 
Response-evaluable subjects will have a baseline disease assessment, receive study treatment, and have a post-baseline 
assessment or discontinue due to documented disease progression, clinical progression, treatment-related AEs, or death. 
Tucatinib PO BID + Trastuzumab IV Day 1, 15 + Ramucirumab IV Day 1, 15 + Paclitaxel Day 1, 8, 15 q28 days a 
Enroll 6 subjects at paclitaxel 60 mg/m² 
Paclitaxel recommended dose is 80 mg/m²  
SMC recommends discontinuation 
of study or evaluation of alternate 
dose levels/schedules  
Enroll approximately 30 response-evaluable subjects,c,d for a total of approximately 
30 subjects treated at the recommended dose, including subjects from dose optimization. 
Further evaluate safety and undertake an initial assessment of anti-tumor activity 
Paclitaxel dose optimization stage 
Dose expansion stage 
ORR per RECIST v1.1 according to investigator assessment in 
response-evaluable subjects 36%? 
Discontinue study 
Open Phase 3 portion 
No 
Yes 
Enroll 6 subjects at paclitaxel 80 mg/m² 
≤1 DLT in first cycle 
Paclitaxel recommended dose is 60 mg/m²  
Cohort 2A: HER2-positive by blood based NGS assayb 
Exploratory Cohort 2B: HER2-negative by blood based NGS assay, HER2+ by IHC/ISH tumor tissue assayb 
Enroll approximately 30 response-evaluable subjects,c,d for a total of approximately 
30 subjects treated at the recommended dose, including subjects from dose optimization. 
Further evaluate safety and undertake an initial assessment of anti-tumor activity 
2 DLT in first cycle 
Enroll 3 more subjects 
>2 DLT in first cycle 
>2 DLT in first cycle 
≤2 DLT in first cycle 
≤1 DLT in first cycle 
2 DLT in first cycle 
Enroll 3 more subjects 
>2 DLT in first cycle 
>2 DLT in first cycle 
≤2 DLT in first cycle 
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3.1.2 Phase 3 
Approximately 500 subjects who have HER2 amplification in a blood-based NGS assay will 
be randomized in approximately an 8:8:1 ratio to either Arm 3A (tucatinib, trastuzumab, 
ramucirumab, and paclitaxel; 235 subjects), Arm 3B (tucatinib placebo, trastuzumab placebo, 
ramucirumab, and paclitaxel; 235 subjects), or Arm 3C (tucatinib, trastuzumab placebo, 
ramucirumab, and paclitaxel; 30 subjects) (Figure 3). Efficacy in Arms 3A and 3B will be 
formally compared to demonstrate the benefit of adding tucatinib plus trastuzumab to 
standard of care ramucirumab plus paclitaxel. Efficacy in Arm 3C will be analyzed 
separately. Randomization will be stratified by region (Asia vs Rest of World), time to 
progression on first-line therapy for locally-advanced unresectable or metastatic disease 
(<6 months vs ≥6 months), and history of prior gastrectomy (yes vs no). Subjects randomized 
to Arm 3B will receive a tucatinib placebo and a trastuzumab placebo; subject randomized to 
Arm 3C will receive a trastuzumab placebo. Subjects, investigators, and staff, and the 
sponsor study team will be blinded to study arm allocation. Subjects who are screened for the 
Phase 3 but are found to be HER2-negative according to the blood-based NGS assay, may be 
enrolled in Cohort 2B of the Phase 2 if it is still enrolling and the subject has HER2-positive 
disease according to assay of a tumor tissue sample obtained after progression on the most 
recent line of therapy. 
In the Phase 3 portion of the study, an Independent Data Monitoring Committee (IDMC) will 
periodically review relevant aggregate safety data and will make recommendations to the 
sponsor on the conduct of the study (see Section 3.1.5 for details concerning the IDMC). 
Safety will also be monitored in an ongoing basis by the sponsor throughout the study. 
Figure 3: 
Phase 3 design 
 
a 
Tucatinib will be administered at 300 mg BID PO; trastuzumab 6 mg/kg will be administered on Cycle 1 Day 1, then 
4 mg/kg in subsequent infusions; ramucirumab will be administered at a dose of 8 mg/kg per infusion; paclitaxel will 
be administered at the recommended dose and schedule determined in the Phase 2 in Arms 3A and 3C and at 80 mg/m² 
in Arm 3B. 
 
Screening/Baseline 
Arm 3A: Investigational agents + Standard of care (235 subjects): 
Tucatinib PO BID + Trastuzumab IV D1, 15 +  
Ramucirumab IV D1, 15 + Paclitaxel IV D1, 8, 15 
q28 days a 
Arm 3B: Placebos + Standard of care (235 subjects): 
Tucatinib placebo PO BID + Trastuzumab placebo IV D1, 15 + 
Ramucirumab IV D1, 15 + Paclitaxel IV D1, 8, 15 
q28 days a 
Randomization 
500 subjects, 
~8:8:1 
HER2-positive 
by blood based 
NGS assay 
Arm 3C: Tucatinib + Standard of care (30 subjects): 
Tucatinib PO BID + Trastuzumab placebo IV D1, 15 + 
Ramucirumab IV D1, 15 + Paclitaxel IV D1, 8, 15 
q28 days
a
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3.1.3 Dose-Limiting Toxicity 
DLTs will be AEs, laboratory abnormalities, or treatment modifications that occur during the 
first cycle of treatment in the Phase 2 paclitaxel dose optimization stage that are related to 
paclitaxel, to tucatinib, or to the combination of tucatinib, trastuzumab, ramucirumab and 
paclitaxel, and that meet any of the criteria listed below. AEs that are attributed only to 
trastuzumab and/or ramucirumab, but not tucatinib or paclitaxel will not be considered DLTs. 
Events for which there is an alternative clinical explanation (e.g., clearly related to an 
intercurrent illness or disease progression), will not be considered DLTs. The severity of AEs 
and laboratory abnormalities will be graded according to the NCI CTCAE Version 5.0. The 
relationship of AEs to study drugs will be determined by the investigator. Subjects who 
experience a DLT may continue on study treatment if treatment discontinuation is not 
required by protocol dose modification criteria (Section 5.2) and the investigator believes it 
to be in the subject's interest. Subjects may resume treatment at a lower dose (i.e., a reduced 
dose of tucatinib, ramucirumab, or paclitaxel) following recovery of the AE to ≤ Grade 1 or 
the baseline grade. Subjects will be considered evaluable for DLT if they received at least 
75% of the planned administrations of each study drug and were followed for at least 1 cycle, 
or if they experienced a DLT during the first cycle. DLT is defined as any of the following: 
Clinical AEs: any of the following AEs if considered related to tucatinib, paclitaxel, or the 
4-drug combination: 
● 
Any AE ≥ Grade 3 except: 
o 
Grade 3 fatigue ≤7 days 
o 
Grade 3 diarrhea, nausea, or vomiting without optimal use of anti-emetics or 
anti-diarrheals 
o 
Grade 3 rash without optimal use of corticosteroids or anti-infectives  
● 
≥ Grade 3 peripheral motor and or sensory neuropathy  
 
Treatment modifications: any of the following due to AEs related to tucatinib, paclitaxel, or 
the 4-drug combination: 
● 
>2 week delay in start of Cycle 2  
● 
Dose delays of >5 days for Day 1, 8, 15 
● 
Dose reduction/discontinuation of tucatinib, ramucirumab, or paclitaxel, or 
discontinuation of trastuzumab  
 
Hematologic 
● 
≥ Grade 3 febrile neutropenia (absolute neutrophil count [ANC] <1.0 × 109/L, with a 
single temperature >38.3°C or a sustained temperature ≥38°C for >1 hour)  
● 
Grade 4 neutropenia (ANC <0.5 × 109/L) for >7 days 
● 
Grade 3 thrombocytopenia (<50 × 109/L) with significant bleeding 
● 
Grade 4 thrombocytopenia (platelet count <25 × 109/L)  
● 
Grade 4 anemia 
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Hepatic: any of the following not due to disease progression or intercurrent illness: 
● 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation 
>5.0 × ULN 
● 
Bilirubin elevation (regardless of transaminases) >3.0 × ULN 
● 
Any instance of AST/ALT elevations >3 × ULN AND total bilirubin elevation 
>2 × ULN  
3.1.4 Safety Monitoring Committee 
The SMC will be responsible for monitoring the safety of subjects in the Phase 2 at regular 
intervals. In particular, the SMC will evaluate DLTs, other safety data, and PK data in the 
paclitaxel dose optimization stage. The SMC will review data on AEs, deaths, other SAEs, 
treatment modifications, 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 paclitaxel dose levels and administration schedules, and make recommendations 
concerning study continuation as planned, protocol amendment, or early discontinuation of 
the study for excessive toxicity. Once the Phase 3 is initiated, the SMC will be discontinued 
and the sponsor will be responsible for monitoring safety data in subjects still on-treatment in 
the Phase 2. 
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. 
3.1.5 Independent Data Monitoring Committee 
The IDMC will be responsible for monitoring the safety of subjects in the Phase 3 at regular 
intervals. The IDMC will review unblinded data including deaths, study treatment and study 
drug discontinuations, dose reductions, AEs, SAEs, and laboratory abnormalities on a regular 
basis. The IDMC will make recommendations to the sponsor regarding the conduct of the 
study, including study continuation as planned or with protocol amendment, or early 
discontinuation of the study for excessive toxicity. An IDMC Charter will outline the 
committee’s composition, members’ roles and responsibilities, and describe IDMC 
procedures. The sponsor will provide a copy of each IDMC recommendation to the 
investigators. 
3.1.6 Stopping Criteria 
Reasons for prematurely terminating the study may include but are not limited to the 
following: 
● 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects, either through a safety review by the sponsor or the SMC, or an 
independent safety assessment by the IDMC. 
● 
Subject enrollment is unsatisfactory. 
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3.1.7 
End of Study 
The study ends when the last subject completes the last visit, last contact, discontinues from 
the study, or is lost to follow-up, whichever occurs first. In addition, the sponsor may 
terminate the study at any time (see Section 10.3.2). 
3.1.8 Method of Assigning Subjects to Treatment Groups 
Phase 2 
Following informed consent and screening assessments, eligible subjects will be assigned to 
the paclitaxel dose level currently enrolling during the paclitaxel dose optimization stage. 
Once the paclitaxel recommended dose is established, subjects will be assigned to either 
Cohort 2A or Cohort 2B based on the results of blood-based NGS assay or, if the former was 
negative, IHC/ISH assay of a tumor tissue sample obtained after progression on the most 
recent line of systemic therapy. 
Phase 3 
Following informed consent and screening assessments, eligible subjects will be randomly 
assigned to Arms 3A, 3B, and 3C in an approximately 8:8:1 ratio. Randomization will be 
performed centrally using a system that will assign a unique subject randomization number 
but will not specify the actual treatment assignment. Randomization procedures are detailed 
in the Study Manual. 
Randomization will be stratified by: 
● 
Region of inclusion: Asia versus Rest of World 
● 
Time to progression on first-line therapy for locally-advanced unresectable or 
metastatic disease: <6 months versus ≥6 months 
● 
History of prior gastrectomy: yes versus no 
3.1.9 Blinding and Unblinding 
Maintaining the blind of the study in the Phase 3 portion is crucial for achieving the study 
objectives. Unblinding an individual subject's treatment assignment may only occur when 
one of the following circumstances is applicable: 
1. At the time of study closure, the study treatment assignment will be provided by sponsor 
to the investigator. 
2. Unblinding a subject’s treatment assignment prior to study closure must be limited to 
emergency circumstances where knowledge of the treatment assignment would affect 
decisions regarding the clinical management of the subject. In the event of such an 
emergency circumstance, a formal unblinding procedure, carried out by a third-party 
organization will be followed to allow the investigator to immediately access a subject’s 
treatment assignment (see Study Manual). Information on study treatment assignment 
should not be distributed to any other personnel involved in the clinical trial, apart from 
the study site pharmacist, who will be unblinded to treatment allocation. In the event of 
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any emergency unblinding, the sponsor is to be notified within 24 hours of the 
occurrence. 
Details regarding unblinding procedures are described in the Study Manual. 
3.1.9.1 Unblinding for Safety Monitoring 
Safety data in the Phase 3 portion is monitored by an IDMC. Unblinding of aggregate safety 
data for ongoing safety monitoring and risk/benefit assessment by the IDMC will be 
performed through an independent Data Coordinating Center to ensure the integrity of the 
study. 
Suspected unexpected serious adverse reactions (SUSARs) will be unblinded in accordance 
with local regulatory reporting requirements. Pre-specified personnel from the sponsor Drug 
Safety Department will unblind the identity of study medication for any unexpected (as per 
the Investigator’s Brochure) SAEs that are considered to be related to the blinded study drugs 
(tucatinib, trastuzumab, or placebo). 
3.2 Discussion and Rationale 
3.2.1 Rationale for Study Design 
GEC which has progressed after first-line therapy is an area of significant unmet medical 
need, with only moderate increases in survival delivered by recent advances in therapy 
(Wilke 2014). In second-line HER2+ GEC, targeted anti-HER2 therapies have so far failed to 
yield benefit. 
This study builds upon the standard of care for second-line treatment of advanced GEC, 
ramucirumab and paclitaxel, by adding the dual HER2 inhibition of tucatinib and 
trastuzumab. As discussed in Section 1.1, ramucirumab and paclitaxel is the current standard 
of treatment for subjects with GEC following failure of first line therapy. The combination of 
tucatinib and trastuzumab has proven efficacy in HER2+ metastatic breast cancer (mBC), 
when given with capecitabine. Additionally, the doublet of tucatinib and trastuzumab, 
without chemotherapy, has shown promising activity in HER2+ metastatic colorectal cancer 
(mCRC). See Section 3.2.2 for the detailed rationale for the evaluation of tucatinib and 
trastuzumab combined with ramucirumab and paclitaxel in this patient population. 
The inclusion of an active, standard of care regimen as the comparator arm (Arm 3B) in this 
blinded, placebo-controlled study and the use of OS, the gold standard for anticancer 
therapies, as a dual primary endpoint will ensure a robust evaluation of the contribution of 
tucatinib and trastuzumab to the activity of the study regimen. The preclinical and clinical 
evidence for the significant contribution of tucatinib to HER2 blockade and treatment 
outcomes when combined with trastuzumab is presented in Section 3.2.2. 
The HER2 status of subjects' disease will be established at screening using a central 
blood-based NGS assay of ctDNA. The evaluation of baseline HER2 status in second-line 
GEC is required, in order to assure that first-line anti-HER2 therapy has not resulted in loss 
of HER2-positivity, as discussed in Section 1.1. Given that the frequency of positive HER2 
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IHC/ISH assays of biopsies in subjects with negative HER2 assays in blood-based NGS is 
unknown in GEC, exploratory Cohort 2B of the Phase 2 dose expansion stage will enroll any 
such subjects identified, in order to determine the correlation between HER2-positivity in 
assays of ctDNA and tumor tissue, and evaluate the antitumor activity and safety of the study 
regimen in such subjects.  
Evaluation of the safety of the study regimen will be undertaken in the Phase 2 portion of the 
study (see Figure 2) in the paclitaxel dose optimization and dose expansion stages. Once the 
safety and tolerability of tucatinib in combination with trastuzumab, ramucirumab, and 
paclitaxel are evaluated, and the regimen had been found to sufficiently active in the 
preliminary evaluation of efficacy in subjects with HER2+ disease by blood-based NGS 
assay in Phase 2, the Phase 3 portion of this study will compare the efficacy of tucatinib and 
trastuzumab versus placebo in 470 subjects with cancer. The activity of tucatinib combined 
with ramucirumab and paclitaxel will also be evaluated in 30 subjects, to establish the 
contribution of tucatinib to the standard of care therapy. All subjects enrolled on the Phase 3 
will be HER2-positive according to the blood-based NGS assay. See Section 3.2.3 for a 
detailed rationale for the selection of doses in this study. 
3.2.2 Rationale for Combination of Tucatinib and Trastuzumab 
The combination of tucatinib and trastuzumab is being evaluated in this study based on 
preclinical data in GEC demonstrating 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 other cancer types 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 activity 
of tucatinib 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 (Peterson 2017). 
Across 3 PDX models and a CDX model of gastric cancer, a nominal dose of tucatinib 
50 mg/kg BID resulted in percent tumor growth inhibition (TGI) of 48% to 110%, while 
trastuzumab 20 mg/kg every 3 days resulted in TGIs of 38% to 93%. The combination of 
tucatinib and trastuzumab resulted in TGIs of 103% to 136%. 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.  
Clinical data from the pivotal HER2CLIMB study (ONT-380-206) clearly demonstrated the 
benefit of adding tucatinib to trastuzumab in HER2+ mBC (Murthy 2020). In this global, 
randomized, double-blind study, 612 subjects who had been treated with 3 prior 
HER2-directed agents (trastuzumab, pertuzumab, and trastuzumab emtansine [T-DM1]) were 
randomized in a 2:1 ratio to receive tucatinib (300 mg BID) or placebo in combination with 
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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 of PFS was positive and highly 
statistically significant in favor of the tucatinib combination, with an HR of 0.54 (95% 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 (HR 0.66; 
95% CI: 0.50-0.88; P = 0.005), PFS in subjects with brain metastases (HR 0.48; 95% CI: 0.34 
to 0.69; p<0.00001) and confirmed ORR (40.6% [95% CI: 35.3-46.0] in the tucatinib arm 
versus 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+ mCRC, based on initial results reported 
from the single-arm, Phase 2 MOUNTAINEER trial (Strickler 2019). In this study, subjects 
with HER2+, RAS-wildtype mCRC who had been previously treated with fluorouracil, 
oxaliplatin, irinotecan, and an anti-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 was ORR, with the study comparing an ORR of 20% (null hypothesis) 
versus 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. 
Following failure of first-line treatment with a trastuzumab-based regimen, patients with 
HER2+ GEC have limited treatment options. Both the preclinical and clinical data 
summarized above support the proposed comparison of tucatinib and trastuzumab versus 
placebo, in combination with ramucirumab and paclitaxel.  
3.2.3 Rationale for Selection of Doses 
3.2.3.1 Rationale for Tucatinib Dose 
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 enzyme test AEs were observed, with all 
grade AST, 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%).  
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The Phase 1b studies ONT-380-004 and ONT-380-005 evaluated the safety of tucatinib 
300 mg 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 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%.  
In ONT-380-005, the most frequent AEs in the tucatinib 300 mg plus trastuzumab and 
capecitabine cohort 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 
liver enzyme laboratory abnormalities were reported in 2 subjects (7%) each. 
In the 18 subjects who received only tucatinib and trastuzumab the most frequent AEs were 
diarrhea (56% of 18 subjects), nausea (33%), constipation (28%), 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 liver enzyme laboratory abnormalities.  
Interim data were reported from 26 subjects with HER2+ mCRC 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 
(IRR; 11.5%); only 2 Grade 3 AEs were reported, for diarrhea and hypertension (3.8% each).  
Based on these studies, the proposed starting dose of tucatinib with trastuzumab, 
ramucirumab, and paclitaxel is 300 mg BID.  
3.2.3.2 Rationale for Trastuzumab Dose and Schedule 
Given the every 28 days schedule of the standard ramucirumab and paclitaxel regimen, 
trastuzumab will be administered on a biweekly schedule. The biweekly trastuzumab 
schedule has been evaluated in various Phase 2 studies and been found to be safe and 
tolerable (Orlando 2014; Qiu 2014; Mondaca 2019). Trastuzumab 4 mg/kg will be 
administered on Day 1 and 15 every 28 days (with a 6 mg/kg loading dose on Cycle 1 
Day 1); this dose corresponds to the same dose intensity as weekly and every 3-week dosing. 
This will simplify the visits for subjects and investigators, and will preserve the rest week 
present in the paclitaxel Day 1, 8, 15 every 28 days schedule.  
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3.2.3.3 Rationale for Ramucirumab Dose and Schedule 
Ramucirumab is being administered at the standard dose and schedule indicated for use in 
second-line treatment of advanced GEC (Wilke 2014). 
3.2.3.4 Rationale for Paclitaxel Dose Levels and Schedule 
To determine the tolerability of tucatinib and paclitaxel in combination, a safety and PK 
paclitaxel dose optimization stage is proposed, using a starting dose of paclitaxel reduced to 
60 mg/m² (administered as a 1-hour IV infusion according to the standard schedule on Days 
1, 8 and 15 every 28 days) for the combination with tucatinib, trastuzumab, and ramucirumab 
(see Section 3.1.1.1).  
Paclitaxel is extensively metabolized, primarily via CYP2C8-mediated metabolism to 
6α-hydroxypaclitaxel and via CYP3A4 to 3’-ρ-hydroxypaclitaxel and 6α-3’-ρ-
dihydroxypaclitaxel (Taxol™ Prescribing Information, Bristol Myers Squibb Company, 
March 2015). Paclitaxel is also a substrate of P-gp. The US Prescribing Information for 
paclitaxel recommends use with caution when co-administering with known CYP2C8 or 
CYP3A4 substrates, inducers or inhibitors. Tucatinib is a strong, mechanism-based inhibitor 
of CYP3A4 and significantly increases the exposure of sensitive CYP3A4 substrates. In a 
clinical study of healthy volunteers (ONT-380-012), midazolam AUCinf and Cmax increased 
5.7- and 3.0-fold, respectively, in the presence of tucatinib. In the same study, tucatinib was 
shown to be a weak CYP2C8 and weak P-gp inhibitor, with repaglinide and digoxin AUCinf 
increasing 1.7- and 1.5-fold, respectively, in the presence of tucatinib (Tukysa™ Prescribing 
Information, Seagen Inc., March 2020). Given the potential for a drug-drug interaction (DDI) 
and/or overlapping toxicity between paclitaxel and tucatinib, the paclitaxel dose optimization 
stage with PK sampling is proposed to support a tolerability assessment of this combination.  
Three studies have investigated the co-administration of paclitaxel (100 mg/m² every 
2 weeks, 3-hour IV infusion) with strong CYP3A4 inhibitors (Nannan Panday 1999; Tulpule 
2002; Cianfrocca 2011). These have shown paclitaxel in combination with strong CYP3A4 
inhibitors to be well tolerated, even with an approximate doubling of paclitaxel AUC (and no 
statistically significant impact on Cmax). Additionally, the combination of 50-80 mg/m² 
paclitaxel (1-hour IV infusion on Days 1, 8 and 15 every 28 days) with weak CYP3A4 
inhibitors (lapatinib and/or pazopanib) resulted in a 26%-43% increase in paclitaxel AUCinf 
(and up to a 62% increase in paclitaxel Cmax) (Tan 2010; Satoh 2014; Tan 2014). 
More recently, the I-SPY2 trial has evaluated the combination of tucatinib, with paclitaxel 
(80 mg/m2 per week), trastuzumab and pertuzumab in the neoadjuvant breast cancer setting. 
Among the 20 chemotherapy-naïve subjects treated for up to 12 weeks, 35% (n=7) reported 
reversible Grade 3 (n=5) or Grade 4 (n=2) elevations of liver transaminases. All Grade 3/4 
elevations of liver transaminases occurred within 4-6 weeks of treatment initiation and were 
resolved or resolving with dose hold or discontinuation of tucatinib and paclitaxel. There 
were no concurrent increases in total bilirubin or alkaline phosphatase, and no subject met 
criteria for Hy’s law. 
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Increases in paclitaxel Cmax and/or AUC at 60 mg/m² in the presence of tucatinib are 
predicted to be below exposures achieved when used at recommended doses (100 mg/m² 
administered as a 1-hour IV infusion weekly; 175 mg/m² administered as a 3-hour IV 
infusion every 3 weeks), where clinical safety is well established. 
The proposed starting dose of 60 mg/m² was chosen as it is predicted to not exceed exposures 
seen at recommended clinical doses when administered in combination with a strong 
CYP3A4 inhibitor, it is a recommended dose level when dose reductions are made due to 
toxicity, and is expected to provide opportunity for clinical benefit with acceptable risk for 
adverse safety events. Should paclitaxel 60 mg/m2 be found to be tolerable by the SMC, 
paclitaxel will be escalated to the standard dose of 80 mg/m2(administered as a 1-hour IV 
infusion on Days 1, 8 and 15 every 28 days) and evaluated in the dose optimization stage 
(See Section 3.1.1.1). 
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4 
STUDY POPULATION 
This study will enroll subjects with locally-advanced unresectable or metastatic HER2+ GEC 
who have received prior treatment with a HER2-directed antibody. Subjects must meet all of 
the enrollment criteria specified in Section 4.1 and Section 4.2 to be eligible for this study. 
Eligibility criteria may not be waived by the investigator and are subject to review in the 
event of a good clinical practice audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or 
metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma 
2. HER2+ disease documented since progression of the most recent line of systemic 
therapy, as follows: 
a. Phase 2 paclitaxel dose optimization stage:  
• 
HER2 amplification in a blood-based NGS assay performed at a central 
laboratory, or  
• 
HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) 
assay of a tumor tissue sample, processed in a CLIA- or ISO-accredited 
laboratory 
b. Phase 2 dose expansion stage: 
i. Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a 
central laboratory 
ii. Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 
overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a 
tumor tissue sample, processed in a CLIA- or ISO‑accredited laboratory 
c. Phase 3: HER2 amplification in a blood-based NGS assay performed at a central 
laboratory 
3. Can supply archival tumor tissue for central assay; if an archival sample is not available, 
the subject may be eligible, following approval by the medical monitor.  
4. History of prior treatment with a HER2-directed antibody  
5. Progressive disease during or after first-line therapy for locally-advanced unresectable or 
metastatic GEC 
6. Phase 2: Measurable disease according to RECIST version 1.1 
Phase 3: Measurable or non-measurable disease according to RECIST version 1.1 
7. Age ≥18 years, or considered an adult by local regulations, at time of consent 
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (see 
APPENDIX B) 
9. Life expectancy of at least 3 months, in the opinion of the investigator 
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10. Adequate hepatic function as defined by the following: 
a. Total bilirubin ≤1.5 × ULN, except for subjects with known Gilbert’s disease, who 
may enroll if the conjugated bilirubin is ≤1.5 × ULN 
b. Transaminases (AST and ALT) ≤2.5 × ULN (≤5 × ULN if liver metastases are 
present) 
11. Adequate baseline hematologic parameters as defined by: 
a. ANC ≥1.5 × 109/L 
b. Platelet count ≥100 × 109/L; subjects with a stable platelet count from 75-100 × 109/L 
may be included with approval from the medical monitor 
c. Hemoglobin ≥9 g/dL; subjects with hemoglobin ≥8-9 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 
12. Estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m² using the Modification 
of Diet in Renal Disease (MDRD) study equation as applicable.  
13. International normalized ratio (INR) ≤1.5, and prothrombin time (PT) and partial 
thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤1.5 × ULN if 
not receiving anticoagulation therapy. Subjects on full-dose anticoagulation must be on a 
stable dose of oral anticoagulant or low molecular weight heparin. If on warfarin, the 
subject must have an INR of ≤3 and have no active bleeding (within ≤14 days prior to 
enrollment or randomization, excluding trace hematuria) or pathological condition that 
carries a high risk of bleeding (i.e., tumor involving major vessels or known varices). See 
Section 5.4.2 for potential drug interactions with tucatinib and oral anticoagulants. 
14. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or 
multi-gated acquisition (MUGA) scan documented within 4 weeks prior to first dose of 
study treatment. 
15. Urinary protein of ≤1+ on dipstick or routine urinalysis. If dipstick or routine analysis 
indicates proteinuria ≥2+, then either a 24-hour urine must be collected and must 
demonstrate <1000 mg of protein in 24 hours or the urine protein/creatinine (UPC) ratio 
must be <1 to allow participation in study 
16. 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. 
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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  
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 7 months after the final dose of any study drug  
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 C, 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.  
17. 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  
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 C, 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  
c. If sexually active with a person who is pregnant or breastfeeding, must consistently 
use one of 2 contraception options, as defined in APPENDIX C, 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  
18. The subject must provide written informed consent 
19. Subject must be willing and able to comply with study procedures, laboratory tests, and 
other requirements of the study 
4.2 Exclusion Criteria 
1. Subjects with squamous cell or undifferentiated GEC 
2. Having received more than 1 line of prior systemic therapy for locally-advanced 
unresectable or metastatic disease 
3. Having received taxanes ≤12 months prior to enrollment, prior treatment with 
ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other 
investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, 
T-DXd, or any other HER2-directed antibody-drug conjugate 
4. History of exposure to the following cumulative doses of anthracyclines: 
a. Doxorubicin >360 mg/m² 
b. Epirubicin >720 mg/m² 
c. Mitoxantrone >120 mg/m² 
d. Idarubicin >90 mg/m² 
e. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) >550 mg/m² 
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5. History of allergic reactions to trastuzumab, ramucirumab, paclitaxel, or compounds 
chemically or biologically similar to tucatinib, except for Grade 1 or 2 IRR to 
trastuzumab or ramucirumab that were successfully managed, or known allergy to any of 
the excipients in the study drugs or placebos 
6. Phase 2 paclitaxel dose optimization stage only: history of prior partial or total 
gastrectomy 
7. Treatment with any systemic anticancer therapy (including hormonal and biologic 
therapy), radiation, or an experimental agent, or participation in another interventional 
clinical trial ≤3 weeks prior to first dose of study treatment.  
8. Major surgery within 28 days prior to enrollment or randomization, central venous access 
device placement within 7 days prior to enrollment or randomization, or planned major 
surgery following initiation of study treatment 
9. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the 
following exceptions: 
● 
Anemia 
● 
Alopecia 
● 
Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the 
time of occurrence, and must have resolved completely 
10. Clinically significant cardiopulmonary disease such as: 
● 
Ventricular arrhythmia requiring therapy 
● 
Symptomatic hypertension or uncontrolled asymptomatic hypertension 
≥150/≥90 mmHg despite standard medical management, as determined by the 
investigator 
● 
Any symptomatic history of CHF, left ventricular systolic dysfunction or decrease in 
ejection fraction 
● 
Severe dyspnea at rest (CTCAE Grade ≥3) due to complications of advanced 
malignancy or hypoxia requiring supplementary oxygen therapy, except when therapy 
is needed for obstructive sleep apnea 
11. Known to be positive for hepatitis B by surface antigen expression. Known to be positive 
for hepatitis C infection (positive by polymerase chain reaction [PCR]). Subjects who 
have been treated for hepatitis C infection are permitted if they have documented 
sustained virologic response of 12 weeks 
12. Presence of known chronic liver disease 
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13. Phase 2: Known to be positive for human immunodeficiency virus (HIV) 
Phase 3: Subjects known to be positive for HIV are excluded if they meet any of the 
following criteria: 
● 
CD4+ T-cell count of <350 cells/uL 
● 
Detectable HIV viral load 
● 
History of an opportunistic infection within the past 12 months 
● 
On stable antiretroviral therapy for <4 weeks 
14. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of 
informed consent until 7 months following the last dose of study drug 
15. Unable to swallow pills 
16. Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the 
inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first 
dose of study treatment.  
17. Other medical, social, or psychosocial factors that, in the opinion of the investigator, 
could impact safety or compliance with study procedures 
18. History of malignancy other than GEC within 2 years prior to screening, with the 
exception of those with a negligible risk of metastasis or death (e.g., 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. 
19. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism during the 3 months prior to enrollment or randomization.  
20. Chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs; e.g., 
indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., 
clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day 
is permitted.  
21. Significant bleeding disorders, vasculitis, or had a significant bleeding episode from the 
gastrointestinal tract within 3 months prior to study entry.  
22. History of any arterial thrombotic event, including myocardial infarction, unstable 
angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to 
enrollment or randomization.  
23. History of gastrointestinal perforation and/or fistulae within 6 months prior to enrollment 
or randomization.  
24. Serious non-healing wound or peptic ulcer or bone fracture within 28 days prior to 
enrollment or randomization 
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25. History of bowel obstruction, history or presence of inflammatory enteropathy or 
extensive intestinal resection (hemicolectomy or extensive small intestine resection with 
chronic diarrhea), Crohn’s disease, ulcerative colitis or chronic diarrhea 
26. Active or uncontrolled clinically serious infection 
27. Known active central nervous system metastases. Irradiated or resected lesions are 
permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, 
and no steroids have been administered for at least 30 days 
4.3 Childbearing Potential 
A person of childbearing potential is anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (e.g., 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. 
A person who can father children is anyone born male who has testes and who has not 
undergone surgical sterilization (e.g. 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). 
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 breast feeding 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/placebo, trastuzumab/placebo, ramucirumab, or paclitaxel) is 
discontinued, study treatment can continue with remaining study drug(s). Subjects who 
discontinue study treatment without documented radiologic disease progression will undergo 
follow-up disease assessments at least every 9 weeks until occurrence of disease progression 
per RECIST version 1.1. Following disease progression, subjects will be followed every 
12 weeks until occurrence of a reason for withdrawal from the study (Section 4.4.2). No 
crossover will be allowed. 
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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 
5 
TREATMENTS 
5.1 Treatments Administered 
Subjects in the Phase 2 portion of the study will receive combination therapy of the 
investigational medicinal products tucatinib and trastuzumab combined with standard-of-care 
ramucirumab and paclitaxel. In the Phase 3, subjects will receive either tucatinib and 
trastuzumab (Arm 3A), tucatinib placebo and trastuzumab placebo (Arm 3B), or tucatinib 
and trastuzumab placebo (Arm 3C), all combined with ramucirumab and paclitaxel. Study 
treatment will be given on a 28-day cycle, with tucatinib (or placebo) every day, trastuzumab 
(or placebo) and ramucirumab on Days 1 and 15, and paclitaxel on Days 1, 8, and 15 (Table 
3). In subjects in the Phase 2 undergoing Cycle 1 PK assessments, the first tucatinib dose will 
be given in the evening on Day 1. In this study, subjects are considered to be on study 
treatment if they are receiving any of the study drugs (tucatinib/placebo, 
trastuzumab/placebo, ramucirumab, and/or paclitaxel). Cycles are defined by paclitaxel 
administration, with a new cycle starting whenever the Day 1 infusion of paclitaxel is 
administered. If paclitaxel is discontinued, cycles will be defined as occurring every 28 days 
from the last Day 1 administration of paclitaxel. 
In the Phase 2, tucatinib should be dosed at approximately the same time as the start of the 
paclitaxel infusion on Cycle 1 Day 8 and Cycle 2 Day 1, when both tucatinib and paclitaxel 
PK are assessed (see Section 7.3). The administration order of the IV study drugs is 
paclitaxel first, then trastuzumab and ramucirumab, or according to institutional standard of 
care. 
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Table 3: 
Treatment schedule 
Agent 
Dose  
Route Cycle 
Daily 
frequency 
Cycle Day 
Day 1 
Day 8 
Day 15 
Phase 2 
Tucatinib 
300 mg  
PO 
All 
BID 
Every day, from Cycle 1 Day 1a 
Trastuzumabb 
4 mg/kg  
(6 mg/kg on Cycle 1 Day 1) 
IV 
All 
Once 
X 
 
X 
Ramucirumab 
8 mg/kg 
IV 
All 
Once 
X 
 
X 
Paclitaxel 
60 or 80 mg/m² c 
IV 
All 
Once 
X 
X 
X 
Phase 3 
Arm 3A 
 
 
 
 
 
 
 
Tucatinib 
300 mg  
PO 
All 
BID 
Every day, from Cycle 1 Day 1 
Trastuzumabb 
4 mg/kg  
(6 mg/kg on Cycle 1 Day 1) 
IV 
All 
Once 
X 
 
X 
Ramucirumab 
8 mg/kg 
IV 
All 
Once 
X 
 
X 
Paclitaxel 
Phase 2 recommended dose 
IV 
All 
Once 
X 
X 
X 
Arm 3B 
 
 
 
 
 
 
 
Tucatinib placebo 
Not applicable 
PO 
All 
BID 
Every day, from Cycle 1 Day 1 
Trastuzumab placebob 
Not applicable 
IV 
All 
Once 
X 
 
X 
Ramucirumab 
8 mg/kg 
IV 
All 
Once 
X 
 
X 
Paclitaxel 
80 mg/m² 
IV 
All 
Once 
X 
X 
X 
Arm 3C 
 
 
 
 
 
 
 
Tucatinib 
300 mg  
PO 
All 
BID 
Every day, from Cycle 1 Day 1 
Trastuzumab placebob 
Not applicable 
IV 
All 
Once 
X 
 
X 
Ramucirumab 
8 mg/kg 
IV 
All 
Once 
X 
 
X 
Paclitaxel 
Phase 2 recommended dose 
IV 
All 
Once 
X 
X 
X 
a 
In subjects in the Phase 2 undergoing Cycle 1 PK assessments, the first tucatinib dose will be given in the evening on 
Day 1. 
b 
Trastuzumab may also be given on a weekly basis at 2 mg/kg IV, but only in circumstances where weekly infusions are 
required to resynchronize with the paclitaxel cycle. 
c 
The paclitaxel dose optimization stage will initially evaluate 60 mg/m² and potentially escalate to 80 mg/m². 
Alternative dose levels/schedules may be evaluated as recommended by the SMC 
 
5.1.1 Investigational Products 
5.1.1.1 Tucatinib or Tucatinib Placebo 
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. 
In the Phase 2, tucatinib will be supplied in an open-label manner, by the sponsor. In the 
Phase 3, treatment allocation to tucatinib or tucatinib placebo will be double-blinded. 
Detailed information describing the preparation, administration, and storage of tucatinib is 
located in the Pharmacy Instructions. 
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 amorphous dispersion of tucatinib 
in polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the 
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pharmaceutical excipients (microcrystalline cellulose, sodium chloride, potassium chloride, 
sodium bicarbonate, silicon dioxide, crospovidone, and magnesium stearate), and 
compressed into tablets. 
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 or tucatinib placebo 
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. In subjects in the Phase 2 
undergoing Cycle 1 Day 1 PK assessments, tucatinib will not be administered in the 
morning of Cycle 1 Day 1; the first dose will be in the evening, after all PK samples 
have been collected. 
In the Phase 3, subjects in Arm 3B receive a tucatinib placebo PO BID. 
Dose modifications of tucatinib or placebo are described in Section 5.2. 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 or placebo and less 
than 6 hours have passed since the scheduled dosing time, the dose should be immediately 
taken. It is recommended that if more than 6 hours have passed since the scheduled dosing 
time, the 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, or dissolved in liquid. On the day of dosing, the 
individual unit dose of the tucatinib or placebo tablet may be exposed to ambient temperature 
for up to 6 hours prior to dose. 
Complete dosing instructions will be provided to the pharmacist prior to the initiation of the 
study. Complete dosing instructions will also be provided to study 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 dosing instructions will be 
assessed with the use of subject diaries or pill count and study drug accountability. 
Storage and Handling 
Tablets of tucatinib (or tucatinib placebo) are packaged in round, high-density polyethylene 
bottles containing a desiccant, with an induction sealed liner and child-resistant plastic 
closure cap. Bottles of tucatinib tablets are to be stored under refrigeration at 2 to 8°C in a 
secure, access-limited location. 
The tablets are coated with a non-hazardous film to prevent any exposure to the active 
pharmaceutical ingredient during routine handling. Avoid breaking or crushing tablets. In the 
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event the tablets are broken or crushed, wash hands and exposed skin thoroughly with soap 
and water.  
Refer to the Pharmacy Instructions for more information. 
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. 
Preparation 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
5.1.1.2 Trastuzumab or Trastuzumab Placebo 
Description 
Trastuzumab is a humanized immunoglobulin G1 (IgG1) kappa mAb 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 for first-line treatment of HER2-overexpressing 
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 cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients 
with HER2-overexpressing metastatic GEC who have not received prior treatment for 
metastatic disease. 
Method of Procurement 
In Phase 2, details regarding trastuzumab sourcing may vary by site and/or region as outlined 
in other documents such as Clinical Trial Agreements. 
In the Phase 3, treatment allocation to trastuzumab or trastuzumab placebo will be 
double-blinded, and will be supplied. 
Dose and Administration 
Trastuzumab will be administered on Day 1 and 15 of every 28-day cycle. A loading dose of 
6 mg/kg IV will be administered on Cycle 1 Day 1 followed by 4 mg/kg with each 
subsequent dose. Trastuzumab placebo will be used in Arms 3B and 3C of the Phase 3. 
Trastuzumab may also be given on a weekly basis at 2 mg/kg IV once weekly, in order to 
resynchronize administration to Day 1 and 15 of the 28-day paclitaxel cycle, after discussion 
with the medical monitor. If dosing of trastuzumab has been held for >4 weeks and the 
medical monitor has agreed to restart trastuzumab, the IV loading dose of 6 mg/kg should be 
given per approved dosing instructions. Trastuzumab infusion rates will be per institutional 
guidelines. 
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To maintain the blind, subjects assigned to receive trastuzumab placebo will receive an IV 
infusion that does not contain trastuzumab. Refer to Pharmacy Manual for additional 
instructions.  
Storage and Handling 
Trastuzumab should be prepared and administered per instructions in the package insert. 
Packaging and Labeling 
Each vial of trastuzumab will be labeled in compliance with applicable regulatory 
requirements. 
Preparation 
Trastuzumab is a lyophilized sterile powder for reconstitution 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.  
5.1.2 Standard of Care 
5.1.2.1 Ramucirumab 
Description 
Ramucirumab (CYRAMZA®) is a recombinant human IgG1 mAb with an approximate 
molecular weight of 147 kDa, produced in genetically engineered mammalian NS0 cells. It is 
a VEGFR2 antagonist that specifically binds VEGFR2 and blocks binding of VEGFR 
ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits 
ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and 
migration of human endothelial cells. It is indicated for the treatment of subjects with 
advanced or metastatic GEC with disease progression on or after prior fluoropyrimidine- or 
platinum-containing chemotherapy as a single agent or in combination with paclitaxel. It is 
also indicated as first-line treatment in combination with erlotinib for metastatic non-small 
cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 substitution mutations, 
treatment of previously-treated metastatic NSCLC in combination with docetaxel, treatment 
in subjects with previously treated mCRC in combination with FOLFIRI, and treatment in 
subjects with previously treated hepatocellular carcinoma. 
Method of Procurement 
Details regarding the sourcing of ramucirumab may vary by site and/or region as outlined in 
other documents such as Clinical Trial Agreements. 
Dose and Administration 
Ramucirumab 8 mg/kg will be administered on Days 1 and 15 of each 28-day cycle. 
Ramucirumab will be administered IV per institutional guidelines, under the direction of the 
investigator. Ramucirumab is for IV infusion only. Do not administer as an IV push or bolus. 
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Calculate the UPC ratio on a urine sample taken within 1 day prior to each dose. If UPC ≥2, 
refer to the ramucirumab dose modification guidelines in Section 5.2.3. 
IRRs related to ramucirumab have been observed. To reduce the risk of IRRs with 
Ramucirumab, subjects will receive premedication/postmedication as described in 
Section 5.3. 
Storage and Handling 
Ramucirumab should be stored according to the package insert. 
Packaging and Labeling 
Commercially available ramucirumab will be used. 
Preparation 
Ramucirumab should be prepared and administered per instructions in the CYRAMZA 
package insert. 
5.1.2.2 Paclitaxel 
Description 
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from 
tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability 
inhibits the normal dynamic reorganization of the microtubule network, which is essential for 
vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays 
or bundles of microtubules throughout the cell cycle and multiple asters of microtubules 
during mitosis. 
Method of Procurement 
Details regarding sourcing of paclitaxel may vary by site and/or region as outlined in other 
documents such as Clinical Trial Agreements. 
Dose and Administration 
Paclitaxel will be administered on Days 1, 8, and 15 of each 28-day cycle. Paclitaxel will be 
administered IV per institutional guidelines, under the direction of the investigator. The 
initial paclitaxel dose to be evaluated in the Phase 2 dose optimization stage is 60 mg/m²; an 
80 mg/m² dose level may be explored. Additional dose levels/schedules may be evaluated as 
recommended by the SMC. In the Phase 3, paclitaxel will be administered at the 
recommended dose identified in Phase 2 in Arms 3A and 3C, and at 80 mg/m² in Arm 3B.  
Subjects with a history of severe hypersensitivity reactions to products containing 
polyoxyl 35 castor oil (e.g., cyclosporin for injection concentrate, teniposide for injection 
concentrate) are not to be treated with paclitaxel. 
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Injection site and hypersensitivity reactions related to paclitaxel are common. To reduce the 
risk of these reactions, subjects will receive premedication as described in Section 5.3. Given 
the possibility of extravasation, it is advisable to closely monitor the infusion site for possible 
infiltration during drug administration. Vital signs should be monitored frequently during the 
paclitaxel infusion. 
Initiate concomitant G-CSF as clinically indicated. 
Table 4 summarizes the conditions, in terms of AEs and laboratory test abnormalities, that 
must be met for before administering paclitaxel. If the conditions are not met on the planned 
Day 1 of a cycle, then the paclitaxel infusion should be delayed until the conditions are met. 
If the conditions are not met on the planned Day 8 or 15, then the paclitaxel infusion should 
be skipped. 
Table 4: 
Criteria for paclitaxel treatment on Day 1, 8, and 15 of each cycle 
AE/abnormality 
Day 1 
Day 8 and 15 
ANC: 
≥1.5 × 109/L 
≥1.0 × 109/L 
Platelets: 
≥75 × 109/L 
Bilirubin: 
≤1.5 × ULN 
AST/ALT: 
≤3 × ULN a (<5 × ULN if liver metastases present) 
Paclitaxel-related AEs: 
Grade ≤1 or baseline (except for alopecia)  
Anemia Grade ≤2 
a 
On Cycle 1 Day 1, AST/ALT is to be ≤2.5 × ULN (≤5 × ULN if liver metastases present). 
 
Storage and Handling 
Paclitaxel should be stored according to the package insert. 
Packaging and Labeling 
Commercially available paclitaxel will be used. 
Preparation 
Paclitaxel should be prepared and administered per instructions in the applicable package 
insert. 
5.2 Dose Modifications 
Dose modification recommendations (including dose holds, dose reduction, or 
discontinuation of drugs) in response to AEs are described in Section 5.2.1 for 
tucatinib/placebo, in Section 5.2.2 for trastuzumab/placebo, in Section 5.2.3 for 
ramucirumab, and in Section 5.2.4 for paclitaxel. Dose reductions or treatment 
interruption/discontinuation for reasons other than those described in the following sections 
may be made by 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.  
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All AEs and clinically significant laboratory abnormalities should be assessed by the 
investigator for relationship to tucatinib/placebo, trastuzumab/placebo, ramucirumab, and 
paclitaxel. 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 
paclitaxel. During paclitaxel cycle delays, ramucirumab and trastuzumab administration 
should continue as planned. When the new paclitaxel cycle starts, ramucirumab should be 
administered on Day 1, even if it was administered the previous week. Trastuzumab should 
not be administered on Day 1 if trastuzumab 4 mg/kg was administrated the previous week; 
instead, to synchronize trastuzumab to a delayed paclitaxel cycle, trastuzumab 2 mg/kg 
should be given on Day 8 followed by trastuzumab 4 mg/kg on Day 15. If paclitaxel cannot 
be administered on Day 8 or Day 15 of a cycle, that day is skipped, ramucirumab and 
trastuzumab are administered as scheduled, and the paclitaxel schedule continues unchanged. 
If paclitaxel is discontinued, protocol-defined visits will proceed using a 28-day cycle 
starting from the last paclitaxel Day 1, regardless of 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 >4 weeks should be discontinued, 
unless a longer delay is approved by the study medical monitor. If one or more study drugs 
are discontinued, study treatment can continue with the remaining study drugs.  
5.2.1 Tucatinib/placebo Dose Modifications 
Up to 3 dose reductions of tucatinib/placebo are allowed (Table 5). Subjects who would 
require a dose reduction to below 150 mg BID should discontinue treatment with 
tucatinib/placebo. Dose reductions of larger intervals than those described in Table 5 may be 
made at the discretion of the investigator with approval by the medical monitor, but dose 
reductions to below 150 mg BID are not allowed.  
Table 5: 
Tucatinib/placebo: Recommended dose reduction schedule for adverse events 
Dose Reduction Schedule 
Tucatinib/Placebo Dose Level 
Starting dose 
300 mg PO BID a 
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 (i.e., 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/placebo may not be dose reduced below 150 mg BID. 
 
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General dose modification guidelines for tucatinib/placebo are provided in Table 6 and 
Table 7. For subjects with documented Gilbert’s disease, contact the medical monitor for 
guidance regarding dose modifications for liver enzyme abnormalities.  
Table 6: 
Dose modifications for clinical adverse events related to tucatinib/placebo  
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 treatment. 
Other adverse reactions 
 
Grade 3 
Hold tucatinib until recovery to ≤ Grade 1 or baseline 
Reduce tucatinib dose 
Grade 4 
Permanently discontinue tucatinib. 
 
Table 7: 
Dose modifications of tucatinib/placebo for liver enzyme abnormalities, 
regardless of relationship to tucatinib/placebo 
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 >3 × ULN AND bilirubin >2 × ULN 
Permanently discontinue tucatinib. 
 
5.2.2 Trastuzumab/placebo Dose Modifications 
In the event of Grade ≥3 trastuzumab-related AEs, hold trastuzumab until the AE has 
resolved to Grade ≤1 or pretreatment levels and initiate or intensify applicable medical 
therapy, as appropriate. Resume trastuzumab at the same dose; the trastuzumab/placebo dose 
may not be reduced. If dosing of trastuzumab is held for >4 weeks and the medical monitor 
has agreed to restart trastuzumab, the IV loading dose of 6 mg/kg should be given per 
approved dosing instructions. 
Trastuzumab dose modification guidelines for left ventricular dysfunction and 
cardiomyopathy are presented in Section 5.2.2.1, for IRR in Section 5.2.2.2, and for 
hypersensitivity reactions in Section 5.2.2.3. 
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5.2.2.1 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/placebo dose modification guidelines for left ventricular dysfunction, 
regardless of relationship to study drug, are provided in Table 8. 
Table 8: 
Trastuzumab and trastuzumab placebo 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 <50% 
 
 
 
 
<10% decrease from baseline 
Resume treatment with trastuzumab  
 
 
 
10% decrease from baseline 
Discontinue trastuzumab  
 
 
- LVEF <45% 
Discontinue trastuzumab  
 
5.2.2.2 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.  
Interrupt trastuzumab infusion in all subjects experiencing dyspnea or clinically significant 
hypotension, and administer supportive therapy (which may include epinephrine, 
corticosteroids, diphenhydramine, bronchodilators, and oxygen). Subjects should be 
evaluated and carefully monitored until complete resolution of signs and symptoms. In 
subsequent infusions, premedicate subjects with antihistamines and/or corticosteroids. 
Discontinue trastuzumab in subjects with Grade 3 to 4 IRR. 
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5.2.2.3 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, i.e., 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. 
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 (Rosello 2017). 
If anaphylaxis occurs, administration of trastuzumab should be immediately and permanently 
discontinued. 
5.2.3 Ramucirumab Dose Modifications 
Up to 2 dose reductions of ramucirumab will be allowed (Table 9). Subjects who would 
require a dose reduction to below 5 mg/kg should discontinue treatment with ramucirumab. 
Table 9: 
Ramucirumab: Recommended dose reduction schedule for adverse events 
Dose Reduction Schedule 
Ramucirumab Dose Level 
Starting dose 
8 mg/kg 
1st dose reduction 
6 mg/kg 
2nd dose reduction 
5 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 
 
General dose modification guidelines for ramucirumab are provided in Table 10. 
Ramucirumab should be held for 28 days prior to any surgery, and resumed no sooner than 
28 days after surgery, once the wound is fully healed and following discussion with the 
medical monitor. 
Ramucirumab dose modification guidelines for hypertension are presented in Section 5.2.3.1, 
for IRR in Section 5.2.3.2, for proteinuria and nephrotic syndrome in Section 5.2.3.3, for 
impaired wound healing in Section 5.2.3.4, and for reversible posterior leukoencephalopathy 
syndrome (RPLS) in Section 5.2.3.5.  
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Table 10: 
Dose modifications for clinical adverse events 
Clinical Adverse Event 
Ramucirumab Dose Modification 
Regardless of relationship to ramucirumab 
Grade 3-4 hemorrhage 
Discontinue ramucirumab 
Gastrointestinal perforation any grade 
Discontinue ramucirumab 
Wound healing complications of any grade that require 
medical intervention 
Discontinue ramucirumab 
Grade 3 or 4 arterial thromboembolic events or any 
pulmonary embolism or deep vein thrombosis occurring or 
worsening during anticoagulant therapy 
Discontinue ramucirumab 
Grade 3-4 hypertension 
Hold until controlled by medical 
management 
Grade 3-4 hypertension not controlled by antihypertensive 
therapy 
Hypertensive crisis or hypertensive encephalopathy 
Discontinue ramucirumab 
Proteinuria  
 
− 
>2+ by dipstick or routine urinalysis 
Evaluate UPC ratio prior to next dose and 
continue ramucirumab if UPC ratio <2 
− 
UPC ratio 2 to ≤3 
Hold ramucirumab for up to 14 days until 
UPC ratio <2 
Resume ramucirumab at reduced dose 
Discontinue ramucirumab if UPC remains 
≥2 after 14 days Discontinue ramucirumab 
if reoccurrence of UPC ≥2 
− 
UPC ratio >3 or nephrotic syndrome 
Discontinue ramucirumab 
RPLS confirmed by MRI 
Discontinue ramucirumab 
Spontaneous development of fistula 
Discontinue ramucirumab 
Hepatic encephalopathy or hepatorenal syndrome 
Discontinue ramucirumab 
Related to ramucirumab 
IRR 
 
− 
Grade 1-2 
Reduce infusion rate by 50% 
− 
 Grade 3-4 
Discontinue ramucirumab 
 
5.2.3.1 Hypertension 
Control hypertension prior to initiating treatment with ramucirumab. Monitor blood pressure 
every two weeks or more frequently as indicated during treatment. Withhold ramucirumab 
for severe hypertension until medically controlled. 
Permanently discontinue ramucirumab for medically significant hypertension that cannot be 
controlled with antihypertensive therapy or in subjects with hypertensive crisis or 
hypertensive encephalopathy. 
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5.2.3.2 Infusion-related Reactions 
Symptoms of IRR occurring after ramucirumab administration have included rigors/tremors, 
back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, 
and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular 
tachycardia, and hypotension.  
Premedicate prior to each ramucirumab infusion (see Section 5.3). Monitor subjects during 
the infusion for signs and symptoms of IRR in a setting with available resuscitation 
equipment.  
Reduce the infusion rate by 50% for Grade 1 to 2 IRR. Permanently discontinue 
ramucirumab for Grade 3 to 4 IRRs. 
5.2.3.3 Proteinuria and Nephrotic Syndrome 
Monitor proteinuria by urine dipstick and/or UPC ratio. If the result of the urine dipstick is 
2+ or greater, evaluate UPC ratio and withhold ramucirumab if UPC ratio is ≥2. Reinitiate 
ramucirumab at a reduced dose once UPC is <2. Permanently discontinue ramucirumab for 
UPC ratio >3, reoccurrence of UPC ratio >2, or in the setting of nephrotic syndrome. 
5.2.3.4 Impaired Wound Healing 
Withhold ramucirumab for 28 days prior to surgery. Do not administer ramucirumab for at 
least 28 days following a major surgical procedure, until the wound is fully healed, following 
discussion with the medical monitor. Discontinue ramucirumab in subjects who develop 
wound healing complications that require medical intervention. 
5.2.3.5 Reversible Posterior Leukoencephalopathy Syndrome 
In the event of RPLS, confirm the diagnosis of RPLS with magnetic resonance imaging 
(MRI) and permanently discontinue ramucirumab. 
5.2.4 Paclitaxel Dose Modifications 
The paclitaxel dose can be reduced by increments of 10 mg/m² (i.e., reductions to 70 mg/m² 
then to 60 mg/m² for a subject initially receiving 80 mg/m²); however, subjects who would 
require a dose reduction to below 60 mg/m² should discontinue treatment with paclitaxel. 
Dose reductions are implemented only at the start of a cycle, not on Day 8 or 15. 
General dose modification guidelines for paclitaxel are provided in Table 11 and Table 12. 
Paclitaxel dose modification guidelines for hepatotoxicity are presented in Section 5.2.4.1 
and for hypersensitivity in Section 5.2.4.2. 
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Table 11: 
Paclitaxel dose modifications for clinical adverse events related to paclitaxel 
Adverse Reaction  
Paclitaxel Dose Modification 
Paclitaxel-related non-hematological 
AEs 
Delay Day 1 administration until recovery to Grade ≤1 or baseline or 
skip Day 8 or 15 
− 
 Grade ≥3 
Reduce paclitaxel dose in next cycle 
Grade 3-4 peripheral neuropathy 
Delay Day 1 administration until recovery to Grade ≤1 or baseline or 
skip Day 8 or 15 
Reduce paclitaxel dose in next cycle 
Grade 3-4 hypersensitivity reaction 
Discontinue paclitaxel 
Table 12: 
Paclitaxel dose modifications for hematological abnormalities, regardless of 
relationship to paclitaxel 
Hematological Abnormality 
Paclitaxel Dose Modification 
ANC <1.5 × 109/L 
Delay Day 1 administration until recovery to ≥1.5 × 109/L 
ANC <1.0 × 109/L 
Delay Day 1 administration recovery to ≥1.5 × 109/L or  
skip Day 8 or 15 administration 
Platelet count <75 × 109/L 
Delay Day 1 administration recovery to ≥75 × 109/L or  
skip Day 8 or 15 administration 
Grade 4 hematological abnormalities 
Reduce paclitaxel dose in next cycle 
 
5.2.4.1 Hepatotoxicity 
Dose modification for paclitaxel in the case of liver enzyme abnormalities, regardless of 
relationship to study drug, are summarized in Table 13. A rise in indirect bilirubin with a 
normal direct bilirubin believed to be attributable to Gilbert’s disease does not require change 
in dose or a drug hold. 
Table 13: 
Paclitaxel dose modification guidelines for liver enzyme abnormalities, 
regardless of relationship to paclitaxel 
Liver enzyme abnormality  
Action 
Bilirubin elevation >1.5–3 × ULN 
Delay Day 1 administration until recovery to ≤1.5 × ULN or  
skip Day 8 or 15 infusions 
Bilirubin elevation >3-10 × ULN 
Delay Day 1 administration until recovery to ≤1.5 × ULN or  
skip Day 8 or 15 infusions 
Reduce paclitaxel dose in next cycle 
Bilirubin elevation >10 × ULN 
Permanently discontinue paclitaxel. 
AST or ALT elevation >5-20 × ULN 
Delay Day 1 administration until recovery to ≤3 × ULN or  
return to baseline level in subjects with known liver metastasis or 
skip Day 8 or 15 infusions 
Reduce paclitaxel dose 
AST or ALT elevation >20 × ULN 
Permanently discontinue paclitaxel 
ALT or AST >3 × ULN AND  
bilirubin >2 × ULN 
Permanently discontinue paclitaxel 
 
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5.2.4.2 Hypersensitivity Reactions 
Paclitaxel treatment interruption is not required for minor symptoms of hypersensitivity, such 
as flushing, skin reactions, dyspnea, hypotension, or tachycardia.  
Paclitaxel should be discontinued and aggressive symptomatic therapy applied in the event of 
severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema, or generalized urticaria.  
5.3 Required Premedication and Postmedication 
Suggested premedication to be administered prior to each paclitaxel infusion is presented in 
Table 14. Paclitaxel premedication can be adjusted according to standard institutional 
practice. 
Table 14: 
Paclitaxel premedication 
Pre-medication 
Dose 
Administration time prior to paclitaxel 
Dexamethasone 
8-10 mg PO or  
8-10 mg IV 
30 to 60 min 
Diphenhydramine or equivalent 
12.5-50 mg IV 
30 to 60 min 
Ranitidine 
50 mg IV 
30 to 60 min 
 
Ramucirumab pre-medication with an IV histamine-1 receptor antagonist (e.g., 
diphenhydramine hydrochloride) may be given prior to each ramucirumab infusion at the 
discretion of the investigator. For subjects who have experienced a Grade 1 or 2 IRR 
considered at least possibly related to ramucirumab, premedicate with a histamine-1 receptor 
antagonist, dexamethasone (or equivalent), and acetaminophen prior to each ramucirumab 
infusion. 
Subjects who have experienced dyspnea or clinically significant hypotension related to 
trastuzumab during or following the previous infusion should be premedicated with 
antihistamines and/or corticosteroids prior to subsequent trastuzumab infusions. 
5.4 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given 
for a study protocol-related AEs should be recorded from the time of informed consent. 
5.4.1 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 any study drug are to be recorded in the medical records 
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● 
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  
● 
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, following 
consultation with the medical monitor  
● 
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 warranted and 
following institutional policies and recommendations.  
● 
Subjects stabilized on chronic oral anticoagulation therapy are eligible, provided that 
the coagulation parameters defined in the inclusion criteria are met.  
● 
Routine prophylaxis with vaccines is permitted, if vaccines used do not contain live 
micro-organisms 
5.4.2 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  
● 
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 
RECIST version 1.1 requires prior approval by the medical monitor. Tucatinib and 
paclitaxel must be held 7 days prior to and 7 days after radiation therapy.  
● 
Live vaccines 
● 
Strong inducers of CYP3A4 are prohibited as concomitant medications during study 
treatment (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 treatment (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, 
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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. 
● 
NSAIDs (e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other 
anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin 
use at doses up to 325 mg/day is permitted. Ongoing aspirin therapy at doses 
exceeding 325 mg/day is not permitted. 
● 
Subjects who develop venous thromboembolism during study treatment may continue 
study therapy and receive anticoagulation. Subjects who begin anticoagulation 
therapy during treatment on study must receive low molecular weight heparin (not 
oral anticoagulation). 
5.4.3 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 (e.g., exact amount of tucatinib administered, subject weight) 
and AEs, if any. 
Refer to the package insert for overdose information for trastuzumab, ramucirumab, and 
paclitaxel. 
5.5 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 or 
pill counts. The pharmacist or designee will record the number of investigational study drug 
(tucatinib or placebo) 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, ramucirumab, and paclitaxel will 
also be collected by the site after each cycle. Dose modifications and interruptions of any 
study drug will be documented in the source documents and the CRF. 
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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 7.8.1.3). Any study protocol-related AE (defined in Section 
7.8.1.1) as well as any concomitant medications given for treatment of the AE, should be 
recorded from the time of informed consent. 
Clinical laboratory assessments (blood chemistry panel, complete blood count [CBC] with 
differential, coagulation panel, and urinalysis [see Section 7.8.3]), vital signs, weight, 
physical exam, 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. 
A schedule of events is provided in APPENDIX A. Study activities are listed by visit in this 
section and descriptions of all study assessments are presented in Section 7. 
6.2 Screening Visit (Days –28 to -1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
Height 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight 
● 
Blood sample for NGS assay of HER2 amplification for biomarker analysis 
● 
Collection of archived tumor tissue sample (or freshly-cut slides following 
consultation with the medical monitor) sampled following progression during/after 
the most recent line of therapy, or performed prior to the first line therapy for 
advanced disease 
● 
Blood sample for hepatitis B and C serology (see Section 7.8.3) 
● 
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), 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 (e.g., 
nuclear bone scan imaging for bone lesions). For each subject, the same imaging 
modality as used at baseline should be used throughout the study. 
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6.2.1 Baseline Visit (Days –7 to 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 
respiration rate) and weight 
● 
Physical exam 
● 
ECOG performance status 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3): 
• 
CBC with differential  
• 
Blood chemistry panel 
• 
Coagulation panel  
• 
Urinalysis; if urinalysis indicates proteinuria ≥2+, then either a 24-hour urine 
must be collected and must demonstrate <1000 mg of protein in 24 hours or the 
UPC ratio must be <1 to allow participation in study  
6.3 Randomization (Days –5 to 1) 
Randomization occurs in the Phase 3 portion after eligibility per inclusion/exclusion 
criteria is confirmed. Randomization MUST occur on or before Cycle 1 Day 1, such that 
dosing commences within 5 days after randomization. See Section 3.1.8 for a description 
of randomization and stratification procedures. 
6.4 Treatment Period (28-day cycles) 
6.4.1 Cycle 1 Day 1 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Physical exam * 
● 
ECOG performance status * 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3): 
• 
CBC with differential * 
• 
Blood chemistry panel * 
• 
Urinalysis * 
● 
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 
● 
Paclitaxel dose optimization stage and in the first 6 subjects in the Phase 2 dose 
expansion stage with a gastrectomy: Paclitaxel PK samples (see Section 7.3) 
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● 
Phase 3 only: HRQoL questionnaires (Section 7.7; to be completed prior to 
evaluation by study personnel [physical examination, review of AEs] and 
administration of study treatment): 
• 
EORTC QLQ-C30 
• 
EORTC QLQ-OG25 
• 
EQ-5D-3L 
● 
Dispense tucatinib or placebo and provide dosing diary to subject. Administer the 
first dose of tucatinib/placebo. (Subject will self-administer the remainder of doses 
during the treatment cycle and document in the diary.). 
In subjects in the Phase 2 undergoing Cycle 1 paclitaxel PK assessment, do not 
administer the first dose of tucatinib until the evening, when all PK samples have 
been drawn. 
● 
Administer paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B 
● 
Administer trastuzumab 6 mg/kg IV loading dose or trastuzumab placebo IV 
● 
Administer ramucirumab 8 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.4.2 Cycle 1 Day 8 (±1 day) 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Blood samples for laboratory testing (as listed in Section 7.8.3) 
• 
CBC with differential * 
• 
Blood chemistry panel * 
● 
Paclitaxel dose optimization stage and in the first 6 subjects in the Phase 2 dose 
expansion stage with a gastrectomy: Tucatinib and paclitaxel PK samples (see 
Section 7.3). Record the date and time of the subject's last meal prior to tucatinib 
administration. 
● 
Administer paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration. 
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6.4.3 Cycle 1 Day 15 (±1 day) 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3: 
• 
CBC with differential * 
• 
Blood chemistry panel * 
• 
Urinalysis * 
● 
Administer paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B 
● 
Administer trastuzumab 4 mg/kg IV or trastuzumab placebo IV 
● 
Administer ramucirumab 8 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.4.4 Cycle 1 Day 22 (±1 day) 
● 
Blood samples for laboratory testing (as listed in Section 7.8.3) 
• 
CBC with differential * 
• 
Blood chemistry panel * 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.4.5 Cycles >1 Day 1 (-1 to +3 days) 
● 
Phase 3 only: HRQoL questionnaires (Section 7.7) and HCRU (Section 7.6); to be 
completed prior to evaluation by study personnel (physical examination, review of 
AEs) and administration of study treatment: 
• 
EORTC QLQ-C30 
• 
EORTC QLQ-OG25 
• 
EQ-5D-3L 
• 
Review HCRU since the last study visit 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Physical exam * 
● 
ECOG performance status * 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3: 
• 
CBC with differential * 
• 
Blood chemistry panel * 
• 
Urinalysis * 
• 
Coagulation 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 
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● 
PK samples (see Section 7.3): 
• 
Paclitaxel dose optimization stage and in the first 6 subjects in the Phase 2 dose 
expansion stage with a gastrectomy: Cycle 2: Tucatinib and paclitaxel PK 
samples  
• 
All other subjects: Cycles 2 to Cycle 6: Tucatinib predose sample 
Record the date and time of the subject's last meal prior to tucatinib 
administration. 
● 
Review subject diary or pill count for tucatinib (or tucatinib placebo in Phase 3) drug 
compliance from previous cycle, dispense tucatinib (or tucatinib placebo in Phase 3), 
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 paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B  
● 
Administer trastuzumab 4 mg/kg IV or trastuzumab placebo IV 
● 
Administer ramucirumab 8 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
6.4.6 Cycles >1 Day 8 (±1 day) 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Blood samples for laboratory testing (as listed in Section 7.8.3 
• 
CBC with differential * 
• 
Blood chemistry panel * 
● 
Administer paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B  
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration. 
6.4.7 Cycles >1 Day 15 (±1 day) 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight * 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3: 
• 
CBC with differential * 
• 
Blood chemistry panel * 
• 
Urinalysis * 
● 
Administer paclitaxel IV at the current dose level in the Phase 2, the recommended 
dose in Arms 3A and 3C, and at 80 mg/m² in Arm 3B  
● 
Administer trastuzumab 4 mg/kg IV or trastuzumab placebo IV 
● 
Administer ramucirumab 8 mg/kg IV 
* Predose assessments do not need to be repeated if performed within 1 day prior to dose 
administration 
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6.4.8 Every 6 Weeks as Determined by Cycle 1 Day 1, through Week 36, then 
Every 9 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 
modalities used in Screening/Baseline should be repeated, unless otherwise clinically 
indicated 
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 
6.4.9 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.  
6.5 End of Treatment Visit (30 to 37 days after last dose of any 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.  
● 
Phase 3 only: HRQoL questionnaires (Section 7.7) and HCRU (Section 7.6); to be 
completed prior to evaluation by study personnel (physical examination, review of 
AEs) and administration of study treatment: 
• 
EORTC QLQ-C30 
• 
EORTC QLQ-OG25 
• 
EQ-5D-3L 
• 
Review HCRU since the last study visit 
● 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature, and 
respiration rate) and weight 
● 
Physical exam 
● 
ECOG performance status 
● 
Blood and urine samples for laboratory testing (as listed in Section 7.8.3: 
• 
CBC with differential  
• 
Blood chemistry panel 
• 
Coagulation panel  
• 
Urinalysis  
● 
ECG 
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● 
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 modalities used in 
Screening/Baseline should be repeated, unless otherwise clinically indicated. Not 
required if imaging was performed within 30 days of discontinuing study treatment. 
● 
Review subject diary or pill count for tucatinib (or tucatinib placebo in Phase 3) 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 study treatment. 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 4.4.1). If a subject discontinues study treatment, every attempt 
should be made to follow the subject until death or administrative study closure. 
6.6.1 Follow-up Until Disease Progression (At Least Every 9 Weeks ±1 week) 
For subjects who discontinue study treatment prior to disease progression (per RECIST 
version 1.1), the following assessments must be undertaken at least every 9 weeks (±1 week) 
starting from the date of the last imaging scan, until investigator-assessed disease progression 
(per RECIST version 1.1), death, withdrawal of consent, or study closure: 
● 
Phase 3 only: HRQoL questionnaires (Section 7.7) and HCRU (Section 7.6); to be 
completed prior to evaluation by study personnel: 
• 
EORTC QLQ-C30 
• 
EORTC QLQ-OG25 
• 
EQ-5D-3L 
• 
Review HCRU since the last study visit 
● 
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 
modalities used in Screening/Baseline should be repeated, unless otherwise clinically 
indicated. 
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● 
Cardiac function should be assessed (echocardiogram or MUGA) every 6 months 
until 24 months from the last administration of trastuzumab 
● 
For persons of childbearing potential (for 7 months after the last dose of study 
treatment): 
• 
Confirm with the subject that monthly pregnancy tests have been performed and 
review results 
○ 
Remind subject that monthly pregnancy tests should be performed for 7 months 
after the last dose of study treatment 
6.6.2 Survival Follow-up (Every 12 Weeks After Disease Progression 
±2 weeks) 
Once subjects have experienced disease progression (per RECIST version 1.1) as assessed by 
the investigator during follow-up or discontinued study treatment after documentation of 
disease progression, they will undergo long-term survival follow-up every 12 weeks 
(±14 days) from the EOT visit or from the date of the last progression follow-up visit, 
whichever is later, 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. 
● 
Cardiac function should be assessed (echocardiogram or MUGA) every 6 months 
until 24 months from the last administration of trastuzumab 
● 
For persons of childbearing potential (for 7 months after the last dose of study 
treatment): 
• 
Confirm with the subject that monthly pregnancy tests have been performed and 
have been negative 
• 
Remind subject that monthly pregnancy tests should be performed for 7 months 
after the last dose of study treatment  
More frequent long-term follow-up may be conducted as needed for OS event tracking 
6.7 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 4.1 and Section 4.2 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, and APPENDIX A: physical exam, height, vital signs, weight, 
ECOG performance status, CT with contrast/PET-CT/MRI scan for baseline disease 
assessment, CBC with differential, blood chemistry panel, coagulation panel, urinalysis, 
ECG, echocardiogram/MUGA, Hepatitis B and C screening, blood sample for biomarker 
assay, and serum or urine β-hCG pregnancy test (for females of childbearing potential). 
7.1.1 Evaluation of HER2 Status at Screening 
A blood sample will be drawn at screening to establish baseline HER2 amplification using an 
NGS assay, performed at a central laboratory.  
Archival tumor blocks (or freshly-cut slides, following consultation with the medical 
monitor) sampled following progression during/after the most recent line of therapy, or other 
archival tumor tissue samples collected prior to the first line therapy for advanced disease, 
are to be collected at screening. 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, and lavage samples are not acceptable. Tumor 
tissue should be of good quality based on total and viable tumor content; e.g., samples should 
contain a minimum of 100 tumor cells that preserve cellular context and tissue architecture, 
regardless of the needle gauge used to collect the sample or the retrieval method. See the 
Laboratory Manual for details concerning tissue samples. 
HER2 expression in the tumor tissue sample will be evaluated using tissue-based NGS and 
according to the 2016 guideline of the ASCO/CAP "HER2 Testing and Clinical Decision 
Making in Gastroesophageal Adenocarcinoma", processed in a CLIA- or ISO‑accredited 
laboratory.  
See the Central Laboratory Manual for more details. 
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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), as assessed by the 
investigator and by the BICR (Phase 3). Radiographic scans and additional imaging 
assessments (if applicable) will be performed at protocol-specified time points outlined in 
Section 6 and APPENDIX A. Clinical management decisions will be based on local 
investigator assessment to ensure that treatment decisions are made in a timely manner; 
results of centralized review will not be available to investigators for clinical decision 
making.  
Disease assessments will be performed at screening, and every 6 weeks for the first 36 weeks 
then every 9 weeks, irrespective of dose holds or interruptions. Subjects that discontinue 
study treatment for reasons other than documented progressive disease will continue to have 
disease assessments at least every 9 weeks until the occurrence of documented progression 
per RECIST version 1.1, death, withdrawal of consent, or study closure. 
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 a CT scan with 
contrast is contraindicated (i.e., 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. At the investigator’s discretion, other appropriate imaging (e.g., nuclear 
bone scan imaging for bone lesions) should be used to assess additional known sites of 
measurable disease. The same imaging modalities employed in Screening/Baseline should be 
used for all subsequent response assessments during study treatment and in the follow-up 
period, unless otherwise clinically indicated. If any other radiographic or assessment exam, 
including pathology from any on-study biopsies or procedures, is conducted per standard of 
care, the assessment information will be collected in the CRF. In the Phase 3, all imaging 
will be collected for retrospective BICR. 
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 or clinical 
progression is documented. Demonstration of an unequivocal new lesion constitutes disease 
progression. 
In the Phase 2, subjects will be considered evaluable for response if they meet the following 
3 criteria: (1) had baseline disease assessment, (2) received study treatment, and (3) had 
post-baseline disease assessment or discontinued treatment due to documented disease 
progression, clinical progression, treatment-related AE(s), or death. 
In the Phase 3, all randomized subjects with measurable disease at baseline will be 
considered evaluable for response. 
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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. In the 
Phase 3, all imaging will be submitted or uploaded for retrospective BICR as soon as 
reasonably possible (e.g., 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 third-party imaging core laboratory for BICR. 
7.3 Pharmacokinetic Assessments 
Blood samples for tucatinib, ONT-993, paclitaxel, and paclitaxel metabolites PK assessment 
will be collected at protocol-defined timepoints; Table 15 specifies tucatinib and ONT-993 
PK and biomarker sample collection timepoints for all subjects in Phase 2 and Phase 3, while 
Table 16 specifies additional tucatinib, paclitaxel, and their metabolites PK collection 
timepoints for subjects in the paclitaxel dose optimization stage and the first 6 subjects with 
and without a gastrectomy (without maintenance of the pylorus). 
In all subjects in the paclitaxel dose optimization stage and in the first 6 subjects in the 
Phase 2 dose expansion stage with a gastrectomy, tucatinib and ONT-993 concentrations will 
be sampled on Cycle 1 Day 8 and Cycle 2 Day 1; concentrations of paclitaxel and its 
metabolites will be sampled on Cycle 1 Days 1 and 8 and Cycle 2 Day 1. Subjects with a 
gastrectomy can come from Cohort 2A or Cohort 2B. 
In all subjects in the Phase 2 and Phase 3, tucatinib trough drug concentrations will be 
sampled on Day 1 of Cycles 2 to 6 prior to administration of tucatinib or placebo.  
The date and time of the subject's last meal prior to tucatinib administration must be recorded 
on all days when tucatinib PK draws are made. 
Plasma concentrations of tucatinib, ONT 993, paclitaxel, and its metabolites will be 
determined using validated liquid chromatography (LC)-mass spectrometry (MS)/MS 
methods. PK parameters of tucatinib, paclitaxel, and their respective metabolites will be 
calculated using standard noncompartmental methods. PK parameters to be estimated may 
include, but are not limited to: AUClast, Cmax, Ctrough, Tmax, and MRAUC. 
Trough PK samples should continue to be collected on schedule regardless of dose holds or 
interruptions. The Cycle 1 and Cycle 2 post-dose samples should not be collected during 
dose hold or interruptions. 
 
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Table 15: 
PK and biomarker sample collection timepoints: All subjects in Phase 2 and Phase 3 
Visit 
Cycle day Time 
Window 
Relative time 
Tucatinib and ONT-993 PK HER2 status and biomarkers 
Screening  
 
−28 days 
Initiation of study treatment  
 
Blood sample for NGS and biomarker assay 
Archival tumor tissue sample assaya 
Cycles 2−6  1 
Predose −2 hours 
Time of administration of tucatinib X 
 
EOT 
 
 
30 to 37 days Last dose of any study drug 
 
Blood sample for biomarker assay 
a 
 Archival tumor blocks (or freshly-cut slides, following consultation with the medical monitor) performed following progression during/after the most recent line of therapy, 
or other archival tumor tissue samples collected prior to the first line therapy for advanced disease, are to be collected. 
 
Table 16: 
PK sample collection timepoints: Phase 2 paclitaxel dose optimization stage and first 6 subjects with a gastrectomy in 
Phase 2 dose expansion stage 
 
Cycle day 
Time 
Window 
Relative time 
Paclitaxel and 
metabolites PK 
Tucatinib and ONT-993 
PK 
Cycle 1 1 
Predose 
-24 hours 
START of paclitaxel infusion 
X 
 
EOI 
Within 15 min after end of paclitaxel infusion 
X 
 
2 hours 
±15 min 
X 
 
4 hours 
±15 min 
X 
 
6 hours 
±30 min 
X 
 
8 hours 
±30 min 
X 
 
8 a 
Predose 
-2 hours 
START of paclitaxel infusion  
(co-administer with tucatinib dose) 
X 
Xa 
EOI 
Within 15 min after end of paclitaxel infusion 
X 
X 
2 hours 
±15 min 
X 
X 
4 hours 
±15 min 
X 
X 
6 hours 
±30 min 
X 
X 
8 hours 
±30 min 
X 
X 
Cycle 2 1 
Predose 
-2 hours 
START of paclitaxel infusion  
(co-administer with tucatinib dose) 
X 
Xa 
 
EOI 
Within 15 min after end of paclitaxel infusion 
X 
X 
 
2 hours 
±15 min 
X 
X 
 
4 hours 
±15 min 
X 
X 
 
6 hours 
±30 min 
X 
X 
 
8 hours 
±30 min 
X 
X 
EOI=end of infusion. 
For assessment of PK in 6 subjects with a gastrectomy (without maintenance of the pylorus), subjects can come from Cohort 2A or Cohort 2B. 
a 
Tucatinib should be dosed at approximately the same time as the start of the paclitaxel infusion on the PK day. 
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7.4 Biomarker Studies 
HER2 status will be determined by blood-based NGS in samples taken at screening (unless 
previously determined by the Sponsor, since the end of prior therapy). A blood sample for 
biomarker assay will be drawn at EOT (Table 15). Archival tumor blocks (or freshly-cut 
slides, following consultation with the medical monitor) sampled following progression 
during/after the most recent line of therapy, or other tumor tissue samples collected prior to 
the first line therapy for advanced disease are to be collected at screening. HER2 expression 
in the tumor tissue sample will be evaluated following the ASCO/CAP 2016 guideline for 
HER2 testing in gastroesophageal adenocarcinoma, processed in a CLIA- or ISO‑accredited 
laboratory. HER2 status by tissue-based NGS will also be evaluated. Blood samples for 
biomarker assay will be drawn at screening and at EOT. 
Biomarker assessments may include an exploratory assessment of HER2 mutations or other 
mutations as potential biomarkers of response. Additional exploratory analyses including but 
not limited to IHC and NGS analysis may be performed to interrogate biomarkers that are 
associated with tumor growth, survival, and resistance to targeted therapeutics. This 
assessment may enable the correlation of additional biomarkers with treatment outcome and 
may ultimately guide or refine patient selection strategies to better match tucatinib regimens 
with tumor phenotype/genotype in the future.  
7.5 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 and the identification of 
biomarkers. Blood and tissue samples donated for future research will be retained for a 
period of up to 25 years. If additional consent is not provided, any remaining biological 
samples will be destroyed after the study has been completed and all applicable regulatory 
obligations have been met. 
7.6 Healthcare Resource Utilization 
In the Phase 3, all healthcare encounters related to the subject’s cancer, cancer treatment, or 
cancer-related assessments will be collected for all subjects until the EOT visit or the end of 
follow-up for progression, whichever is later. HCRU data include, but are not limited to, 
procedures that occur on study, such as length of stay, hospitalizations, emergency 
department visits, planned/unplanned provider visits, medication use, radiology, and other 
treatments and procedures. See APPENDIX A and Section 6 for timing of HCRU data 
collection, and see the Study Manual for detailed guidance. 
7.7 Patient-Reported Outcomes 
In the Phase 3, the EORTC QLQ-C30, EORTC QLQ-OG25, and EQ-5D-5L questionnaires 
will be administered according to the schedule specified in APPENDIX A and Section 6, 
until the EOT visit or the end of follow-up for progression, whichever is later. The objective 
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is to compare improvements, deteriorations, and stabilization in HRQoL between treatment 
arms. 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. 
7.7.1 EORTC QLQ-C30 
The EORTC QLQ was developed to measure aspects of HRQoL pertinent to subjects with a 
broad range of cancers who are participating in international clinical trials (Aaronson 1993). 
The recall period is the past week. The core instrument, the QLQ-C30 (version 3.0), is a 
30-item questionnaire consisting of the following: 
● 
5 functional domains (physical, role, cognitive, emotional, social) 
● 
3 symptom scales (fatigue, pain, nausea, and vomiting) 
● 
Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease 
● 
2 global items (health, overall HRQoL) 
 
See APPENDIX G for a sample EORTC QLQ-C30 form. 
7.7.2 EORTC QLQ-OG25 
The EORTC questionnaires for assessing HRQoL for esophageal cancer (QLQ-OES18) and 
stomach cancer (QLQ-STO22) were combined into a single questionnaire for tumors of the 
esophagus, esophago-gastric junction or stomach (EORTC QLQ-OG25; APPENDIX H) 
(Lagergren 2007). The QLQ-OG25 is a 25-item questionnaire consisting of the following 
subscales: dysphagia, eating restrictions, reflux, odynophagia, pain, and anxiety. The recall 
period is the past week. 
7.7.3 EQ-5D-5L – Utility Measurement 
The European Quality of Life (EuroQol) 5-Dimension 5-Level (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 (EQ) visual analog scale (VAS; APPENDIX I).  
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. 
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7.8 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, physical examination findings, vital signs including 
weight, ECGs, ECOG performance status, concomitant medication, pregnancy testing, and 
laboratory tests. Assessment of cardiac ejection fraction will be performed using MUGA 
scan or echocardiogram.  
Safety will be monitored throughout the course of the study by the sponsor, and by the SMC 
during the Phase 2 and the IDMC during the Phase 3, as described in Section 9.3.11. 
7.8.1 Adverse Events 
7.8.1.1 Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug 
(IND) Safety Reporting, an AE is any untoward medical occurrence in a subject 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 Cycle 1 Day 1 that increase in 
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 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 
(see Section 7.8.1.3). Complications that occur in association with any procedure 
(e.g., biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 
or results in study termination, study treatment discontinuation, or dose 
modifications. When recording an AE resulting from a laboratory abnormality, the 
resulting medical condition rather than the abnormality itself should be recorded (e.g., 
record “anemia” rather than “low hemoglobin”). 
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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the 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 Section 7.8.1.2 for the definition of 
potential DILI.) 
 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 5.0. These criteria are provided 
in the study manual. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above). 
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Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (tucatinib, trastuzumab, ramucirumab, 
and paclitaxel) should be evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug 
and the AE, such as: 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome) 
One or more occurrences of an event that is not commonly 
associated with drug exposure, but is otherwise uncommon in the 
population exposed to the drug (e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying 
disease or occurs commonly in the study population), or a temporal 
sequence cannot be established with the onset of the AE and 
administration of the study treatment, or a causal relationship is 
considered biologically implausible 
 
7.8.1.2 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. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
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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. 
Progression of Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of 
Disease”, or “Malignant disease progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported as AEs or SAEs. 
Pregnancy 
Notification to Drug Safety 
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 7 months after the last dose of study drug(s) 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. 
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Collection of data on the CRF 
All pregnancies (as described above) that occur within 30 days of the last dose of study 
drug(s) will also be recorded on the Adverse Events CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.8.1.1) 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 (i.e., elevated alkaline 
phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements 
Any potential Hy’s Law case should be handled as a SAE and reported 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 ALT or AST to >3 × ULN should be followed by repeat testing 
within 48 to 72 hours of 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. 
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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. 
7.8.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through 
30 days after the last study treatment. However, all study protocol-related AEs are to be 
recorded from the time of informed consent. All SAEs that occur after the safety reporting 
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.  
7.8.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
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.  
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7.8.1.5 Adverse Events of Special Interest 
An AE of special interest (AESI) can be any serious or nonserious AE that is of scientific or 
medical concern as defined by the sponsor and specific to the program, for which ongoing 
monitoring and rapid communication to the sponsor may be appropriate.  
The AESIs will need to be reported to the sponsor irrespective of regulatory seriousness 
criteria or causality within 24 hours (Section 7.8.1.4). 
AESIs for this study are: 
● 
Hepatotoxicity: either of the following types of liver enzyme 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 >20.0 × ULN 
• 
Bilirubin elevations >10.0 × 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. 
7.8.1.6 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs to the sponsor (see Section 7.8.1.4). The sponsor 
will report all SAEs, including SUSARs to regulatory authorities as required per local 
legislation or regulatory reporting requirements. 
7.8.2 Vital Signs 
Vital signs measures are to include heart rate, systolic and diastolic blood pressure, 
respiratory rate, and temperature. 
7.8.3 Clinical Laboratory Tests 
Local laboratory testing will include institutional standard tests for evaluating safety at 
scheduled timepoints (see APPENDIX A) during the course of the study and making clinical 
decisions:  
● 
The blood chemistry panel is to include the following tests: albumin, alkaline 
phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, creatinine, 
chloride, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total bilirubin (and direct bilirubin when total bilirubin is >ULN), and total 
protein 
● 
The CBC with differential is to include, but not limited to, the following tests: CBC 
with white blood cell count, red blood cell count, platelet count, hemoglobin, and 
hematocrit, with differential (neutrophils, lymphocytes) 
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● 
The coagulation panel is to include the following tests: INR, PT, PTT, and aPTT 
● 
The estimated GFR should be calculated using the MDRD equation as applicable, 
with serum creatinine (Scr) reported in mg/dL.  
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) 
Consider monitoring renal function with alternative markers, which are not based on 
creatinine to determine whether renal function is impaired. 
● 
Urinalysis 
• 
Standard urinalysis (Note: specify ± reflexive microscopy if clinically indicated) 
• 
Urine protein and urine creatinine for UPC ratio 
• 
If dipstick or routine analysis indicates proteinuria ≥2+ during treatment, a urine 
collection should be done to calculate the UPC ratio 
● 
Hepatitis screening: hepatitis B surface antigen, antibodies to hepatitis B core, and 
antibodies to hepatitis C; if hepatitis C serology is positive, hepatitis C virus RNA test 
by PCR is required to confirm  
● 
A serum or urine β-hCG pregnancy test for subjects of childbearing potential 
7.8.4 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of height 
obtained within the prior 12 months may be utilized. 
7.8.5 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, within 7 days prior to Day 1 of each 
treatment cycle, and at the EOT visit. A negative pregnancy result is required before the 
subject may receive study drug. After the last dose of study treatment, pregnancy tests will be 
performed once a month for 7 months. Subjects may do monthly home pregnancy tests and 
report interim results at long-term follow-up visits. Pregnancy tests may also be repeated as 
requested per Institutional review board/independent ethics committee (IRB/IEC) or if 
required by local regulations. 
7.8.6 Cardiac Function 
7.8.6.1 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 cardiac 
echocardiogram or MUGA should be performed every 12 weeks as determined by the date of 
the most recent interim assessment. Additionally, if a subject discontinues trastuzumab for 
any reason, assessment of cardiac function (echocardiogram or MUGA) must be conducted 
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every 6 months until 24 months from the last administration of trastuzumab. The modality 
chosen in screening should be used for all subsequent cardiac assessments throughout the 
study for comparison. 
7.8.6.2 Electrocardiogram 
ECGs will be performed at baseline and at the EOT visit. To correct for heart rate, QTc 
intervals should be calculated using the Fridericia formula.  
7.9 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.  
In the Phase 3 part, the efficacy of study treatment will be evaluated using OS, the gold 
standard for evaluation of anticancer therapies, and PFS according to RECIST version 1.1 
(Eisenhauer 2009), which are standardized criteria for evaluating response in GEC. Given 
that the randomization and blinding of the Phase 3 portion of the study reduces the potential 
for investigator bias in disease assessments, investigator assessment, rather than BICR 
assessment, will be used to determine date of progression for the primary PFS endpoint. The 
intervals of evaluation in this protocol are considered appropriate for disease management. 
The QLQ-C30 (version 3.0) is a validated questionnaire developed by the EORTC to assess 
the HRQoL of cancer subjects (Aaronson 1993; Sneeuw 1998). The QLQ-OG25 is a 
validated questionnaire developed by the EORTC to assess the HRQoL of subjects with 
esophagus, esophago-gastric junction, or stomach cancer (Lagergren 2007). The EQ-5D-5L 
is a validated instrument for use as a measure of HRQoL (Janssen 2013). These PROs have 
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 electronic CRF (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 eCRF. 
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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. 
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. 
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, electronic patient diaries (eDiary), 
and electronic transfer of BICR review findings may be utilized. If any of these instruments 
are utilized, the data will be transmitted to the eCRF from those instruments. 
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8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by 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 
9.1.1 Phase 2 
Up to approximately 78 DLT-evaluable and/or response-evaluable subjects will be enrolled 
in the phase 2 portion: up to 18 DLT-evaluable subjects in the paclitaxel dose optimization 
stage and up to 30 response-evaluable subjects in each of Cohorts 2A and 2B. Up to 
9 subjects enrolled in the dose optimization stage may count towards the 60 subjects in 
Cohorts 2A and 2B, if they are response-evaluable and receive the recommended paclitaxel 
dose.  
The preliminary activity of the study regimen will be formally evaluated using ORR 
irrespective of confirmation per investigator in approximately 30 response evaluable subjects 
from the dose optimization stage or the dose expansion stage (Cohort 2A) who are HER2+ 
by the blood-based NGS assay and who were treated at the paclitaxel recommended dose. 
The Phase 3 will be initiated if the observed ORR is 36%. With the sample size of 30, it is 
expected that at least 11 responders will be observed if the underlying ORR is 36%. Table 
17 provides the point estimate and 95% CI for ORR under different underlying ORR for the 
sample size of 30. 
Table 17: 
Expected 95% CI under different underlying true ORRs for a sample size of 30 
ORR 
Number of responses in 30 subjects 
Lower bound of 95% CI 
Upper bound of 95% CI 
30% 
9 
14.7% 
49.4% 
36% 
11 
19.4% 
55.5% 
40% 
12 
22.7% 
59.4% 
47% 
14 
28.6% 
66.0% 
50% 
15 
31.3% 
68.7% 
 
9.1.2 Phase 3 
The sample size for the Phase 3 was calculated based on maintaining 90% power for the dual 
primary endpoint of PFS with an alpha of 0.02 and 88% power for the dual primary endpoint 
of OS with an alpha of 0.03. For PFS, 317 events from Arm 3A or Arm 3B are required with 
90% power to detect a HR of 0.67 (4.5 months median PFS in Arm 3B versus 6.75 months in 
Arm 3A) using a 2-sided log-rank test and alpha of 0.02. For OS, 354 events from Arm 3A or 
Arm 3B are required with 88% power to detect a HR of 0.70 (10 months median OS in 
Arm 3B versus 14.3 months in Arm 3A) using a 2-sided log-rank test and alpha of 0.03. The 
2 primary endpoints will be evaluated using parallel testing, with alpha recycling if only one 
of them meets statistical significance. Approximately 470 subjects are needed with equal 
randomization to Arm 3A and Arm 3B.  
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Therefore, approximately 500 subjects will be randomized in an approximately 8:8:1 ratio to 
Arm 3A, Arm 3B, or Arm 3C, with approximately 30 subjects randomized to Arm 3C. 
Assuming an accrual period of 30 months and a 5% yearly drop-out rate, it is expected that 
317 PFS events and 354 OS events from Arm 3A or Arm 3B will be observed approximately 
25 and 39 months after first subject randomized, respectively.  
9.2 Study Endpoint Definitions 
9.2.1 PFS 
PFS is defined as the time from the date of treatment initiation (Phase 2) or randomization 
(Phase 3) 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/randomization. PFS per investigator and per BICR are based on investigator 
response assessments and BICR response assessments, respectively. 
Detailed methodology, including handling rules for missing assessments and censoring 
approaches for the analysis of PFS, is provided in the statistical analysis plan (SAP). 
9.2.2 Overall Survival 
OS is defined as the time from treatment initiation (Phase 2) or randomization (Phase 3) 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 
(i.e., the date of last contact). Subjects lacking data beyond the day of treatment 
initiation/randomization will have their survival time censored on the date of treatment 
initiation/randomization (i.e., OS duration of 1 day). 
9.2.3 Objective Response Rate 
ORR is defined as the proportion of subjects with best overall response of CR or PR 
according to RECIST version 1.1. Only response assessments before first documented 
disease progression or new anticancer therapies will be considered. Confirmed ORR and 
ORR irrespective of confirmation will be evaluated. ORR per investigator and per BICR are 
based on investigator response assessments and BICR response assessments, respectively. 
9.2.4 Duration of Response 
DOR is defined as the time from first documentation of objective response of CR or PR to 
the first documentation of disease progression per RECIST version 1.1 or death from any 
cause, whichever occurs earlier. Only subjects with an objective response will be included in 
the analysis of DOR. DOR per investigator and per BICR are based on investigator response 
assessments and BICR response assessments, respectively. 
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9.2.5 Disease Control Rate 
DCR is defined as the proportion of subjects with CR, PR, or stable disease (SD or 
non-CR/non-progressive disease) according to RECIST version 1.1. DCR per investigator 
and per BICR are based on investigator response assessments and BICR response 
assessments, respectively. 
9.2.6 Exploratory Endpoints 
9.2.6.1 Pharmacokinetic Analysis 
PK parameters such as AUClast, Cmax, Tmax, Ctrough, and MRAUC will be calculated using 
non-compartmental analysis for tucatinib, paclitaxel, and their metabolites in Phase 2 and 
tucatinib in Phase 3. 
9.2.6.2 Biomarker Analysis 
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.  
9.2.6.3 Healthcare Resource Utilization 
HCRU data collected from the eCRF and will include procedures that occur on study, length 
of stay, hospitalizations, emergency department visits, planned/unplanned provider visits, 
medication use, radiology, and other treatments and procedures. 
9.2.6.4 Patient-Reported Outcomes 
PRO assessments will be analyzed to determine if treatment affects PRO scores. PRO scores 
will be analyzed using longitudinal models. All subscales and individual item scores will be 
tabulated. Descriptive summaries of observed data at each scheduled assessment timepoint 
may be presented. Time to deterioration will be assessed in specific pre-specified single 
items from either the EORTC QLQ-C3, EORTC QLQ-OG250, or EQ-5D-5L.  
Additional statistical modeling for PRO and HCRU measures may be performed separately 
in post hoc analyses. 
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 (e.g., adding baseline assessments 
to define a subgroup). The SAP will be finalized prior to database lock. 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 
Hereafter, "treatment group" will be used to designate the following: 
For analyses based on the All-Treated analysis set: 
● 
Each dose level evaluated in the Phase 2,  
For analyses based on the Phase 2 Recommended Dose analysis set,  
● 
Subjects with HER2+ disease according to blood-based NGS assay treated at the 
paclitaxel recommended dose in the dose optimization stage or Cohort 2A 
● 
Subjects with HER2-negative disease according to blood-based NGS but HER2+ 
disease according to IHC/ISH assay of a tumor tissue sample, treated at the paclitaxel 
recommended dose in the dose optimization stage or Cohort 2B 
For Phase 3 analyses, 
● 
Each randomization arm in the Phase 3. 
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 per category for categorical data, by treatment group.  
Unless otherwise specified, CIs will be calculated at 2-sided 95% level. 
The 2-sided 95% exact CI using Clopper-Pearson method (Clopper 1934) will be calculated 
for the response rates where applicable (e.g., ORR).  
For time-to-event endpoints, the median survival time will be estimated using the 
Kaplan-Meier method; the associated 95% CI will be calculated based on the complementary 
log-log transformation (Collett 1994). 
9.3.1.1 Randomization and Blinding 
The Phase 2 portion has a 2-stage, 2-cohort, open-label design. 
The randomized, double-blind, placebo-controlled, active comparator, international, 
multicenter Phase 3 portion of this study will enroll approximately 500 subjects. Subjects 
will be randomized in an approximately 8:8:1 ratio to receive tucatinib and trastuzumab, or 
tucatinib placebo and trastuzumab placebo, or tucatinib and trastuzumab placebo in 
combination with ramucirumab and paclitaxel. Randomization will be stratified using the 
stratification factors described in Section 3.1.9. 
Randomization will be performed centrally using a system that will assign a unique subject 
randomization number but will not specify the actual treatment assignment. Randomization 
procedures are detailed in the Study Manual. 
The blinding plan for the safety and efficacy data will be specified in the SAP. 
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9.3.1.2 Adjustments for Covariates 
There will be no adjustment for covariates in the Phase 2. 
In the Phase 3, stratified analyses will include adjustment for the stratification factors as 
recorded at randomization (described in Section 3.1.9). If the sample size of one stratum by a 
stratification factor is too small, the statistical analysis will not include this randomization 
stratification factor in the statistical analysis, such as stratified log-rank test and stratified 
Cox regression model. This minimum sample size requirement will be specified in the SAP. 
Covariates may be considered for adjustment in exploratory analyses. 
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 in the Phase 2. 
In the Phase 3, to maintain strong control of the family-wise type I error rate at 0.05, the dual 
primary endpoints of PFS per investigator assessment and OS will be evaluated in Arms 3A 
and 3B using parallel testing, at the two-sided type I error rate of 0.02 and 0.03, respectively. 
If only one of the primary endpoints is positive at the specified level, alpha recycling will be 
applied to evaluate the other endpoint at a level of 0.05. OS will be tested twice with an 
overall two-sided alpha of 0.03. The first test of OS will be performed at the same time as the 
primary PFS analysis when approximately 317 PFS events per investigator assessment from 
Arms 3A or 3B are observed. The final test of OS will occur when approximately 354 OS 
events from Arms 3A or 3B are observed. The Lan-DeMets spending functions with O'Brien 
and Fleming boundaries (Chen 2014) will be used for the calculation of the alpha level at the 
first and final tests of OS, based on the actual number of OS events observed at the interim. If 
both PFS and OS are statistically significant at either the first or the final analysis, a formal 
statistical test of ORR per investigator assessment will be performed. Detailed rejection 
boundaries of P-values will be specified in the SAP. 
9.3.1.6 Data Transformations and Derivations 
Time variables based on 2 dates (e.g., start date and end date) will be calculated as (end date 
– start date +1 [in days]) unless otherwise specified in the planned analysis section. 
Baseline values used in all statistical analyses will be the most recent non-missing 
measurement prior to the first dose of study treatment unless otherwise specified in the SAP. 
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9.3.1.7 Analysis Sets 
Phase 2 
The All-Treated set is defined as all subjects in the Phase 2 who received any amount of any 
study drug. 
The Phase 2 Recommended Dose analysis set is defined as all subjects in the Phase 2 who 
started paclitaxel at the dose that was finally adopted following evaluation in the dose 
optimization stage.  
Phase 3 
The intent-to-treat (ITT) analysis set is defined as all randomized subjects. Subjects will be 
included in the treatment group assigned at randomization regardless of the actual treatment 
received. Subjects in Arm 3C will be analyzed separately from Arms 3A and 3B.  
The Safety Analysis set will include all randomized subjects who receive any component of 
combination therapy (or placebo). Treatment groups will be determined using the actual 
treatment received, regardless of the randomization treatment assignment. Subjects in 
Arm 3C will be analyzed separately from Arms 3A and 3B.  
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. The 
subgroups and detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
Phase 2 
In the Phase 2, safety analyses will be undertaken by the SMC when the first 
6 DLT-evaluable subjects in each paclitaxel dose level have been followed for at least 
1 cycle (paclitaxel dose optimization stage). The SMC will conduct additional analyses of 
safety and PK should a dose level be expanded to include a total of 9 subjects. The SMC will 
undertake similar analyses if alternative paclitaxel dose levels/schedules are evaluated. Once 
the paclitaxel dose optimization stage is completed, the SMC will evaluate the safety of the 
study regimen throughout the remainder of Phase 2.  
Final efficacy analyses will be undertaken separately for subjects with HER2+ disease 
according to blood-based NGS assay (from the dose optimization stage and Cohort 2A) and 
subjects without HER2 amplification by blood-based NGS but with HER2+ disease 
according to IHC/ISH assay of a tumor tissue sample (from the dose optimization stage and 
Cohort 2B). The final analyses will occur when approximately 30 response-evaluable 
subjects have been treated at the recommended paclitaxel dose and have been followed for at 
least 6 weeks in each group.  
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Phase 3 
There is only one formal analysis of the dual primary endpoint PFS per investigator 
assessment. The analysis cutoff date for this analysis will be determined once approximately 
317 PFS events per investigator assessment have been observed in the ITT analysis set in 
Arms 3A and 3B and subject enrollment is complete. This is estimated to be approximately 
25 months after randomization of the first subject. 
The dual primary endpoint of OS may be analyzed twice. The first, interim, analysis will be 
performed at the same time as the primary analysis of PFS per investigator assessment (see 
Section 9.3.11.2 for details). If OS is not statistically significant at the interim analysis, the 
final analysis of OS will occur when approximately 354 OS events in the ITT analysis set 
Arms 3A and 3B have occurred. The final OS analysis is estimated to occur approximately 
14 months after completion of the primary analysis of PFS. Confirmed ORR by investigator 
assessment in the response-evaluable subjects in Phase 3 for Arms 3A and 3B will be 
formally tested if both PFS and OS are statistically significant. 
9.3.2 Subject Disposition 
An accounting of study subjects by treatment group will be tabulated and the number of 
subjects in each analysis set will be summarized. Subjects who discontinue study treatment 
and subjects who are off the study will be summarized with reason for drug or study 
discontinuation. 
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. 
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 treatment. 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. 
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9.3.6 Efficacy Analyses 
9.3.6.1 Phase 2 
ORR, confirmed ORR, DOR, and DCR per RECIST version 1.1 according to investigator 
assessment will be evaluated by treatment group in response-evaluable subjects in the 
Phase 2 Recommended Dose set (see Section 7.2 for the definition of response-evaluable). 
PFS will be evaluated by treatment group in all subjects in the Phase 2 Recommended Dose 
set. See Section 9.3.1 for the definition of treatment groups. 
The point estimate of ORR, confirmed ORR, and DCR and their corresponding 95% 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 95% CIs will be calculated by treatment 
group, as appropriate. Detailed methodology will be provided in the SAP. 
9.3.6.2 Phase 3 
Primary Efficacy Analyses 
The stratified log-rank test will be used in the primary evaluation of differences in PFS 
according to investigator assessment and OS between Arms 3A and 3B in the ITT analysis 
set, using a two-sided significance level of 0.02 for PFS and 0.03 for OS. The multiplicity 
adjustment is described in Section 9.3.1.5. 
Stratified Cox proportional-hazards (PH) models will be used to estimate the hazard ratios 
and their 95% CIs. Both stratified log-rank and Cox PH models will take into account the 
stratification factors for randomization. If the sample size of one stratum from a stratification 
factor is too small, statistical analysis may not include this stratification factor. The minimum 
sample size for a stratum to be included in the statistical model will be specified in the SAP. 
All events entered in the database at the times of analysis will be included in the analysis of 
PFS and OS, even if there are more than the prespecified number of events. 
Kaplan-Meier curves depicting PFS and OS in all treatment groups will be generated for 
Arms 3A and 3B and Arm 3C in the ITT set. Additionally, median PFS and OS and the 
2-sided 95% CIs for the medians will be reported using the complementary log-log 
transformation method (Collett 1994). Detailed methodology is provided in the SAP. 
Secondary Efficacy Analyses 
Objective Response Rate  
Data summaries for confirmed ORR (per investigator and per BICR) and ORR irrespective 
of confirmation (per investigator and per BICR) will be provided for response-evaluable 
subjects in Arms 3A and 3B and in Arm 3C. The 95% CIs of ORRs will be estimated for 
each treatment group. If both PFS per investigator and OS are statistically significant in the 
comparison of Arm 3A and Arm 3B, then confirmed ORR per investigator in 
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response-evaluable subjects will be formally compared between two treatment groups at the 
two-sided alpha level of 0.05, using a stratified Cochran-Mantel-Haenszel test. 
Disease Control Rate 
The point estimates and 95% CIs of DCR per investigator and per BICR will be provided for 
each treatment group in the ITT set. 
Progression-free survival 
The secondary endpoint of PFS according to BICR assessment in the Phase 3 will be 
analyzed using same methods used for the primary endpoints. 
Duration of Response 
Only subjects with an objective response will be included in the analysis of DOR per 
investigator and per BICR. DOR will be graphically described using Kaplan-Meier 
methodology. The median DOR and its 95% CI will be provided for all treatment groups. 
9.3.7 Pharmacokinetic Analyses 
Individual (subject) plasma concentrations at each sampling time will be listed for tucatinib, 
paclitaxel, and their metabolites in the Phase 2, and tucatinib and ONT-993 in the Phase 3; 
corresponding summary statistics at each sampling time will also be calculated. 
The PK parameters to be calculated (if applicable) may include but are not limited to: 
AUClast, Cmax, Tmax, Ctrough, and MRAUC. The PK parameters of tucatinib and ONT-993 in 
subjects with and without gastrectomy (without maintenance of the pylorus) will be 
evaluated. 
Exploratory analyses investigating the relationship between tucatinib, paclitaxel, and/or their 
metabolites exposure and efficacy and safety endpoints may be conducted. Additional 
exploratory PK analyses may be conducted. 
Details will be described separately in the SAP or Biomarker Analysis Plan (BAP). 
9.3.8 Biomarker Analyses 
Relationships of biomarker parameters (e.g., baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and PK parameters will be explored. Relationships and 
associated data that are determined to be of interest will be summarized. Details will be 
described separately in the SAP or BAP. 
9.3.9 Patient Reported Outcomes and HCRU Analyses 
In the Phase 3, assessments based on the EORTC QLQ-C30, EORTC QLQ-OG25, 
EQ-5D-5L and HCRU data will summarized using descriptive statistics by treatment group 
for Arms 3A and 3B of the ITT set. 
PRO assessments will be analyzed to determine if treatment affects PRO scores. PRO scores 
will be analyzed using longitudinal models. All subscales and individual item scores will be 
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tabulated. Descriptive summaries of observed data at each scheduled assessment timepoint 
may be presented. Time to deterioration will be assessed in specific pre-specified single 
items from either the EORTC QLQ-C30 or EORTC QLQ-OG25 and deterioration is defined 
as a 10-point increase from baseline in the symptom scales and a 10-point decrease from 
baseline for overall HRQoL. Further investigation of missing patterns and details of 
imputation will be provided in the SAP. 
Additional statistical modeling for PRO and HCRU measures may be performed separately 
in post hoc analyses. 
9.3.10 Safety Analyses 
Safety analyses will, in general, be conducted by treatment group using the All-Treated set in 
the Phase 2 and the Safety Analysis set in the Phase 3. 
9.3.10.1 
Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all AEs, 
treatment-emergent AEs, treatment-related AEs, grade 3 and higher AEs, SAEs, 
treatment-related SAEs, deaths, and AEs leading to study treatment discontinuation. AEs will 
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 study phase, treatment group, study site, subject 
number, and cycle. Separately, all serious AEs and AESIs (see Section 7.8.1.5) will be 
analogously listed. 
9.3.10.2 
Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. A separate listing of all on-study deaths will be presented. 
9.3.10.3 
Clinical Laboratory Results 
For laboratory results, summary statistics for actual values and for change from baseline may 
be tabulated as appropriate by scheduled visit. Laboratory values will be listed with grade per 
NCI CTCAE version 5.0 and flagged when values are outside the normal reference range. 
Changes from baseline in laboratory values (hematology, coagulation, chemistry, and liver 
function) will be summarized by study phase, treatment group and scheduled visit. 
Laboratory shift tables will also be provided by treatment group and scheduled visit. 
Abnormal values (relative to respective normal ranges) will be flagged in listings. 
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Additional analytical methods for a more thorough investigation of liver enzyme tests 
(including temporal/simultaneous summaries and figures) will be specified in the SAP. 
9.3.10.4 
Other Safety Analyses 
Vital Signs and Physical Examinations 
The frequency and percentage of subjects with post-baseline clinically significant vital signs 
will be summarized, by study phase and treatment arm. Abnormal physical examination 
findings may be collected as AEs. 
ECOG Performance Status 
ECOG performance status will be summarized by study phase and treatment arm for each 
visit. 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 by study phase and treatment arm for each scheduled ECG, and shifts 
from baseline may be tabulated. 
9.3.11 Interim Analyses 
9.3.11.1 
Phase 2 
The SMC will undertake safety and PK analyses once the first 6 subjects evaluable for DLT 
in each dose level in the paclitaxel dose optimization stage have been followed for at least 
1 cycle. The SMC will conduct additional analyses of safety and PK should a dose level be 
expanded to include a total of 9 subjects. If alternative paclitaxel dose levels/schedules are 
evaluated, the SMC will undertake similar assessments. 
9.3.11.2 
Phase 3 
No formal interim analysis is planned for the dual primary endpoint of PFS. There is one 
planned interim analysis of the dual primary endpoint of OS, at the time of the final analysis 
of PFS. The final analysis of OS will be performed when approximately 354 OS events from 
Arms 3A and 3B of the ITT set have occurred. Approximately 61% of the total OS events are 
expected to have occurred by the time of the interim analysis. The Lan-DeMets 
O'Brien-Fleming approximation spending function (Chen 2014) will be used for calculation 
of the alpha level at the first and final tests of OS based on the actual number of OS events 
observed at the interim. Detailed rejection boundaries of p-values will be specified in the 
SAP. 
The IDMC will periodically review relevant aggregate safety data from the Phase 3 portion, 
and will make recommendations to the sponsor on the conduct of the study (see IDMC 
charter). 
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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. 
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, or legally acceptable representative, if applicable to this study, by 
obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures. 
For Phase 1 studies, it is preferable for a subject to provide consent themselves. If informed 
consent is obtained from a legally acceptable representative for a subject who is unable to 
provide informed consent at study entry (if applicable), but the subject is later able to provide 
informed consent, the investigator must obtain written informed consent from the subject. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
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10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study 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. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and 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 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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Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-
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Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 
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APPENDIX A: SCHEDULE OF EVENTS 
Screening and 
Baseline 
Treatment Period 
EOT visit  
30 days post 
last dose 
Follow-up  
D–28  D–7 to 
Cycle 1 
Cycles >1 
Every 6 
weeks a 
Every  
Every  
9 weeks until 
progressionb 
Every  
12 weeks after 
progressionc 
to D–1 
D1 
D1 
D8 
D15 D22 
D1 
D8 D15 
12 weeks 
Visit window (days) 
 
 
 
±1 
±1 
±1 -1, +3 ±1 
±1 
±7 
±14 
+7 
±7 
±14 
Screening/  
Baseline 
Informed consent d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for NGS assay of HER2 
amplification  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen collection for HER2 status e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for hepatitis B and C f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
treatment 
Tucatinib (or placebo)g 
 
 
BID every day, from Cycle 1 Day 1h 
 
 
 
 
Paclitaxel  
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Trastuzumab (or placebo) 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Ramucirumab 
 
 
X 
 
X 
  
X 
 
X 
 
 
 
 
 
Safety 
assessments 
Vital signsi, including weight j 
X 
X 
X 
X 
X 
  
X 
X 
X 
 
  
X 
 
 
Physical exam j 
 
X 
X 
 
 
  
X 
 
 
 
  
X 
 
 
ECOG performance status j 
 
X 
X 
 
 
  
X 
 
 
 
  
X 
 
 
CBC with differential j  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
X 
 
 
Blood chemistry panel j 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
X 
 
 
Coagulation panel j 
 
X 
 
 
 
 
Xk 
 
 
 
 
X 
 
 
Urinalysis j,l  
 
X 
X 
 
X 
  
X  
  
X 
 
  
X 
 
 
ECG  
X 
 
 
 
 
 
 
 
 
 
  
X 
 
 
Echocardiogram or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
Xm 
Xm 
Xn 
Xn 
Serum or urine β-hCG pregnancy test (for 
FOCBP) 
 
X 
Xo 
 
 
 
Xo 
 
 
 
 
Xp 
Xp 
Xp 
AEs and concomitant medication 
Collected throughout study reporting period, from screening to EOT visit q 
 
 
Disease  
CT-scan, PET-CT, and/or MRI assessmentsr 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Survival and further therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK 
Blood samples for tucatinib and ONT-993 PK 
 
 
 
Xt 
 
 
Xs,t 
 
 
 
 
 
 
 
Blood samples for paclitaxel and metabolites 
PK in Phase 2 
 
 
Xt 
Xt 
 
  
Xt 
 
 
 
 
 
 
 
Blood sample for biomarker assay 
Xu 
 
 
 
 
 
 
 
 
 
 
X 
 
 
PRO/ 
HCRU 
EORTC QLQ-C30, EORTC QLQ-OG25, 
EQ-5D-5L (Phase 3 only) 
 
 
X 
 
 
 
Xv 
 
 
 
 
X 
X 
 
 FOCBP=females of childbearing potential.
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a 
Scheduling determined by date of Cycle 1, Day 1 visit.  
b 
Scheduling determined by date of the last imaging scan. To be performed every 9 weeks 
until the occurrence of documented disease progression, withdrawal of consent, death, or 
study closure. 
c 
Every 12 weeks (±2 weeks) from the date of the last imaging scan, 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). 
d 
All subjects must sign informed consent for the study before Screening/ Baseline procedures 
are conducted.  
e 
Archival tumor blocks (or freshly-cut slides, following consultation with the medical 
monitor) performed following progression during/after the most recent line of therapy, or 
other archival tumor tissue samples collected prior to the first line therapy for advanced 
disease, are to be collected. 
f 
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 PCR is 
required to confirm. 
g 
On days when tucatinib PK blood draws are done, record the date and time of the subject's 
last meal prior to tucatinib administration. 
h 
In subjects in the Phase 2 undergoing Cycle 1 paclitaxel PK assessment, the first tucatinib 
dose will be given in the evening on Day 1 
i 
Vital signs to be collected are systolic and diastolic blood pressure, heart rate, temperature, 
and respiratory rate 
j 
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. 
k 
Coagulation panel should be assessed on Day 1 every 2 cycles, starting from Cycle 2. 
l 
If the urine protein is ≥2+ on a dipstick, at baseline either a 24-hour urine must be collected 
and must demonstrate <1000 mg of protein in 24 hours or the UPC ratio must be <1 to allow 
participation in the study. If the urine protein is ≥2+ during treatment, urine should be 
collected and the UPC ratio calculated. 
m 
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). 
n 
Cardiac function should be assessed (echocardiogram or MUGA) every 6 months until 
24 months from the last administration of trastuzumab. 
o 
Pregnancy test must be performed within 7 days prior to Day 1 of each treatment cycle. 
p 
FOCBP only: After the last dose of study treatment, pregnancy tests will be performed once 
a month for 7 months. 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. 
q 
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 7.8.1.3). 
r 
At minimum, disease assessments, preferably using CT-scans, must include the chest, 
abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease such 
as bone imaging. Scans should be performed at screening, during treatment, and at the EOT 
visit. During treatment, scans will be performed every 6 weeks (based on Cycle 1 Day 1) 
through Week 36 then every 9 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. After study treatment discontinuation, disease 
assessments should be undertaken 9 weeks until the occurrence of documented disease 
progression, withdrawal of consent, death, or study closure. Disease should be evaluated 
using the same modality as at screening/baseline. If bone imaging is collected, any 
RECIST-appropriate imaging modality may be used. 
s 
In all subjects in Phase 2 and Phase 3: tucatinib predose trough concentration will be 
assessed in Cycles 2 to 6. 
t 
In all subjects in the paclitaxel dose optimization stage and in the first 6 subjects in the 
Phase 2 dose expansion stage with gastrectomy (without maintenance of the pylorus): 
tucatinib and ONT-993 PK assessments will be done on Cycle 1 Day 8 and Cycle 2 Day 1, 
and PK assessments of paclitaxel and its metabolites will be done Cycle 1 Days 1 and 8 and 
Cycle 2 Day 1. Subjects with gastrectomy can come from either Cohort 2A or Cohort 2B. 
u 
There is no need for a separate blood sample for biomarker analysis at screening, as is taken 
as part of the blood sample for NGS assay of HER2 amplification. 
v 
Day 1 of every second cycle from Cycle 2 
 
 
 
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APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky  
 
 
ECOG 
Percent 
Description 
 
 
Score 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
 
 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
 
 
40 
Disabled, requires special care 
and assistance. 
 
 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
 
 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
 
 
0 
Dead. 
 
 
5 
Dead. 
 
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APPENDIX C: 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). 
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 (e.g., 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 
Contraception options for male subjects sexually active with a person who is pregnant or 
breast feeding 
Subjects born male and who are sexually active with a pregnant or breastfeeding person must 
use the contraceptives in Option 1 or 2: 
• 
Option 1: Male condom (with or without spermicide) and cervical cap 
• 
Option 2: Male condom (with or without spermicide) and diaphragm 
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 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/ucm093664.ht
m#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 
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/ucm093664.ht
m#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, darunavir
a, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatin
b, midazolam, 
naloxegol, nisoldipine, saquinavir
a, 
simvastatin
b, sirolimus, tacrolimus, tipranavir
a, 
triazolam, vardenafil 
alprazolam, aprepitant, atorvastatin
c, 
colchicine, eliglustat
d, pimozide, 
rilpivirine, rivaroxaban, tadalafil 
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir
a, lurasidone, 
maraviroc, quetiapine, sildenafil, ticagrelor, 
tolvaptan 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5fold with strong index inhibitors of a given 
metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of 
≥2 to <5fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of 
CYP3A with ≥10fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line. 
Other elimination pathways may also contribute to the elimination of the substrates listed in the table above and should be 
considered when assessing the drug interaction potential. 
a 
Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
b 
Acid form is an organic anion transporting polypeptide 1B1 (OATP1B1) substrate. 
c 
Listed based on pharmacogenetic studies. 
d 
Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
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: EORTC QLQ-C30 
ENGLISH 
 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you 
provide will remain strictly confidential. 
Please fill in your initials: 
|_|_|_|_| 
Your birthdate (Day, Month, Year): 
|_|_|_|_|_|_|_|_| 
Today's date (Day, Month, Year): 
31 |_|_|_|_|_|_|_|_| 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
Please go on to the next page 
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ENGLISH 
 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, like reading a 
 
newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For 
the 
following 
questions 
please 
circle 
the 
number 
between 
1 
and 
7 
that  
best applies to you 
 
 
29. How would you rate your overall health during the past week? 
  
1 
 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
1 
 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
 
 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
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APPENDIX H: EORTC QLQ-OG25 
ENGLISH 
 
EORTC QLQ – OG25 
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
During the past week: 
 
 
 
Not at 
all 
A  
little 
Quite  
a bit 
Very 
much 
31. Have you had problems eating solid foods? 
1 
2 
3 
4 
32. Have you had problems eating liquidised or soft foods? 
1 
2 
3 
4 
33. Have you had problems drinking liquids? 
1 
2 
3 
4 
34. Have you had trouble enjoying your meals? 
1 
2 
3 
4 
35. Have you felt full up too quickly after beginning to eat? 
1 
2 
3 
4 
36. Has it taken you a long time to complete your meals? 
1 
2 
3 
4 
37. Have you had difficulty eating? 
1 
2 
3 
4 
38. Have you had acid indigestion or heartburn? 
1 
2 
3 
4 
39. Has acid or bile coming into your mouth been a problem? 
1 
2 
3 
4 
40. Have you had discomfort when eating? 
1 
2 
3 
4 
41. Have you had pain when you eat? 
1 
2 
3 
4 
42. Have you had pain in your stomach area? 
1 
2 
3 
4 
43. Have you had discomfort in your stomach area? 
1 
2 
3 
4 
44. Have you been thinking about your illness? 
1 
2 
3 
4 
45. Have you worried about your health in the future? 
1 
2 
3 
4 
46. Have you had trouble with eating in front of other people? 
1 
2 
3 
4 
47. Have you had a dry mouth? 
1 
2 
3 
4 
48. Have you had problems with your sense of taste? 
1 
2 
3 
4 
49. Have you felt physically less attractive as a result of your 
 
disease or treatment? 
1 
2 
3 
4 
Please go on to the next page 
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ENGLISH 
During the past week: 
 
 
 
 
Not at 
all 
A  
little 
Quite  
a bit 
Very 
much 
50. 
Have you had difficulty swallowing your saliva? 
1 
2 
3 
4 
51. 
Have you choked when swallowing? 
1 
2 
3 
4 
52. 
Have you coughed? 
1 
2 
3 
4 
53. 
Have you had difficulty talking? 
1 
2 
3 
4 
54. 
Have you worried about your weight being too low? 
1 
2 
3 
4 
55. 
Answer this question only if you lost any hair: 
 
If so, were you upset by the loss of your hair? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© EORTC QLQ-OG25 Copyright 2007 EORTC Quality of life group. All rights reserved 
 
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APPENDIX I: 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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Under each heading, please tick the ONE box that best describes your health TODAY.
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
I have no problems doing my usual activities 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
PAIN / DISCOMFORT 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
❑ 
❑ 
❑ 
❑ 
❑ 
 
 
 
2 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
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• We would like to know how good or bad your health is TODAY. 
 
• This scale is numbered from 0 to 100. 
 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
• Mark an X on the scale to indicate how your health is TODAY. 
 
• Now, please write the number you marked on the scale in the box 
below. 
 
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
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APPENDIX J: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled  
MOUNTAINEER-02: A randomized, double-blind, placebo-controlled, active comparator 
Phase 2/3 study of tucatinib in combination with trastuzumab, ramucirumab, and paclitaxel in 
subjects with previously treated, locally-advanced unresectable or metastatic HER2+ gastric 
or gastroesophageal junction adenocarcinoma (GEC) 
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 K: 
DOCUMENT HISTORY 
Version 
Date 
Original 
08-Apr-2020 
Amendment 1 
26-Jun-2020 
Amendment 2 
02-Apr-2021 
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SUMMARY OF CHANGES IN AMENDMENT 1 
Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Throughout the 
protocol 
Added identification of study as 
MOUNTAINEER-02 
Study name newly designated 
Throughout the 
protocol 
Changed the Phase 2 safety lead-in stage, in 
which the tucatinib dose would potentially be 
de-escalated, to a paclitaxel dose optimization 
stage, to determine the recommended dose of 
paclitaxel administered with tucatinib, 
trastuzumab, and ramucirumab. 
Concerns over a potential 
drug-drug interaction between 
tucatinib and paclitaxel led to the 
initial evaluation of a lower 
paclitaxel dose. 
Throughout the 
protocol 
Changed the Phase 2 Safety and activity 
assessments stage to Dose expansion stage. 
To be consistent with paclitaxel 
dose optimization stage. 
Throughout the 
protocol 
Added Cohort 2B to the dose expansion stage of 
the Phase 2 to enroll subjects who are human 
epidermal growth factor receptor 2 
(HER2)-negative according to blood-based next 
generation sequencing (NGS) assay of circulating 
tumor DNA (ctDNA) but HER2-positive 
(HER2+) according to tissue biopsy 
In order to evaluate the study 
regimen in this subject population. 
Throughout the 
protocol 
Added the designations "Cohort 2A" and 
"Cohort 2B" in the Phase 2 dose expansion stage, 
changed the designations "Arm A" and "Arm B" 
to "Arm 3A" and "Arm 3B", and added the 
designation "Arm 3C" for the new arm in the 
Phase 3. 
For the sake of clarity. 
Throughout the 
protocol 
Added an arm to Phase 3 to evaluate tucatinib, 
trastuzumab placebo, ramucirumab, and 
paclitaxel in 30 subjects 
To establish the activity of 
tucatinib without trastuzumab 
when combined with ramucirumab 
and paclitaxel 
Section 2, 
Synopsis 
Added an objective and an endpoint to determine 
the recommended dose of paclitaxel. 
To implement the paclitaxel dose 
optimization stage. 
Section 2, 
Synopsis 
Specified that the secondary objective to evaluate 
the preliminary activity of tucatinib in 
combination with trastuzumab, ramucirumab, and 
paclitaxel applies to subjects that have HER2+ 
disease according to blood-based NGS assay. 
Clarification required given the 
addition of Cohort 2B. 
Section 2, 
Synopsis 
Added objective response rate (ORR) irrespective 
of confirmation per Response evaluation criteria 
in solid tumors (RECIST) version 1.1 according 
to investigator assessment, and confirmed ORR 
per RECIST version 1.1 according to blinded 
independent central review (BICR) assessment to 
Phase 3 efficacy endpoints. 
To expand sensitivity analyses of 
ORR. 
Section 2, 9.2.3, 
9.2.5, 9.3.6.1, 
Synopsis 
Changed the first efficacy first endpoint in the 
Phase 2 to ORR irrespective of confirmation, 
added an endpoint for confirmed ORR, changed 
duration of response (DOR) and disease control 
rate (DCR) to use response irrespective of 
confirmation. 
In order to be able to undertake the 
Phase 2 efficacy assessment once 
30 subjects in Cohort 2A have 
been followed for 6 weeks rather 
than 12 weeks. 
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Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Section 2, 
Synopsis 
Added an exploratory objective to evaluate the 
preliminary activity of tucatinib in combination 
with trastuzumab, ramucirumab, and paclitaxel 
applies to subjects that have HER2-negative 
disease according to blood-based NGS assay but 
are HER2+ according to assay of biopsy. 
As part of the addition of 
Cohort 2A. 
Section 2, 
Synopsis 
Added an exploratory objective to evaluate the 
correlation between HER2 blood-based 
amplification assay and HER2 
overexpression/amplification in assays of biopsies 
To evaluate the relative 
frequencies in the pretreated GEC 
population of the different types of 
HER2 positivity. 
Section 2, 9.3.6.2, 
Synopsis 
Added efficacy endpoints for ORR irrespective of 
confirmation per investigator and per BICR to the 
primary Phase 3 objective. 
 
Section 2, 
Synopsis 
Added secondary and exploratory objectives, 
respectively, to evaluate the anti-tumor activity of 
tucatinib in combination with ramucirumab and 
paclitaxel, and to evaluate the safety and 
tolerability of tucatinib in combination with 
ramucirumab, and paclitaxel to the Phase 3. 
To implement the addition of 
Arm 3C to the Phase 3. 
Section 3.1.1.2, 
3.1.2, 3.1.8, 3.2.1, 
4.1, Synopsis 
Changed the inclusion criteria for HER2+ 
disease, specifying that subjects need to have 
HER2+ according to assay of blood-based NGS 
or biopsy in the dose optimization stage, 
according to blood-based NGS for Cohort 2A and 
the Phase 3, and be HER2 negative according to 
blood-based NGS and HER2+ according to 
biopsy for Cohort 2B. 
To implement the addition of 
Arm 3C to the Phase 3. 
Section 4.1, 
Synopsis 
Added an inclusion criteria to require that 
subjects have to supply archival tumor tissue for 
central assay; if an archival sample is not 
available, the subject may be eligible, following 
approval by the medical monitor. 
In order to evaluate biomarker 
objectives. 
Section 4.1, 
Synopsis 
Added the specification that subjects with 
hemoglobin ≥8 and <9 g/dL may be included with 
approval from the Medical Monitor 
According to feedback from 
investigators. 
Section 4.1, 
Synopsis 
In the inclusion criteria for subjects who can 
father children who are sexually active with a 
person who is pregnant or breastfeeding, changed 
the contraception requirements from 2 highly 
effective methods to 1 of 2 contraception options. 
Update of Seattle Genetics 
standard contraception criteria. 
Section 4.2, 
Synopsis 
Added an exclusion criteria against having 
received more than 1 line of prior systemic 
therapy for locally-advanced unresectable or 
metastatic disease 
Clarification of eligibility criteria. 
Section 4.2, 
Synopsis 
Changed exclusion criteria for having received 
prior taxanes to having received taxanes ≤12 
months prior to enrollment 
To allow use of taxanes in 
neoadjuvant therapy. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 127 of 133 
Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Section 4.2, 
Synopsis 
Added an exclusion criteria making subjects with 
gastrectomy ineligible for the Phase 2 dose 
optimization stage. 
In order that potential tucatinib 
pharmacokinetic (PK) differences 
in subjects with gastrectomies will 
not affect the PK evaluation of the 
paclitaxel dose-finding stage.  
Section 4.2, 
Synopsis 
Added an exclusion criteria against subjects with 
major surgery planned for after treatment 
initiation. 
To avoid treatment interruption 
and potential co-morbidities. 
Sections 3.1, 
3.1.1.1, 3.1.1.2, 
3.1.2, 9.1.2, 
9.3.1.1, Synopsis 
Changed the planned number of Phase 2 subjects 
from 30 to 66, and the planned number of Phase 3 
subjects from 470 to 500. 
Phase 2: addition of Cohort 2B. 
Phase 3: addition of Arm 3C. 
Sections 3.1.1.2, 
5.2.1, Synopsis 
Removed mentions of additional subjects 
possibly being enrolled if alternative tucatinib 
doses or administration schedules were evaluated. 
The study design is now directed 
towards modification of the 
paclitaxel dose/schedule, rather 
than that of tucatinib.  
Section 3.1.1.2, 
9.3.1.9, Synopsis 
Changed the follow-up required for a Phase 2 
subject to be evaluable for response from 
12 weeks to 6 weeks. 
Only 6 weeks is required that the 
formal analysis of ORR in the 
dose expansion cohort is using 
ORR irrespective of confirmation, 
rather than confirmed ORR. 
Sections 3.1.1.1, 
3.1.3, 5.1, 5.1.2, 
9.3.11.1, 9.3.11.1, 
Synopsis 
Added that paclitaxel dose levels for assessment 
are 60 and 80 mg/m², that 6 subjects are to be 
evaluated in each paclitaxel dose level, that if 
≤2 dose-limiting toxicities (DLT) are observed at 
60 mg/m² the paclitaxel dose can be escalated, 
definition of evaluable for DLT, and added 
definitions of DLT. 
To implement the paclitaxel dose 
optimization stage. 
Sections 3.1.1.2, 
9.1.1, Synopsis 
Specified that 30 response-evaluable subjects are 
to be treated in each cohort of the dose expansion 
stage, and that they could have been enrolled in 
the dose optimization stage if treated at the 
recommended paclitaxel dose. 
To implement the formal 
evaluation of activity in Phase 2. 
Sections 3.1.1.2, 
9.1.1, Synopsis 
Added a formal efficacy gate to the Phase 2 
(ORR 36%) to determine whether the Phase 3 
can be initiated. 
In order to have a more rigorous 
assessment of Phase 2 efficacy. 
Sections 3.1.2, 
3.1.8, 9.1.2, 
9.3.1.1, Synopsis 
Changed the randomization ratio from 1:1 to 
8:8:1. 
To adjust randomization to have 
approximately 235 subjects each 
in Arms 3A and 3B, and 
30 subjects in Arm 3C. 
Sections 3.1.1.1, 
6.4.5, Synopsis 
Added a full PK assessment for tucatinib and 
paclitaxel on Cycle 2 Day 1. 
Given the potential drug-drug 
interaction (DDI) of tucatinib and 
paclitaxel, a more thorough 
evaluation of PK is required.  
Sections 3.1.1.1, 
3.1.1.2, 3.1.2, 5.1, 
6.4.1, 6.4.2, 6.4.3, 
6.4.5, 6.4.6, 6.4.7, 
Synopsis 
Changed the paclitaxel dose from a uniform 
80 mg/m² to 1) according to enrolling dose level 
in the Phase 2 dose optimization stage, 2) dose 
recommended by the dose optimization in the 
Phase 2 dose expansion stage and Arms 3A and 
3C of the Phase 3, 3) 80 mg/m² in Arm 3B of the 
Phase 2. 
Changes required by 
implementation of paclitaxel dose 
escalation, and by the need to use 
full dose paclitaxel in the standard 
of care comparator arm. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 128 of 133 
Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Section 3.1.1, 
5.1.1.1, Synopsis 
Removed language pertaining to tucatinib dose 
de-escalation. 
Tucatinib dose de-escalation 
replaced by paclitaxel dose 
escalation. 
Sections 3.1.1.2, 
Synopsis 
Specified that subjects with gastrectomy 
undergoing PK can come from Cohort 2A or 2B. 
The evaluation of the effect of 
gastrectomies on tucatinib PK will 
not be affected by cohort.  
Sections 3.1.1.1, 
3.1.3, 3.1.4, 7.8, 
Synopsis 
Removed mentions of clinically significant 
adverse events (AEs). 
Assessment of clinically 
significant AEs is replaced by 
assessment of DLTs. 
Sections 3.1.2, 
Synopsis 
Specified that formal Phase 2 assessment of 
activity is to be done in all subjects treated at the 
recommended paclitaxel dose who were HER2+ 
according to the blood-based NGS assay. 
Clarification given addition of 
Cohort 2B. 
Sections 3.1.4, 
Synopsis 
Added evaluation of PK data to SMC assessment 
of safety in paclitaxel dose levels.  
PK data is important for the 
assessment of dose escalation 
given the potential DDI of 
tucatinib and paclitaxel. 
Sections 5.1.1, 
5.5, 6.4.5, 6.5 
Added specification that tucatinib compliance 
may be evaluated by pill counts. 
Either pill counts or patient diaries 
may be used in this study. 
Section 5.1.2 
Removed specification that subjects can receive 
paclitaxel with ongoing Grade 2 peripheral 
neurotoxicity, rather than Grade 1 
Grade 2 peripheral neuropathy 
deemed too severe for paclitaxel 
administration. 
Section 5.2.4 
Updated paclitaxel dose reduction levels to take 
into account that subjects may not start at 
80 mg/m². 
To take into account subjects 
starting at 60 mg/m². 
Section 5.2.4 
Removed exception for Grade 2 peripheral 
neuropathy from paclitaxel dose modification 
table. 
Changed because paclitaxel 
administration is now not allowed 
in the event of Grade 2 peripheral 
neurotoxicity. 
Section 5.4.2 
For inducers of CYP34A and CYP2C8, it is no 
longer required to avoid their administration with 
2 weeks after tucatinib discontinuation. Strong 
inhibitors of CYP2C8 can be administered 
starting 1 week after discontinuation of tucatinib, 
rather than 2. Moderate inhibitors of CYP2C8 are 
now to be used with caution. 
Re-evaluation of tucatinib DDI. 
Sections 6.2, 
7.1.1, 7.3, 
APPENDIX A  
Changed tumor tissue collection specification to 
no longer require a fresh tissue biopsy to be 
performed at screening, Rather available tissue 
samples performed following progression 
during/after the most recent line of therapy, or 
performed prior to the first line therapy for 
advanced disease, are to be collected. 
On-study biopsies are no longer 
mandated. Appropriate tissue 
samples will be analyzed only if 
available. 
Section 6.4.1, 
6.4.2, 6.4.3, 6.4.5, 
7.3, APPENDIX 
A 
Removed "without gastrectomy" from the 
specification that PK would be performed in the 
first 6 subjects in the Phase 2 with gastrectomy 
and without gastrectomy. 
Not necessary to specifically call 
out 6 subjects without 
gastrectomy, as all subjects in the 
dose optimization stage will now 
be without gastrectomy. 
Section 6.4.4, 
APPENDIX A 
Added a complete blood count (CBC) with 
differential and a chemistry panel on Cycle 1 
Day 22.  
In order to fully evaluate 
laboratory abnormalities occurring 
during the first cycle. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 129 of 133 
Amendment A01 
 
 
Section(s) 
Change 
Rationale 
Section 7.8.1.2 
Added a section specifying which event name and 
severity grading to use for events of left 
ventricular ejection fraction (LVEF) decreased. 
In order to harmonize reporting of 
LVEF events. 
Section 7.8.5, 
APPENDIX A 
Specified that monthly pregnancy tests during 
follow-up can be done using home pregnancy 
test. 
For subject convenience. 
Section 9 
Deleted tables showing objectives, endpoints, 
corresponding measurements, and time points. 
No longer required per Seattle 
Genetics template. 
Section 9.1.1, 
Synopsis 
Updated table of 95% CIs according to number of 
responses observed for the case of 36% ORR. 
Adjustment for efficacy gate. 
Section 9.3.11.2, 
Synopsis 
Added the information time (approximately 61% 
of the total OS events) for the OS interim 
analysis. 
More completely specify the 
nature of the Phase 3 interim 
analysis. 
APPENDIX E 
Changed the list of strong CYP2C8 inhibitors, 
added a list of moderate inhibitors, and changed 
the list of strong inducers to moderate inducers. 
Updates to referenced lists. 
Throughout the 
protocol 
Administrative changes. 
 
 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 130 of 133 
SUMMARY OF CHANGES IN AMENDMENT 2 
Amendment A02 
 
 
Section(s) 
Change 
Rationale 
Synopsis 
Revised the planned number of subjects from 
66 to 78. 
Due to each dose level in the 
paclitaxel dose optimization 
stage potentially enrolling 
9 subjects, rather than 6. 
Section 1.1 
Added information regarding the approval of 
T-DXd in previously-treated gastric cancer, and 
revised the paragraph in consequence of this 
information. 
Clarification. 
Section 2, 
Synopsis 
In the first exploratory phase 2 objective, added 
specification that HER2+ status is determined by 
IHC/ISH assay of a tumor tissue sample. 
Clarification. 
Section 3.1.1.1, 
3.1.1.2, 4.1, 
Synopsis 
Revised inclusion criterion #2 to remove the 
requirement for central confirmation of IHC/ISH 
assay of a tumor tissue sample. 
Local assessment of a tumor 
tissue sample processed in a 
CLIA- or ISO‑accredited 
laboratory is deemed sufficient to 
determine the presence of 
HER2+ disease. 
Section 3.1.1.1, 
Figure 1, Figure 
2, Synopsis 
Revised the DLT evaluation in the Paclitaxel Dose 
Optimization stage to enroll 3 more subjects at a 
dose level if 2 DLT are observed, and to require 
≤1 DLT in 6 subjects or ≤2 DLT in 9 subjects to 
escalate the dose or identify the recommended 
dose. 
To more thoroughly evaluate a 
dose level if 2 DLT are observed 
in 6 subjects. 
Section 3.1.1.2, 
Synopsis 
Replaced statements that 24 to 30 subjects will be 
enrolled in the expansion cohorts with statements 
that 30 subjects will be enrolled in the expansion 
cohorts. 
Clarified the manner in which 
subjects from the dose 
optimization stage may count 
towards the sample size of the 
expansion cohorts. 
Section 3.1.1.2, 
4.1, 7.1.1, 7.4, 
Synopsis 
Revised the inclusion criterion #2 concerning 
determination of HER2+ status to specify that 
assays of tumor tissue should be processed in a 
CLIA- or ISO‑accredited laboratory, rather than 
following the package insert of FDA-approved 
tests. 
To ensure that appropriate tests 
are available in all countries. 
Sections 3.1.3, 
7.8.1.5 
Changed the specification of hepatic DLTs and 
hepatotoxicity AESIs to elevations with respect to 
the ULN, rather than grades. 
For consistency with other 
specifications of liver enzyme 
elevations. 
Section 3.2.3.4 
Added information regarding the evaluation of 
tucatinib, trastuzumab, paclitaxel, and pertuzumab 
in the I-SPY2 study. 
Further information regarding 
the combination of tucatinib and 
paclitaxel. 
Section 3.2.3 
Subdivided the rationale for dose and schedule of 
trastuzumab, ramucirumab, and paclitaxel into 
separate subsections. 
For the sake of clarity. 
Section 3.2.3.4 
Added information regarding the evaluation of 
tucatinib, trastuzumab, paclitaxel, and pertuzumab 
in the I-SPY2 study. 
Further information regarding 
the combination of tucatinib and 
paclitaxel. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 131 of 133 
Amendment A02 
 
 
Section(s) 
Change 
Rationale 
Section 4.1, 
Synopsis 
In inclusion criterion #2, changed "HER2+ disease 
at screening" to "HER2+ disease documented since 
progression of the most recent line of systemic 
therapy" and removed similar statements from #2.a 
and #2.b.ii. 
This statement applies to all 
clauses of inclusion criterion #2. 
Section 4.1, 
Synopsis 
In inclusion criterion #2.b.ii, specified that subjects 
cannot have HER2 amplification by blood-based 
NGS assay in Cohort 2B. 
Consistency. 
Section 4.1, 
Synopsis 
In inclusion criterion #13: Added the specification 
that subjects on full-dose anticoagulation must be 
on a stable dose of oral anticoagulant or low 
molecular weight heparin. If on warfarin, the 
subject must have an INR of ≤3 and have no active 
bleeding (within ≤14 days prior to enrollment or 
randomization, excluding trace hematuria) or 
pathological condition that carries a high risk of 
bleeding (i.e., tumor involving major vessels or 
known varices). 
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Sections 4.1, 
5.1.2.1, 6.2.1, 
Synopsis 
In inclusion criterion #15: specified that a UPC 
ratio <1 is sufficient to allow enrollment in the 
event of proteinuria ≥2+, as an alternative to a 
24-hour urine collection showing <1000 mg of 
protein. 
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Section 4.2, 
Synopsis 
Removed exclusion criterion #11, regarding 
myocardial infarction or unstable angina. 
Already covered by exclusion 
criterion #22 (formerly #24). 
Section 4.2, 
Synopsis 
Removed prohibition on enteral feeding from 
exclusion criterion #15 (formerly #16). 
Inability to swallow pills is an 
adequate restriction on the study 
population. 
Section 4.2, 
Synopsis 
Removed exclusion criterion #21, regarding 
therapeutic anti-coagulation.  
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Section 5.1.1.2  
Removed the specification of trastuzumab vial size. 
Vial size of commercially 
available formulation may vary 
between countries. 
Section 5.1.1.2 
Changed trastuzumab storage and handling 
specifications to "should be prepared and 
administered per instructions in the package 
insert." 
To ensure that applicable 
package insert is followed. 
Section 5.1.2.1 
Added that ramucirumab is also indicated as 
first-line treatment in combination with erlotinib 
for metastatic NSCLC with EGFR exon 19 
deletions or exon 21 substitution mutations. 
Update of ramucirumab 
indications. 
Section 5.2.1 
Added specifications concerning the resumption of 
tucatinib at the same dose, when applicable, to 
tucatinib dose modification tables. 
Clarification. 
Section 5.2.2.1 
Revised trastuzumab dose modifications for left 
ventricular dysfunction. 
Consistency with revised 
trastuzumab prescribing 
information. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 132 of 133 
Amendment A02 
 
 
Section(s) 
Change 
Rationale 
Section 5.2.3 
In the ramucirumab dose modification table, 
specified that ramucirumab should be discontinued 
for Grade 3 or 4 arterial thromboembolic events, 
rather than any grade, and also for any pulmonary 
embolism or deep vein thrombosis occurring or 
worsening during anticoagulant therapy. 
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Sections 5.2.3, 
5.2.3.3 
Modified the ramucirumab dose modification 
guidelines in the event of proteinuria, using UPC 
ratio rather than protein in a 24-hour urine 
collection to guide dose modifications. 
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Section 5.4.1 
Added specification that subjects stabilized on 
chronic oral anticoagulation therapy are eligible, 
provided that the coagulation parameters defined in 
the inclusion criteria are met 
Revised ramucirumab treatment 
guidelines. 
Section 5.4.2 
Removed the prohibition of therapeutic 
anticoagulation with warfarin, low-molecular 
weight heparin or similar agents.  
Added that subjects who develop venous 
thromboembolism may continue study therapy and 
receive anticoagulation with low molecular weight 
heparin (not oral anticoagulation).  
Revised ramucirumab treatment 
guidelines. 
Section 5.4.2 
Added specification that ongoing aspirin therapy at 
doses exceeding 325 mg/day is not permitted. 
Revised ramucirumab treatment 
guidelines. 
Sections 6.1, 
6.2.1, 6.4, 6.5, 7.1, 
Schedule of 
Events 
Changed "serum chemistry" to "blood chemistry". 
To allow for plasma chemistry 
tests. 
Sections 6.1, 7.4 
Added specification that a blood sample for 
biomarker assay will be drawn at EOT. 
Consistency with Schedule of 
Events. 
Section 6.4.5 
For PK assessment in the paclitaxel dose 
optimization stage and in the first 6 subjects in the 
Phase 2 dose expansion stage with a gastrectomy, 
specified that tucatinib PK is done as well as 
paclitaxel PK. 
Consistency. 
Sections 6.4.2, 
6.4.5, 7.3, 
Schedule of 
Events 
Added the specification that the date and time of 
the subject's last meal prior to tucatinib 
administration is to be recorded on days when 
tucatinib PK draws are made. 
To evaluate the food effect on 
the potential tucatinib-paclitaxel 
DDI. 
Sections 6.6.1, 
6.6.2, 7.8.6.1, 
Schedule of 
Events 
Added requirement that subjects undergo LVEF 
assessments every 6 months for 24 months after 
discontinuation of trastuzumab.  
Harmonization with trastuzumab 
prescribing information. 
Section 7.1.1 
Removed forceps from the list of biopsy methods 
that are not acceptable for submitted tumor tissue 
samples. 
Removed because primary tissue 
biopsy can be done 
endoscopically.  
Section 7.4 
Deleted the specification that tumor biopsies 
performed while the subject is on study should be 
made available to the Sponsor. 
These biopsies will not be 
assayed. 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)


 
Study SGNTUC-022  
Clinical Protocol 
Amendment 2, 02-Apr-2021 
Tucatinib  
Seagen Inc. - Confidential 
Page 133 of 133 
Amendment A02 
 
 
Section(s) 
Change 
Rationale 
Section 7.8.1.1 
Added the specification that laboratory values that 
result in dose modifications will be reported as 
AEs. 
Previously, only treatment 
interruptions were mentioned. 
Section 7.8.1.6 
Added Sponsor Safety Reporting to Regulatory 
Authorities section 
Change to protocol template. 
Section 7.8.3, 
Schedule of 
Events 
In the event that a dipstick or routine analysis 
indicates proteinuria ≥2+, specified that UPC ratio 
should be calculated, rather than evaluation of 
protein in a 24-hur urine collection. 
Revised treatment guidelines 
from the ramucirumab marketing 
authorization holder. 
Section 9.1.1 
Added a paragraph detailing the planned phase 2 
sample size. Also added the specification that ORR 
used in the evaluation of activity in the phase 2 will 
be ORR irrespective of confirmation. 
Clarification. 
Sections 9.3.1.9, 
9.3.11.1, Synopsis 
Added the specification that the SMC will conduct 
additional analyses of safety and PK should a dose 
level be expanded to include a total of 9 subjects. 
To implement the modified DLT 
evaluation schema. 
Throughout the 
document 
Changed the Sponsor name, Seattle Genetics, to 
Seagen. 
Company name change. 
Throughout the 
protocol 
Changed liver function tests to liver enzyme tests. 
Liver enzyme tests refers more 
specifically to AST, ALT, and 
bilirubin. 
Throughout the 
protocol 
Changed "biopsy" to "tumor tissue sample" when 
not referring to the act of taking a biopsy. 
To avoid confusion regarding the 
need to undertake on-study 
biopsies. 
Throughout the 
protocol 
Changed non-SI units to SI units. 
Consistency. 
Throughout the 
protocol 
Administrative changes. 
 
 
090177e1a14f9746\Approved\Approved On: 01-Aug-2024 03:16 (GMT)

SAP_001.pdf: 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seagen, Inc. and must not be disclosed or used except as authorized in writing by Seagen, Inc.
STATISTICAL ANALYSIS PLAN
Protocol Number:
SGNTUC-022
Version:
1.0
Date
17JAN2024
Protocol Title:
MOUNTAINEER-02: A randomized, double-blind, placebo-
controlled, active comparator Phase 2/3 study of tucatinib in 
combination with trastuzumab, ramucirumab, and paclitaxel in 
subjects with previously treated, locally-advanced unresectable 
or metastatic HER2+ gastric or gastroesophageal junction 
adenocarcinoma
Sponsor:
Seagen Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
090177e1a1314ab7\Approved\Approved On: 17-Jan-2024 21:03 (GMT)


Study SGNTUC-022 
Statistical Analysis Plan 
Version 1.0 17JAN2024 
Tucatinib 
 Seagen, Inc. - Confidential 
Page 2 of 27 
APPROVAL SIGNATURES 
 
Product: 
Tucatinib 
Protocol Number/Amendment: 
SGNTUC-022/Amendment 2 
SAP Version: 
1.0 
Version Date: 
17JAN2024 
 
The individuals signing below have reviewed and approve this statistical analysis plan. 
 
 
 
, PhD 
 
Seagen, Inc. 
 
Date 
 
 
 
, PhD 
 
Seagen, Inc. 
 
Date 
 
 
 
, PharmD, BCOP 
 
Seagen, Inc. 
 
Date 
 
 
 
, DO 
 
Seagen, Inc. 
 
Date 
 
 
 
090177e1a1314ab7\Approved\Approved On: 17-Jan-2024 21:03 (GMT)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study SGNTUC-022 
Statistical Analysis Plan 
Version 1.0 17JAN2024 
Tucatinib 
 Seagen, Inc. - Confidential 
Page 3 of 27 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objectives ................................................................................................................................ 6 
2.2 
Secondary Objectives ............................................................................................................................ 6 
3 
STUDY ENDPOINTS .................................................................................................................................... 6 
3.1 
Primary Endpoints ................................................................................................................................. 6 
3.2 
Secondary Endpoints ............................................................................................................................. 7 
3.2.1 
Efficacy Endpoints ................................................................................................................... 7 
3.2.2 
Safety Endpoints ....................................................................................................................... 7 
3.2.3 
Pharmacokinetics Endpoints..................................................................................................... 7 
4 
STUDY DESIGN ............................................................................................................................................ 7 
5 
ANALYSIS SETS ........................................................................................................................................... 9 
5.1 
Full Analysis Set ................................................................................................................................... 9 
5.2 
Safety Analysis Set ................................................................................................................................ 9 
5.3 
Response Evaluable Analysis Set .......................................................................................................... 9 
5.4 
Pharmacokinetics Analysis Set............................................................................................................ 10 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................... 10 
6.1 
General Principles ............................................................................................................................... 10 
6.2 
Determination of Sample Size ............................................................................................................. 10 
6.3 
Randomization and Blinding ............................................................................................................... 10 
6.4 
Data Transformations and Derivations ................................................................................................ 11 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 12 
6.6 
Multicenter Studies ............................................................................................................................. 12 
6.7 
Multiple Comparison/Multiplicity....................................................................................................... 12 
6.8 
Examination of Subgroups .................................................................................................................. 12 
6.9 
Covariates ............................................................................................................................................ 12 
6.10 Timing of Analyses ............................................................................................................................. 12 
7 
PLANNED ANALYSES .............................................................................................................................. 12 
7.1 
Disposition .......................................................................................................................................... 12 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 13 
7.3 
Protocol Deviations ............................................................................................................................. 13 
7.4 
Treatment Administration ................................................................................................................... 14 
7.5 
Efficacy Analyses ................................................................................................................................ 15 
7.5.1 
Primary Endpoints .................................................................................................................. 15 
7.5.2 
Key Secondary Endpoints ...................................................................................................... 15 
7.5.3 
Other Secondary Endpoints .................................................................................................... 15 
7.6 
Pharmacokinetics Analyses ................................................................................................................. 16 
7.7 
Health Economics and Outcomes Analyses ........................................................................................ 17 
7.8 
Safety Analyses ................................................................................................................................... 17 
7.8.1 
Adverse Events ....................................................................................................................... 17 
7.8.2 
Adverse Events of Special Interest ......................................................................................... 18 
7.8.3 
Other Adverse Events ............................................................................................................. 19 
7.8.4 
Clinical Laboratory Results .................................................................................................... 19 
7.8.5 
Vital Signs .............................................................................................................................. 20 
7.8.6 
Deaths ..................................................................................................................................... 20 
7.8.7 
Pregnancy ............................................................................................................................... 20 
8 
INTERIM ANALYSIS.................................................................................................................................. 20 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 20 
9.1 
Changes from the Study Protocol ........................................................................................................ 20 
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9.2 
Changes from the Original SAP .......................................................................................................... 20 
10 REFERENCES .............................................................................................................................................. 21 
11 APPENDICES ............................................................................................................................................... 22 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ......................... 22 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 24 
APPENDIX C: IMPUTATION OF PARTIAL MISSING START AND END DATE OF PRIOR SYSTEMIC 
THERAPY AND SUBSEQUENT CANCER-RELATED THERAPY ........................................................ 25 
APPENDIX D: IMPUTATION OF PARTIAL MISSING DATE FOR DISEASE DIAGNOSIS DATE ........... 26 
APPENDIX E: IMPUTATION OF PARTIAL MISSING DEATH DATES ....................................................... 27 
 
LIST OF IN-TEXT TABLES 
Table 1 PFS analysis censoring rules ................................................................................................................... 16 
 
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LIST OF ABBREVIATIONS 
ADI 
absolute dose intensity 
AE  
adverse event  
AESI  
adverse event of special interest  
ALT  
alanine aminotransferase  
AST  
aspartate aminotransferase  
AUC  
area under the plasma concentration-time curve  
AUClast  
AUC to the time of the last quantifiable concentration  
BID  
twice daily  
CI 
confidence interval 
Cmax  
maximum observed concentration  
CR  
complete response  
CTCAE  
Common Terminology Criteria for Adverse Events  
Ctrough  
trough concentration  
DCR  
disease control rate  
DOR  
duration of response  
ECOG  
Eastern Cooperative Oncology Group  
EOT  
end of treatment  
GEC  
gastric or gastroesophageal junction adenocarcinoma  
IDI 
intended dose intensity 
IV  
intravenous  
KM 
Kaplan-Meier 
LLOQ 
lower limit of quantification 
MRAUC  
metabolic ratio based on AUC  
NCI  
National Cancer Institute  
NGS  
next generation sequencing  
ORR  
objective response rate  
PD 
progression of disease 
PFS  
progression-free survival  
PR  
partial response  
PT  
preferred terms 
RDI 
relative dose intensity 
SMC  
Safety Monitoring Committee  
SOC 
system organ classifications  
TEAE 
treatment-emergent adverse event 
Tmax  
time of the maximum observed concentration  
ULN  
upper limit of normal  
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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGNTUC-022, entitled “MOUNTAINEER-02: A randomized, double-blind, 
placebo-controlled, active comparator Phase 2/3 study of tucatinib in combination with 
trastuzumab, ramucirumab, and paclitaxel in subjects with previously treated, locally-
advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction 
adenocarcinoma (GEC)”.  Results of the proposed analyses will become the basis of the 
clinical study report for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final clinical study report. Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report.  
After completion of the Phase 2 dose optimization stage, further enrollment to the study was 
closed by the sponsor. A recommended paclitaxel dose will not be identified, and the study 
will be terminated upon the last subject completing the last visit. This document only 
includes statistical analysis plan of the Phase 2 dose optimization portion of the study.  
2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
● 
To determine the recommended dose of paclitaxel when administered in combination 
with tucatinib, trastuzumab, and ramucirumab.  
● 
To evaluate the safety and tolerability of tucatinib in combination with trastuzumab, 
ramucirumab, and paclitaxel. 
2.2 Secondary Objectives 
● 
To evaluate the preliminary activity of tucatinib in combination with trastuzumab, 
ramucirumab, and paclitaxel in subjects with previously treated locally-advanced 
unresectable or metastatic GEC that is HER2+ according to blood-based next 
generation sequencing (NGS) assay of circulating tumor DNA (ctDNA).  
● 
To evaluate the pharmacokinetics (PK) of tucatinib and the tucatinib metabolite ONT-
993.  
● 
To evaluate the PK of paclitaxel and its metabolites in the presence and absence of 
tucatinib.  
3 
STUDY ENDPOINTS 
3.1 Primary Endpoints 
● 
Frequency of dose-limiting toxicities (DLTs) during the first cycle of treatment with 
tucatinib, trastuzumab, ramucirumab, and paclitaxel.  
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● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) and 
laboratory abnormalities.  
● 
Vital signs and other relevant safety variables.  
● 
Frequency of dose holds, dose reductions, and discontinuations of tucatinib, paclitaxel, 
trastuzumab, and ramucirumab. 
3.2 Secondary Endpoints 
3.2.1 Efficacy Endpoints 
• Objective response rate (ORR; complete response [CR] or partial response [PR]) per 
RECIST version 1.1 according to investigator assessment.  
• Confirmed ORR per RECIST version 1.1 according to investigator assessment.  
• PFS per RECIST version 1.1 according to investigator assessment.  
• Duration of response (DOR; CR or PR) per RECIST version 1.1 according to 
investigator assessment.  
• Disease control rate (DCR; CR, PR, or stable disease) per RECIST version 1.1 
according to investigator assessment.  
3.2.2 Safety Endpoints 
• Type, incidence, severity, seriousness, and relatedness of AEs and laboratory 
abnormalities.  
• Vital signs and other relevant safety variables.  
• Frequency of dose holds, dose reductions, and discontinuations of tucatinib, 
trastuzumab, ramucirumab, and paclitaxel.  
3.2.3 Pharmacokinetics Endpoints 
• The PK parameters to be calculated for tucatinib, paclitaxel, and their respective 
metabolites (if applicable) may include but are not limited to: area under the plasma 
concentration-time curve (AUC) to the time of the last quantifiable concentration 
(AUClast), maximum observed concentration (Cmax), time of Cmax (Tmax), trough 
concentration (Ctrough), and metabolic ratio based on AUC (MRAUC). 
4 
STUDY DESIGN 
This was an international, multicenter Phase 2/3 study in subjects with locally-advanced 
unresectable or metastatic HER2+ GEC who have received prior treatment with a HER2-
directed antibody and have received 1 prior line of therapy in the advanced disease setting 
(overall study design illustrated in Figure 1). After completion of the Phase 2 dose 
optimization stage, further enrollment to the study was closed by the sponsor.  
• Paclitaxel dose optimization stage 
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This single-arm stage is to determine the recommended dose of paclitaxel when 
combined with tucatinib, trastuzumab, and ramucirumab. The initial paclitaxel dose will 
be 60 or 80 mg/m² intravenous (IV) on Days 1, 8, and 15 of each 28-day cycle, in 
combination with tucatinib 300 mg orally (PO) twice daily (BID), trastuzumab (6 mg/kg 
IV loading dose on Cycle 1 Day 1, 4 mg/kg IV on Cycle 1 Day 15 and Days 1 and 15 of 
each cycle thereafter), and ramucirumab (8 mg/kg IV on Days 1 and 15).  
During the study, if any study drug is discontinued, the subject can continue to receive study 
treatment with the remaining agents. Study treatment (defined as the administration of any of 
the four study drugs, without initiation of new anti-cancer treatment) will continue until 
unacceptable toxicity, disease progression, withdrawal of consent, death, or study closure.  
Disease response and progression will be assessed using RECIST version 1.1 (Eisenhauer 
2009). While on study treatment, radiographic disease evaluations will be done every 6 
weeks for the first 36 weeks, and every 9 weeks thereafter, irrespective of dose holds or 
interruptions. If study treatment is discontinued before documentation of disease progression, 
radiographic evaluations will be performed at least every 9 weeks until the occurrence of 
progression, withdrawal of consent, or study closure. After occurrence of disease 
progression, subjects will continue to be followed for survival every 12 weeks, until death, 
consent withdrawal, or study closure.  
  
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Figure 1: Study visits and overall study design* 
 
Pac=paclitaxel; plbo=placebo; Ramu=ramucirumab; Tuc=tucatinib; Trast=trastuzumab  
*Enrollment to study closed after completion of the paclitaxel dose optimization stage 
**As of September 30th, 2022, progression follow-up and survival follow-up have been discontinued. 
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized. The use of each analysis set 
will be discussed in Section 7. 
5.1 Full Analysis Set 
The full analysis set will include all subjects who received any amount of any study drug. 
5.2 Safety Analysis Set 
The safety analysis set is the same as the Full Analysis Set. 
5.3 Response Evaluable Analysis Set  
The Phase 2 response evaluable analysis set will include all subjects who meet all following 
criteria:  
1. had baseline disease assessment, 
2. received study treatment, 
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3. had post baseline disease assessment or discontinued treatment due to documented 
disease progression, clinical progression, AEs, or death. 
5.4 
Pharmacokinetics Analysis Set  
The PK analysis set will include subjects in the full analysis set who received at least one 
dose of tucatinib or paclitaxel and have at least one evaluable PK assessment.  
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
In this document, "treatment group" is defined by the paclitaxel dose level each subject 
initiated treatment with. 
 
In general, descriptive statistics by treatment group will be presented including the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, frequencies, and percentages for categorical variables.  
Unless otherwise specified, confidence intervals (CIs) will be calculated at a two-sided 95% 
level. The two-sided 95% exact CI using Clopper-Pearson method (Clopper 1934) will be 
calculated for the response rates where applicable (e.g., ORR).  
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
Multiplicity adjustment for alpha level is discussed in Section 6.7. 
Any analysis not described in this plan will be considered exploratory and will be 
documented in the Clinical Study Report (CSR) as a post hoc analysis or a change to the 
planned analysis. 
To comply with regulatory electronic submission guidelines, all clinical data will be 
submitted as electronic data sets. To facilitate data review for the study report, only pertinent 
data listings will be created and attached to the appendix of the CSR. 
All statistical tables, listings, and figures will be produced using SAS, version 9.3 or more 
recent. Other statistical software, if used, will be described in the CSR. 
6.2 Determination of Sample Size 
In the paclitaxel dose optimization stage, 6 to 18 subjects will be enrolled to determine the 
recommended paclitaxel dose. Additional subjects may be enrolled in the paclitaxel dose 
optimization stage, based on recommendations from the Safety Monitoring Committee 
(SMC). 
6.3 Randomization and Blinding 
The Phase 2 portion is open label with no randomization or blinding.  
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6.4 Data Transformations and Derivations 
The following data conventions will be used for the tables, listings, and figures.  
Age: Reported age in years will be used. 
Baseline: Unless otherwise specified, baseline values used in all analyses will be the most 
recent non-missing measurement prior to the first dose of any study treatment.  
Study Day: Study Day for analyses will be calculated as (Date – Date of First Dose + 1) for 
dates on or after the first dose date. The date of first dose will be Study Day 1. For dates prior 
to the first dose date, Study Day will be calculated as (Date – First Dose Date). For all 
calculations of Study Day, the First Dose Date will be the earliest date of administration of 
any study treatment.  
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section. 
The following unit conversion will be implemented unless otherwise specified: 
Months = Days/30.4375 
Years = Days/365.25 
End-of-Treatment (EOT): The EOT date will be the date the EOT visit is performed or the 
decision-making date if EOT visit date is not available. 
Response assessment date: At each response assessment time point, scans to evaluate tumor 
lesions can be performed on multiple dates.  
• The date of response for CR or PR will be recorded as the date of the last 
radiographic evaluation included in the series for that assessment. 
• The date of response for SD will be recorded as the date of the earliest radiographic 
evaluation included in the series for that assessment.  
• The date of progression (PD) will be recorded as the earliest date that PD has been 
documented, i.e., the earliest of the following: 
o Date of target lesion assessment when the target lesion response is PD, 
o Date of non-target lesion assessment when the lesion status is unequivocal 
progression, and 
o Date of documenting new lesion.  
In the cases where a PD occurs due to the fact that an equivocal new lesion was later 
confirmed to be an unequivocal new lesion, the PD date should be back dated to the visit 
when the equivocal new lesion was first identified if the equivocal new lesion continued 
to be present. If an equivocal new lesion was later absent or confirmed to be a benign 
lesion, then this new lesion is not considered to define a PD. Note: in cases where PD 
occurs at a date after an equivocal new lesion is identified, but the progression is not due 
to a change of the equivocal new lesion to an unequivocal lesion, but rather from 
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progression of other lesions, the PD date will not be back dated, but will be the date when 
definitive PD is recorded.  
6.5 Handling of Dropouts and Missing Data 
Except for the scenarios covered in this section, missing data will not be imputed. 
Missing disease history date will be imputed for the purpose of calculating the time from 
diagnosis to the first dose date (Appendix D).  
Missing AE dates will be imputed for the purpose of calculating duration of events 
(Appendix A).  
Missing start and end date of subsequent cancer-related therapy, and prior treatment date will 
be imputed for the purpose of deriving the time-to-event endpoints, and other applicable 
analysis as applicable (Appendix C).  
Unless otherwise specified, lab values which are recorded or provided as being less than the 
lower limit of quantification (LLOQ), will be included in figures and summaries as LLOQ. 
PK values which are recorded as being less than the lower limit of quantification (LLOQ), 
will be included in summaries as LLOQ/2. 
6.6 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will accrue 
enough subjects to warrant an analysis by center. 
6.7 Multiple Comparison/Multiplicity 
There is no formal hypothesis testing in the Phase 2 portion.  
6.8 Examination of Subgroups 
Not applicable due to the small sample size.  
6.9 Covariates 
There will be no adjustment for covariates in the Phase 2 portion.  
6.10 Timing of Analyses 
Safety analyses will be undertaken by the sponsor when the first 6 DLT-evaluable subjects in 
each paclitaxel dose level have been followed for at least one cycle (paclitaxel dose optimization 
stage). The SMC will review the results of the safety.  
The final analysis for the phase 2 portion will be performed after the last patient has completed 
their last visit in this study. 
7 
PLANNED ANALYSES 
7.1 Disposition 
Analysis set: Full Analysis Set or All Screened Subjects 
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An accounting of study subjects by disposition will be tabulated by treatment group and total. 
Reasons for discontinuation of treatment and study will be summarized. The number and 
percentage of subjects who signed informed consent and the number of subjects in each analysis 
set will be summarized by treatment group and total. Number of screen failures and the 
percentage relative to the total number of subjects screened will be summarized. A listing of 
subjects who failed screening will be produced with reasons for screen failure and available 
demographic information.  
The number of subjects enrolled in each country and at each site will be summarized by 
treatment group and total.  
7.2 Demographic and Baseline Characteristics 
Analysis set: Full Analysis Set 
Demographic and baseline characteristics will be summarized and listed by treatment group and 
total using counts and percentages for categorical variables and summary statistics (mean, 
median, standard deviation, and range) for continuous variables.  
Characteristics to be summarized include the following:    
• 
Subject demographics: age, sex, race, ethnicity, and ECOG performance status 
• 
Disease history and baseline disease characteristics:  
o Time (months) from diagnosis of GEC to date of first dose of study treatment  
o Disease diagnosis (gastric adenocarcinoma, gastroesophageal junction 
adenocarcinoma) 
o Histological subtype (diffuse, intestinal, other) 
o Stage at diagnosis  
o History of unresectable locally advanced disease (yes, no, unknown) 
o Time (months) from diagnosis of the earliest diagnosis of locally advanced 
unresectable disease to the first dose date 
o History of metastatic disease sites at study entry (yes, no, unknown) 
o Time (months) from the earliest diagnosis of distant metastatic disease to the first dose 
date 
o Locally advanced unresectable or metastatic disease sites at study entry  
• 
Prior disease-related therapies  
o Prior systemic therapy  
o Prior radiation therapy 
o Prior surgical treatment 
7.3 Protocol Deviations 
Analysis set: Full Analysis Set 
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Important protocol deviations are those that represent a divergence from the protocol that could 
have a significant effect on the integrity of the study data, or on the subject’s rights, safety, or 
welfare. Important protocol deviations also include exemptions to the study inclusion/exclusion 
criteria. Important protocol deviations will be summarized by category and treatment group. A 
list of subjects with important protocol deviations will be presented. 
7.4 Treatment Administration 
Analysis set: Full Analysis Set 
Exposure will be summarized by treatment group using counts and percentages for categorical 
variables and summary statistics (mean, median, standard deviation, and range) for continuous 
variables. The following information will be summarized by dose level and total separately for 
tucatinib, trastuzumab, ramucirumab, and paclitaxel:  
• 
total number of treatment cycles per subject  
• 
total cumulative dose  
• 
duration of treatment (months) 
• 
dose modification by type (dose reduced, dose interrupted, dose held, drug withdrawn) 
and by reason 
• 
dose holds by reason  
• 
duration of dose holds 
• 
absolute dose intensity (ADI) and relative dose intensity (RDI) for tucatinib, 
ramucirumab and paclitaxel.  
Duration of treatment (not for calculating dose intensity) is defined as the time from first dose 
date to the earliest of the following dates: 
• 
the exposure end date: 
o for tucatinib, the last dose date; 
o for trastuzumab, 
▪ 
the last infusion date + 6 if planned dose is 2 mg/kg, 
▪ 
the last infusion date + 13 if planned dose is 4 mg/kg or 6 mg/kg; 
o for ramucirumab, last infusion date + 13; 
o for paclitaxel,  
▪ 
if the last infusion was the first or second paclitaxel infusion in the last cycle, 
the last infusion date + 6,  
▪ 
if the last infusion was the third paclitaxel infusion in the last cycle, the later 
date of the last infusion date + 13, and the date of paclitaxel discontinuation -
1; 
• 
date of death; 
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• 
end of study date; 
• 
analysis data cutoff (DCO) date if the subject is still on treatment at the time of DCO. 
Cumulative Dose is defined as the sum of the actual dose amount that a subject received 
across all cycles. For example, for paclitaxel, it is calculated as the sum of (intended dose 
(mg) received in each infusion / body surface area at each infusion (m2)) over all infusions.  
Intended dose intensity (IDI) is defined as the intended dose of drug per unit of time.  
• 
Tucatinib IDI = 300 mg BID = 600 (mg/day) 
• 
Ramucirumab IDI = 8 mg/kg twice a cycle = 16/28 mg/kg/days 
Paclitaxel IDI = dose three times a cycle = (dose x 3/28) mg/m2/days. Absolute dose intensity 
(ADI) = cumulative dose / (exposure end date – first dose date + 1) 
Relative dose intensity (RDI) = ADI/IDI * 100% 
7.5 Efficacy Analyses 
Analysis set: Response Evaluable Analysis Set 
7.5.1 Primary Endpoints 
Not applicable 
7.5.2 Key Secondary Endpoints 
Not applicable. 
7.5.3 Other Secondary Endpoints 
7.5.3.1 Objective Response Rate by Investigator Assessment 
ORR per investigator assessment is defined as the proportion of subjects achieving a best 
overall response of CR or PR per RECIST 1.1 by investigator assessment. Only tumor 
assessments on or before the first documented PD or new anti-cancer therapies will be 
considered. For a response to be considered as confirmed, the subsequent response needs to 
be at least 4 weeks after the initial response.  
The ORR and confirmed ORR by investigator and the corresponding exact two-sided 95% 
confidence interval using the Clopper-Pearson method (Collett 1991) will be calculated.  
7.5.3.1.1 Progression Free Survival 
Progression-free survival (PFS) time is defined as the time from the first dose date to the date 
of documented disease progression (as determined by investigator assessment using RECIST 
1.1) or death due to any cause, whichever occurs first.  
Specifically, 
PFS=Date of first documented PD or death or censoring – Date of first dose + 1.  
PFS event and censoring rules are described in Error! Reference source not found.Error! 
Reference source not found.. 
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Table 1 PFS analysis censoring rules 
Scenario  
Progression/Censoring Date  
Outcome  
No post-baseline baseline assessment  
Date of first dose  
Censored  
No documented progression or death 
Date of last tumor assessment of CR, PR, or 
SD  
Censored  
New anti-cancer treatment started 
before PD or death observed 
Date of last CR, PR, or SD on or prior to date 
of new anti-cancer treatment 
Censored  
Progressive disease (PD)  
Date of PD 
Event 
Death before first PD assessment  
Date of death  
Event 
Death or progression right after two or 
more consecutively missed tumor 
assessments 
Date of last tumor assessment of CR, PR, or 
SD 
Censored  
Note: CT, PET/CT scans are performed every 6 weeks starting at screening through Week 36 and then every 9 weeks until 
documented PD, death, withdrawal of consent, or study closure.  
KM curves depicting PFS will be generated. Additionally, KM estimates of the median and 
quartiles will be reported for each treatment group. The two-sided 95% CI for the medians 
and quartiles will be calculated using the complementary log-log transformation method 
(Collett 1994). 
7.5.3.1.2 Duration of Response 
DOR is defined as the time from first objective response (CR or PR per investigator) to the 
date of the first documented PD per RECIST 1.1 or death due to any cause, whichever occurs 
first. The same derivation of PD date and censoring rules as for primary PFS analysis will 
apply for DOR.  
DOR will only be calculated for the subgroup of subjects achieving a CR or PR. KM curves 
will be provided. The median DOR and its two-sided 95% CI using the complementary log-
log transformation method (Collett 1994) will be calculated. 
7.5.3.1.3 Disease Control Rate 
DCR is defined as the proportion of subjects with CR, PR, or SD, as best overall response. A 
subject will have a best overall response of SD if there is at least one SD assessment ≥ 5 
weeks after the first dose date and the subject does not qualify for CR or PR. The proportion 
of subjects with disease control determined by investigator will be calculated, with the exact 
two-sided 95% confidence interval using the Clopper-Pearson method (Collett 1991). 
7.6 Pharmacokinetics Analyses 
Analysis set: PK Analysis Set 
Blood samples for PK assessments of paclitaxel and tucatinib will be collected at protocol-
defined time points. Plasma concentrations of tucatinib, ONT-993, paclitaxel and its 
metabolites will be analyzed using validated mass spectrometry methods. Remaining PK 
samples will be archived and may be used for the analysis of administrated compounds or 
related species with exploratory, non-validated assays.  
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PK parameters will be calculated using standard non-compartmental methods. PK parameters 
to be estimated may include, but are not limited to, area under the plasma concentration-time 
curve to the time of the last quantifiable concentration (AUClast), maximum observed 
concentration (Cmax), observed trough concentration in plasma (Ctrough; tucatinib only), and 
time of Cmax (Tmax). 
Descriptive statistics (N, mean, geometric mean, SD, %CV, median, min and max) will be 
used to summarize the calculated PK parameters for tucatinib and paclitaxel by treatment 
group. For Tmax, only N, median, min, and max will be presented.  
The effect of tucatinib on the PK of paclitaxel will be assessed using the ratio and 90% 
confidence intervals (CIs) of the geometric least-squares (LS) means of the paclitaxel plasma 
PK parameter AUClast and other paclitaxel metabolites PK parameters as appropriate. 
Estimates on the original scale of measurement will be obtained by exponentiating point 
estimates on the natural log scale. Geometric LS means will be provided for each treatment 
group. In all comparisons, paclitaxel administered alone will be used as the reference. No 
adjustments will be made for multiplicity.  
For the calculation of summary statistics, <LLOQ results are imputed to ½ LLOQ value. The 
summary statistics for a timepoint will not be calculated if more than 50% of the results are 
<LLOQ. 
7.7 Health Economics and Outcomes Analyses 
Not applicable. 
7.8 Safety Analyses 
Analysis set: Safety Analysis Set  
Frequency of DLT during the first cycle of treatment will be summarized per treatment group 
and total. Frequencies and descriptive statistics will be provided for type, incidence, severity, 
seriousness and relatedness of AEs and laboratory abnormality per treatment group and total. 
Dose modifications of each component of the treatment will be summarized per treatment 
group and total.  
Adverse event will be coded by standard preferred terms (PT) and system organ 
classifications (SOC) using Medical Dictionary for Regulatory Activities (MedDRA, version 
26.0 or higher). 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(version 2023Mar B3 or higher). 
7.8.1 Adverse Events 
Adverse events (AEs) will be summarized by MedDRA preferred term in descending 
frequency of occurrence in Arm 3A unless otherwise specified. For incidence reporting, if a 
subject reports more than one AE that was coded to the same SOC or PT, the subject will be 
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counted only once for that specific SOC or PT. For summaries by severity, only the worst 
grade for an AE will be counted for a subject. 
A treatment-emergent AE (TEAE) is defined as a newly occurring or worsening AE after the 
first dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel) and up to 
30 days after the last dose of study treatment (tucatinib, trastuzumab, ramucirumab, or 
paclitaxel, whichever is later).  
Treatment-related AE is defined as AE assessed by the investigator as ‘related’ to tucatinib, 
trastuzumab, ramucirumab, or paclitaxel. 
Summary of AEs by treatment group and total will be provided for the following: 
● 
All TEAEs 
● 
TEAEs by PT 
● 
Grade 3 or higher of TEAEs by PT 
● 
Serious TEAEs by PT 
● 
TEAEs leading to dose modification by PT, by types of dose modification and drug 
discontinuation 
● 
TEAEs leading to death by PT  
● 
TEAEs by SOC and PT 
● 
Treatment-related TEAEs by PT by components of study treatment 
● 
Treatment-related SAEs by PT by components of study treatment 
● 
Treatment-related Grade 3 or higher TEAEs by PT by components of study treatment 
● 
TEAEs by SOC, PT, and maximum severity. At each SOC or PT, multiple occurrences 
of events within a subject are counted only once at the highest severity  
All TEAEs, grade 3 or higher TEAEs, serious TEAEs, TEAEs leading to treatment 
discontinuation, and TEAEs leading to death will be listed. 
7.8.2 Adverse Events of Special Interest  
AESI for this study is hepatoxicity, which includes the following types of liver function test 
elevation: 
• AST or ALT elevations that are > 3 x ULN with concurrent elevation (within 21 days 
of AST and/or ALT elevations) of total bilirubin > 2 x ULN 
• AST or ALT elevations > 20 x ULN 
• Bilirubin > 10 x ULN 
The incidence of treatment emergent AESI will be summarized by lab values and listings.  
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7.8.3 Other Adverse Events 
In addition to the protocol defined AESIs, the incidence of treatment emergent adverse 
events for additional risks will be summarized by PT and listings will also be produced. 
Other AEs include:  
1. Hepatotoxicity: defined by drug related hepatic disorders – comprehensive search 
SMQ (Narrow) 
2. Diarrhea: defined as a single PT of “Diarrhoea”. 
Use of anti-diarrheal medications will also be summarized. 
Time to onset or resolution will be analyzed as appropriate. 
Time to onset of a specific AE will be calculated as time from the first dose of study drug to 
the start of first treatment-emergent event that meets the respective search criteria.  
Resolution is defined as event outcome of ‘recovered/resolved’ or ‘recovered/resolved with 
sequelae’. Time to resolution is defined as time from the start of AE to the end date of AE 
with an outcome of ‘recovered/resolved’ or ‘recovered/resolved with sequelae’. 
Time to onset will be summarized at the subject level. Time to resolution will be summarized 
at the event level. 
7.8.4 Clinical Laboratory Results 
Clinical laboratory results to be collected during the study are specified in the protocol 
section of 7.8.3, including serum chemistry and hematology samples. The collection 
schedules are specified in Appendix A in the study protocol. 
Both observed value and changes from baseline will be summarized with descriptive 
statistics for each scheduled visit by treatment group. Shift from baseline to maximum post-
baseline NCI CTCAE grade will be summarized for each lab test by treatment group. 
Treatment-emergent laboratory abnormalities will also be summarized. 
Laboratory results and NCI CTCAE grades for hematology and serum chemistry will be 
presented in data listings. Normal ranges will be documented, and out-of-range values will be 
flagged. A separate listing of laboratory results with CTCAE grade 3 or higher will be 
presented. 
7.8.4.1 Incidence of Liver Abnormalities  
The incidence of potential drug-induced liver injury will be summarized. In addition to the 
laboratory abnormalities defined for AESI in Section 7.8.2, (AST and/or ALT) > 3 × ULN + 
Total Bilirubin > 2 × ULN + Alkaline Phosphatase < 1.5 × ULN and (AST and/or ALT) > 3 
× ULN, 5 × ULN, and 10 × ULN will also be summarized. 
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7.8.4.2 Ejection Fraction 
The minimal post baseline cardiac ejection fraction and the maximum decrease from baseline 
will be summarized for each treatment group. Time to maximum decrease from baseline 
ejection fraction may also be tabulated. 
7.8.5 Vital Signs 
Vital signs (weight, body temperature, respiratory rate, heart rate, and systolic and diastolic 
blood pressure) will be listed by subject and visit for each treatment group.  
The frequency and percentage of subjects with post baseline clinically significant vital signs 
will be summarized. The clinically significant vital signs include: systolic blood pressure >= 
120 mmHg or diastolic blood pressure >= 80 mmHg, systolic blood pressure >= 140 mmHg 
or diastolic blood pressure >= 90 mmHg, systolic blood pressure >= 160 mmHg or diastolic 
blood pressure >= 100 mmHg, heart rate > 100 bpm, temperature >= 38.0 degrees C (100.4 
F) and respiratory rate > 20 breaths per min.;  
For weight, the maximum percent decrease from baseline will also be summarized. 
7.8.6 Deaths 
Death information will be summarized in table and listed by subject. 
7.8.7 Pregnancy 
Positive pregnancy test will be listed by subject. 
8 
INTERIM ANALYSIS 
No interim analysis is planned.  
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Study Protocol 
After completion of the Phase 2 dose optimization stage, further enrollment to the study was 
closed by the sponsor. A recommended paclitaxel dose will not be identified, and the study 
will be considered terminated upon the last subject completing the last visit. This document 
only includes statistical analysis plan of the Phase 2 dose optimization portion of the study.  
Study protocol specified PK analysis in subgroups of subjects with and without a 
gastrectomy. Due the small sample size, this analysis will not be conducted. 
9.2 Changes from the Original SAP 
Not Applicable. 
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10 REFERENCES 
Chen LM, Ibrahim JG, Chu H (2014). Flexible stopping boundaries when changing primary endpoints after 
unblinded interim analyses. J Biopharm Stat 24(4): 817-33.  
Collett D (1991). Statistical inference for binary data. Modelling Binary Data. London, Chapman and Hall: 23-
26. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D and Verweij J (2009). New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 228-47. 
Royston P and Parmar MK (2011). The use of restricted mean survival time to estimate the treatment effect in 
randomized clinical trials when the proportional hazards assumption is in doubt. Stat Med 30: 2409-21. 
Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, Schrag D, Takeuchi M, Uyama Y, Zhao L, Skali H, 
Solomon S, Jacobus S, Hughes M, Packer M and Wei LJ (2014). Moving beyond the hazard ratio in quantifying 
the between-group difference in survival analysis. J Clin Oncol 32: 2380-5. 
 
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11 APPENDICES 
Appendix A: Imputation of Partially Unknown Adverse Event Dates 
For an AE with a partial start or end date, if it can be determined that the event occurred prior 
to the date of first dose of study treatment, the partial date will not be imputed. Otherwise, 
the partial date will be imputed using the rules described below. AE start dates should be 
imputed before imputation of AE condition end date in all cases.  
Incomplete AE Start Date: 
AE day only is missing. 
• If the month/year is the same as the month/year of first dose of any study treatment, then 
AE start date will be imputed as the first dose date of any study treatment. 
• If the month/year is after the month/year of first dose of any study treatment, then AE 
start date will be imputed as the first day of the month. 
AE day and month are missing. 
If the year is the same as the year of first dose of any study treatment, then AE start date 
will be imputed as the first dose date of any study treatment. 
If the year is after the year of first dose of any study treatment, then AE start date will be 
imputed as January 1st. 
AE day, month and year are missing. 
AE start date will be imputed as the first dose date of any study treatment. 
 
If AE condition end date is known with a full date, and the imputed start date is after the end 
date, the start date will be set to the AE end date. 
Incomplete AE End Date: 
If AE outcome is “not recovered/resolved”, “unknown”, or blank, then AE condition end date 
will not be imputed. 
If AE outcome is “recovering/resolving”, “recovered/resolved”, “recovered/resolved with 
sequelae”, or “fatal”, then apply the following:  
AE day only is missing. 
AE condition end date will be imputed as the minimum of (death date, DCO date or data 
extraction date sans DCO, last day of the AE end date month/year, EOS date). 
AE day and month are missing. 
• If the year is equal to the year of the last dose date, then AE end date will be imputed as 
the minimum of (last dose date + 30, death date, DCO date or data extraction date sans 
DCO, December 31st of the end date year, EOS date). 
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• If the year is not equal to the year of the last dose date, then AE end date will be imputed 
as the minimum of (death date, DCO date or data extraction date sans DCO, December 
31st of the end date year, EOS date). 
AE day, month and year are missing. 
AE end date will not be imputed. 
Within a single record, if the imputed end date is before the start date, then the imputed end 
date will be set to the start date. 
Example 
AE Number 4:  Condition/Event NAUSEA 
First dose date 02APR2012 
Prior to imputation 
Log Line 
Start date 
Condition end date 
Severity Outcome 
1 
25APR2012 
UNAPR2012 
2 
recovering/resolving 
2 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
Post imputation 
Log Line 
Start date 
Condition end date 
Severity 
Outcome 
1 
25APR2012 
30APR2012 
2 
recovering/resolving 
2 
02APR2012 
04MAY2012 
1 
recovered/resolved 
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Appendix B: Definition of the Term “Treatment-Emergent” with Respect to AE 
Classification 
A treatment-emergent adverse event (TEAE) is defined as any AE which is newly occurring 
or worsening in severity, with starting date on or after the first dose of any study treatment 
(i.e., tucatinib, trastuzumab, ramucirumab, or paclitaxel) and before the last dose of study 
treatment + 30 days. 
 
 
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Appendix C: Imputation of Partial Missing Start and End Date of Prior 
Systemic Therapy and Subsequent Cancer-Related Therapy 
Partial missing date will be imputed when both month and year are present and only day is 
missing.  
• Prior therapy start date: first day of the month 
• Prior therapy end date: the earlier of  
o Last day of the month and year 
o First dose date of study drug if received any study treatment, enrollment date 
otherwise 
• Subsequent therapy start date: the later of  
o First day of the month and year 
o First dose date of study drug if received any study treatment, enrollment date 
otherwise 
• Subsequent therapy end date: the earlier of  
o Last day of the month 
o End of study date 
o Death date 
 
 
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Appendix D: Imputation of Partial Missing Date for Disease Diagnosis Date 
Disease diagnosis date (including initial diagnosis, earliest date disease was considered 
unresectable locally advanced and earliest date disease was considered distant metastatic)    
will be imputed as the 1st of the month if both month and year are present and only day is 
missing, and will be imputed as 01 January if only year is present and both day and month 
are missing.  
 
 
 
 
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Appendix E: Imputation of Partial Missing Death Dates 
Death dates are imputed if only the day is missing.  
The imputation of partial missing death date depends on the last-know-alive date derived 
from eCRF. 
If the last-known-alive date is in the same month and year of the partial missing death date, 
then the partial missing death date is imputed as the last-known-alive date. 
If the last-known-alive date is not in the same month and year of the partial missing death 
date, then the partial missing death date is imputed as day fifteen of the month and year. 
 
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