Clinical trial NCT02614794
Conditions: HER2 Positive Breast Cancer
Keywords: Tucatinib Capecitabine Trastuzumab Xeloda Herceptin Breast Cancer ARRY-380 ONT-380 HER2 Positive Breast Carcinoma HER2 Positive Locally Advanced Breast Cancer HER-2 Positive Breast Cancer HER-2 Positive Breast Carcinoma HER-2 Positive Locally Advanced Breast Cancer Recurrent Breast Carcinoma Stage IV Breast Cancer Metastatic Breast Cancer Breast Carcinoma Metastatic Malignant Neoplasm in the Brain Brain Metastases in Breast Cancer Asymptomatic Brain Metastases in Breast Cancer Low Symptomatic Brain Metastases in Breast Cancer Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2016-01-28; Completion date: 2022-08-11
Enrollment: 612 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer.

There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was "blinded," neither patients nor their doctors knew whether a patient got tucatinib or placebo.

The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.

Detailed description:
This is a randomized, international, multi-center study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. There are two phases to this trial: the Double-blind Phase and the Unblinded Phase. In the Double-blind phase, participants were randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. In the Unblinded Phase, patients on placebo may be offered tucatinib.

Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).

Safety assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter.

For the blinded phase, contrast brain MRI was performed at baseline. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilized RECIST 1.1 and included patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment was performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain was required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions were made based upon investigator assessment. All patients underwent a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression.

For the unblinded phase, RECIST assessments will be performed per standard clinical practice as determined by investigator with a maximum interval of 12 weeks.

Arms: arm 1: Tucatinib + capecitabine + trastuzumab arm 2: Placebo + capecitabine + trastuzumab
Interventions: intervention 1: tucatinib intervention 2: capecitabine intervention 3: trastuzumab intervention 4: placebo
Intervention descriptions: intervention 1: 300 mg orally twice daily intervention 2: 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle intervention 3: 8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab. intervention 4: Oral dose twice daily

Protocol documents:
Prot_002.pdf: 


Tucatinib (ONT-380) 
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SPONSOR PROTOCOL APPROVAL PAGE 
Protocol Number: 
ONT-380-206 
Protocol Title: 
Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib 
vs. Placebo in Combination with Capecitabine and Trastuzumab in 
Patients with Pretreated Unresectable Locally Advanced or Metastatic 
HER2+ Breast Carcinoma 
(HER2CLIMB) 
Investigational Product: 
Tucatinib (ONT-380) 
Version: 
Version 12, 30-Jun-2021 
The sponsor agrees to be responsible for implementing and maintaining quality control 
and quality assurance systems with written procedures to ensure that the clinical trial is 
conducted and data are generated, documented, and reported in compliance with this 
protocol, accepted standards of good clinical practice, and all applicable federal, state, 
and local laws, rules, regulations, requirements, and guidelines (including all foreign laws 
and governmental requirements as applicable) relating to the conduct of the clinical trial. 
The individuals signing below have reviewed and approve this protocol. 
 
 
 
 
 
 
 
Date  
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
ONT-380-206 
Protocol Title: 
Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib 
vs. Placebo in Combination with Capecitabine and Trastuzumab in 
Patients with Pretreated Unresectable Locally Advanced or Metastatic 
HER2+ Breast Carcinoma 
(HER2CLIMB) 
Investigational Product: 
Tucatinib (ONT-380) 
Version: 
Version 12, 30-Jun-2021 
By signing this protocol, the investigator confirms that they have read and understood the 
protocol and agrees to conduct the clinical trial in accordance with this protocol, 
generally accepted standards of good clinical practice, and all applicable federal, state, 
and local laws, rules, regulations, requirements, and guidelines (including all foreign laws 
and governmental requirements as applicable) relating to the conduct of the clinical trial. 
In addition, the investigator agrees to provide the sponsor with such information and 
certifications as the sponsor shall reasonably request from time to time regarding direct 
and indirect financial interests and other arrangements between sponsor and investigator, 
to allow the sponsor to submit complete and accurate certification and disclosure 
statements as required. 
I understand that all documentation provided to me by Seagen or its designated 
representatives concerning the study that has not been published previously will be kept 
in the strictest confidence. This documentation includes the study protocol, Investigator’s 
Brochure, case report forms and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). No changes will 
be made to the study protocol without the prior written approval of Seagen and the 
IRB/IEC, except where necessary to eliminate an immediate hazard to the patient. 
 
 
 
 
Principal Investigator Name (Printed) 
 
 
 
Title 
Principal Investigator’s Signature 
 
 
 
Date  
Site Address and Telephone Number 
 
 


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Table of Contents 
1 
GLOSSARY AND TERMS ..................................................................................................................... 9 
2 
PROTOCOL SYNOPSIS ....................................................................................................................... 12 
3 
BACKGROUND AND RATIONALE .................................................................................................. 37 
3.1 
HER2+ Breast Cancer ................................................................................................................. 37 
3.1.1 
Brain Metastases in HER2+ Breast Cancer ..................................................................... 38 
3.2 
Tucatinib 39 
3.2.1 
Product Description and Mechanism of Action .............................................................. 39 
3.2.2 
Nonclinical Studies ......................................................................................................... 39 
3.2.3 
Clinical Studies ............................................................................................................... 39 
3.2.4 
Tucatinib in the Treatment of Brain Metastases .............................................................. 39 
3.3 
Potential Risks, Benefits and Rationale for the Combination of Tucatinib with Capecitabine and 
Trastuzumab in a Phase 2 Study .................................................................................................. 40 
3.3.1 
Trastuzumab .................................................................................................................... 40 
3.3.2 
Capecitabine .................................................................................................................... 41 
3.3.3 
Double-blind Phase Study Rationale ............................................................................... 41 
3.3.4 
Unblinded Phase Study Rationale ................................................................................... 42 
4 
STUDY OBJECTIVES .......................................................................................................................... 44 
4.1 
Double-blind Phase ..................................................................................................................... 44 
4.1.1 
Primary Objective ........................................................................................................... 44 
4.1.2 
Secondary Objectives ...................................................................................................... 44 
4.1.2.1 
Safety Objective ............................................................................................. 44 
4.1.2.2 
Pharmacokinetic Objective ............................................................................ 45 
4.1.3 
Exploratory Objectives .................................................................................................... 45 
4.2 
Unblinded Phase .......................................................................................................................... 45 
5 
STUDY DESIGN ................................................................................................................................... 46 
5.1 
Overview of Study Design .......................................................................................................... 46 
5.1.1 
Double-blind Phase ......................................................................................................... 46 
5.1.2 
Unblinded Phase .............................................................................................................. 49 
5.1.3 
Continuation on Study Treatment After CNS-Only Progression .................................... 53 
5.2 
Rationale for the Study Design .................................................................................................... 55 
5.2.1 
Rationale for the Patient Population ................................................................................ 55 
5.2.2 
Rationale for the Dose and Regimen ............................................................................... 56 
5.2.2.1 
Rationale for Regimen in Patients with Brain Metastases ............................. 57 
5.2.3 
Rationale for Efficacy Assessments ................................................................................ 59 
5.2.3.1 
Rationale for CNS Efficacy Assessments ...................................................... 60 
5.2.4 
Rationale for PK Assessment Plan .................................................................................. 60 
5.2.5 
Rationale for Health Economics Assessments ................................................................ 61 
5.2.6 
Rationale for Exploratory Endpoints ............................................................................... 61 
5.2.6.1 
Biomarker Assessments ................................................................................. 61 
5.3 
Double-blind Phase Endpoints .................................................................................................... 62 
5.3.1 
Double-blind Phase Primary Endpoint ............................................................................ 62 
5.3.2 
Double-blind Phase Secondary Endpoints ...................................................................... 62 
5.3.3 
Double-blind Phase Exploratory Endpoints .................................................................... 63 
5.4 
Unblinded Phase Endpoints ......................................................................................................... 63 
5.5 
Study Stopping Rules and Discontinuation Criteria .................................................................... 63 
5.6 
End of Study ................................................................................................................................ 63 
5.7 
Post-study Care ............................................................................................................................ 64 
5.8 
Minimization of Bias ................................................................................................................... 64 
5.8.1 
Double-blind Phase Randomization ................................................................................ 64 
5.8.2 
Double-blind Phase Blinding .......................................................................................... 64 
5.8.3 
Double-blind Phase Unblinding ...................................................................................... 64 
5.9 
Ethical Considerations ................................................................................................................. 65 


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6 
SELECTION AND WITHDRAWAL OF PATIENTS .......................................................................... 66 
6.1 
Double-blind Phase Inclusion Criteria ........................................................................................ 66 
6.2 
Double-blind Phase Exclusion Criteria ....................................................................................... 68 
6.3 
Unblinded Phase Crossover Criteria ............................................................................................ 71 
6.3.1 
Crossover Inclusion Criteria ............................................................................................ 71 
6.3.2 
Crossover Exclusion Criteria ........................................................................................... 74 
6.4 
Criteria for Discontinuation of Study Treatment ......................................................................... 77 
7 
TREATMENTS ADMINISTERED....................................................................................................... 79 
7.1 
Standard of Care Treatment ......................................................................................................... 79 
7.1.1 
Capecitabine .................................................................................................................... 79 
7.1.1.1 
Risks Associated with Capecitabine ............................................................... 79 
7.1.2 
Trastuzumab .................................................................................................................... 79 
7.1.2.1 
Risks Associated with Trastuzumab............................................................... 80 
7.2 
Tucatinib 80 
7.2.1 
Double-blind Phase Tucatinib and Placebo ..................................................................... 80 
7.2.2 
Unblinded Phase Tucatinib ............................................................................................. 81 
7.2.3 
Dosing Instructions ......................................................................................................... 81 
7.2.4 
Risks Associated with Tucatinib alone and in Combination with Trastuzumab and 
Capecitabine .................................................................................................................... 81 
7.2.5 
Description of Active Ingredient ..................................................................................... 82 
7.2.6 
Packaging and Labeling .................................................................................................. 82 
7.2.7 
Storage and Handling ...................................................................................................... 83 
7.3 
Study Drug Accountability .......................................................................................................... 83 
7.3.1 
Accountability of Tucatinib Tablets and Placebo ............................................................ 83 
7.3.2 
Accountability of Capecitabine and Trastuzumab ........................................................... 83 
7.4 
Dose Modifications ..................................................................................................................... 83 
7.4.1 
Tucatinib or Placebo Dose Reductions ............................................................................ 84 
7.4.2 
Trastuzumab Dose Modifications.................................................................................... 85 
7.4.3 
Capecitabine Dose Modifications.................................................................................... 86 
7.4.4 
Dose Modifications for Hepatotoxicity ........................................................................... 87 
7.4.5 
Trastuzumab Dose Modifications for Left Ventricular Dysfunction ............................... 88 
7.5 
Concomitant Therapy .................................................................................................................. 89 
7.5.1 
Required Concomitant Therapy ...................................................................................... 89 
7.5.2 
Allowed Concomitant Therapy ....................................................................................... 89 
7.5.3 
Prohibited Concomitant Therapy .................................................................................... 90 
7.5.4 
Potential Concomitant Drug Interactions ........................................................................ 91 
7.6 
Treatment Compliance ................................................................................................................ 91 
7.7 
Duration of Participation ............................................................................................................. 91 
7.7.1 
Follow-up After Discontinuation of Study Treatment ..................................................... 92 
8 
TRIAL PROCEDURES ......................................................................................................................... 93 
8.1 
Double-blind Phase ..................................................................................................................... 93 
8.1.1 
Screening/Baseline (Days -28 to 1) ................................................................................. 93 
8.1.2 
Cycle 1 Day 1 .................................................................................................................. 95 
8.1.3 
Cycle 1 Day 12 (± 3 days) ............................................................................................... 95 
8.1.4 
Cycle 2 Day 1 and Day 1 of All Subsequent Cycles (- 1 day to +3 days) ....................... 95 
8.1.5 
Cycle 2 Day 12 (± 3 days) ............................................................................................... 96 
8.1.6 
Every Six Weeks as Determined by Cycle 1 Day 1, Through Week 24 (- 7 days) ......... 96 
8.1.7 
Every 12 Weeks as Determined by Screening Exam (-7 days) ....................................... 97 
8.1.8 
Beginning Week 24, Every 9 Weeks Through End of Treatment (- 7 Days) .................. 97 
8.1.9 
30-Day Follow-up Visit (30 days, + 7 days, after last dose of study treatment) ............. 97 
8.1.10 Long-Term Follow-up ..................................................................................................... 98 
8.2 
Unblinded Phase .......................................................................................................................... 99 
8.2.1 
Experimental Arm Continuing on Treatment .................................................................. 99 
8.2.2 
Experimental Arm in the Long-term Follow-up .............................................................. 99 
8.2.3 
Control Arm Continuing on Treatment or in Long-term Follow-up ............................... 99 


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8.2.3.1 
Control Arm Patients who do not meet Crossover Criteria .......................... 100 
8.2.4 
Screening for Crossover Criteria ................................................................................... 100 
8.2.5 
Crossover to the Experimental Arm, Cycle 1 Day 1 ..................................................... 101 
8.2.6 
Crossover to the Experimental Arm, Cycle 1 Day 12 (± 3 days) .................................. 102 
8.2.7 
Crossover to the Experimental Arm, Cycle 2 Day 1 (- 1 day to +3 days) ..................... 102 
8.2.8 
Crossover to the Experimental Arm, Cycle 2 Day 12 (± 3 days) .................................. 103 
8.2.9 
Day 1 of All Subsequent Cycles (- 1 day to +3 days) ................................................... 103 
8.2.10 Every 12 Weeks as Determined by Crossover Screening Exam or Most Recent Exam (-
7 days) ........................................................................................................................... 104 
8.2.11 Tumor Assessments after Crossover Screening Through End of Treatment ................. 104 
8.2.12 After Last Dose of Study Treatment - 30-Day Follow-up Visit (30 days, + 7 days) ..... 104 
8.2.13 Long-Term Follow-up ................................................................................................... 105 
9 
STUDY ASSESSMENTS .................................................................................................................... 106 
9.1 
Efficacy Assessments ................................................................................................................ 106 
9.1.1 
Double-blind Phase ....................................................................................................... 106 
9.1.2 
Unblinded Phase ............................................................................................................ 107 
9.2 
Health Economic Assessments .................................................................................................. 107 
9.2.1 
Double-blind Phase ....................................................................................................... 107 
9.2.2 
Unblinded Phase ............................................................................................................ 107 
9.3 
Pharmacokinetic Assessments ................................................................................................... 107 
9.3.1 
Double-blind Phase ....................................................................................................... 107 
9.3.2 
Unblinded Phase ............................................................................................................ 108 
9.4 
Safety Assessments ................................................................................................................... 108 
9.4.1 
Data Monitoring Committee ......................................................................................... 108 
9.4.1.1 
Double-blind Phase ...................................................................................... 108 
9.4.1.2 
Unblinded Phase........................................................................................... 108 
9.4.2 
Clinical Laboratory Evaluation ..................................................................................... 108 
9.4.3 
Safety Plan for Cardiotoxicity ....................................................................................... 109 
9.4.4 
Safety Plan for Hepatotoxicity ...................................................................................... 109 
9.4.5 
Safety Plan for Patients with Brain Metastases ............................................................. 109 
9.4.6 
Safety Plan for Prevention of Pregnancy ....................................................................... 110 
9.4.7 
Adverse Events .............................................................................................................. 110 
9.4.7.1 
Definitions .................................................................................................... 110 
9.4.7.2 
Procedures for Eliciting and Recording of Adverse Events Eliciting Adverse 
Events ........................................................................................................... 114 
9.4.7.3 
Reporting Periods and Follow-up of Adverse Events and Serious Adverse 
Events ........................................................................................................... 115 
9.4.7.4 
Serious Adverse Event and Event of Special Interest Reporting Procedures
...................................................................................................................... 115 
9.4.7.5 
Sponsor Safety Reporting to Regulatory Authorities ................................... 116 
9.4.7.6 
Pregnancy Reporting .................................................................................... 116 
10 DATA QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 118 
10.1 Site Monitoring and Training .................................................................................................... 118 
10.2 Data Management ...................................................................................................................... 118 
10.3 Quality Assurance Audits .......................................................................................................... 118 
11 STATISTICS ....................................................................................................................................... 119 
11.1 Double-blind Phase ................................................................................................................... 119 
11.1.1 Statistical Methods ........................................................................................................ 119 
11.1.1.1 
General Considerations ................................................................................ 119 
11.1.1.2 
Patient Disposition ....................................................................................... 120 
11.1.1.3 
Baseline Characteristics ............................................................................... 120 
11.1.1.4 
Efficacy Analyses......................................................................................... 121 
11.1.1.5 
Pharmacokinetic Analyses ........................................................................... 123 
11.1.1.6 
Safety Analyses ............................................................................................ 124 


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11.1.1.7 
Handling of Missing Data ............................................................................ 125 
11.1.1.8 
Interim Analyses .......................................................................................... 125 
11.1.1.9 
Multiple Comparison and Multiplicity ......................................................... 126 
11.1.2 Determination of Sample Size ....................................................................................... 126 
11.2 Unblinded Phase ........................................................................................................................ 127 
12 INFORMED CONSENT, ETHICAL REVIEW, AND ADMINISTRATIVE AND REGULATORY 
CONSIDERATIONS ........................................................................................................................... 128 
12.1 Informed Consent ...................................................................................................................... 128 
12.2 Ethical Review .......................................................................................................................... 128 
12.3 Administrative and Regulatory Considerations ......................................................................... 129 
12.3.1 Investigator Information ................................................................................................ 129 
12.3.2 Protocol Amendments and Study Termination ............................................................. 130 
12.3.3 Payments, Insurance, and Publications.......................................................................... 130 
12.4 Study Documentation, Privacy, and Records Retention ............................................................ 130 
13 REFERENCES ..................................................................................................................................... 132 
Appendix A.1 
Schedule of Events – Double-blind Phase ................................................................ 137 
Appendix A.2 
Schedule of Events – Experimental Arm Continuing on Treatment in the Unblinded 
Phase 
 .................................................................................................................................. 141 
Appendix A.3 
Schedule of Events – Control Arm Continuing on Treatment in the Unblinded Phase
 
 
 .................................................................................................................................. 142 
Appendix B 
RECIST 1.1 Criteria .................................................................................................. 144 
Appendix C 
Selected Strong Inhibitors and Inducer of CYP2C8 and Their Elimination Half-Lives
 
 
 .................................................................................................................................. 148 
Appendix D 
Selected Strong Inhibitors or Inducers of CYP3A4 and Their Elimination Half-Lives
 
 
 .................................................................................................................................. 149 
Appendix E 
Examples of Clinical Substrates for CYP3A-Mediated Metabolism ........................ 150 
Appendix F 
Adverse Event Severity Grading Scale (CTCAE Version 4.03) ............................... 151 
Appendix G 
List of Selected Substrates or Inhibitors of P-gp and Substrates of BCRP Oral Drugs
 
 
 .................................................................................................................................. 152 
Appendix H 
Drugs Accepted or Possibly Associated with Risk of QT Prolongation or Torsade de 
Pointes 
 .................................................................................................................................. 153 
 
 
 


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List of Tables 
Table 7-1 
Recommended Tucatinib or Placebo Dose Reduction Schedule ............................................ 85 
Table 7-2 
Dose Modifications of Tucatinib or Placebo and Trastuzumab for Clinical Adverse Events 
Other Than Left Ventricular Dysfunction Related to  Trastuzumab, or Hepatocellular 
Toxicity* ................................................................................................................................ 86 
Table 7-3 
Dose Modification of Capecitabine for Clinical Adverse Events Considered Related to 
Capecitabine ........................................................................................................................... 87 
Table 7-4 
Dose Modifications of Tucatinib or Placebo and Capecitabine for Liver Function 
Abnormalities ......................................................................................................................... 88 
Table 7-5 
Trastuzumab Dose Modifications for Left Ventricular Dysfunction ...................................... 88 
Table 9-1 
Pharmacokinetic Sampling ................................................................................................... 107 
List of Figures 
Figure 5-1 
Double-blind Study Schematic ............................................................................................... 46 
Figure 5-2 
Unblinded Phase Study Schematic ......................................................................................... 50 
Figure 11-1 
Type I Error Reallocation Strategy Following Closed Testing Principle ............................. 126 
 


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1 
GLOSSARY AND TERMS 
5FU 
5-fluorouracil 
ADL 
activities of daily living 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic-pyruvate transaminase 
ANC 
absolute neutrophil count 
anti-HBc 
antibodies to Hepatitis B core 
anti-HCV 
antibodies to Hepatitis C virus 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
AR 
adverse reaction 
AST/SGOT 
aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
AUC 
area under the curve 
BICR 
blinded independent central review 
BID 
twice daily 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum concentration observed 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
DCC 
Data Coordinating Center 
DDI 
drug-drug interaction 
DFS 
disease-free survival 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
ED 
emergency department 
EGFR 
epidermal growth factor receptor 
EOI 
event of interest 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 


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HC 
Health Canada 
Hct 
Hematocrit 
HER1 
human epidermal growth factor receptor 1 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IAR 
infusion-associated reaction 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IUD 
intrauterine device 
IV 
Intravenous 
IRB/IEC  
Institutional Review Board/Independent Ethics Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
kg 
Kilogram 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LMD 
leptomeningeal disease 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum-tolerated dose 
MUGA 
multiple-gated acquisition scan 
NCI 
National Cancer Institute 
ONT-380 
(tucatinib) 
Investigational small molecule inhibitor of HER2 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PIC 
powder in capsule 
PK 
Pharmacokinetics 
PO 
oral administration 
PPE 
palmar-plantar erythrodysaesthesia 


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PR 
partial response 
PT 
prothrombin time 
PVP-VA 
polyvinylpyrrolidine-vinyl acetate copolymer 
QTc 
corrected QT 
RANO-BM 
Response Assessment in Neuro-Oncology – Brain Metastases 
RD 
recommended dose 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP  
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
SRS 
stereotactic radiosurgery 
SUSAR 
suspected unexpected serious adverse reaction 
T-DM1 
ado-trastuzumab emtansine or trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tucatinib  
(ONT-380) 
Investigational small molecule inhibitor of HER2 
ULN 
upper limit of normal 
WBRT 
whole brain radiation therapy 


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2 
 PROTOCOL SYNOPSIS 
Protocol Number: 
ONT-380-206 
Version: 
Version 12, 30-Jul-2021 
Phase:  
2 
Product Name: 
Tucatinib 
Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021 
Protocol Title 
Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs. Placebo in Combination with 
Capecitabine and Trastuzumab in Patients with Pretreated Unresectable Locally Advanced or Metastatic 
HER2+ Breast Carcinoma 
(HER2CLIMB) 
Previously, the study sponsor, Seagen, performed the per-protocol primary analysis of this trial. At the time 
of the primary analysis, the trial met the primary endpoint of progression-free survival (PFS), showing that 
the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in 
the risk of disease progression or death (hazard ratio [HR]=0.54 [95% Confidence Interval [CI]: 0.42, 
0.71]; p<0.00001). The trial also met the two key secondary endpoints at interim analysis. The tucatinib 
arm demonstrated an improvement in overall survival (OS), with a 34 percent reduction in the risk of death 
(HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048) compared to trastuzumab and capecitabine alone. For patients 
with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with a 52 percent 
reduction in the risk of disease progression or death compared to those who received trastuzumab and 
capecitabine alone (HR=0.48 (95% CI: 0.34, 0.69); p<0.00001). Due to the statistically significant results, 
these interim analyses of OS and PFS in patients with brain metastases are considered the final analyses of 
these endpoints. 
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated with a 
manageable safety profile. The most frequent adverse events in the tucatinib arm included diarrhea, palmar-
plantar erythrodysaesthesia syndrome (PPE), nausea, fatigue, and vomiting. Grade 3 or greater adverse 
events in the tucatinib arm compared to the control arm included diarrhea (12.9 vs. 8.6 percent), increased 
aspartate aminotransferase (AST) (4.5 vs. 0.5 percent), increased alanine aminotransferase (ALT) (5.4 vs. 
0.5 percent) and increased bilirubin (0.7 vs. 2.5 percent). There was no requirement for prophylactic 
antidiarrheals. Adverse events leading to discontinuations were infrequent in both the tucatinib arm and the 
control arm (5.7 and 3.0 percent). 
Based on these results, the Sponsor decided to unblind this trial and offer tucatinib to patients on the control 
arm. Protocol Version 11 established a new Unblinded Phase of the study, and presented study procedures 
for these 2 distinct phases: the Double-blind Phase and the Unblinded Phase.  
An analysis of OS and PFS conducted approximately 2 years after the last patient was randomized to the 
study demonstrated that the OS benefit with tucatinib was maintained, and PFS per investigator assessment 
was consistent with the primary analysis (Curigliano 2021). Moreover, the number of OS events observed 
exceeded the number required for the originally planned final analysis. These data will be included in an 
addendum to the clinical study report and no additional analyses are planned.  


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Based on these data, the Sponsor will end the study and a last visit/contact will occur for patients who are 
still in the study. 
Double-blind Phase Study Objectives 
Double-blind Phase Primary Objective 
• 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on 
PFS per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 based on blinded 
independent central review (BICR) 
Double-blind Phase Secondary Objectives 
• 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab in 
patients with brain metastases at baseline, defined as patients with a history of brain metastases, 
current brain metastases, or equivocal brain lesions at baseline, using RECIST 1.1 based on BICR 
• 
To assess the effects of tucatinib vs. placebo in combination with capecitabine and trastuzumab on 
OS 
• 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on 
PFS per RECIST 1.1 based on investigator assessment  
• 
To assess the effects of tucatinib vs. placebo in combination with capecitabine and trastuzumab on 
objective response rate (ORR) per RECIST 1.1 based on BICR and by the investigator 
• 
To assess the duration of response (DOR) of tucatinib in combination with capecitabine and 
trastuzumab per RECIST 1.1 based on BICR and by the investigator 
• 
To assess the clinical benefit rate (CBR) [stable disease (SD) or non-complete response (CR)/non-
progressive disease (PD) for ≥ 6 months, or best response of CR or partial response (PR)] of 
tucatinib vs. placebo in combination with capecitabine and trastuzumab per RECIST 1.1 based on 
BICR 
• 
To assess the health-related quality of life and health economics associated with tucatinib vs. 
placebo in combination with capecitabine and trastuzumab based on patient health status collected 
using the EQ-5D-5L instrument and health resources utilized in patient care 
Double-blind Phase Safety Objective 
• 
To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab 
Double-blind Phase Pharmacokinetic Objective 
• 
To evaluate the pharmacokinetics of tucatinib and metabolite ONT-993 when administered in 
combination with capecitabine and trastuzumab 
Double-blind Phase Exploratory Objectives 
• 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab 
using RANO-BM by BICR in patients with brain metastases at baseline 


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• 
To identify potential biomarkers of response, including human epidermal growth factor receptor 2 
(HER2) mutations and other mutations by DNA sequence analyses of ctDNA isolated from 
plasma samples 
• 
To assess the effect of tucatinib on progression in brain in patients with brain metastases at 
baseline 
Double-blind Phase Endpoints 
Double-blind Phase Primary Endpoint 
• 
PFS, defined as the time from randomization to documented disease progression (as determined 
by BICR per RECIST 1.1), or death from any cause, whichever occurs first 
Double-blind Phase Secondary Endpoints 
Efficacy 
Key Secondary Endpoints 
• 
PFS in patients with brain metastases at baseline using RECIST 1.1 as determined by BICR 
• 
OS  
Other Secondary Endpoints 
• 
PFS, defined as the time from randomization to investigator-assessed documented disease 
progression (per RECIST 1.1), or death from any cause, whichever occurs first 
• 
ORR (RECIST 1.1) as determined by BICR as well as the investigator 
• 
DOR (RECIST 1.1) as determined by BICR as well as the investigator 
• 
CBR (RECIST 1.1) as determined by BICR as well as the investigator 
Safety 
• 
Adverse events (AEs) 
• 
Clinical laboratory assessments 
• 
Vital signs and other relevant safety variables 
• 
Frequency of dose holding, dose reductions, and discontinuations of capecitabine 
• 
Frequency of dose holding, dose reductions, and discontinuations of tucatinib 
• 
Frequency of dose holding and discontinuations of trastuzumab 
Pharmacokinetics 
• 
Plasma concentrations of tucatinib and metabolite 
Heath Economics and Outcomes 


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• 
Cumulative incidence of health resource utilization, including length of stay, hospitalizations and 
emergency department (ED) visits 
• 
Health-related quality of life / health status using the EQ-5D-5L instrument 
Double-blind Phase Exploratory Endpoints 
• 
ORR in brain per RANO-BM as determined by BICR 
• 
Duration of response in brain per RANO-BM as determined by BICR 
• 
Time to brain progression in patients with brain metastases at baseline per RANO-BM as 
determined by BICR 
• 
Presence of HER2 mutations or other potential biomarkers of response 
 
Unblinded Phase Study Objectives 
• 
To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab 
• 
To assess PFS per RECIST 1.1 by investigator 
• 
To assess OS 
 
Unblinded Phase Endpoints 
• 
Adverse events (AEs) 
• 
Clinical laboratory assessments 
• 
Vital signs and other relevant safety variables 
• 
Frequency of dose holding, dose reductions, and discontinuations of capecitabine 
• 
Frequency of dose holding, dose reductions, and discontinuations of tucatinib 
• 
Frequency of dose holding and discontinuations of trastuzumab 
• 
PFS per RECIST 1.1 as determined by investigator 
• 
OS  
 
Study Population 
Patients with pretreated unresectable locally advanced or metastatic HER2+ breast cancer who have had 
prior treatment with trastuzumab, pertuzumab, and T-DM1 (ado-trastuzumab emtansine or trastuzumab 
emtansine). 


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Double-blind Phase Eligibility Criteria 
Double-blind Phase Inclusion 
Patients must meet the following criteria to be eligible for the study: 
1. Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ 
hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry 
(IHC) methodology 
a. 
Tissue blocks or slides must be submitted to confirm HER2 positivity (using ISH 
or FISH) by a sponsor-designated central laboratory prior to randomization 
b. Centrally confirmed HER2 results (either IHC, ISH, or FISH) from a previous 
study can be used to determine eligibility for this study with approval from the 
sponsor 
2. Have received previous treatment with trastuzumab, pertuzumab, and T-DM1 
3. Have progression of unresectable locally advanced or metastatic breast cancer after last 
systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy 
4. Have measurable or non-measurable disease assessable by RECIST 1.1 
5. Be at least 18 years of age at time of consent 
6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 
7. Have a life expectancy of at least 6 months, in the opinion of the investigator  
8. Have adequate hepatic function as defined by the following:  
a. 
Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with 
known Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 X 
ULN 
b. Transaminases [aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic 
transaminase (ALT/SGPT)] ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases are 
present)  
9. Have adequate baseline hematologic parameters as defined by: 
a. 
Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL 
b. Platelet count ≥ 100 x 103/µL; patients with stable platelet count from 75-
100 x 103/µL may be included with approval from medical monitor 
c. 
Hemoglobin ≥ 9 g/dL 


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d. In patients transfused before study entry, transfusion must be ≥ 14 days prior to 
start of therapy to establish adequate hematologic parameters independent from 
transfusion support 
10. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines or, in 
patients ≤ 45 kg in weight, a serum creatinine within institutional normal limits 
11. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
≤ 1.5 X ULN unless on medication known to alter INR and aPTT. (Note: Warfarin and 
other coumarin derivatives are prohibited.) 
12. Have left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram 
(ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to 
first dose of study treatment  
13. If female of childbearing potential, must have a negative result of serum or urine pregnancy 
test performed within 7 days prior to first dose of study treatment. A woman is considered 
of childbearing potential, i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state 
is defined as no menses for 12 months without an alternative medical cause. 
Postmenopausal patients with known β-HCG secreting tumors may be eligible when 
β-HCG-based urine or serum pregnancy tests yield false positive if they meet the definition 
of postmenopausal state and have a negative uterine ultrasound 
14. Women of childbearing potential (as defined above) and men with partners of childbearing 
potential must agree to use a highly effective birth control method, i.e. methods that achieve 
a failure rate of less than 1% per year when used consistently and correctly. Such methods 
include: combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-
only hormonal contraception associated with inhibition of ovulation (oral, injectable, or 
implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal 
occlusion/ligation; vasectomized partner; or sexual abstinence. Male patients with partners 
of childbearing potential must use barrier contraception. All study patients should practice 
effective contraception, as described above, starting from the signing of informed consent 
until 7 months after the last dose of study medication or investigational medicinal product.  
15. Patient must provide signed informed consent per a consent document that has been 
approved by an institutional review board or independent ethics committee (IRB/IEC) prior 
to initiation of any study-related tests or procedures that are not part of standard-of-care for 
the patient’s disease 
16. Patients must be willing and able to comply with study procedures 


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CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), patients must have 
one of the following: 
17. No evidence of brain metastases 
18. Untreated brain metastases not needing immediate local therapy. For patients with 
untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and 
approval from the medical monitor is required prior to enrollment 
19. Previously treated brain metastases 
a. 
Brain metastases previously treated with local therapy may either be stable since 
treatment or may have progressed since prior local CNS therapy, provided that 
there is no clinical indication for immediate re-treatment with local therapy in the 
opinion of the investigator 
b. Patients treated with CNS local therapy for newly identified lesions found on 
contrast brain MRI performed during screening for this study may be eligible to 
enroll if all of the following criteria are met: 
i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to 
first dose of study treatment, time since stereotactic radiosurgery (SRS) is 
≥ 7 days prior to first dose of study treatment, or time since surgical 
resection is ≥ 28 days  
ii. Other sites of disease assessable by RECIST 1.1 are present 
c. 
Relevant records of any CNS treatment must be available to allow for 
classification of target and non-target lesions  
Double-blind Phase Exclusion 
Patients will be excluded from the study for any of the following reasons: 
1. Have previously been treated with: 
a. 
lapatinib within 12 months of starting study treatment (except in cases where lapatinib 
was given for ≤ 21 days and was discontinued for reasons other than disease 
progression or severe toxicity) 
b. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor 
(EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously 
2. Have previously been treated with capecitabine (or other fluoropyrimidine [e.g., 
5-fluorouracil]) for metastatic disease (except in cases where capecitabine was given for 
≤ 21 days and was discontinued for reasons other than disease progression or severe 
toxicity) Note: Patients who have received capecitabine for adjuvant or neoadjuvant 
treatment at least 12 months prior to starting study treatment are eligible. 


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3. History of exposure to the following cumulative doses of anthracyclines:  
a. 
Doxorubicin > 360 mg/m2  
b. Epirubicin > 720 mg/m2  
c. 
Mitoxantrone > 120 mg/m2  
d. Idarubicin > 90 mg/m2  
e. 
Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2 
4. History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or 
biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to 
trastuzumab that were successfully managed, or known allergy to one of the excipients in 
the study drugs 
5. Have received treatment with any systemic anti-cancer therapy (including hormonal 
therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of study 
treatment or are currently participating in another interventional clinical trial. An exception 
for the washout of hormonal therapies is gonadotropin releasing hormone (GnRH) agonists 
used for ovarian suppression in premenopausal women, which are permitted concomitant 
medications 
6. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with 
the following exceptions:  
• 
alopecia and neuropathy, which must have resolved to ≤ Grade 2; and  
• 
congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time 
of occurrence, and must have resolved completely 
• 
anemia, which must have resolved to ≤ Grade 2 
7. Have clinically significant cardiopulmonary disease such as: 
• 
ventricular arrhythmia requiring therapy,  
• 
uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg 
and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), or 
• 
any history of symptomatic CHF 
• 
severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced 
malignancy 
• 
hypoxia requiring supplementary oxygen therapy except when oxygen therapy is 
needed only for obstructive sleep apnea  
• 
presence of ≥ Grade 2 QTc prolongation on screening ECG  


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• 
conditions potentially resulting in drug-induced prolongation of the QT interval or 
torsade de pointes: 
a. 
Congenital or acquired long QT syndrome 
b. Family history of sudden death 
c. 
History of previous drug induced QT prolongation 
d. Current use of medications with known and accepted associated risk of QT 
prolongation (see row “Accepted Association” in Appendix H) 
8. Have known myocardial infarction or unstable angina within 6 months prior to first dose of 
study treatment 
9. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease 
10. Are known to be positive for human immunodeficiency virus (HIV) 
11. Are pregnant, breastfeeding, or planning a pregnancy 
12. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants 
are allowed) 
13. Have inability to swallow pills or significant gastrointestinal disease which would preclude 
the adequate oral absorption of medications 
14. Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or 
have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study 
treatment (see Appendix C and Appendix D) 
15. Have known dihydropyrimidine dehydrogenase deficiency 
16. Unable for any reason to undergo contrast MRI of the brain 
17. Have any other medical, social, or psychosocial factors that, in the opinion of the 
investigator, could impact safety or compliance with study procedures  
18. Have evidence within 2 years of the start of study treatment of another malignancy that 
required systemic treatment 
CNS Exclusion – Based on screening brain MRI, patients must not have any of the following:  
19. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and 
approval for enrollment is given 
20. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a 
total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a 
chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible 
with discussion and approval by the medical monitor 


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21. Any brain lesion thought to require immediate local therapy, including (but not limited to) a 
lesion in an anatomic site where increase in size or possible treatment-related edema may 
pose risk to patient (e.g. brain stem lesions). Patients who undergo local treatment for such 
lesions identified by screening contrast brain MRI may still be eligible for the study based 
on criteria described under CNS inclusion criteria 19b 
22. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
23. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest 
neurologic progression due to brain metastases notwithstanding CNS-directed therapy 
 
Unblinded Phase Crossover Criteria 
Crossover Inclusion Criteria 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) must meet the 
inclusion criteria below at the time of crossover screening to be eligible to crossover to the experimental 
arm. Prior scans and imaging may be used for crossover inclusion/exclusion criteria and tumor burden if 
these were collected within 6 weeks prior to the time of the patients signing the crossover consent for this 
Unblinded Phase of the study. 
1. Have measurable or non-measurable disease assessable by RECIST 1.1 
2. For patients who were randomized to the control arm and on the long-term follow-up 
period at the time of the crossover screening: have progression of unresectable locally 
advanced or metastatic breast cancer after last systemic therapy (as confirmed by 
investigator), or be intolerant of last systemic therapy 
3. Have ECOG PS 0 or 1 
4. Have a life expectancy of at least 6 months, in the opinion of the investigator  
5. Have adequate hepatic function as defined by:  
a. 
Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with 
known Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 X 
ULN 
b. Transaminases [aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic 
transaminase (ALT/SGPT)] ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases are 
present)  
6. Have adequate hematologic parameters as defined by: 
a. 
Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL 


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b. Platelet count ≥ 100 x 103/µL; patients with stable platelet count from 
75-100 x 103/µL may be included with approval from medical monitor 
c. 
Hemoglobin ≥ 9 g/dL 
d. In patients transfused before crossover screening, transfusion must be ≥ 14 days 
prior to start of crossover treatment to establish adequate hematologic parameters 
independent from transfusion support 
7. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines or, in 
patients ≤ 45 kg in weight, a serum creatinine within institutional normal limits 
8. Have left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram 
(ECHO) or multiple-gated acquisition scan (MUGA) documented within 6 weeks prior to 
the time of crossover screening  
9. For patients 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 starting crossover study treatment. A subject with a false 
positive result and documented verification that the patient is not pregnant is eligible 
for starting crossover study treatment. 
b. Must agree not to try to become pregnant during the study and for at least 7 months 
after the final dose of study drug administration 
c. 
Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 7 months after the final dose of study drug administration 
d. If sexually active in a way that could lead to pregnancy, must consistently use highly 
effective methods of birth control (i.e., methods that achieve a failure rate of <1% 
per year when used consistently and correctly) starting at the time of informed 
consent and continuing throughout the study and for at least 7 months after the final 
dose of study drug administration. 
Highly effective methods of birth control include: 
● 
Non-hormone releasing intrauterine device 
● 
Bilateral tubal occlusion/ligation 
● 
Vasectomized partner 
● 
Sexual abstinence when it is the preferred and usual lifestyle choice of the 
subject 
10. For patients who can father children, the following stipulations apply: 


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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 study drug 
administration 
b. If sexually active with a person of childbearing potential in a way that could lead to 
pregnancy, must consistently use a barrier method of birth control starting at time of 
informed consent and continuing throughout the study and for at least 7 months after 
the final dose of study drug administration 
c. 
If sexually active with a person who is pregnant or breastfeeding, must consistently 
use a barrier method of birth control starting at time of informed consent and 
continuing throughout the study and for at least 7 months after the final dose of study 
drug administration 
11. Patient must provide signed informed consent per a consent document that has been 
approved by an institutional review board or independent ethics committee (IRB/IEC) prior 
to initiation of any study-related tests or procedures that are not part of standard-of-care for 
the patient’s disease 
12. Patients must be willing and able to comply with study procedures 
CNS Inclusion – Based on crossover screening contrast brain magnetic resonance imaging (MRI) within 
6 weeks prior to the time of crossover screening, patients must have one of the following: 
13. No evidence of brain metastases 
14. Untreated brain metastases not needing immediate local therapy. For patients with 
untreated CNS lesions > 2.0 cm on the crossover screening contrast brain MRI, discussion 
with and approval from the medical monitor is required prior to enrollment 
15. Previously treated brain metastases 
a. 
Brain metastases previously treated with local therapy may either be stable since 
treatment or may have progressed since prior local CNS therapy, provided that 
there is no clinical indication for immediate re-treatment with local therapy in the 
opinion of the investigator 
b. Patients treated with CNS local therapy for newly identified lesions found on 
contrast brain MRI performed during crossover screening may be eligible to enroll 
if all of the following criteria are met: 
i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to 
start of crossover (tucatinib) treatment, time since stereotactic 
radiosurgery (SRS) is ≥ 7 days prior to start of crossover (tucatinib) 
treatment, or time since surgical resection is ≥ 28 days prior to start of 
crossover (tucatinib) treatment 
ii. Other sites of disease assessable by RECIST 1.1 are present  


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Crossover Exclusion Criteria 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) will be excluded 
if they meet any of the exclusion criterion below. Prior scans and imaging may be used for crossover 
inclusion/exclusion criteria and tumor burden if these were collected within 6 weeks prior to the time of the 
patients signing the crossover consent for this Unblinded Phase of the study. 
1. Discontinuation of study treatment (placebo + trastuzumab + capecitabine) due to an 
adverse event while on the double-blind phase of the study. If the adverse event leading to 
discontinuation of study treatment has resolved, the patient may be allowed to crossover 
with approval from the medical monitor. 
2. History of exposure to the following cumulative doses of anthracyclines:  
a. 
Doxorubicin > 360 mg/m2  
b. Epirubicin > 720 mg/m2  
c. 
Mitoxantrone > 120 mg/m2  
d. Idarubicin > 90 mg/m2  
e. 
Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2 
3. History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or 
biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to 
trastuzumab that were successfully managed, or known allergy to one of the excipients in 
the study drugs 
4. Have received treatment with any systemic anti-cancer therapy (including hormonal 
therapy), non-CNS radiation, or experimental agent ≤ 3 weeks prior to start of crossover 
(tucatinib) treatment or are currently participating in another interventional clinical trial. 
Ongoing treatment with trastuzumab + capecitabine as part of this trial is not exclusionary. 
An exception for the washout of hormonal therapies is gonadotropin releasing hormone 
(GnRH) agonists used for ovarian suppression in premenopausal women, which are 
permitted concomitant medications 
5. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1 
(ongoing treatment with trastuzumab + capecitabine as part of this trial is not exclusionary), 
with the following exceptions:  
• 
alopecia and neuropathy, which must have resolved to ≤ Grade 2;  
• 
congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time 
of occurrence, and must have resolved completely 
• 
anemia, which must have resolved to ≤ Grade 2 
6. Have clinically significant cardiopulmonary disease such as: 


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• 
ventricular arrhythmia requiring therapy,  
• 
uncontrolled hypertension as determined by investigator, 
• 
any history of symptomatic CHF, 
• 
severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced 
malignancy, or 
• 
hypoxia requiring supplementary oxygen therapy except when oxygen therapy is 
needed only for obstructive sleep apnea  
7. Have known myocardial infarction or unstable angina within 6 months prior to start of 
crossover (tucatinib) treatment  
8. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease 
9. Are known to be positive for HIV 
10. Are pregnant, breastfeeding, or planning a pregnancy 
11. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants 
are allowed) 
12. Have inability to swallow pills or significant gastrointestinal disease which would preclude 
the adequate oral absorption of medications 
13. Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a 
CYP2C8 or CYP3A4 inducer within 5 day prior to start of crossover (tucatinib) treatment. 
Strong CYP2C8 inhibitors and CYP2C8 or CYP3A4 inducers are also prohibited in the 
2 weeks following discontinuation of tucatinib treatment. Use of sensitive CYP3A 
substrates should be avoided 2 weeks prior to start of crossover (tucatinib) treatment 
14. Have known dihydropyrimidine dehydrogenase deficiency 
15. Unable for any reason to undergo contrast MRI of the brain 
16. Have any other medical, social, or psychosocial factors that, in the opinion of the 
investigator, could impact safety or compliance with study procedures  
17. Have evidence within 2 years prior to start of crossover (tucatinib) treatment of another 
malignancy that required systemic treatment 
CNS Exclusion – Based on crossover screening contrast brain MRI within 6 weeks prior to the time of 
crossover screening, patients must not have any of the following:  
18. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and 
approval for crossover enrollment is given 
19. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a 
total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a 


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chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible 
with discussion and approval by the medical monitor 
20. Any brain lesion thought to require immediate local therapy, including (but not limited to) a 
lesion in an anatomic site where increase in size or possible treatment-related edema may 
pose risk to patient (e.g. brain stem lesions). Patients who undergo local treatment for such 
lesions identified by crossover screening contrast brain MRI may still be eligible for 
crossover enrollment based on criteria described under CNS inclusion criteria 15b 
21. Known or suspected leptomeningeal disease (LMD) as documented by the investigator 
22. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest 
neurologic progression due to brain metastases notwithstanding CNS-directed therapy 
 
Study Design 
DOUBLE-BLIND PHASE 
A Double-blind Phase study schematic is presented in Figure 5-1. 
In this phase, the study is a randomized, international, multi-center, double-blind study of tucatinib or 
placebo in combination with capecitabine and trastuzumab in patients with pretreated unresectable locally 
advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab, 
and T-DM1. After signing informed consent and meeting all eligibility criteria, patients will be randomized 
in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. 
Randomization will be made using a dynamic hierarchical randomization schema. Stratification factors will 
include presence or history of treated or untreated brain metastases or brain lesions of equivocal 
significance (yes/no), ECOG PS (0 vs. 1), and region of world (US vs. Canada vs. Rest of World). 
Stratification for presence of brain metastases will be based upon medical history and investigator 
assessment of screening contrast brain MRI.  
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally 
twice daily (PO BID). Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of each 21-day 
cycle. Trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV) followed by 6 mg/kg 
once every 21 days, except in specific circumstances where it may be given weekly to compensate for 
modifications in treatment schedule. In instances of subcutaneous trastuzumab use, a fixed dose of 600 mg 
is administered without a loading dose. Following an IV loading dose of trastuzumab, 6 mg/kg of 
trastuzumab is administered once every 21 days, except in specific circumstances where it may be given 
weekly to compensate for modifications in treatment schedule. Subcutaneous trastuzumab is given only 
once every three weeks as there is no allowance for weekly dosing. There is no ability to modify the 
trastuzumab dose when administered subcutaneously. Dose modifications of tucatinib or placebo and 
capecitabine will be allowed. Dose holding or discontinuation of tucatinib or placebo, capecitabine, and 
trastuzumab will also be allowed as needed for patient safety. Patients who discontinue either capecitabine 


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or trastuzumab (but not both) may remain on study treatment. Patients who discontinue tucatinib or 
placebo, or both capecitabine and trastuzumab will not be allowed to remain on study treatment but will 
continue to be followed for efficacy assessments per protocol schedule. 
Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study 
closure. In the absence of clear evidence of disease progression (per RECIST 1.1), development of CNS 
symptoms, or radiographic changes thought to pose potential immediate risk to the patient, all efforts 
should be made to continue treatment until unequivocal evidence of radiologic progression occurs, as 
defined in RECIST 1.1.  
After discontinuing study treatment, patients may receive further care as determined by their physician. No 
crossover from placebo to tucatinib will be allowed while patients are on this phase of the study. It is 
planned that patients will be followed for efficacy endpoints after treatment discontinuation until the 
protocol specified number of events (both PFS and OS) are observed or the primary and key secondary 
endpoints are met. 
Safety monitoring will be performed by the sponsor throughout the study on a blinded basis. An 
independent Data Monitoring Committee (DMC) will regularly review all relevant safety data (blinded and 
unblinded) as outlined in a separate DMC charter. Ad hoc meetings of the DMC may be held upon the 
request of the sponsor or DMC. 
UNBLINDED PHASE 
An Unblinded Phase study schematic is presented in Figure 5-2. 
With the implementation of protocol version 11, the double-blind phase of the study ended and all patients 
were unblinded to their treatment assignment.  
● 
Patients who were randomized to the experimental arm (tucatinib + trastuzumab + capecitabine) 
and are receiving study treatment at the time of unblinding will continue on that treatment arm 
with a modified schedule of events beginning at the Day 1 of All Subsequent Cycles visit (See 
Section 8.2.9 and Appendix A.2). For these patients, the treatment cycle counting will continue 
from prior to the unblinding, and patients will continue study treatment at the same doses they 
were given in the double-blind phase of the study.   
● 
Patients who were randomized to the experimental arm (tucatinib + trastuzumab + capecitabine), 
ended study treatment and are in the long-term follow-up are not eligible for additional treatment 
on the experimental arm in this study and will remain in long-term follow-up. 
● 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) and are 
receiving study treatment at the time of unblinding may crossover to the experimental arm if 
crossover criteria are met. 
○ 
If the patient does not meet crossover criteria, the patient will continue trastuzumab 
+ capecitabine therapy. At the start of the next scheduled cycle, the patient will 
continue trastuzumab + capecitabine therapy with a modified schedule of events 
beginning at the Day 1 of All Subsequent Cycles visit (See Section 8.2.9 and 


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Appendix A.3). These patients will continue trastuzumab + capecitabine therapy at 
the same doses they were given in the double-blind phase of the study. 
● 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) and are 
in long-term follow-up at the time of unblinding may crossover to the experimental arm if 
crossover criteria are met. 
○ 
If the patient does not meet crossover criteria, the patient will remain in long-term 
follow-up 
Treatments Administered in the Unblinded Phase 
In the unblinded phase of the study, tucatinib will be given in combination with trastuzumab and 
capecitabine. Treatment will be administered in repeating 21-day cycles. 
● 
Patients randomized to the experimental arm will continue tucatinib + trastuzumab + capecitabine 
at the same doses they were given in the double-blind phase of the study, using a modified 
schedule of events as outlined in Appendix A.2. 
● 
Patients who were randomized to the control arm and meet crossover criteria will be given: 
○ 
Tucatinib 300 mg orally twice daily (PO BID) every day (Days 1–21) of each 21-day 
cycle using a modified schedule of events as outlined in Appendix A.3.  
○ 
Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of each 21-day 
cycle. For patients who required dose reductions of capecitabine, capecitabine must 
be given at the same reduced dose most recently given in the double-blind phase of 
the study.  
○ 
The initial dose of trastuzumab will be given as a loading dose of 8 mg/kg 
intravenously (IV), unless trastuzumab was administered within the prior 4 weeks, 
then the initial dose of trastuzumab will be administered at a dose of 6 mg/kg.  Each 
trastuzumab dose is given once every 21 days, except in specific circumstances 
where it may be given weekly to compensate for modifications in treatment 
schedule. Subcutaneous trastuzumab is given only once every three weeks as there is 
no allowance for weekly dosing. There is no ability to modify the trastuzumab dose 
when administered subcutaneously. 
Dose modifications of tucatinib and capecitabine will be allowed. Dose holding of tucatinib or dose holding 
and/or discontinuation of capecitabine and trastuzumab will also be allowed as needed for patient safety. 
Patients who discontinue either capecitabine or trastuzumab may remain on study treatment. In instances 
where capecitabine and trastuzumab have been discontinued, patients may remain on study treatment with 
tucatinib alone. Patients who discontinue tucatinib will not be allowed to remain on study treatment. 
Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study 
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Number of Planned Patients and Investigators/Centers 
The study will enroll approximately 600 patients. It will involve approximately 100 sites in North America 
and approximately 100 sites in the rest of the world, with planned enrollment over approximately 
48 months. This study completed enrollment during the Double-blind Phase; no additional patients will be 
enrolled during the Unblinded Phase. 
Study Assessments 
DOUBLE-BLIND PHASE 
Baseline Assessments 
Optional prescreening to confirm HER2 positivity by central review is permitted at any time prior to study 
screening, after signing a separate pre-screening consent form. There will be a screening period of up to 28 
days after patients sign main informed consent. During that time, contrast MRI of the brain will be 
performed in all patients. All patients will also undergo high quality spiral contrast computed tomography 
(CT), PET/CT (if high quality CT scan included) and/or contrast MRI scan imaging, including at a 
minimum the chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of 
disease (e.g., skin lesion photography, bone imaging). Blood samples for hematology, coagulation, 
chemistry, and liver function tests will be drawn. Testing for Hepatitis B and C, urinalysis, and ECG will 
also be performed, along with assessment of cardiac ejection fraction by MUGA or ECHO. Pregnancy 
testing (except in men or in women of non-childbearing potential) will be performed within 7 days of first 
study treatment. Patients will also have a blood sample drawn to assess for certain biomarkers of response, 
including analysis of mutations in circulating tumor DNA (ctDNA).  
Safety Assessments 
Patients will be assessed throughout the study for safety. Safety assessments including physical exam and 
collection of AEs and laboratory abnormalities will be performed at a minimum of once every three weeks 
throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be 
performed locally. During Cycle 1, an in-person safety assessment will be performed on Days 1 and 12. 
During Cycle 2, an in-person safety assessment will be performed on Day 1 and liver function tests 
(AST/ALT and total bilirubin) will be collected on Cycle 2 Day 12. An in-person safety assessment will 
then be performed on Day 1 of each cycle throughout the remainder of the study or as clinically indicated. 
Assessment of cardiac ejection fraction will be performed by MUGA or ECHO at screening and at least 
once every 12 weeks thereafter until study discontinuation irrespective of dose delays or interruption, and 
30 days after the last dose of study drugs (unless done within 12 weeks prior to 30-day follow-up visit). 
Efficacy Assessments 
Efficacy assessments will include measurement of all known sites of metastatic or locally advanced 
unresectable disease (including at a minimum the chest, abdomen, and pelvis) by high quality spiral 
contrast CT, PET/CT (if high quality CT scan included) and/or MRI scan as appropriate, as well as 
appropriate imaging of any other known sites of disease (e.g. skin lesion photography, bone imaging) at 
baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter, irrespective of dose 


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holdings or interruptions. Efficacy assessments for each patient will continue until a PFS event has been 
documented. Follow-up for survival will continue until death, withdrawal of consent, or study closure. 
Contrast MRI of the brain will be required on this same schedule only in those patients with prior history of 
brain metastases or with brain metastases or equivocal brain lesions at screening. Contrast brain MRI may 
also be performed in patients without known brain metastases if there is clinical suspicion of new brain 
lesions. Additional imaging such as nuclear medicine bone scan or other unscheduled scans may be 
performed at the discretion of the investigator. Treatment decisions will be made based upon local 
assessment of radiologic scans. Patients in both arms of the study will continue to be followed for OS after 
completion of study treatment as well as after the occurrence of disease progression.  
Pharmacokinetic Assessments 
Pharmacokinetic assessments of trough levels of tucatinib and metabolite drug levels will be performed on 
Day 1 of Cycles 2-6 prior to administration of tucatinib or placebo. On Day 1 of Cycle 3, pharmacokinetic 
assessments of peak levels of tucatinib and metabolite drug levels will be performed 1–4 hours after 
administration of tucatinib or placebo.  
Health Economic Assessments 
The EQ-5D-5L questionnaire will be administered to assess patient health-related quality of life / health 
status information. Administration will occur at Cycle 1 Day 1 prior to the start of study drug treatment and 
then every six weeks for 24 weeks and then every 9 weeks until disease progression, death, toxicity, 
withdrawal of consent or study closure. Additionally, a post-treatment assessment will occur approximately 
30-days post end of treatment. Health resource utilization data are also collected, including procedures that 
occur on study, length of stay, hospitalizations, ED visits, planned and unplanned provider visits, 
medication use, radiology, and other treatments or procedures. 
Assessments after Treatment Discontinuation 
A final routine, safety assessment including physical examination and laboratory assessments will be 
required approximately 30 days after discontinuation of study treatment. For patients who discontinue 
study treatment for reasons other than disease progression per RECIST 1.1, repeat imaging of all known 
areas of metastatic or locally advanced unresectable disease will also be requested until disease progression 
per RECIST 1.1 or death. A repeat contrast MRI of the brain is required in all patients following treatment 
discontinuation (unless a contrast brain MRI was performed within 30 days of treatment discontinuation or 
prior documentation of CNS progression while on study). Patients will also have a blood sample drawn to 
assess for the presence of certain potential biomarkers of response, including analysis of mutations in 
ctDNA. 
Blinding  
This phase of the study will be double-blinded. The patients, personnel in contact with study patients, data 
collection personnel, and others associated with patient procedures or data handling will be blinded to the 
treatment allocation. The sponsor will have limited access to treatment allocation only in the event of a 


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suspected unexpected serious adverse reaction (SUSAR) where unblinding for regulatory purposes 
becomes necessary. All SUSARs will be reported in accordance with local regulatory requirements.  
Unblinded data including deaths, discontinuations, dose reductions, AEs, and serious adverse events 
(SAEs) will be monitored regularly by an independent DMC. Further details will be provided in the DMC 
charter.  
UNBLINDED PHASE 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) and are receiving 
study treatment at the time of unblinding will continue trastuzumab + capecitabine treatment at the same 
doses they were given in the double-blind phase of the study. 
Screening for Crossover Criteria  
Patients who were randomized to the control arm who wish to crossover to receive tucatinib will undergo a 
screening period of up to 28 days after signing the revised informed consent. During that time patients will 
also undergo contrast MRI brain scan imaging in addition to CT, PET/CT, or MRI imaging to include, at a 
minimum, the chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of 
disease (e.g., skin lesion photography, bone imaging) for an assessment of tumor burden. Based on this 
crossover screening imaging, new baseline RECIST lesions will be selected by the investigator. 
Cardiac ejection fraction will be assessed by MUGA and ECHO. If an MRI of the brain, systemic imaging 
for assessment of tumor burden (e.g., CT, PET/CT, or MRI), or cardiac imaging for assessment of ejection 
fraction have been performed while on the double-blind phase of the study or as part of standard of care 
within the prior 6 weeks, those assessments can be used for crossover screening purposes. Blood samples 
for hematology, chemistry, and liver function tests will be drawn. Pregnancy testing (except in men or in 
women of non-childbearing potential) will be performed within 7 days prior to start of crossover (tucatinib) 
treatment. 
Tumor Response Assessments 
The investigator will determine the frequency and method of tumor assessments performed for patient care 
decisions according to routine clinical practice, with a maximum interval of 12 weeks between tumor 
assessments. Investigators should continue to use RECIST 1.1 for tumor assessments and for patient care 
decisions. 
Safety Assessments 
Patients will be assessed throughout the study for safety. Safety assessments including physical exam and 
collection of AEs and laboratory abnormalities will be performed at a minimum of once every three weeks 
throughout study treatment and 30 days after the last dose of study drugs. Cardiac ejection fraction 
assessments should be continued to be assessed by MUGA scan or ECHO at least once every 12 weeks. 
Laboratory assessments will be performed locally.  
Assessments after Treatment Discontinuation 


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A final routine, safety assessment including physical examination and laboratory assessments will be 
required approximately 30 days after discontinuation of study treatment. Patients will continue in long-term 
follow-up per the schedule of events as outlined in Appendix A.2 and in Appendix A.3, as appropriate.  
BOTH the Double-blind and Unblinded Phases 
Continuation on Study Treatment After CNS-Only Progression 
If a patient is found to have radiographic progressive disease per RECIST 1.1 based on isolated progression 
in the CNS (including either parenchymal brain or dural metastases but not skull-based or leptomeningeal 
metastases) and does not have progression of disease outside the CNS, the patient may be eligible to 
continue on study drugs after completion of local treatment (radiotherapy or surgery) of the brain/dural 
metastases to allow for clinical benefit. Continuation of study treatment requires discussion with and 
documented approval from the study medical monitor and may continue until either systemic progression 
or a second isolated CNS progression. Because this approach approximates common practice off-study in 
this clinical scenario, the duration of treatment after the CNS-only progression will be analyzed as an 
exploratory objective. The patient will remain on the same treatment regimen that they were receiving prior 
to receipt of CNS-directed therapy, and may continue on study provided the following criteria are met and 
the patient continues to receive clinical benefit: 
• 
The patient is not experiencing any worsening of cancer-related symptoms. Patients who are 
clinically deteriorating and unlikely to receive further benefit from continued treatment should 
discontinue study treatment. 
• 
The patient is tolerating study drug 
• 
Approval by the medical monitor 
• 
Patient has no evidence of unequivocal systemic progression 
• 
Patient has not had a previous isolated CNS progression on tucatinib while on study  
Study treatment may be held up to 6 weeks to allow local CNS therapy. Longer holds must be discussed 
and approved by the medical monitor. Oral study drugs (tucatinib/placebo and capecitabine) are to be held 
1 week prior to planned CNS-directed therapy. The potential for radiosensitization with tucatinib is 
unknown. Capecitabine is a known radiation sensitizer and therefore needs to be held prior to CNS-directed 
radiotherapy. Trastuzumab has been shown not to potentiate radiation and therefore may continue as per 
protocol schedule during radiotherapy. Oral study drugs may be re-initiated 7 days or more after 
completion of SRS/SRT, 21-days or more after WBRT and 28-days or more after surgical resection. Plans 
for holding and re-initiating study drugs before and after local therapy will require discussion with, and 
documented approval from, the medical monitor.  
Following CNS-directed therapy for isolated CNS disease progression, RECIST 1.1 criteria would continue 
to measure a CNS target lesion(s) if previously identified and used in the overall estimation of the sum of 
diameters measuring total disease burden. However, following treatment, measurement of the treated CNS 
target lesion(s) would use the immediate pre-CNS treatment measurement. If a subsequent decrease in the 


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size of a treated CNS lesion post-treatment is seen, the immediate pre-CNS treatment longest diameter 
would be used for RECIST measurement. Should a treated CNS lesion enlarge following CNS-directed 
therapy that was identified as a target lesion, the new and larger longest diameter is to be used for RECIST 
measurement. 
For patients in the double-blind phase: because the primary endpoint of the study is PFS, every effort 
should be made to avoid radiation or surgery to target lesions in the brain in the absence of progressive 
disease by RECIST 1.1 unless clinically necessary in the opinion of the investigator. The rationale for this 
is that target lesions, once treated with local CNS therapy, cannot be adequately assessed for subsequent 
response to systemic therapy. Because of this, if a patient continues on assigned study therapy after local 
CNS treatment to a target lesion, special consideration must be given for evaluation of the treated target 
lesion and the impact on the overall RECIST 1.1 assessment.  
Dose Modifications 
Dose modification is required for certain clinical AEs and for significant changes in hepatoxicities or 
measured cardiac ejection fraction. Dose modification for other toxicity is permitted at the investigator’s 
discretion. 
Dose reduction of tucatinib or placebo may be made in 50, 100, or 150 mg/dose steps. Dose reduction of 
capecitabine must be performed as outlined in the protocol and dose reduction of trastuzumab is not 
allowed. Doses of any study drug may be held for up to six weeks for toxicity, surgical procedure, or 
during radiation therapy; longer holds will require approval from the medical monitor.  
Prohibited Concomitant Therapies 
Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a CYP2C8 or CYP3A4 
inducer within 5 days prior to first dose of study treatment (for double-blind) or prior to the start of 
crossover (tucatinib) treatment (see Appendix C and Appendix D). Strong CYP2C8 inhibitors and CYP2C8 
or CYP3A4 inducers are also prohibited as concomitant medications during the study and in the 2 weeks 
following discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates should be avoided 
2 weeks before enrollment (for both double-blind and unblinded phases) and during study treatment. 
Warfarin therapy, or therapy with other coumarin derivatives is not permitted on the study. The use of 
corticosteroids at a daily dose of > 2 mg dexamethasone or equivalent for control of symptoms of brain 
metastases is not permitted at the time of study entry. 
Allowed Concomitant Therapy  
Standard supportive care measures, including anti-emetics, anti-diarrheal medications, permitted 
concomitant medications, and hematopoietic support, are permitted but not required. 
Statistical Methods 
DOUBLE-BLIND PHASE 
Data collected in this study will be presented using summary tables, patient data listings, and figures. 
Continuous variables will be summarized using descriptive statistics, specifically the mean, median, 


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standard deviation, minimum, and maximum. Categorical variables will be summarized by frequencies and 
percentages. Confidence intervals, 95% 2-sided, will be presented where needed to gauge the strength of 
evidence for a corresponding estimated treatment effect. 
Disease evaluations will be performed both by BICR and by investigators using RECIST 1.1 criteria. 
Discrepancies between the BICR and investigator’s assessment will be summarized descriptively. For the 
exploratory efficacy endpoints, disease evaluation will be performed using RANO-BM criteria. 
Efficacy Analyses 
For the primary endpoint of centrally-reviewed PFS, the two treatment groups will be compared using a 
2-sided log-rank test. To reflect the method of randomization (dynamic randomization), a re-randomization 
based procedure will be implemented (Rosenberger 2015) taking into account the stratification factors: 
[known history of treated or untreated brain metastases (yes/no); ECOG PS (0 vs. 1); and region of world 
(US vs. Canada vs. Rest of World)]. The first 480 randomized patients will be included in the primary 
analysis of PFS. Kaplan-Meier methodology will be used to estimate the PFS time curves, including the 
median. Similar analysis methods will be used to analyze the key secondary endpoints of PFS for the 
subgroup of patients with brain metastases at baseline (PFSBM), as well as for OS in the overall ITT 
population.  
Health-Related Quality of Life 
The treatment and placebo group index value changes will be summarized. Longitudinal and descriptive 
data analysis will be used to evaluate patient-reported outcomes. 
Health Care Resource Utilization 
Analysis of health utilization by resource utilization category will rely primarily on descriptive summary 
statistics and confidence intervals.  
Pharmacokinetic Analyses 
Individual (patient) plasma tucatinib and ONT-993 concentrations at each sampling time will be listed and 
summarized. Additional exploratory pharmacokinetics analyses may be conducted.  
Exploratory analyses investigating the relationship between tucatinib exposure and efficacy and safety 
endpoints may be conducted. 
Safety Analyses 
Safety will be assessed through summaries of AEs, changes in laboratory test results, changes in vital signs, 
changes in ECOG PS, 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 Common Toxicity Criteria for Adverse Events (CTCAE v4.03) 
criteria. Separately, all SAEs and AEs of special interest (e.g., any drug-induced liver injury, asymptomatic 
left ventricular systolic dysfunction, and/or cerebral edema) will also be listed. 


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All collected AE data will be listed. All treatment-emergent AEs will be summarized by treatment group, 
as follows: 
• 
All AEs (regardless of grade) 
• 
All Grade 3/4/5 AEs 
• 
All drug-related AEs (regardless of grade) 
• 
All AEs leading to study drug discontinuations 
• 
All SAEs, including deaths 
• 
All AEs of special interest (regardless of grade) 
A separate listing of all on-study deaths will be presented. 
Laboratory values (hematology, chemistry, and liver function) will be summarized by treatment group. 
Abnormal laboratory values (relative to respective normal ranges) will be flagged in listings. 
The frequency and percentage of patients with post-baseline clinically significant vital signs will be 
summarized. Abnormal physical examination findings may be collected as AEs. Cardiac ejection fraction 
data will also be summarized by treatment group, along with corresponding shift tables. 
Extent of exposure for tucatinib, capecitabine, and trastuzumab including frequency of dose holding, dose 
reductions, and dose discontinuations, as well as treatment compliance (percent of actual to planned 
dosing) will be summarized by treatment group. 
Sample Size Considerations 
The sample size for this study was calculated based on maintaining 90% power for the primary endpoint 
PFS with an alpha of 0.05 and 80% power for OS with an alpha of 0.02.  
For PFS, 288 events are required with 90% power to detect a hazard ratio of 0.67 (4.5 months median PFS 
in the control arm versus 6.75 months in the experimental arm) using a 2-sided log-rank test and alpha of 
0.05.  
For OS, 361 events are required with 80% power to detect a hazard ratio of 0.70 (15 months median OS in 
the control arm vs. 21.4 months in the experimental arm) using a 2-sided log-rank test and alpha of 0.02. 
With 361 OS events, it will provide 88% power using a 2-sided log-rank test and alpha of 0.05. 
For PFSBM, 220 events are required with 80% power to detect a hazard ratio of 0.67 (4.5 months median 
PFSBM in the control arm versus 6.75 months in the experimental arm) using a 2-sided log-rank test at alpha 
of 0.05. The power will be 74% at 2-sided alpha of 0.03. 
Approximately, 600 patients will be randomized in a 2:1 ratio to either the experimental arm or the control 
arm. Assuming an accrual period of 48 months and a 5% yearly drop-out rate, it is expected that 361 OS 
events will be observed approximately 59 months after first patient randomized. 
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Safety data will be summarized for the patients who receive study treatment in the unblinded phase. PFS 
per RECIST 1.1 by investigator and OS will be summarized at approximately 2 years after the last patient 
was randomized in this study.  


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3 
BACKGROUND AND RATIONALE 
3.1 HER2+ Breast Cancer 
Breast cancer is the most common form of cancer in women worldwide (Bray 2017), and 
the second leading cause of cancer-related death in the United States (U.S. Cancer 
Statistics Working Group 2010).Approximately 20% of breast cancers overexpress the 
human epidermal growth factor receptor 2 (HER2) (3, 4) HER2 is a transmembrane 
tyrosine kinase receptor that mediates cell growth, differentiation, and survival. Tumors 
that overexpress HER2 are more aggressive and historically have been associated with 
poorer overall survival (OS) compared to HER2 negative cancers (Slamon 1987).  
The introduction of HER2-targeted therapy using either antibody-based therapy or a 
small molecule tyrosine kinase inhibitor (TKI) has led to significant and ongoing 
improvements in disease-free survival (DFS), progression-free survival (PFS), and OS in 
both the adjuvant and metastatic settings (Slamon 2001; Geyer 2006; Baselga 2012b; 
Verma 2012). Trastuzumab, a humanized anti-HER2 antibody, remains the backbone of 
treatment in the adjuvant and first-line metastatic settings, usually in combination with a 
taxane. Anti-HER2 therapy in combination with cytotoxic chemotherapy allows for 
concurrent treatment with agents having two different mechanisms of action, leading to 
greater efficacy than with either agent alone (TYKERB Prescribing Information, Novartis 
Pharmaceuticals Corp., Feb 2021) (Slamon 2001; Vogel 2002). 
Despite the improvements in outcomes for early stage HER2+ breast cancer, up to a 
quarter of all patients treated with anti-HER2 therapy in the adjuvant setting relapse. The 
development of new HER2 targeted therapies such as pertuzumab and T-DM1 
(ado-trastuzumab emtansine or trastuzumab emtansine) for metastatic HER2+ breast 
cancer has led to a meaningful prolongation in the median survival of these patients; 
however, essentially all patients in the metastatic setting ultimately progress. Treatment 
failures may result from primary or acquired resistance to HER2 blockade (Lu 2001; 
Nahta 2006; Scaltriti 2007; Pohlmann 2009).There is evidence that dual targeting of 
HER2, either through combination of 2 different HER2-targeted antibodies or through 
use of an antibody-based therapy such as trastuzumab and a TKI, can lead to further 
improvements in efficacy in metastatic disease (Baselga 2012a; Baselga 2012b). In 
particular, combination of a small molecule TKI with an antibody-based therapy may be 
effective, as it may help overcome resistance to antibody-mediated inhibition through 
utilization of an alternative mechanism of receptor inhibition. Lapatinib, a dual epidermal 
growth factor receptor (EGFR)/HER2 oral TKI, has been shown to have increased 
activity in combination with trastuzumab compared to lapatinib alone, even when given 
to patients who have previously progressed on prior trastuzumab-based therapy 
(Blackwell 2010; Blackwell 2012).Use of lapatinib, however, has been limited by the 
anti-EGFR/human epidermal growth factor receptor 1 (HER1) activity of the drug, which 
results in toxicities such as rash, diarrhea, and fatigue. There is therefore a need for a 


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more selective small molecule inhibitor of HER2 that could be combined with other anti-
HER2 therapies to improve clinical outcomes.  
The current standard of care for patients with HER2+ metastatic disease consists of 
treatment with pertuzumab plus trastuzumab and a taxane as first-line treatment for 
metastatic disease, followed by T-DM1 in second line (Giordano 2014). Treatment 
options for patients who progress after treatment with both pertuzumab and T-DM1 
remain relatively limited. Patients are generally treated with a continuation of anti-HER2 
therapy (in the form of trastuzumab or lapatinib) in combination with cytotoxic 
chemotherapy, such as capecitabine. Combined HER2 therapy with trastuzumab and 
lapatinib can also be considered. However, no single regimen is considered the standard 
of care in this setting and better options for these patients are needed. 
3.1.1 
Brain Metastases in HER2+ Breast Cancer 
Perhaps the greatest unmet medical need in the post-trastuzumab era is treatment and 
prevention of brain metastases. Recent data suggest that the incidence of first relapse 
occurring in the brain is increasing in patients who have received trastuzumab-based 
adjuvant therapy, (Clayton 2004) and approximately 30-50% of HER2+ patients with 
metastatic disease will develop brain metastases (Clayton 2004; Goldhirsch 2013; 
Pestalozzi 2013).The increasing prevalence of brain metastases in HER2+ breast cancer 
patients may be due to several factors. First, HER2+ breast cancer appears to display 
tropism for the brain. Second, with better control of non-CNS disease, patients may be 
living longer allowing brain metastases to become more of a critical clinical issue. 
Finally, the brain may represent a sanctuary site for HER2+ disease as large molecules, 
such as trastuzumab, do not penetrate the blood-brain barrier (Lin 2004). 
Treatment options for brain metastases are limited. There is no specific systemic 
treatment regimen approved for brain metastases, and treatment currently relies heavily 
on the use of local therapies such as whole brain radiation therapy (WBRT), stereotactic 
radiation (SRS), or surgery. Patients may also receive chemotherapy alone, or 
capecitabine and either lapatinib or trastuzumab, although brain response rates are 
generally modest (Ekenel 2007; Ramakrishna 2014). The development of HER2-targeted 
systemic therapies with clinical benefit in both brain and non-CNS sites of disease could 
lead to improved clinical outcomes, both by improving overall PFS and OS as well as by 
avoiding or delaying the use of radiation therapy and its associated toxicities, including 
neurocognitive impairment. 
 


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3.2 Tucatinib  
3.2.1 
Product Description and Mechanism of Action 
Tucatinib is an orally available, reversible HER2 small molecule tyrosine kinase inhibitor 
that is being developed as a novel treatment for HER2+ breast cancer. One of the key 
features of tucatinib is its potency and selectivity for HER2 compared to the closely 
related kinase EGFR. With a >1000 fold increase in potency for HER2 inhibition 
compared to EGFR, tucatinib has the potential to inhibit HER2 signaling while avoiding 
known EGFR-related side effects [e.g., severe skin rash and gastrointestinal (GI) 
toxicity]. This unique feature differentiates tucatinib from other HER2 inhibitors, 
including neratinib and lapatinib, which inhibit HER2 and EGFR with similar potency 
and have been associated with side effects associated with EGFR inhibition. 
3.2.2 
Nonclinical Studies  
A detailed description of nonclinical studies can be found in the Investigator’s Brochure 
(IB).  
3.2.3 
Clinical Studies 
See the IB for current data on all tucatinib studies. 
3.2.4 
Tucatinib in the Treatment of Brain Metastases 
Both Study ONT-380-004 (tucatinib + T-DM1) and Study ONT-380-005 (tucatinib + 
capecitabine, trastuzumab or capecitabine and trastuzumab) have enrolled patients with 
either previously treated stable brain metastases, untreated brain metastases, or previously 
treated and progressive brain metastases. Patients were considered evaluable for  
response in brain if they had brain lesions that had never been treated, or lesions that had 
clearly progressed after prior local therapy (either WBRT, SRS, or surgical resection). 
Patients were considered not evaluable for response in brain if they had a history of brain 
metastases which were previously treated with local therapy, but which were stable or 
decreased in size since local therapy. Response in brain was evaluated using a modified 
RECIST 1.1 criteria which assessed response by considering the unidimensional sum of 
the longest diameters of identified target brain metastases only, as well as considerations 
for neurological deterioration and steroid use. Refer to the Investigator’s Brochure for 
additional information. 
Tucatinib has demonstrated early signs of activity in brain metastases using multiple 
combinations, including combinations with either capecitabine and/or trastuzumab. In 
some patients, treatment resulted in radiographic tumor responses as well as prolonged 
stabilization of disease, even in patients with progressing brain metastases at the time of 
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3.3 Potential Risks, Benefits and Rationale for the Combination of 
Tucatinib with Capecitabine and Trastuzumab in a Phase 2 Study 
Overall, tucatinib has been associated with an acceptable safety profile and has 
demonstrated both single-agent and combination anti-tumor activity, including in patients 
with progression after multiple prior HER2-directed therapies, and in patients with either 
untreated or previously radiated brain metastases. The combination of tucatinib with 
capecitabine and trastuzumab in a Phase 1b study ONT-380-005 has demonstrated 
acceptable toxicity, with the majority of AEs Grade 1 or 2 in severity. Infrequent Grade 3 
or greater AEs and ALT/AST elevations not due to progressive disease have been 
reversible with interruption of dosing and/or dose reduction. 
Given the overall safety profile of tucatinib, and the signs of clinical activity seen in 
Phase 1 studies, the potential benefits of tucatinib outweigh the risks in patients with 
progressive, incurable, unresectable locally advanced or metastatic HER2+ breast cancer 
after prior treatment with standard of care first and second-line therapies. This study 
proposes to further evaluate the potential benefit of tucatinib by adding tucatinib or 
placebo to the combination of capecitabine and trastuzumab in a randomized, blinded 
trial. 
3.3.1 
Trastuzumab 
Trastuzumab is a humanized anti-HER2 antibody that binds to subdomain IV of the 
HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, 
stimulating antibody-dependent, cell-mediated cytotoxicity and inhibiting ligand-
independent HER2-mediated mitogenic signaling (Arteaga 2011). 
The clinical benefit of trastuzumab in women with metastatic breast cancer has been 
demonstrated in multiple clinical studies. One large open label randomized Phase 3 study 
(Slamon 2001), showed that, compared to chemotherapy alone, the addition of 
trastuzumab significantly increased PFS, ORR, median duration of response, and OS. 
Based on these data, trastuzumab was approved for use in HER2-overexpressing 
metastatic breast cancer (MBC) in combination with paclitaxel for first-line treatment and 
as a single agent for patients whose cancers progressed after prior chemotherapy for 
metastatic disease. 
Since this initial pivotal clinical trial, data have emerged demonstrating efficacy of 
trastuzumab in the metastatic setting combined with a variety of chemotherapeutic agents 
as well as other targeted HER2 agents. Data support the use of trastuzumab in multiple 
lines of treatment in the setting of metastatic disease, even after failure of first line 
regimens that included trastuzumab and a taxane (Giordano 2014). The value of 
continued use of trastuzumab was demonstrated in a randomized trial comparing 
capecitabine vs. capecitabine plus trastuzumab in patients who had progressed through a 
prior trastuzumab-containing regimen. Patients who received the combination 


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experienced superior PFS and OS compared to patients assigned to capecitabine alone 
(von Minckwitz 2009). In a randomized Phase 3 trial comparing lapatinib, an oral 
EGFR/HER2 TKI, with or without trastuzumab in patients with trastuzumab-refractory 
breast cancer, the combination was associated with a prolongation of PFS and OS, 
supporting the concept of dual HER2 blockade, even in the setting of progression on 
prior trastuzumab-containing regimens (Blackwell 2010; Blackwell 2012). 
3.3.2 
Capecitabine  
Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues 
to form fluorouracil which is the active moiety. Fluorouracil is a fluorinated pyrimidine 
antimetabolite that inhibits thymidylate synthetase, blocking the methylation of 
deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA 
synthesis.  
The clinical benefit of capecitabine in women with metastatic breast cancer has been 
demonstrated in multiple clinical studies. Use of capecitabine as monotherapy was 
evaluated in an open-label, single-arm trial in 162 patients with stage IV breast cancer 
(XELODA Prescribing Information, Genentech, Inc., May 2021). Capecitabine was given 
at 1250 mg/m2 BID for 2 weeks followed by a one week rest period. Among patients with 
measurable disease, there was a response rate of 18.5% (1 CR, 24 PRs, with a median 
time to progression of 90 days, and a median OS of 306 days). Lower doses, such as 1000 
mg/m2 PO BID, have been studied as monotherapy in metastatic breast cancer, and have 
shown comparable efficacy with less toxicity (Rossi 2007). Capecitabine has also been 
approved to be used in combination with the oral HER2/EGFR inhibitor lapatinib at a 
dose of 1000 mg/m2 PO BID based on the results of studies showing an increase in PFS 
by adding lapatinib to capecitabine when compared to capecitabine alone (TYKERB 
Prescribing Information, Novartis Pharmaceuticals Corp., Feb 2021). In addition, as 
mentioned above in Section 3.3.1, the addition of capecitabine to trastuzumab in patients 
who had previously progressed on trastuzumab showed an improvement in efficacy when 
compared to capecitabine alone. Treatment with capecitabine in combination with 
trastuzumab has also been shown to result in increased PFS when compared to 
capecitabine plus lapatinib. 
3.3.3 
Double-blind Phase Study Rationale  
Despite the marked improvements in PFS and OS with the introduction of new agents for 
the treatment of HER2+ breast cancer, patients with unresectable locally advanced or 
metastatic breast cancer are not cured with currently available therapy and represent an 
ongoing medical need. 
The standard of care for patients with HER2+ advanced disease currently consists of 
treatment with pertuzumab plus trastuzumab and a taxane as first-line therapy, followed 
by T-DM1 as second-line therapy (Blackwell 2012). After patients progress on these 


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therapies, there is no single preferred regimen that is considered standard of care; 
treatment generally consists of combining trastuzumab with either a second HER2-
targeted agent (lapatinib), or with a cytotoxic agent, such as the combination of 
trastuzumab and capecitabine. The median PFS and OS in patients receiving third-line 
therapy after prior pertuzumab and T-DM1 based regimens has not been established. 
However, in the TH3RESA study, in which patients received T-DM1 vs. physician’s 
choice (including trastuzumab and capecitabine) for progressive disease after prior 
treatment with trastuzumab- and lapatinib- based treatments, the median PFS for the 
physician’s choice arm was only 3.3 months. 
Based on the anti-tumor activity and safety observed to date, tucatinib in combination 
with capecitabine and trastuzumab has the potential to provide dual HER2 inhibition in 
the context of a cytotoxic agent. This three drug combination may lead to improved 
clinical outcomes for HER2+ breast cancer patients who have progressive disease 
following prior treatment with pertuzumab, trastuzumab, and T-DM1 compared to the 
combination of capecitabine and trastuzumab alone, potentially establishing a new 
standard of care for these patients and addressing an ongoing medical need.  
Early clinical data also indicate that tucatinib may have activity against brain metastases, 
particularly when combined with other agents, including capecitabine and trastuzumab. 
As discussed, up to 50% of patients with HER2+ metastatic breast cancer may develop 
brain metastases (Pestalozzi 2013). With no approved systemic therapies for treatment of 
HER2+ brain metastases, treatment options for these patients are limited. An effective 
HER2-directed systemic treatment that controls both in brain as well as non-brain 
metastases could help address a significant unmet medical need in the post-trastuzumab 
era. The combination of tucatinib with capecitabine and trastuzumab has the potential to 
meet this need and provide a new treatment option for these patients.  
The intent of this Phase 2 randomized, double-blinded trial is to determine if tucatinib 
provides additional benefit to the combination of capecitabine plus trastuzumab in 
patients with incurable, progressing, unresectable locally advanced or metastatic HER2+ 
breast cancer who have previously been treated with trastuzumab, pertuzumab, and T-
DM1. Control arm patients will be treated with a combination of capecitabine and 
trastuzumab, a combination recommended in this patient population for whom no single 
standard of care therapy exists (Giordano 2014). Patients with brain metastases may also 
be eligible as outlined in the CNS Inclusion/Exclusion Criteria (Sections 6.1 and 6.2).  
3.3.4 
Unblinded Phase Study Rationale  
Previously, the study sponsor, Seagen, performed the per-protocol primary analysis of 
this trial. At the time of the primary analysis, the trial met the primary endpoint of 
progression-free survival (PFS), showing that the addition of tucatinib was superior to 
trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease 


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progression or death (hazard ratio [HR]=0.54 [95% Confidence Interval [CI]: 0.42, 0.71]; 
p<0.00001). The trial also met the two key secondary endpoints at interim analysis. The 
tucatinib arm demonstrated an improvement in overall survival, with a 34 percent 
reduction in the risk of death (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048) compared to 
trastuzumab and capecitabine alone. For patients with brain metastases at baseline, the 
tucatinib arm also demonstrated superior PFS, with a 52 percent reduction in the risk of 
disease progression or death compared to those who received trastuzumab and 
capecitabine alone (HR=0.48 (95% CI: 0.34, 0.69); p<0.00001). Due to the statistically 
significant results, these interim analyses of OS and PFS in patients with brain metastases 
are considered the final analyses of these endpoints. 
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated 
with a manageable safety profile. The most frequent adverse events in the tucatinib arm 
included diarrhea, palmar-plantar erythrodysaesthesia syndrome (PPE), nausea, fatigue, 
and vomiting. Grade 3 or greater adverse events in the tucatinib arm compared to the 
control arm included diarrhea (12.9 vs. 8.6 percent), increased aspartate aminotransferase 
(AST) (4.5 vs. 0.5 percent), increased alanine aminotransferase (ALT) (5.4 vs. 0.5 
percent) and increased bilirubin (0.7 vs. 2.5 percent). There was no requirement for 
prophylactic antidiarrheals. Adverse events leading to discontinuations were infrequent in 
both the tucatinib arm and the control arm (5.7 and 3.0 percent). 
Based on these results, the Sponsor decided to unblind this trial and offer tucatinib to 
patients on the control arm. Protocol Version 11 established a new Unblinded Phase of 
the study, and presented study procedures for these 2 distinct phases: the Double-blind 
Phase and the Unblinded Phase.  
 


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4 
STUDY OBJECTIVES  
4.1 Double-blind Phase  
4.1.1 
Primary Objective 
• To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on PFS per RECIST 1.1 based on blinded independent central review 
(BICR) 
4.1.2 
Secondary Objectives 
• To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab in patients with brain metastases at baseline, defined as patients with 
a history of brain metastases, current brain metastases, or equivocal brain lesions 
at baseline, using RECIST 1.1 based on (BICR) 
• To assess the effects of tucatinib vs. placebo in combination with capecitabine 
and trastuzumab on OS 
• To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on PFS per RECIST 1.1 based on investigator assessment  
• To assess the effects of tucatinib vs. placebo in combination with capecitabine 
and trastuzumab on objective response rate (ORR) per RECIST 1.1 based on 
BICR and by the investigator 
• To assess the duration of response (DOR) of tucatinib in combination with 
capecitabine and trastuzumab per RECIST 1.1 based on BICR and by the 
investigator 
• To assess the clinical benefit rate (CBR) [stable disease (SD) or non-complete 
response (CR)/non-progressive disease (PD) for ≥ 6 months, or best response of 
CR or partial response (PR)] of tucatinib vs. placebo in combination with 
capecitabine and trastuzumab per RECIST 1.1 based on BICR and by the 
investigator 
• To assess health-related quality of life and health economics associated with 
tucatinib vs. placebo in combination with capecitabine and trastuzumab based on 
patient health status collected using the EQ-5D-5L instrument and health care 
resources utilized in patient care 
4.1.2.1 
Safety Objective 
• To assess the safety and tolerability of tucatinib in combination with capecitabine 
and trastuzumab 


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4.1.2.2 
Pharmacokinetic Objective 
• To evaluate the pharmacokinetics of tucatinib and metabolite ONT-993 when 
administered in combination with capecitabine and trastuzumab 
4.1.3 
Exploratory Objectives 
• To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab using RANO-BM based on BICR in patients with brain metastases at 
baseline  
• To identify potential biomarkers of response, including human epidermal growth 
factor receptor 2 (HER2) mutations and other mutations by DNA sequence 
analyses of ctDNA isolated from plasma samples 
• To assess the effect of tucatinib on progression in brain in patients with brain 
metastases at baseline 
4.2 Unblinded Phase  
• To assess the safety and tolerability of tucatinib in combination with capecitabine 
and trastuzumab 
• To assess PFS per RECIST 1.1 by investigator 
• To assess OS 
 


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5 
STUDY DESIGN 
5.1 Overview of Study Design 
Figure 5-1 
Double-blind Study Schematic 
 
a Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study 
closure. Patients with CNS progression may undergo local therapy to CNS lesions and continue on study 
treatment with approval from the medical monitor for clinical benefit. 
b Contrast CT, PET/CT (CT must be of diagnostic quality), and/or MRI, and brain contrast MRI scan at 
baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter until PD, initiation of a 
new therapy, withdrawal of consent, or study closure. Patients without brain metastases at baseline do not 
require brain contrast MRIs while on treatment. A brain contrast MRI is required at the 30-Day Follow-up 
Visit for all patients.  
c Assessment of overall survival and/or disease recurrence, as well as collection of information regarding 
any additional anti-cancer therapies administered after completion of study treatment. 
d. If study treatment is discontinued for reasons other than disease progression (per RECIST 1.1) or death, 
every reasonable effort will be made to obtain contrast CT, PET/CT and/or MRI, and contrast brain MRI 
(only in patients with known brain metastases) approximately every 9 weeks until disease progression (per 
RECIST 1.1), death, withdrawal of consent, or study closure. 
5.1.1 
Double-blind Phase 
In this phase, the study is a randomized, international, multi-center, double-blind study of 
tucatinib or placebo in combination with capecitabine and trastuzumab in patients with 
unresectable locally advanced or metastatic HER2+ breast cancer who have had prior 
treatment with trastuzumab, pertuzumab and T-DM1. After signing informed consent and 
meeting all eligibility criteria, patients will be randomized in a 2:1 ratio to receive 
tucatinib or placebo in combination with capecitabine and trastuzumab.  


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Randomization will be made using a dynamic hierarchical randomization schema. 
Stratification factors will include presence or history of treated or untreated brain 
metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative 
Oncology Group Performance Status (ECOG PS) (0 vs. 1), and region of world (US vs 
Canada vs Rest of World). Stratification for presence of brain metastases will be based 
upon medical history and investigator assessment of screening contrast brain MRI. 
Patients who have prior brain metastases (treated or untreated) or unequivocal presence 
of brain metastases on screening MRI will be considered a “Yes” for stratification 
purposes, and subsequent efficacy assessments. Patients with no prior history of brain 
metastases and lesions of equivocal significance on screening contrast brain MRI will 
also be considered a “Yes” for purposes of stratification and follow-up.  
Treatment will be administered in cycles of 21 days each. Tucatinib or placebo will be 
given PO BID. The tucatinib dose will be 300 mg. Capecitabine will be given at 
1000 mg/m2 PO BID on Days 1–14 of each 21-day cycle. Trastuzumab will be given as a 
loading dose of 8 mg/kg IV. In instances of subcutaneous trastuzumab use, a fixed dose 
of 600 mg is administered without a loading dose. Following an IV loading dose of 
trastuzumab, 6 mg/kg of trastuzumab is administered once every 21 days, except in 
specific circumstances where it may be given weekly to compensate for modifications in 
treatment schedule. Subcutaneous trastuzumab is given only once every three weeks as 
there is no allowance for weekly dosing. There is no ability to modify the trastuzumab 
dose when administered subcutaneously. Dose modifications of tucatinib or placebo and 
capecitabine will be allowed.  
Dose holding or discontinuation of tucatinib or placebo, capecitabine, and trastuzumab 
will also be allowed as needed for patient safety. Patients who discontinue either 
capecitabine or trastuzumab (but not both) may remain on study treatment. Patients who 
discontinue tucatinib or placebo, or both capecitabine and trastuzumab will not be 
allowed to remain on study treatment but will continue to be followed for efficacy 
assessments per protocol schedule.  
Treatment will continue until unacceptable toxicity, disease progression, withdrawal of 
consent, or study closure. In the absence of clear evidence of disease progression (per 
RECIST 1.1), development of CNS symptoms or radiographic changes thought to pose 
potential immediate risk to patient, all efforts should be made to continue treatment until 
unequivocal evidence of radiologic progression occurs, as defined in RECIST 1.1.  
After discontinuing study treatment, patients may receive further care as determined by 
their physician. No crossover from placebo to tucatinib will be allowed while patients are 
in this phase of the study. It is planned that patients will be followed for efficacy 
endpoints after treatment discontinuation until the protocol specified number of events 
(both PFS and OS) are observed or the primary and key secondary endpoints are met.  


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Tumor Response Assessments 
Contrast brain MRI will be performed at baseline in all patients regardless of prior history 
of brain metastases. Efficacy assessments will include measurement of all known sites of 
metastatic or locally advanced unresectable disease (including at a minimum the chest, 
abdomen, and pelvis) by high quality spiral contrast CT, PET/CT (if high quality CT scan 
included) and/or MRI scan as appropriate, as well as appropriate imaging of any other 
known sites of disease (e.g., skin lesion photography, bone imaging) at baseline, every 
6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat contrast brain 
MRI will be required on this same schedule only in those patients with prior history of 
brain metastases, brain metastases found at screening, or brain lesions of equivocal 
significance found at screening. Contrast brain MRI may also be performed in patients 
without known brain metastases if there is clinical suspicion of new brain lesions. 
Additional imaging such as nuclear medicine bone scan or other unscheduled scans may 
be performed at the discretion of the investigator. Treatment decisions will be made 
based upon investigator assessment of radiologic scans. All patients will undergo a repeat 
contrast MRI of the brain within 30 days of the end of treatment, unless a contrast MRI of 
the brain has already been performed within 30 days or there is prior documentation of 
progression in the brain on study. If study treatment is discontinued for reasons other than 
disease progression (per RECIST 1.1), patients will continue to be followed for 
progressive disease including submission of subsequent imaging so as to define PFS. All 
patients in the study will continue to be followed for OS after completion of study 
treatment. Patients who were randomized but did not receive treatment will also be 
followed for PFS and OS. 
For patients who undergo local therapy to brain metastases incidentally found on 
screening contrast brain MRI, and then continue onto study treatment, the performance of 
a repeat contrast MRI after completion of local therapy is as follows: For patients who 
receive brain radiotherapy during the screening period, the original baseline contrast 
brain MRI will serve as the baseline for comparison for further response assessments. For 
patients who undergo surgical resection of brain metastases during the screening period, a 
post-operative contrast brain MRI will serve as the baseline. Contrast brain MRIs should 
then be done per the protocol defined schedule of events even if all lesions in the brain 
receive local treatment after the screening MRI. However, treated lesions will not be 
considered as target lesions. Treatment changes which may mimic progression will be 
taken into account, and patients with possible “pseudo-progression” should continue on 
study until unequivocal evidence of radiographic or clinical progression is present. 
Safety Assessments 
Safety monitoring will be performed by the sponsor throughout the study on a blinded 
basis. Safety assessments including physical exam, collection of AEs, and laboratory 
assessments will be performed at a minimum of once every three weeks throughout study 


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treatment and 30 days after the last dose of study drugs. Laboratory assessments will be 
performed locally at sites. Cardiac ejection fraction will be assessed by MUGA scan or 
ECHO at screening and at least once every 12 weeks thereafter.  
During the Double-blind phase, an independent Data Monitoring Committee (DMC) will 
regularly review all relevant safety data including (but not limited to) deaths, 
discontinuations, dose reductions, AEs, serious adverse events (SAEs), and cases of 
progressive disease within 6 weeks of study entry (blinded and unblinded) as outlined in 
a separate DMC charter. Ad hoc meetings of the DMC may be held upon the request of 
the sponsor or DMC. During the Unblinded Phase, the monitoring responsibility of the 
independent DMC will be considered completed and no more DMC reviews will occur. 
Pharmacokinetics and Biomarker Assessments 
Pharmacokinetic assessments of tucatinib will be performed. Blood samples will also be 
taken for possible evaluation of potential biomarkers of response, including circulating 
tumor DNA (ctDNA). 
HEOR and QoL 
Health-related quality of life and health care economics will be assessed by use of the 
EQ-5D-5L quality of life instrument and collection of health care resource utilization 
data. 
5.1.2 
Unblinded Phase 
Based on the positive results of the per-protocol primary analysis of this trial, the Sponsor 
decided to unblind this trial and offer tucatinib to patients on the control arm. Protocol 
Version 11 established a new Unblinded Phase of the study, and presented study 
procedures for these 2 distinct phases: the Double-blind Phase and the Unblinded Phase.  
 


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Figure 5-2 
Unblinded Phase Study Schematic 
 
 


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With the implementation of protocol version 11, the double-blind phase of the study 
ended, and all patients were unblinded to their treatment assignment. 
● 
Patients who were randomized to the experimental arm (tucatinib + trastuzumab + 
capecitabine) and are receiving study treatment at the time of unblinding will 
continue on that treatment arm with a modified schedule of events beginning at 
the Day 1 of All Subsequent Cycles visit (See Section 8.2.9 and Appendix A.2). 
For these patients, the treatment cycle counting will continue from prior to the 
unblinding, and patients will continue study treatment at the same doses they were 
given in the double-blind phase of the study.  
● 
Patients who were randomized to the experimental arm (tucatinib + trastuzumab + 
capecitabine), ended study treatment and are in the long-term follow-up are not 
eligible for additional treatment on the experimental arm in this study and will 
remain in long-term follow-up. 
● 
Patients who were randomized to the control arm (placebo + trastuzumab + 
capecitabine) and are receiving study treatment at the time of unblinding may 
crossover to the experimental arm if crossover criteria are met. 
○ 
If the patient does not meet crossover criteria, the patient will continue 
trastuzumab + capecitabine therapy. At the start of the next scheduled 
cycle, the patient will continue trastuzumab + capecitabine therapy 
with a modified schedule of events beginning at the Day 1 of All 
Subsequent Cycles visit (See Section 8.2.9 and Appendix A.3). These 
patients will continue trastuzumab + capecitabine therapy at the same 
doses they were given in the double-blind phase of the study. 
● 
Patients who were randomized to the control arm (placebo + trastuzumab + 
capecitabine) and are in long-term follow-up at the time of unblinding may 
crossover to the experimental arm if crossover criteria are met. 
○ 
If the patient does not meet crossover criteria, the patient will remain 
in long-term follow-up  
Treatments Administered in the Unblinded Phase  
In the unblinded phase of the study, tucatinib will be given in combination with 
trastuzumab and capecitabine. Treatment will be administered in repeating 21-day cycles. 
● 
Patients randomized to the experimental arm will continue tucatinib + 
trastuzumab + capecitabine at the same doses they were given in the double-blind 
phase of the study, using a modified schedule of events as outlined in 
Appendix A.2.  
● 
Patients who were randomized to the control arm and meet crossover criteria will 
be given: 


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○ 
Tucatinib 300 mg orally twice daily (PO BID) every day (Days 1–21) 
of each 21-day cycle using a modified schedule of events as outlined 
in Appendix A.3.  
○ 
Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of 
each 21-day cycle. For patients who required dose reductions of 
capecitabine, capecitabine must be given at the same reduced dose 
most recently given in the double-blind phase of the study. 
○ 
The initial dose of trastuzumab will be given as a loading dose of 
8 mg/kg intravenously (IV), unless trastuzumab was administered 
within the prior 4 weeks, then the initial dose of trastuzumab will be 
administered at a dose of 6 mg/kg.  Each trastuzumab dose is given 
once every 21 days, except in specific circumstances where it may be 
given weekly to compensate for modifications in treatment schedule. 
Subcutaneous trastuzumab is given only once every three weeks as 
there is no allowance for weekly dosing. There is no ability to modify 
the trastuzumab dose when administered subcutaneously. 
Dose modifications of tucatinib and capecitabine will be allowed. Dose holding of 
tucatinib or dose holding and/or discontinuation of capecitabine and trastuzumab will 
also be allowed as needed for patient safety. Patients who discontinue either capecitabine 
or trastuzumab may remain on study treatment. In instances where capecitabine and 
trastuzumab have been discontinued, patients may remain on study treatment with 
tucatinib alone. Patients who discontinue tucatinib will not be allowed to remain on study 
treatment. Treatment will continue until unacceptable toxicity, disease progression, 
withdrawal of consent, or study closure. 
Screening for Crossover Criteria  
Patients who were randomized to the control arm who wish to crossover to receive 
tucatinib will undergo a crossover screening period of up to 28 days after signing the 
revised informed consent. During that time patients will also undergo contrast MRI brain 
scan imaging in addition to CT, PET/CT, or MRI imaging to include, at a minimum, the 
chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of 
disease (e.g., skin lesion photography, bone imaging) for an assessment of tumor burden. 
Based on this crossover screening imaging, new baseline RECIST lesions will be selected 
by the investigator. 
Cardiac ejection fraction will be assessed by MUGA and ECHO. If an MRI of the brain, 
systemic imaging for assessment of tumor burden (e.g., CT, PET/CT, or MRI), or cardiac 
imaging for assessment of ejection fraction have been performed while on the double-
blind phase of the study or as part of standard of care within the prior 6 weeks, those 
assessments can be used for crossover screening purposes. Blood samples for 


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hematology, chemistry, and liver function tests will be drawn. Pregnancy testing (except 
in men or in women of non-childbearing potential) will be performed within 7 days prior 
to start of crossover (tucatinib) treatment. 
Tumor Response Assessments 
The investigator will determine the frequency and method of tumor assessments 
performed for patient care decisions according to routine clinical practice, with a 
maximum interval of 12 weeks between tumor assessments. Investigators should 
continue to use RECIST 1.1 for tumor assessments and for patient care decisions. 
Safety Assessments 
Patients will be assessed throughout the study for safety. Safety assessments including 
physical exam and collection of AEs and laboratory abnormalities will be performed at a 
minimum of once every three weeks throughout study treatment and 30 days after the last 
dose of study drugs. Cardiac ejection fraction assessments should be continued to be 
assessed by MUGA scan or ECHO at least once every 12 weeks. Laboratory assessments 
will be performed locally.  
Assessments after Treatment Discontinuation 
A final routine, safety assessment including physical examination and laboratory 
assessments will be required approximately 30 days after discontinuation of study 
treatment. Patients will continue in long-term follow-up per the schedule of events as 
outlined in Appendix A.2 and in Appendix A.3, as appropriate. 
5.1.3 
Continuation on Study Treatment After CNS-Only Progression 
For patients in both the Double-blind and Unblinded Phases, patients may continue study 
treatment for clinical benefit after a PFS event in brain with medical monitor approval. 
If a patient is found to have radiographic progressive disease per RECIST 1.1 based on 
isolated progression in the CNS (including either parenchymal brain or dural metastases 
but not skull-based or leptomeningeal metastases) and does not have progression of 
disease outside the CNS, the patient may be eligible to continue on study drugs after 
completion of local treatment (radiotherapy or surgery) of the brain/dural metastases to 
allow for clinical benefit. Continuation of study treatment requires discussion with and 
documented approval from the study medical monitor and may continue until either 
systemic progression or a second isolated CNS progression. Because this approach 
approximates common practice off-study in this clinical scenario, the duration of 
treatment after the CNS-only progression will be analyzed as an exploratory objective. 
The patient will remain on the same treatment regimen that they were receiving prior to 
receipt of CNS-directed therapy, and may continue on study provided the following 
criteria are met and the patient continues to receive clinical benefit: 


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• The patient is not experiencing any worsening of cancer-related symptoms. 
Patients who are clinically deteriorating and unlikely to receive further benefit 
from continued treatment should discontinue study treatment. 
• The patient is tolerating study drug 
• Approval by the medical monitor 
• Patient has no evidence of unequivocal systemic progression 
• Patient has not had a previous isolated CNS progression on tucatinib while on 
study  
Study treatment may be held up to 6 weeks to allow local CNS therapy. Longer holds 
must be discussed and approved by the medical monitor. Oral study drugs 
(tucatinib/placebo and capecitabine) are to be held 1 week prior to planned CNS-directed 
therapy. The potential for radiosensitization with tucatinib is unknown. Capecitabine is a 
known radiation sensitizer and therefore needs to be held prior to CNS-directed 
radiotherapy. Trastuzumab has been shown not to potentiate radiation and therefore may 
continue as per protocol schedule during radiotherapy. Oral study drugs may be 
re-initiated 7 days or more after completion of SRS/SRT, 21-days or more after WBRT 
and 28-days or more after surgical resection. Plans for holding and re-initiating study 
drugs before and after local therapy will require discussion with, and documented 
approval from, the medical monitor.  
Following CNS-directed therapy for isolated CNS disease progression, RECIST 1.1 
criteria would continue to measure a CNS target lesion(s) if previously identified and 
used in the overall estimation of the sum of diameters measuring total disease burden. 
However, following treatment, measurement of the treated CNS target lesion(s) would 
use the immediate pre-CNS treatment measurement. If a subsequent decrease in the size 
of a treated CNS lesion post-treatment is seen, the immediate pre-CNS treatment longest 
diameter would be used for RECIST measurement. Should a treated CNS lesion enlarge 
following CNS-directed therapy that was identified as a target lesion, the new and larger 
longest diameter is to be used for RECIST measurement. 
For patients in the double-blind phase: because the primary endpoint of the study is PFS, 
every effort should be made to avoid radiation or surgery to target lesions in the brain in 
the absence of progressive disease by RECIST 1.1 unless clinically necessary in the 
opinion of the investigator. The rationale for this is that target lesions, once treated with 
local CNS therapy, cannot be adequately assessed for subsequent response to systemic 
therapy. Because of this, if a patient continues on assigned study therapy after local CNS 
treatment to a target lesion, special consideration must be given for evaluation of the 
treated target lesion and the impact on the overall RECIST 1.1. assessment.  


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5.2 Rationale for the Study Design 
5.2.1 
Rationale for the Patient Population 
Eligible patients for this study are those with progressive, unresectable locally advanced 
or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, 
pertuzumab, and T-DM1 (Freedman 2012; Cardoso 2014; Giordano 2014; Ramakrishna 
2014).There is currently no single standard of care therapy for these patients. Treatment 
options that do exist include continued use of a HER2-directed agent either in 
combination with a cytotoxic agent (e.g., trastuzumab and capecitabine, or vinorelbine, or 
lapatinib and capecitabine) or with a second HER2-directed agent (i.e., trastuzumab + 
lapatinib), with no currently available data to recommend one regimen over another. 
Treatment selection is generally based upon physician and patient preference (Giordano 
2014). There are currently limited published data reporting a median PFS or OS for 
pertuzumab and T-DM1 experienced patients who require further treatment. The most 
similar reference population from recent clinical studies may be the control arm of the 
TH3RESA trial, which evaluated T-DM1 vs. physician’s choice of therapy in patients 
receiving third-line treatment or beyond for metastatic HER2+ breast cancer. The median 
PFS in the physician’s choice control group was only 3.3 months. Given that, and the fact 
that none of these patients had yet been exposed to T-DM1, the actual PFS for patients 
receiving third-line therapy after current first- and second-line standard of care may be 
even shorter (Krop 2014). A well-tolerated regimen which could improve upon overall 
PFS and OS in patients who have failed current standard of care for metastatic disease 
would therefore help address an important unmet medical need. In the ongoing Phase 1b 
study ONT-380-005, tucatinib was associated with anti-tumor activity and an acceptable 
safety profile when combined with capecitabine and trastuzumab in T-DM1 and 
pertuzumab treated patients, and therefore may be able to meet this need (Wolff 2013). 
Certain patients with brain metastases are also eligible for this trial, including patients 
with untreated brain metastases not requiring immediate radiotherapy and patients with 
prior radiotherapy with stable to minimally progressive metastases. Treatment options for 
patients with HER2+ disease and brain metastases are currently limited, and there is no 
currently recommended systemic therapy (Ramakrishna 2014). Treatment modalities 
include radiation therapy (either WBRT, SRS or SRT) or surgery for selected patients. 
Radiation therapy can be associated with significant morbidity due to treatment-related 
injury. There is therefore a need for alternative treatment options. Systemic treatment 
options that have demonstrated some activity include single agent cytotoxic agents, 
including capecitabine, as well as combination treatment with capecitabine and lapatinib. 
However, the toxicity associated with these regimens can be substantial, particularly for 
the combination of capecitabine and lapatinib which has been associated with >50% rate 
of Grade 3 events (Verma 2012), and none of these systemic regimens have been 
approved for use in the setting of brain metastases. Data from Phase 1b combination 


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studies with tucatinib have shown clinical activity in patients with either untreated brain 
metastases or brain metastases progressing after prior radiation therapy. As there are 
currently no approved systemic therapies for patients with brain metastases from HER2+ 
MBC, this clinical scenario represents a significant unmet medical need. An effective 
systemic treatment with CNS activity could potentially improve overall PFS and OS for 
patients with brain metastases, as well as allow patients to delay exposure to radiation 
therapy and its associated negative neurologic toxicities. In addition, patients with 
progression after prior radiotherapy represent a particular unmet need, since additional 
treatment options are even more limited due to the increased risks of tissue necrosis from 
additional radiation to previously irradiated brain tissue. 
Patients with asymptomatic brain lesions found during screening not thought to need 
immediate local therapy are eligible for this study. These patients are being included as 
there are currently no data showing that early initiation of radiation therapy leads to 
improved OS, or that delay of initiation of radiation therapy until after a trial of systemic 
therapy has a negative impact on OS (Ramakrishna 2014).  
Patients with high-risk brain metastases, including those with lesions identified during 
screening that are thought to require immediate local therapy, those with rapidly 
progressing lesions, those requiring > 2mg dexamethasone or equivalent corticosteroid at 
the start of the study for control of neurologic symptoms, and those with larger untreated 
lesions, may be excluded from the trial. However, if these patients are amenable to 
immediate therapy with either surgery or radiation, they may undergo local CNS-directed 
therapy and then be eligible for the trial.  
For patients in the double-blind phase, the study DMC will be monitoring blinded and 
unblinded safety data in an ongoing fashion throughout the blinded phase of the study to 
ensure that patients with brain metastases are not put at excessive risk. 
To ensure that patients without true HER2 overexpression who are unlikely to benefit 
from HER2 directed therapy are excluded from this trial, HER2+ status will be confirmed 
using a centralized laboratory prior to patient randomization according to ASCO/CAP 
Guidelines (Gianni 2012). 
5.2.2 
Rationale for the Dose and Regimen 
All patients will receive a treatment backbone of capecitabine and trastuzumab, a 
combination recommended in current treatment guidelines in this patient population for 
whom no single standard of care therapy exists. In the CEREBEL study, patients treated 
with the combination of capecitabine plus trastuzumab were shown to have a 
significantly prolonged PFS when compared to capecitabine plus lapatinib, another 
common therapeutic option in this setting. The safety profile of capecitabine plus 
trastuzumab was also similar to capecitabine plus lapatinib, but with a lower incidence of 
diarrhea, nausea, rash, and hyperbilirubinemia. The use of the combination of 


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capecitabine and trastuzumab as the control treatment in this study also allows a 
randomized, double-blinded study design, thus minimizing bias and allowing a more 
accurate assessment of the contribution of tucatinib itself to clinical outcomes. 
The addition of tucatinib to both capecitabine and trastuzumab, which provides not only 
dual inhibition of HER2 but also combination with a cytotoxic agent, has the potential to 
further improve efficacy compared to available therapies for patients previously treated 
with approved first- and second-line regimens for metastatic disease. The addition of 
tucatinib to this backbone will provide dual HER2 inhibition through 2 different 
mechanisms of action. Dual blockade of HER2 has been shown in multiple settings to 
provide benefit over single agent blockade, even in the setting of previous progression on 
trastuzumab-containing regimens (Blackwell 2010; Baselga 2012b; Blackwell 2012; 
Gianni 2012). The addition of the small molecule HER2 inhibitor lapatinib to 
capecitabine has also been shown to be superior to capecitabine alone, even in the setting 
of previous progression on trastuzumab-containing regimens (Geyer 2006). Furthermore, 
the greater selectivity of tucatinib compared to other oral anti-HER2 agents offers the 
potential to provide HER2 blockade with fewer toxicities than currently available agents. 
Selection of the tucatinib dosing regimen for the current study was based upon the RP2D 
from the Phase 1b dose-escalation study of tucatinib in combination with capecitabine 
and trastuzumab in patients with advanced HER2+ breast carcinoma (ONT-380-005) that 
included pharmacokinetic analysis. The dose of trastuzumab is the full dose approved for 
single-agent use when administered on a q 21 day cycle. 
The dosing regimen of capecitabine to be used in both arms of this study is based on the 
dose used in the Phase 1b combination trial, ONT-380-005. That study used a 
capecitabine dose of 1000 mg/m2, the approved dose for combination therapy with 
lapatinib, an oral inhibitor of HER2/EGFR. The dose of capecitabine (1000 mg/m2) has 
also been shown to have similar efficacy to the single-agent approved dose of 
1250 mg/m2 BID when used as monotherapy, with less toxicity (Rossi 2007). For patients 
in the control arm who will be receiving capecitabine plus trastuzumab without tucatinib, 
this capecitabine dose is within the single agent RD range of 1000–1250 mg/m2 given in 
published guidelines (NCCN 2021). When given as a single agent, capecitabine at the 
lower dose of 1000 mg/m2 has been shown to have similar efficacy as well as higher 
overall dose intensity when compared to 1250 mg/m2 due to the frequent need for dose 
interruptions and dose reductions in patients started at the higher dose (Bajetta 2005; 
Pivot 2015). 
5.2.2.1 
Rationale for Regimen in Patients with Brain Metastases  
Patients with brain metastases have frequently been excluded from trials with systemic 
cancer therapies due to difficulties in imaging assessment in the brain and a lack of 
flexibility with regard to treatment discordant responses in CNS and non-CNS locations. 


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Perhaps as a result of this, no systemic therapies are currently approved for the treatment 
of brain metastases in patients with HER2+ MBC. However, effective systemic therapies 
are needed which could potentially delay the use of radiation or treat lesions which have 
progressed after radiation. Selected patients with brain metastases will therefore be 
eligible for this trial in order to assess the effectiveness of this study treatment on 
intracranial metastases. 
All patients in this study will receive capecitabine, an agent which is known to be active 
both as a single agent and in combination therapy in the CNS (Wang 2001; Ekenel 2007; 
Bachelot 2013). Capecitabine as a single agent is recommended as one option for the 
treatment of HER2+ brain metastases in ASCO Guidelines (Ramakrishna 2014). The 
addition of capecitabine has been shown to markedly improve the low CNS response 
rates of lapatinib alone in patients progressing on lapatinib monotherapy (Eisenhauer 
2009). In this study, trastuzumab will also be given in both treatment arms, which has 
been shown to improve control of systemic disease even after progression on prior 
trastuzumab (Park 2009; von Minckwitz 2009; Giordano 2014). No other approved 
HER2-directed agents, including lapatinib, have been shown to be superior to 
trastuzumab in combination with capecitabine in the treatment of or prevention of brain 
metastases (Larsen 2013; Pivot 2015). 
Because of the limited data set that is currently available for the use of tucatinib in the 
treatment of brain metastases, patients with high-risk brain metastases, such as those 
requiring high-dose corticosteroids at the time of study entry (> 2 mg/day of 
dexamethasone or an equivalent dose of corticosteroid) or those with poorly controlled 
generalized or complex partial seizures or symptomatic neurologic progression in patients 
with brain metastases notwithstanding CNS-directed therapy will be excluded from the 
study. However, high-risk patients who could benefit from immediate CNS-directed 
therapy, such as those who have untreated lesions in anatomically sensitive areas, may 
undergo surgery or radiation therapy after screening and then enter the study (7 or more 
days after SRS/SRT, 21 or more days after WBRT and 28 or more days after 
lesionectomy) if neurologically stable and on reduced dose of steroids as protocol 
specified.  
As noted in Section 3.2.4, there have been early signs of responses in brain and durable 
control of brain metastases in patients treated with tucatinib with capecitabine, 
trastuzumab, or capecitabine and trastuzumab in a Phase 1b study (Study ONT-380-005). 
For patients in the treatment arm of this study, tucatinib will be added to the active 
regimen of capecitabine and trastuzumab with the objective of evaluating the impact of 
tucatinib on the time and incidence of progression in brain as well as the rate and duration 
of response in brain.  
As there are often differences in response to systemic therapies in intracranial vs. 
extracranial locations due to differences in penetration, tumor heterogeneity, and other 


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factors, patients who have non-CNS disease control but with isolated brain progression 
are often given local therapy to the CNS with continuation of systemic therapy until non-
CNS progression. This allows the continuation of a therapy that is effective systemically 
while allowing control of brain metastases, and mirrors clinical practice and established 
guidelines (Park 2009; Ramakrishna 2014; NCCN 2021). In this trial, patients who have 
isolated CNS-only (brain or dura) progression on trial may be eligible to continue on 
study drugs for clinical benefit after undergoing local therapy to the CNS, as described in 
Section 5.1.3. For the analysis of overall PFS, these patients will be considered to have 
progressed at the time of initial CNS progression as outlined in Section 11.1.1.4.  
5.2.3 
Rationale for Efficacy Assessments 
Efficacy will be assessed looking at all sites of disease using RECIST 1.1 (Eisenhauer 
2009). The primary endpoint will be PFS, as assessed per BICR RECIST 1.1. The two 
key secondary endpoints, PFS in patients with baseline brain metastases assessed 
centrally using RECIST 1.1 and OS in the entire study population, will determine 
efficacy in the brain metastases subgroup and OS in all randomized patients. Exploratory 
endpoints of DOR, ORR, and time to brain progression will be bi-compartmental using 
RANO-BM as assessed by BICR. These criteria were published to standardize response 
and progression criteria for patients with brain metastases as well as non-CNS disease. 
Selected details regarding RECIST 1.1 are provided in Appendix B, and in the radiology 
study binder. To standardize efficacy assessments using the RECIST 1.1 criteria in this 
multi-center study, the primary endpoint of this study will be based on independent, 
blinded, centralized review. However, local response assessments will be used for patient 
management decisions to ensure that treatment decisions can be made in a timely manner. 
Results of centralized review will not be available to investigators for clinical decision-
making. 
For the Double-blind Phase of the study, efficacy assessments will be performed once 
every 6 weeks for the first 24 weeks on study, and then once every 9 weeks. These 
intervals are consistent with standard of care practice and schedule used in prior studies 
in similar populations (Verma 2012; Krop 2014).In addition, given the predicted duration 
of time on study for patients in both the treatment and control arms, this schedule will be 
adequate to measure any clinically meaningful treatment effect without increasing 
radiation exposure above what is anticipated from standard of care assessments. 
For the Unblinded Phase of the study, the investigator will determine the frequency and 
method of tumor assessments performed for patient care decisions according to routine 
clinical practice, with a maximum interval of 12 weeks between tumor assessments. 
 


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5.2.3.1 
Rationale for CNS Efficacy Assessments 
Contrast MRI of the brain will be performed at baseline for all patients. This is being 
performed to more thoroughly evaluate the activity of tucatinib in brain by establishing a 
baseline in all patients, even those with asymptomatic unsuspected brain metastases. 
Contrast brain MRIs during study treatment will only be performed in patients with 
documented brain metastases (historically or at screening) and in patients with brain 
lesions of equivocal significance in order to follow for effects of treatment and for 
possible progression and will be consistent in schedule with systemic imaging. Patients 
without a history of brain metastases and without evidence of brain metastases or brain 
lesions of equivocal significance at baseline will not undergo regular brain MRIs during 
study treatment, consistent with current recommendations for radiographic follow-up for 
these patients (Cardoso 2014; Ramakrishna 2014) and due to the low rate of development 
of brain metastases in patients without brain metastases at baseline during the expected 
time frame of this study treatment (Pivot 2015).  
During the Double-blind Phase of the study, an additional contrast MRI of brain will be 
performed in all patients once off study treatment to assess for the development of 
clinically silent brain metastases in both treatment and control groups. These additional 
MRIs in patients without brain metastases will expose patients to no additional radiation, 
and will help to more fully evaluate the effect of tucatinib on brain metastases in this 
patient population. 
Response in brain will also be assessed as an exploratory endpoint by BICR per the 
RANO-BM Criteria, which takes into account not only radiographic changes, but clinical 
status and the use of corticosteroids. The use of these criteria will allow a more rigorous 
look at the activity of tucatinib in the brain, where radiographic assessment has 
historically proven challenging. It will also allow for more accurate assessment of acute 
changes which can be seen in the brain after local therapy which can mimic progression 
but which do not constitute true disease progression, such as temporary edema after the 
use of radiation or surgery. 
5.2.4 
Rationale for PK Assessment Plan 
Pharmacokinetic assessments of trough levels of tucatinib and metabolite drug levels will 
be performed on Day 1 of Cycles 2-6 prior to administration of tucatinib or placebo, and 
peak level on Day 1 of Cycle 3 within 1–4 h after administration of tucatinib or placebo. 
Patients will be asked to take study drug at clinic on days of PK assessments. The sparse 
sampling of patients during the described study period will allow for the periodic 
assessment of the drug trough level at steady state on multiple occasions. The 
pharmacokinetics of the drug can be related to individual patient characteristics and 
variability in PK can also be assessed. Data from studies ONT-380-004 and 


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ONT-380-005 indicated that pharmacokinetics evaluation of capecitabine and 
trastuzumab is not warranted. 
PK assessments will not be performed during the Unblinded Portion of this study. 
5.2.5 
Rationale for Health Economics Assessments 
Health-related quality of life is an important outcome from both clinical and economic 
perspectives. A substantial body of literature supports the validity and reliability of the 
health questionnaire EQ-5D-5L instrument for assessing quality of life in a health 
economic assessment and is therefore the rationale for the use of this instrument in the 
current study. The objective is to compare improvements, deteriorations and stabilization 
in health-related quality of life in patients treated with the tucatinib vs. the placebo arm of 
this study.  
The quality of life instrument, the EQ-5D-5L, will be administered at Cycle 1 Day 1 prior 
to the start of treatment and every six weeks for 24 weeks, and then every nine weeks 
until disease progression, death, toxicity, withdrawal of consent or study closure. 
Additionally, a post-treatment assessment will occur approximately 30 days following 
end of treatment.  
To enable cost-effectiveness evaluations, detailed health care resource utilization 
information will be collected within the following categories (but not limited to): length 
of stay and length of procedures, hospitalizations/ED visits, planned and unplanned 
provider visits, medication, radiology, and other treatments/procedures. Within these 
categories, information will include planned and unplanned treatments, procedures, and 
planned and unplanned provider visits, and treatment of adverse events.  
Health economics assessments will not be performed during the Unblinded Portion of this 
study. 
5.2.6 
Rationale for Exploratory Endpoints 
5.2.6.1 
Biomarker Assessments  
Biomarker assessments may include the confirmation of HER2 status by ISH or FISH, 
and an exploratory assessment of HER2 mutations or other mutations as potential 
biomarkers of response. HER2 status will be verified by central laboratory analysis using 
ASCO/CAP guidelines. Next generation DNA sequence analysis may be performed to 
interrogate the mutation status of a panel of oncogenes and tumor suppressor genes that 
are associated with tumor growth, survival and resistance to targeted therapeutics. This 
assessment may enable the correlation of treatment outcome to either preexisting or 
acquired cancer gene mutations and may ultimately guide or refine patient selection 
strategies to better match tucatinib regimens with tumor genotype in the future. 


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5.3 Double-blind Phase Endpoints 
5.3.1 
Double-blind Phase Primary Endpoint 
• PFS, defined as the time from randomization to documented disease progression 
(as determined by BICR per RECIST 1.1), or death from any cause, whichever 
occurs first 
5.3.2 
Double-blind Phase Secondary Endpoints 
Efficacy 
Key Secondary Endpoints 
• PFS in patients with brain metastases at baseline using RECIST 1.1 based on 
BICR 
• OS  
Other Secondary Endpoints 
• PFS, defined as the time from randomization to investigator-assessed documented 
disease progression (per RECIST 1.1), or death from any cause, whichever occurs 
first 
• ORR (RECIST 1.1) as determined by BICR as well as the investigator 
• DOR (RECIST 1.1) as determined by BICR as well as the investigator 
• CBR (RECIST 1.1) as determined by BICR as well as the investigator 
Safety 
• Adverse events (AEs) 
• Clinical laboratory assessments 
• Vital signs and other relevant safety variables 
• Frequency of dose holding, dose reductions, and discontinuations of capecitabine 
• Frequency of dose holding, dose reductions, and discontinuations of tucatinib 
• Frequency of dose holding and discontinuations of trastuzumab 
Pharmacokinetics 
• Plasma concentrations of tucatinib and metabolite 
Heath Economics and Outcomes 
• Cumulative incidence of health resource utilization, including length of stay, 
hospitalizations, and ED visits 
• Health-related quality of life / health status using the EQ-5D-5L instrument 


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5.3.3 
Double-blind Phase Exploratory Endpoints 
• ORR in brain per RANO-BM as determined by BICR 
• Duration of response in brain per RANO-BM as determined by BICR 
• Time to brain progression in patients with brain metastases at baseline per 
RANO-BM as determined by BICR 
• Presence of HER2 mutations or other potential biomarkers of response 
5.4 Unblinded Phase Endpoints 
• Adverse events (AEs) 
• Clinical laboratory assessments 
• Vital signs and other relevant safety variables 
• Frequency of dose holding, dose reductions, and discontinuations of capecitabine 
• Frequency of dose holding, dose reductions, and discontinuations of tucatinib 
• Frequency of dose holding and discontinuations of trastuzumab 
• PFS per RECIST 1.1 as determined by investigator 
• OS  
5.5 Study Stopping Rules and Discontinuation Criteria 
Reasons for terminating the study may include but are not limited to the following: 
• The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to patients, either through a safety review by the sponsor or an 
independent safety assessment by the DMC.  
• Patient enrollment is unsatisfactory.  
5.6 End of Study 
An analysis of OS and PFS conducted approximately 2 years after the last patient was 
randomized to the study demonstrated that the OS benefit with tucatinib was maintained, 
and PFS per investigator assessment was consistent with the primary analysis (Curigliano 
2021). Moreover, the number of OS events observed exceeded the number required for 
the originally planned final analysis. These data will be included in an addendum to the 
clinical study report and no additional analyses are planned.  
Based on these data, the Sponsor will end the study and a last visit/contact will occur for 
patients who are still in the study. 


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5.7 Post-study Care 
At the time of study closure, patients will revert to physician care. When applicable, the 
Sponsor will assist with post-trial access to tucatinib. 
5.8 Minimization of Bias  
5.8.1 
Double-blind Phase Randomization 
Patients will be randomized in a 2:1 ratio to receive tucatinib or placebo in combination 
with capecitabine and trastuzumab by a dynamic hierarchical randomization scheme 
using an Interactive Response Technology (IRT) system. 
Randomization will be stratified by the following stratification factors:  
• Known history of treated or untreated brain metastases (yes/no);  
• ECOG PS (0, 1); and  
• Region of world (United States, Canada, Rest of World). 
The first stratification factor (i.e., known history of treated or untreated brain metastases) 
will be based upon investigator assessment of the screening contrast brain MRI as well as 
documented patient history. Patients with brain lesions of equivocal significance 
identified on screening MRI will be considered a “Yes” for stratification purposes.  
The employed dynamic hierarchical randomization scheme will include specifications for 
a biased-coin assignment when the imbalance at a given hierarchical level (overall 
treatment group balance, then treatment group balance within each of the listed 
stratification factors) has exceeded a specified threshold.  
Under no circumstances will patients who are randomized and treated be permitted to 
re-enroll for a second course of treatment. 
5.8.2 
Double-blind Phase Blinding  
This phase of the study will be double-blinded, and every attempt will be made to 
maintain the blind throughout the study. The investigator, study center personnel, clinical 
research organization staff, and sponsor personnel (except for pre-specified Safety 
personnel) will not have access to the randomization scheme during the study except in 
the case of an emergency. Safety data will be monitored by an independent DMC. 
Suspected unexpected serious adverse reactions (SUSARs) will be unblinded in 
accordance with local regulatory reporting requirements. 
5.8.3 
Double-blind Phase Unblinding 
As per local regulatory reporting requirements, the sponsor Safety Department will 
unblind the identity of study medication for any unexpected (as per the IB) SAEs that are 
considered to be related to the blinded study drug (tucatinib/placebo). All other sponsor 


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personnel will remain blinded. All such cases of safety unblinding require the approval of 
the medical monitor. Please see study binders for further detail regarding unblinding 
procedures. 
In the case of a concerning drug related safety event, it is recommended that the 
Investigator contact and consult with the Medical Monitor. In emergency situations the 
Investigator may break the treatment code immediately, or as quickly as possible if 
he/she finds it is in the best interest of the trial patient. The investigator has unrestricted 
and immediate access to break the treatment code through the IRT system. The 
investigator will not provide the sponsor with the results of the unblinding. In the event of 
any unblinding, the sponsor must be notified within one working day (if not involved in 
the unblinding decision). The patient must subsequently be discontinued from study 
treatment but must continue in the long-term follow-up period of the study.  
Unblinding for ongoing safety monitoring and risk/benefit assessment by the DMC, will 
be performed through an independent Data Coordinating Center (DCC) to ensure 
integrity of the study. 
At the time of the primary analysis for the primary endpoint (PFS), specific sponsor 
personnel will be unblinded, however sponsor personnel directly involved in the conduct 
of the study will remain blinded to individual subject treatment assignments 
(tucatinib/placebo) until the final analysis for the key secondary endpoint of PFSBM. 
5.9 Ethical Considerations 
Despite the advances that have been made, unresectable locally advanced or metastatic 
HER2+ breast cancer is incurable. The primary goals of treatment remain to extend life 
and palliate symptoms while preserving quality of life. At present, no single treatment 
regimen can be considered the global standard of care for treatment of locally advanced 
or metastatic HER2+ breast cancer after treatment with trastuzumab, pertuzumab, and 
T-DM1.  
As demonstrated in Phase 1 and 1b trials, tucatinib has shown activity in heavily 
pretreated patients with unresectable locally advanced or metastatic HER2+ breast cancer 
including those with brain metastases with a manageable safety profile and few EGFR-
like toxicities. All patients enrolled in this study will receive either tucatinib or placebo in 
combination with capecitabine and trastuzumab, a recommended regimen for treatment 
of patients who have progressed after prior treatment with pertuzumab and T-DM1 
combinations (4). Patients in the control arm, including patients with brain metastases, 
will receive an active recommended regimen for this clinical scenario.  
Previously, the study sponsor, Seagen, performed the per-protocol primary analysis of 
this trial. Based on the positive results of this analysis, the Sponsor decided to unblind 
this trial and offer tucatinib to patients on the control arm. 


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6 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1 Double-blind Phase Inclusion Criteria 
Patients must meet the following criteria to be eligible for the study: 
1. Have histologically confirmed HER2+ breast carcinoma, with HER2+ 
defined by ISH or FISH or IHC methodology  
a. Tissue blocks or slides must be submitted to confirm HER2 
positivity (using ISH or FISH) by a sponsor-designated central 
laboratory prior to randomization 
b. Centrally confirmed HER2 results (either IHC, ISH, or FISH) from a 
previous study can be used to determine eligibility for this study with 
approval from the sponsor 
2. Have received previous treatment with trastuzumab, pertuzumab, and T-
DM1 
3. Have progression of unresectable locally advanced or metastatic breast 
cancer after last systemic therapy (as confirmed by investigator), or be 
intolerant of last systemic therapy 
4. Have measurable or non-measurable disease assessable by RECIST 1.1 
5. Be at least 18 years of age at time of consent 
6. Have ECOG PS 0 or 1 
7. Have a life expectancy of at least 6 months, in the opinion of the 
investigator  
8. Have adequate hepatic function as defined by the following:  
a. Total bilirubin ≤1.5 X ULN, except for patients with known 
Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 
X ULN 
b. Transaminases AST/SGOT and ALT/SGPT ≤ 2.5 X ULN (≤ 5 X 
ULN if liver metastases are present)  
9. Have adequate baseline hematologic parameters as defined by: 
a. ANC ≥ 1.5 x 103/µL 
b. Platelet count ≥ 100 x 103/µL; patients with stable platelet count 
from 75-100 x 103/µL may be included with approval from medical 
monitor 
c. Hemoglobin ≥ 9 g/dL 


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d. In patients transfused before study entry, transfusion must be ≥ 14 
days prior to start of therapy to establish adequate hematologic 
parameters independent from transfusion support 
10. Have creatinine clearance ≥ 50 mL/min as calculated per institutional 
guidelines or, in patients ≤ 45 kg in weight, serum creatinine within 
institutional normal limits 
11. INR and aPTT ≤ 1.5 X ULN unless on medication known to alter INR and 
aPTT. (Note: Warfarin and other coumarin derivatives are prohibited.) 
12. Have LVEF ≥ 50% as assessed by ECHO or MUGA scan documented 
within 4 weeks prior to first dose of study treatment  
13. If female of childbearing potential, must have a negative result of serum or 
urine pregnancy test performed within 7 days prior to first dose of study 
treatment. A woman is considered of childbearing potential, i.e. fertile, 
following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical 
cause. Postmenopausal patients with known β-HCG secreting tumors may 
be eligible when β HCG-based urine or serum pregnancy tests yield false 
positive if they meet the definition of postmenopausal state and have a 
negative uterine ultrasound. 
14. Women of childbearing potential (as defined above) and men with partners 
of childbearing potential must agree to use a highly effective birth control 
method, i.e. methods that achieve a failure rate of less than 1% per year 
when used consistently and correctly. Such methods include: combined 
(estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal); 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable); intrauterine device; intrauterine 
hormone-releasing system; bilateral tubal occlusion/ligation; vasectomized 
partner; or sexual abstinence. Male patients with partners of childbearing 
potential must use barrier contraception. All study patients should practice 
effective contraception, as described above, starting from the signing of 
informed consent until 7 months after the last dose of study medication or 
investigational medicinal product 
15. Patient must provide signed informed consent per a consent document that 
has been approved by an IRB/IEC prior to initiation of any study-related 


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tests or procedures that are not part of standard-of-care for the patient’s 
disease 
16. Patients must be willing and able to comply with study procedures 
CNS Inclusion – Based on screening contrast brain MRI, patients must have one of the 
following: 
17. No evidence of brain metastases 
18. Untreated brain metastases not needing immediate local therapy. For 
patients with untreated CNS lesions > 2.0 cm on screening contrast brain 
MRI, discussion with and approval from the medical monitor is required 
prior to enrollment 
19. Previously treated brain metastases 
a. Brain metastases previously treated with local therapy may either be 
stable since treatment or may have progressed since prior local CNS 
therapy, provided that there is no clinical indication for immediate 
re-treatment with local therapy in the opinion of the investigator 
b. Patients treated with CNS local therapy for newly identified lesions 
found on contrast brain MRI performed during screening for this 
study may be eligible to enroll if all of the following criteria are met: 
i. Time since WBRT is ≥ 21 days prior to first dose of 
treatment, time since SRS is ≥ 7 days prior to first dose of 
treatment, or time since surgical resection is ≥ 28 days  
ii. Other sites of disease assessable by RECIST 1.1 are present 
c. Relevant records of any CNS treatment must be available to allow 
for classification of target and non-target lesions  
6.2 Double-blind Phase Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Have previously been treated with: 
a. lapatinib within 12 months of starting study treatment (except in cases 
where lapatinib was given for ≤ 21 days and was discontinued for 
reasons other than disease progression or severe toxicity) 
b. neratinib, afatinib, or other investigational HER2/ EGFR or HER2 TKI 
at any time previously 
2. Have previously been treated with capecitabine (or other fluoropyrimidine 
[e.g., 5-fluorouracil]) for metastatic disease (except in cases where 


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capecitabine was given for ≤ 21 days and was discontinued for reasons other 
than disease progression or severe toxicity)  
Note: Patients who have received capecitabine for adjuvant or neoadjuvant 
treatment at least 12 months prior to starting study treatment are eligible 
3. History of exposure to the following cumulative doses of anthracyclines:  
a. Doxorubicin > 360 mg/m2  
b. Epirubicin > 720 mg/m2  
c. Mitoxantrone > 120 mg/m2  
d. Idarubicin > 90 mg/m2  
e. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2 
4. History of allergic reactions to trastuzumab, capecitabine, or compounds 
chemically or biologically similar to tucatinib, except for Grade 1 or 2 
infusion related reactions to trastuzumab that were successfully managed, or 
known allergy to one of the excipients in the study drugs 
5. Have received treatment with any systemic anti-cancer therapy (including 
hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of 
first dose of study treatment or are currently participating in another 
interventional clinical trial. An exception for the washout of hormonal 
therapies is GnRH agonists used for ovarian suppression in premenopausal 
women, which are permitted concomitant medications 
6. Have any toxicity related to prior cancer therapies that has not resolved to 
≤ Grade 1, with the following exceptions:  
• alopecia and neuropathy, which must have resolved to ≤ Grade 2; and  
• CHF, which must have been ≤ Grade 1 in severity at the time of 
occurrence, and must have resolved completely 
• anemia, which must have resolved to ≤ Grade 2 
7. Have clinically significant cardiopulmonary disease such as: 
• ventricular arrhythmia requiring therapy,  
• uncontrolled hypertension (defined as persistent systolic blood pressure 
> 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on 
antihypertensive medications), or  
• any history of symptomatic CHF 
• severe dyspnea at rest (CTCAE Grade 3 or above) due to complications 
of advanced malignancy  


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• hypoxia requiring supplementary oxygen therapy except when oxygen 
therapy is needed only for obstructive sleep apnea 
• presence of ≥ Grade 2 QTc prolongation on screening ECG  
• conditions potentially resulting in drug-induced prolongation of the QT 
interval or torsade de pointes 
a. Congenital or acquired long QT syndrome 
b. Family history of sudden death 
c. History of previous drug induced QT prolongation 
d. Current use of medications with known and accepted 
associated risk of QT prolongation (see row “Accepted 
Association” in Appendix H) 
8. Have known myocardial infarction or unstable angina within 6 months prior 
to first dose of study treatment 
9. Are known carriers of Hepatitis B or Hepatitis C or have other known 
chronic liver disease 
10. Are known to be positive for HIV 
11. Are pregnant, breastfeeding, or planning a pregnancy 
12. Require therapy with warfarin or other coumarin derivatives (non-coumarin 
anticoagulants are allowed) 
13. Have inability to swallow pills or significant gastrointestinal disease which 
would preclude the adequate oral absorption of medications 
14. Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the 
inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days 
prior to first dose of study treatment (see Appendix C and Appendix D) 
15. Have known dihydropyrimidine dehydrogenase deficiency 
16. Unable for any reason to undergo contrast MRI of the brain 
17. Have any other medical, social, or psychosocial factors that, in the opinion 
of the investigator, could impact safety or compliance with study procedures  
18. Have evidence within 2 years of the start of study treatment of another 
malignancy that required systemic treatment. 
CNS Exclusion – Based on screening brain MRI, patients must not have any of the 
following: 


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19. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical 
monitor and approval for enrollment is given 
20. Ongoing use of systemic corticosteroids for control of symptoms of brain 
metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). 
However, patients on a chronic stable dose of ≤ 2 mg total daily of 
dexamethasone (or equivalent) may be eligible with discussion and approval 
by the medical monitor 
21. Any brain lesion thought to require immediate local therapy, including (but 
not limited to) a lesion in an anatomic site where increase in size or possible 
treatment-related edema may pose risk to patient (e.g. brain stem lesions). 
Patients who undergo local treatment for such lesions identified by 
screening contrast brain MRI may still be eligible for the study based on 
criteria described under CNS inclusion criteria 19b 
22. Known or suspected LMD as documented by the investigator  
23. Have poorly controlled (> 1/week) generalized or complex partial seizures, 
or manifest neurologic progression due to brain metastases notwithstanding 
CNS-directed therapy  
6.3 Unblinded Phase Crossover Criteria  
6.3.1 
Crossover Inclusion Criteria 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) 
must meet the inclusion criteria below at the time of crossover screening to be eligible to 
crossover to the experimental arm. Prior scans and imaging may be used for crossover 
inclusion/exclusion criteria and tumor burden if these were collected within 6 weeks prior 
to the time of the patients signing the crossover consent for this Unblinded Phase of the 
study. 
1. Have measurable or non-measurable disease assessable by RECIST 1.1 
2. For patients who were randomized to the control arm and on the long-term 
follow-up period at the time of the crossover screening: have progression of 
unresectable locally advanced or metastatic breast cancer after last systemic 
therapy (as confirmed by investigator), or be intolerant of last systemic 
therapy 
3. Have ECOG PS 0 or 1 
4. Have a life expectancy of at least 6 months, in the opinion of the 
investigator  
5. Have adequate hepatic function as defined by:  


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a. Total bilirubin ≤1.5 X ULN, except for patients with known 
Gilbert’s disease, who may enroll if the conjugated bilirubin is 
≤1.5 X ULN 
b. Transaminases AST/SGOT and ALT/SGPT ≤ 2.5 X ULN 
(≤ 5 X ULN if liver metastases are present)  
6. Have adequate hematologic parameters as defined by: 
a. ANC ≥ 1.5 x 103/µL 
b. Platelet count ≥ 100 x 103/µL; patients with stable platelet count 
from 75-100 x 103/µL may be included with approval from medical 
monitor 
c. Hemoglobin ≥ 9 g/dL 
d. In patients transfused before crossover screening, transfusion must 
be ≥ 14 days prior to start of crossover treatment to establish 
adequate hematologic parameters independent from transfusion 
support 
7. Have creatinine clearance ≥ 50 mL/min as calculated per institutional 
guidelines or, in patients ≤ 45 kg in weight, serum creatinine within 
institutional normal limits 
8. Have LVEF ≥ 50% as assessed by ECHO or MUGA scan documented 
within 6 weeks prior to the time of crossover consent 
9. For patients 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 
starting crossover study treatment. A subject with a false positive 
result and documented verification that the patient is not pregnant is 
eligible for starting crossover study treatment. 
b. Must agree not to try to become pregnant during the study and for at 
least 7 months after the final dose of study drug administration 
c. Must agree not to breastfeed or donate ova, starting at time of 
informed consent and continuing through 7 months after the final 
dose of study drug administration 
d. If sexually active in a way that could lead to pregnancy, must 
consistently use highly effective methods of birth control (i.e., 
methods that achieve a failure rate of <1% per year when used 


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consistently and correctly) starting at the time of informed consent 
and continuing throughout the study and for at least 7 months after 
the final dose of study drug administration.  
Highly effective methods of birth control include: 
● 
Non-hormone releasing intrauterine device 
● 
Bilateral tubal occlusion/ligation 
● 
Vasectomized partner 
● 
Sexual abstinence when it is the preferred and usual lifestyle 
choice of the subject 
10. For patients 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 study drug administration 
b. If sexually active with a person of childbearing potential in a way 
that could lead to pregnancy, must consistently use a barrier method 
of birth control starting at time of informed consent and continuing 
throughout the study and for at least 7 months after the final dose of 
study drug administration 
c. If sexually active with a person who is pregnant or breastfeeding, 
must consistently use a barrier method of birth control starting at 
time of informed consent and continuing throughout the study and 
for at least 7 months after the final dose of study drug administration 
11. Patient must provide signed informed consent per a consent document that 
has been approved by an IRB/IEC prior to initiation of any study-related 
tests or procedures that are not part of standard-of-care for the patient’s 
disease 
12. Patients must be willing and able to comply with study procedures 
CNS Inclusion – Based on crossover screening contrast brain magnetic resonance 
imaging (MRI) within 6 weeks prior to the time of crossover consent, patients must have 
one of the following: 
13. No evidence of brain metastases 
14. Untreated brain metastases not needing immediate local therapy. For 
patients with untreated CNS lesions > 2.0 cm on screening contrast brain 
MRI, discussion with and approval from the medical monitor is required 
prior to enrollment 


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15. Previously treated brain metastases 
a. Brain metastases previously treated with local therapy may either be 
stable since treatment or may have progressed since prior local CNS 
therapy, provided that there is no clinical indication for immediate 
re-treatment with local therapy in the opinion of the investigator 
b. Patients treated with CNS local therapy for newly identified lesions 
found on contrast brain MRI performed during crossover screening 
for this study may be eligible to enroll if all of the following criteria 
are met: 
i. Time since whole brain radiation therapy (WBRT) is ≥ 21 
days prior to start of crossover (tucatinib) treatment, time 
since stereotactic radiosurgery (SRS) is ≥ 7 days prior to start 
of crossover (tucatinib) treatment, or time since surgical 
resection is ≥ 28 days prior to start of crossover (tucatinib) 
treatment 
ii. Other sites of disease assessable by RECIST 1.1 are present 
6.3.2 
Crossover Exclusion Criteria 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) 
will be excluded if they meet any of the exclusion criterion below. Prior scans and 
imaging may be used for crossover inclusion/exclusion criteria and tumor burden if these 
were collected within 6 weeks prior to the time of the patients signing the crossover 
consent for this Unblinded Phase of the study. 
1. Discontinuation of study treatment (placebo + trastuzumab + capecitabine) 
due to an adverse event while on the double-blind phase of the study. If the 
adverse event leading to discontinuation of study treatment has resolved, the 
patient may be allowed to crossover with approval from the medical 
monitor. 
2. History of exposure to the following cumulative doses of anthracyclines: 
a. Doxorubicin > 360 mg/m2  
b. Epirubicin > 720 mg/m2  
c. Mitoxantrone > 120 mg/m2  
d. Idarubicin > 90 mg/m2  
e. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2 
3. History of allergic reactions to trastuzumab, capecitabine, or compounds 
chemically or biologically similar to tucatinib, except for Grade 1 or 2 


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infusion related reactions to trastuzumab that were successfully managed, or 
known allergy to one of the excipients in the study drugs 
4. Have received treatment with any systemic anti-cancer therapy (including 
hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks 
prior to start of crossover (tucatinib) treatment or are currently participating 
in another interventional clinical trial. Ongoing treatment with trastuzumab 
+ capecitabine as part of this trial is not exclusionary. An exception for the 
washout of hormonal therapies is GnRH agonists used for ovarian 
suppression in premenopausal women, which are permitted concomitant 
medications 
5. Have any toxicity related to prior cancer therapies that has not resolved to ≤ 
Grade 1 (ongoing treatment with trastuzumab + capecitabine as part of this 
trial is not exclusionary), with the following exceptions:   
• alopecia and neuropathy, which must have resolved to ≤ Grade 2; and  
• CHF, which must have been ≤ Grade 1 in severity at the time of 
occurrence, and must have resolved completely 
• anemia, which must have resolved to ≤ Grade 2 
6. Have clinically significant cardiopulmonary disease such as: 
• ventricular arrhythmia requiring therapy,  
• uncontrolled hypertension as determined by investigator, 
• any history of symptomatic CHF 
• severe dyspnea at rest (CTCAE Grade 3 or above) due to complications 
of advanced malignancy, or  
• hypoxia requiring supplementary oxygen therapy except when oxygen 
therapy is needed only for obstructive sleep apnea 
7. Have known myocardial infarction or unstable angina within 6 months prior 
to start of crossover (tucatinib) treatment 
8. Are known carriers of Hepatitis B or Hepatitis C or have other known 
chronic liver disease 
9. Are known to be positive for HIV 
10. Are pregnant, breastfeeding, or planning a pregnancy 
11. Require therapy with warfarin or other coumarin derivatives (non-coumarin 
anticoagulants are allowed) 


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12. Have inability to swallow pills or significant gastrointestinal disease which 
would preclude the adequate oral absorption of medications 
13. Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or 
have used a CYP2C8 or CYP3A4 inducer within 5 day prior to start of 
crossover (tucatinib) treatment. Strong CYP2C8 inhibitors and CYP2C8 or 
CYP3A4 inducers are also prohibited in the 2 weeks following 
discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates 
should be avoided 2 weeks prior to start of crossover (tucatinib) treatment 
14. Have known dihydropyrimidine dehydrogenase deficiency 
15. Unable for any reason to undergo contrast MRI of the brain 
16. Have any other medical, social, or psychosocial factors that, in the opinion 
of the investigator, could impact safety or compliance with study procedures  
17. Have evidence within 2 years prior to start of crossover (tucatinib) treatment 
of another malignancy that required systemic treatment. 
CNS Exclusion – Based on crossover screening contrast brain MRI within 6 weeks prior 
to the time of crossover screening, patients must not have any of the following: 
18. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical 
monitor and approval for enrollment is given 
19. Ongoing use of systemic corticosteroids for control of symptoms of brain 
metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). 
However, patients on a chronic stable dose of ≤ 2 mg total daily of 
dexamethasone (or equivalent) may be eligible with discussion and approval 
by the medical monitor 
20. Any brain lesion thought to require immediate local therapy, including (but 
not limited to) a lesion in an anatomic site where increase in size or possible 
treatment-related edema may pose risk to patient (e.g. brain stem lesions). 
Patients who undergo local treatment for such lesions identified by 
crossover screening contrast brain MRI may still be eligible for the study 
based on criteria described under CNS inclusion criteria 15b 
21. Known or suspected LMD as documented by the investigator  
22. Have poorly controlled (> 1/week) generalized or complex partial seizures, 
or manifest neurologic progression due to brain metastases notwithstanding 
CNS-directed therapy 


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6.4 Criteria for Discontinuation of Study Treatment 
No randomized patients will be replaced, including patients who have not received study 
treatment. Reasons for patient withdrawal from study treatment may be due to any of the 
following: 
• AE 
• Progressive disease  
• Second disease progression after isolated progression in brain 
• Death 
• Withdrawal of consent 
• Lost to follow-up 
• Physician decision due to clinical progression 
• Physician decision (other) 
• Patient decision 
• Protocol violation 
• Study termination by sponsor 
• Pregnancy or begins breastfeeding while on trial 
• Other 
For both phases, the reason for withdrawal from study treatment must be recorded in the 
patient’s eCRF. Evaluations scheduled for the 30-Day Follow-up Visit and Long-Term 
Follow-up Visits will be completed, unless the patient withdraws consent from the study 
in writing. Patients also may choose to withdraw consent for procedures and visits but 
remain on study for PFS and OS follow-up through medical records, public records, or 
public platform.  
In the double-blinded phase of the study, patients should also be followed for progressive 
disease (per RECIST 1.1) at least until a PFS event has been observed. If an AE is the 
cause for withdrawal from study treatment, then “Adverse Event” should be recorded as 
the reason for treatment discontinuation rather than physician decision or patient 
decision. Treatment discontinuation due to AE should be noted any time that a patient has 
an AE such that the patient may not re-start tucatinib, either due to investigator discretion 
or due the requirements of dose modification described in Section 7.4 (e.g. requiring dose 
reduction to <150 mg BID tucatinib, holding tucatinib >6 weeks due to toxicity, or lack 
of resolution of AE to a sufficient grade to re-start tucatinib). Patients who discontinue 
tucatinib or placebo or both capecitabine and trastuzumab should be recorded as an 


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“adverse event” for the reason for treatment discontinuation if AE led to discontinuation 
of study drugs.  
In the double-blinded phase of the study, because the primary study endpoint is defined 
as PFS as determined by central radiologic assessment, every effort should be made to 
confirm disease progression (per RECIST 1.1) whenever possible. However, in instances 
where patients appear to have progressive symptoms and signs of metastatic breast cancer 
for whom it is not possible or feasible to undergo radiologic assessment, investigators 
may remove the patient from study treatment due to “physician decision due to clinical 
progression.” These patients will be censored in the final analysis of the primary 
endpoint, so use of this reason for removing such patients from study treatment should be 
restricted to those cases in which it is not clinically appropriate for the patient to undergo 
further radiologic assessment and where there is clinical confidence for cancer 
progression in the absence of radiographic confirmation. Special consideration should be 
given to ensure that other possible reasons, particularly AEs, are not a more accurate 
description of the reason for study drug discontinuation in these cases. 
For both phases, long-term follow-up after discontinuation of study treatment will 
continue until the patient completely withdraws from the study. Patients also may choose 
to withdraw consent for procedures and visits but remain on study for PFS and OS 
follow-up through medical records, public records, or public platform. Reasons for 
patient withdrawal from the study may be due to any of the following: 
• Death 
• Withdrawal of consent for follow-up 
• Lost to follow-up 
• Physician Decision 
• Study termination by sponsor 
• Other 


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7 
TREATMENTS ADMINISTERED 
Patients in the study will receive a combination treatment of capecitabine, trastuzumab, 
and either tucatinib or placebo. All treatments will be given on a 21-day cycle.  
7.1 Standard of Care Treatment 
Treatment with capecitabine and trastuzumab will be administered to all patients as 
standard of care therapy for their HER2+ locally advanced or metastatic breast cancer.  
7.1.1 
Capecitabine 
Capecitabine will be given at 1000 mg/m2 PO BID for Days 1-14 only of a 21-day cycle.  
As capecitabine is an oral drug available in fixed doses, the dose administered may not 
exactly match the calculated dose. Determination of the rounding of capecitabine doses 
for administration should be made according to local institutional practices, with 
documentation of both the calculated and administered dose. 
Capecitabine will be obtained as described in the pharmacy binder. 
Capecitabine should be prepared and administered per instructions in the package insert. 
Capecitabine will be administered orally based on instructions provided by the 
investigator. Per package insert, it is recommended that capecitabine be administered 
with food. Capecitabine should be stored according to the package insert. 
7.1.1.1 
Risks Associated with Capecitabine 
Risks associated with capecitabine include diarrhea, coagulopathy, cardiotoxicity, 
hand-and-foot syndrome (also known as PPE), hyperbilirubinemia, and hematologic 
toxicity. Please see the capecitabine (Xeloda®) SmPC or Package Insert/national 
prescribing information for more details. 
Management of capecitabine toxicities may require temporary interruption, dose 
reduction, or treatment discontinuation with capecitabine as per guidelines in Table 7-3. 
7.1.2 
Trastuzumab 
Intravenous 
Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once 
every 21 days. However, a loading dose of trastuzumab will not be given to patients who 
have received trastuzumab within 4 weeks of Cycle 1 Day 1. These patients will receive 
trastuzumab at 6 mg/kg each cycle, including Cycle 1. Trastuzumab may also be given on 
a weekly basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab 
infusion has been delayed, and weekly infusions are required to resynchronize the cycle 
length to 21 days, after discussion with the medical monitor. Trastuzumab infusion rates 
will be per institutional guidelines. If dosing of trastuzumab has been held for >4 weeks, 
the IV loading dose of 8 mg/kg should be given per approved dosing instructions. 


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Subcutaneous 
Alternatively trastuzumab may be administered as a subcutaneous dose, given as a fixed 
dose of 600 mg once every 3 weeks. Subcutaneous trastuzumab does not require a 
loading dose nor is a weekly schedule available for the subcutaneous formulation. 
Patients are permitted to crossover from IV trastuzumab to subcutaneous trastuzumab or 
from subcutaneous to IV trastuzumab.  
Biosimilar 
Approved trastuzumab biosimilars (intravenous or subcutaneous formulations) may be 
used in the study as either the initial therapy or at a later time if crossover to a biosimilar 
is determined appropriate by the investigator. However, a trastuzumab biosimilar may 
only be used during the study if approved for use by national regulatory authorities. 
General 
Trastuzumab will be obtained as described in the pharmacy binder.  
Trastuzumab should be prepared and administered per instructions in the package insert. 
Trastuzumab will be administered IV or subcutaneously under the direction of the 
investigator. Trastuzumab should be stored according to the package insert.  
7.1.2.1 
Risks Associated with Trastuzumab 
Risks associated with trastuzumab include fever, nausea, vomiting, infusion reactions, 
diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, 
anemia, myalgia, and CHF. Please see the Trastuzumab (Herceptin®) SmPC or Package 
Insert/national prescribing information for more details.  
Management of left ventricular dysfunction, pulmonary toxicity, or infusion reactions 
may require temporary interruption or treatment discontinuation of trastuzumab as per 
guidelines provided in the package insert as well as in Table 7-2 and Table 7-5. 
7.2 Tucatinib 
7.2.1 
Double-blind Phase Tucatinib and Placebo 
Patients will be randomized as described in Section 5.8.1 to receive either tucatinib 
300 mg PO BID or placebo tablets. The placebo tablets do not contain the active 
ingredient but are identical in appearance to active tablets to maintain blinding. 
Capecitabine and tucatinib/placebo may be taken together or in sequence. 
To minimize risks to patients, blinded safety data will be reviewed on an ongoing basis 
throughout the study by the sponsor and blinded and unblinded data will be reviewed at 
regular intervals or ad hoc as needed by an independent DMC. 


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7.2.2 
Unblinded Phase Tucatinib 
Patients will receive tucatinib 300 mg PO BID. Capecitabine and tucatinib may be taken 
together or in sequence. If the patient is currently receiving treatment on the control arm 
(placebo + trastuzumab + capecitabine), does not crossover and remains on trastuzumab 
and capecitabine treatment, placebo tablets do not need to be administered. 
To minimize risks to patients, safety data will be reviewed on an ongoing basis 
throughout the study by the sponsor. 
7.2.3 
Dosing Instructions 
Patients will be instructed to store and take the tucatinib/placebo treatment (as 
appropriate) as follows: 
• Bottles of tucatinib/placebo tablets should be stored in the refrigerator and should 
not be left in hot places (for example, in a car on a hot day). 
• Tucatinib/placebo tablets will be taken by mouth twice each day (one dose in the 
morning, and one dose in the evening).   
• Instructions will be given as to how many tablets to take each morning and each 
evening. All the prescribed number of tablets for morning and evening doses 
should be taken within a 10-minute timeframe. 
• It is recommended that tucatinib/placebo tablets be taken at the same times each 
day, ± 2 hours.  
• Tucatinib/Placebo doses should be ingested with a full 8 oz. glass of water, if 
possible. Doses may be taken either with or without food. 
• Tucatinib/Placebo bottle and all remaining pills should be brought to the clinic for 
each study visit. 
• It is important for us to know that a patient is receiving the correct amount of drug 
while participating on the study. If the patient was not able to take the fully 
prescribed dose or any single tablet of tucatinib/placebo as instructed on any day, 
the patient should contact the study coordinator with the reasons that the correct 
number of tablets or dose were not taken. Missed doses or tablets, or doses that 
are vomited, will not be replaced. 
7.2.4 
Risks Associated with Tucatinib alone and in Combination with 
Trastuzumab and Capecitabine  
Overall, tucatinib has been well tolerated in clinical trials to date (Section 3.2.3). The 
most frequent AEs seen with tucatinib have been mild to moderate in severity, and 
toxicities associated with dual EGFR/HER2 inhibitors such as Grade 3 diarrhea and rash 
have been uncommon.  
In the Phase 1 single-agent study of tucatinib (Study ARRAY 380-101), the most 
common AEs (reported in ≥ 20% of patients) were nausea, diarrhea, fatigue, vomiting, 


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rash, constipation, cough, and pain in extremity. Of these events, the majority were Grade 
1 in severity. Grade 3 TEAEs occurring in > 1 patient included anemia and cellulitis (6% 
each); and abdominal pain, hypokalemia, increased ALT, increased AST, 
musculoskeletal chest pain and vomiting (4% each).  
The most likely potential overlapping toxicities seen for the combination of tucatinib plus 
capecitabine and trastuzumab in this study include GI toxicity, such as nausea, 
constipation, and diarrhea, as well as elevation of liver function tests and fatigue. Refer to 
the Investigator’s Brochure for additional information.  
There have been rare reports of mild heart failure in patients taking tucatinib in 
combination with trastuzumab alone or with capecitabine as well as in combination with 
other cancer treatments.  
While interstitial lung disease (ILD) has not been reported with tucatinib, this event has 
been seen with other HER2-inhibitors, and therefore represents a potential risk.  
Patients will be closely monitored for occurrence of GI, cardiac function and liver 
toxicity. The specific safety plans for monitoring for cardiac toxicity and hepatotoxicity 
are outlined in Sections 9.4.3 and 9.4.4, respectively. In addition, patients will be closely 
monitored throughout the study for the occurrence of any other expected and/or 
unexpected toxicities. Patients will be allowed to use concomitant medication to manage 
GI and other symptoms, per treating physician discretion.  
Dose modifications and treatment interruptions of any of the study drugs will be allowed 
as described in Section 7.4. 
7.2.5 
Description of Active Ingredient 
Tucatinib is a potent, selective, adenosine triphosphate (ATP)-competitive small-
molecule inhibitor of the receptor tyrosine kinase HER2.  
Chemical Name: (N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-
(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine 
Tucatinib drug product is supplied as both a coated yellow oval-shaped tablet in a 150 mg 
dosage strength and a coated yellow round convex tablet in a 50 mg dosage strength for 
PO. The tablets are manufactured from a drug product intermediate 
 
of tucatinib in polyvinylpyrrolidine-vinyl acetate copolymer (PVP-VA), which is then 
combined with standard pharmaceutical excipients and compressed into tablets.  
7.2.6 
Packaging and Labeling 
Each bottle of study drug will be labeled in compliance with applicable regulatory 
requirements. 


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7.2.7 
Storage and Handling  
Bottles of tucatinib drug product (tablets) and placebo tablets are to be stored under 
refrigeration (2 to 8°C).  
7.3 Study Drug Accountability 
7.3.1 
Accountability of Tucatinib Tablets and Placebo 
Tucatinib or placebo used during the course of the study should be handled according to 
the sponsor’s instructions. Tucatinib and placebo are to be tracked and documented from 
the time of receipt at the site, through patient dosing, and until the sponsor approves of 
the final return or destruction. All supplies, including partially used or empty bottles, 
should be tracked.  
The sponsor or designee will conduct drug accountability monitoring during the course of 
the study and will conduct final drug accountability monitoring at site closure. All used 
and unused tucatinib and placebo bottles should be handled according to the sponsor’s 
instructions. 
7.3.2 
Accountability of Capecitabine and Trastuzumab 
Sites will also be required to provide accountability for administration of trastuzumab and 
for the use of capecitabine for entry into the eCRF. 
7.4 Dose Modifications 
Table 7-1 through Table 7-5 provide dose modification guidance for tucatinib or placebo, 
capecitabine, and trastuzumab. 
For the Double-blind Phase of this study, patients who discontinue either capecitabine or 
trastuzumab (but not both) may remain on study treatment. Patients who discontinue 
tucatinib or placebo, or both capecitabine and trastuzumab will not be allowed to remain 
on study treatment but will continue to be followed for efficacy assessments per protocol 
schedule. 
For the Double-blind Phase of this study, patients who continue capecitabine and/or 
trastuzumab after discontinuation of tucatinib/placebo in the absence of progression per 
RECIST 1.1 but who do not initiate additional new anti-cancer therapy, data related to 
administration of trastuzumab and/or capecitabine will continue to be collected. Patients 
will be considered to be no longer receiving study treatment after discontinuation of 
tucatinib/placebo. 
For the Unblinded Phase of this study, patients who discontinue either capecitabine or 
trastuzumab may remain on study treatment. In instances where capecitabine and 
trastuzumab have been discontinued, patients may remain on study treatment with 
tucatinib alone. Patients who discontinue tucatinib will not be allowed to remain on study 
treatment. 


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For both phases of this study, all AEs and laboratory abnormalities should be assessed by 
the investigator for relationship to tucatinib or placebo, capecitabine, and trastuzumab, as 
applicable. An AE may be considered related to tucatinib or placebo alone, capecitabine 
alone, trastuzumab alone, 2 of the 3 drugs, all 3 drugs, or to none. In the event that the 
relationship is unclear, discussion should be held with the medical monitor to discuss 
which study drug(s) should be held and/or modified. Dosing should be modified 
(including holding the dose, dose reduction, or discontinuation of drug) as described 
below.  
Any study drug should be discontinued if a delay of that drug greater than 6 weeks is 
required due to treatment-related toxicity, unless a longer delay is approved by the 
medical monitor.  
Protocol-defined visits and cycle numbering should continue as planned during a 21-day 
cycle even during dose holds or delays. 
Capecitabine should only be taken on Days 1 to 14 of a cycle. No doses should be given 
on Day 15 through Day 21 of a cycle. 
Dose reductions or treatment interruption/discontinuation for reasons other than those 
described below may be made by the investigator if it is deemed in the best interest of 
patient safety.  
Doses held for toxicity will not be replaced. 
Study treatment may be held up to 6 weeks to allow local CNS therapy. Oral study drugs 
(tucatinib/placebo and capecitabine) are to be held 1 week prior to planned CNS-directed 
therapy. The potential for radiosensitization with tucatinib is unknown. Capecitabine is a 
known radiation sensitizer and therefore needs to be held prior to CNS-directed 
radiotherapy. Trastuzumab has been shown not to potentiate radiation and therefore may 
continue as per protocol schedule during radiotherapy. Oral study drugs may be 
re-initiated 7 days or more after completion of SRS/SRT, 21-days or more after WBRT 
and 28-days or more after surgical resection. Plans for holding and re-initiating study 
drugs before and after local therapy will require discussion with, and documented 
approval from, the medical monitor. 
7.4.1 
Tucatinib or Placebo Dose Reductions 
Refer to Table 7-1 through Table 7-5 for the tucatinib or placebo dose modification 
requirements. Dose reductions larger than those required by these tables may be made at 
the discretion of the investigator. Up to 3 dose reductions of tucatinib or placebo are 
allowed, but dose reductions to below 150 mg BID are not allowed. Patients who, in the 
opinion of the investigator, would require a dose reduction to < 150 mg BID, or who 
would require a potential fourth dose reduction of tucatinib, should discontinue study 
treatment. 


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Tucatinib or placebo dose should not be re-escalated after a dose reduction is made. 
Table 7-1 Recommended Tucatinib or Placebo Dose Reduction Schedule 
Starting Dosea 
1st Dose Reduction 
2nd Dose Reduction 
3rd Dose Reduction 
300 mg PO BID 
250 mg PO BID 
200 mg PO BID 
150 mg PO BID 
a.  Dose reductions of greater steps than those listed in this table (i.e. more than 50 mg per dose reduction) may be 
made if considered clinically appropriate by the investigator. However, tucatinib or placebo may not be dose 
reduced below 150 mg BID. 
 
7.4.2 
Trastuzumab Dose Modifications 
There are no dose reductions for trastuzumab. Trastuzumab may also be given on a 
weekly basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab 
infusion has been delayed, and weekly infusions are required to resynchronize the cycle 
length to 21 days, after discussion with the medical monitor. The subcutaneous dose of 
trastuzumab (600 mg) cannot be modified as it is administered only once every 3 weeks. 
If trastuzumab cannot be restarted at the same dose after being held for an AE, it must be 
discontinued. If dosing of trastuzumab has been held for >4 weeks, the IV loading dose 
of 8 mg/kg should be given per approved dosing instructions or the 600 mg subcutaneous 
dose should be re-started. As trastuzumab may be given as an IV infusion, infusion-
associated reactions (IARs), may occur.  
If a significant IAR occurs, the infusion should be interrupted and appropriate medical 
therapies should be administered (see below). Permanent discontinuation should be 
considered in patients with severe IAR. This clinical assessment should be based on the 
severity of the preceding reaction and response to administered treatment for the adverse 
reaction. 
If patients develop an IAR, patients should be treated according to the following 
guidelines, or according to institutional guidelines, at discretion of the investigator: 
1. Stop infusion and notify physician. 
2. Assess vital signs. 
3. Administer acetaminophen 650 mg PO. 
4. Consider administration of: meperidine 50 mg IM, diphenhydramine 50 mg 
IV, ranitidine 50 mg IV or cimetidine 300 mg IV, dexamethasone 10 mg IV 
or famotidine 20 mg IV. 
5. If vital signs stable, resume trastuzumab infusion. 
No standard premedication is required for future treatments if patients have developed an 
infusion syndrome. Patients may be given acetaminophen prior to treatments. Serious 


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reactions have been treated with supportive therapy such as oxygen, beta-agonists, 
corticosteroids and withdrawal of study agent as indicated.  
Table 7-2 Dose Modifications of Tucatinib or Placebo and Trastuzumab for Clinical 
Adverse Events Other Than Left Ventricular Dysfunction Related to  
Trastuzumab, or Hepatocellular Toxicity* 
 
Tucatinib or Placebo 
Trastuzumab 
Clinical Adverse Event 
Related to tucatinib or Placebo 
Related to Trastuzumab 
≥ Grade 3 AEs other than Grade 
3 fatigue lasting ≤ 3 days; 
alopeciaa; nausea; vomiting; 
diarrhea; rash; correctable 
electrolyte abnormalities which 
return to ≤Grade 1 within 7 days. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 3 nausea, vomiting, or 
diarrhea WITHOUT optimal use 
of anti-emetics or anti-diarrheals. 
Hold until severity ≤ Grade 1 or 
pretreatment level. Initiate 
appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Grade 3 nausea, vomiting, or 
diarrhea WITH optimal use of 
anti-emetics or anti-diarrheals. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 4 nausea, vomiting, or 
diarrhea regardless of use of 
anti-emetics or anti-diarrheals. 
Do not administer until severity  
≤ Grade 1. 
Reduce to next lowest dose 
level. 
Do not administer until severity 
≤ Grade 1. Restart without dose 
reduction. 
Grade 3 rash WITHOUT optimal 
use of topical corticosteroids or 
anti-infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. Initiate 
appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Grade 3 rash WITH optimal use 
of topical corticosteroids or anti-
infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reduction. 
Grade 4 rash regardless of use of 
topical corticosteroids or anti-
infectives. 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart without dose reductions. 
a.  No dose modifications are required for alopecia 
*Note that if the AE in question does not recover to the Grade required for restarting study medication as outlined in 
the table, the patient may need to discontinue the drug completely. Patients requiring a hold of tucatinib for 
> 6 weeks must discontinue study treatment, unless a longer delay is approved by the medical monitor.  
7.4.3 
Capecitabine Dose Modifications 
Capecitabine doses must be modified as described below in Table 7-3. 
Capecitabine must be held for any patient who experiences a Grade 2 or greater AE 
considered related to capecitabine or to the combination of tucatinib or placebo and 
capecitabine and/or trastuzumab (attribution as determined by the investigator). Held 
doses of capecitabine should not be made up within each cycle.  


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Capecitabine dose should not be re-escalated after a dose reduction is made. 
Table 7-3 Dose Modification of Capecitabine for Clinical Adverse Events 
Considered Related to Capecitabine 
CTCAE Toxicity Grades 
During a Course of Therapy 
Dose Adjustment for Next 
Treatment (% of Starting Dose)a 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2b 
 
 
1st appearance 
Interrupt until resolved to Grade ≤ 1. 
100% 
2nd appearance 
Interrupt until resolved to Grade ≤ 1. 
75% 
3rd appearance 
Interrupt until resolved to Grade ≤ 1. 
50% 
4th appearance 
Discontinue permanently. 
NA 
Grade 3 
 
 
1st appearance 
Interrupt until resolved to Grade ≤ 1. 
75% 
2nd appearance 
Interrupt until resolved to Grade ≤ 1. 
50% 
3rd appearance 
Discontinue permanently. 
NA 
Grade 4 
 
 
1st appearance 
Discontinue permanently. 
 
Abbreviations: Common Terminology Criteria for Adverse Events (CTCAE); not applicable (NA). 
a.  Dose modification table is based upon XELODA® package insert; dose rounding should be performed per 
institutional guidelines 
b.  In certain instances of asymptomatic or mildly symptomatic Grade 2 laboratory abnormalities (for example, 
anemia), investigators may choose to maintain capecitabine dose level and/or to resume capecitabine prior to 
resolution to Grade 1.  This should be done only when the risk to patient from capecitabine dose interruption 
and/or reduction outweighs the risk to the patient from the adverse event, and when the action is consistent with 
usual and customary clinical practice.   
7.4.4 
Dose Modifications for Hepatotoxicity 
Dose modification may be required in the case of liver function abnormalities.  
For dose modifications of tucatinib or placebo and capecitabine, see Table 7-4 below. 
Dose modification of trastuzumab is not required but dosing can be held at investigator 
discretion. For patients with documented Gilbert’s disease, please contact the medical 
monitor for guidance regarding dose modifications in these patients. 


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Table 7-4 Dose Modifications of Tucatinib or Placebo and Capecitabine for Liver 
Function Abnormalities  
Liver Function Abnormalities 
Action for tucatinib or 
placebo, Regardless of 
Relationship to Drug 
Capecitabine 
Grade 2 elevation of ALT and/or AST  
(> 3 – ≤ 5 x ULN) 
Dose modification not required 
If abnormalities are 
considered related to 
capecitabine, please 
follow guidelines as 
per Table 7-3. 
If abnormalities are 
not considered 
related to 
capecitabine, 
modifications are 
not mandated but 
may be made at the 
discretion of the 
investigator. 
Grade 3 elevation of ALT and/or AST 
(> 5–20 x ULN) 
Hold until severity ≤ Grade1 
Restart at next lowest dose 
level 
Grade 4 elevation of ALT and/or AST 
(> 20 x ULN) 
Discontinue drug 
Elevation of ALT and/or AST (> 3 x ULN) 
AND 
Bilirubin (> 2 x ULN) 
Discontinue drug  
Grade 2 elevation of bilirubin (> 1.5–3 x ULN)  Hold until severity ≤ Grade 1 
Restart at same dose level 
Grade 3 elevation of bilirubin 
(> 3 – ≤ 10 x ULN)  
Hold until severity ≤ Grade 1 
Restart at next lowest dose 
level 
Grade 4 elevation of bilirubin (> 10 x ULN) 
Discontinue drug 
Abbreviations: alanine aminotransferase (ALT); aspartate aminotransferase (AST); upper limit of normal (ULN). 
 
7.4.5 
Trastuzumab Dose Modifications for Left Ventricular Dysfunction 
Trastuzumab dose modification guidelines, regardless of relationship, for left ventricular 
dysfunction are provided in Table 7-5. 
Table 7-5 Trastuzumab Dose Modifications for Left Ventricular Dysfunction 
LVEF at assessment 
Action 
LVEF ≥50%  
Continue treatment with trastuzumab  
LVEF 45% to <50% with <10% decrease from baseline  
Continue treatment with trastuzumab  
LVEF <45% or 45% to <50% with 10% decrease from 
baseline  
Hold trastuzumab, repeat LVEF in 3 
weeks 
 
Repeat LVEF at 3 weeks:  
 
 
 
- LVEF 50% 
Resume treatment with trastuzumab  
 
 
- LVEF 45% to 49% 
 
 
 
 
<10% decrease from baseline 
Resume treatment with trastuzumab  
 
 
 
10% decrease from baseline 
Discontinue trastuzumab  
 
 
- LVEF <45% 
Discontinue trastuzumab  
Symptomatic CHF 
Discontinue trastuzumab 
 
 


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7.5 Concomitant Therapy 
All concomitant medications will be recorded in the eCRF. Concomitant medications can 
be administered at the investigator’s discretion to conform to standard practice during the 
treatment period.  
Any planned surgery (major or minor) not directly related to cancer that occurs on study 
requires consultation with the sponsor medical monitor. Patients are required to suspend 
study treatment 3 to 7 days prior to surgery and depending upon the nature of the surgery 
resume study treatment 3 to 21 days postoperatively. For emergency surgeries, contact 
medical monitor as soon as feasible to discuss resumption of study treatment 
postoperatively. 
7.5.1 
Required Concomitant Therapy 
There are no required concomitant therapies. 
7.5.2 
Allowed Concomitant Therapy  
Patients may continue to use any ongoing medications not prohibited by the 
inclusion/exclusion criteria. However, efforts should be made to maintain stable doses of 
concomitant medications during the course of study treatment. 
• During study treatment, patients may receive supportive care to include 
bisphosphonates, denosumab, hematologic / anti-infectious support and pain 
management  
• Supportive care medications such as anti-diarrheals, anti-emetics, antacids, and 
laxatives are permitted. Prophylactic use of anti-diarrheals is not required but may 
be permitted at the discretion of the investigator 
• Use of topical 10% urea cream or other topical emollients are permitted for 
prophylaxis and treatment of PPE related to capecitabine use  
• Prophylactic and symptomatic treatment of nausea and vomiting may be used per 
standard of care  
• Thoracentesis or paracentesis may be performed, if needed for comfort 
• If surgery or localized radiation become indicated (either for palliation or down-
staging of previously nonresectable tumor), these concomitant procedures are 
permitted for non-target non-CNS lesions only in situations where other disease 
remains assessable by RECIST 1.1 (Appendix B). 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  


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• Acetaminophen may be used to manage drug-related AEs such as fever, myalgias 
or arthralgias and anti-histamines may be used to manage drug-related AEs such 
as pruritus 
• Routine prophylaxis with vaccines is permitted, if vaccines used do not contain 
live micro-organisms 
• Patients requiring systemic corticosteroids for control of brain metastases at a 
dose > 2 mg of dexamethasone (or equivalent) on the first day of study treatment 
are not eligible to begin study treatment, and should not be randomized until 
doses < 2 mg can be achieved. After initiation of study treatment, corticosteroids 
may be initiated for control of CNS symptoms only after consultation and 
approval of the medical monitor. Premedication with corticosteroids solely for 
contrast use in scans or MRI can be used without prior medical monitor approval. 
Patients requiring systemic steroids for control of other comorbidities (e.g., 
asthma or auto-immune diseases) may be eligible after consultation and approval 
of the medical monitor  
• Transfusion support with blood products. (However, note that no transfusions are 
permitted from <14 days prior to starting study treatment until the initiation of 
study treatment in order to establish adequate hematologic parameters for study 
eligibility independent of transfusion support) 
7.5.3 
Prohibited Concomitant Therapy  
The following therapies are prohibited during the study (unless otherwise noted): 
• Investigational drugs and devices 
• Anti-cancer therapy, including but not limited to chemotherapy and hormonal 
therapy 
• Radiation therapy, except for palliative radiotherapy at focal non-CNS sites which 
are not considered target lesions per RECIST 1.1, which may be given after 
consultation with the medical monitor, provided that there remain other sites of 
assessable disease accessible by RECIST 1.1 
• Warfarin or other coumarin derivatives (non-coumarin anti-coagulants are 
permitted) 
• Vaccination with live vaccines 
• Strong inhibitors or inducers of CYP2C8 are prohibited as concomitant 
medications during study treatment and within two weeks of discontinuation of 
tucatinib treatment – Partial and more complete lists of strong inhibitors and 
inducers may be found in other reference material. For additional information, 


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including drug elimination half-lives of strong inhibitors and inducers, see 
Appendix C 
• Strong inducers of CYP3A4 are prohibited as concomitant medications during 
study treatment and within two weeks of discontinuation of study treatment – 
Partial and more complete lists of strong inhibitors and inducers may be found in 
other reference material. For additional information including drug elimination 
half-lives of strong inhibitors and inducers, see Appendix D 
7.5.4 
Potential Concomitant Drug Interactions  
For sensitive substrates of CYP3A (see Appendix E); tucatinib exhibits inhibition of 
human CYP3A enzymes, and therefore has the potential to interact with other 
medications that are substrates of CYP3A. Therefore, concomitant use of tucatinib with 
sensitive CYP3A substrates should be avoided. Consider using an alternate medication 
which is not a sensitive CYP3A substrate. If unavoidable, consider dose reduction of 
CYP3A substrates with narrow therapeutic indices and/or increased monitoring for 
potential adverse reactions as described in the medication’s prescribing information.  
Concomitant use of tucatinib with digoxin, a P-gp substrate, increases digoxin 
concentrations, which may increase the risk for digoxin related adverse reactions (see 
Appendix G). 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. 
7.6 Treatment Compliance 
Compliance will be assessed on a patient-by-patient basis. The pharmacist or designee 
will record the number of tucatinib or placebo tablets dispensed to each individual 
patient, and the number of tablets returned to the clinic at the end of each cycle. Data 
regarding the administration and dose of trastuzumab, as well as the number of tablets of 
capecitabine taken will also be collected by the site after each cycle. Dose modifications 
and interruptions of any study drug will be documented in the source documents and the 
eCRF. 
7.7 Duration of Participation 
Patients will receive study treatments in repeating 21-day cycles. Patients may continue 
to receive study treatment until disease progression per RECIST 1.1 (except for patients 
with CNS-only progression who may continue on study treatment after initial CNS-only 
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7.7.1 
Follow-up After Discontinuation of Study Treatment 
Approximately 30 days after the last study treatment, a 30-Day Follow-up Visit will 
occur.  
In the Double-blind Phase of the study, a brain MRI is required for all patients at the 
30-Day Follow-up Visit, regardless of presence or absence of brain metastases on 
screening MRI, unless progression in the brain was previously documented while on 
study treatment. Additionally, all patients in the double-blind phase of the study for 
whom study treatment is discontinued for reasons other than confirmed disease 
progression (per RECIST 1.1) or death, every effort should be made to collect scans 
approximately every 9 weeks after the previous scan, until disease progression (per 
RECIST 1.1), death, study withdrawal, or study closure.  
Following the 30-Day Follow-up Visit, patients will be considered in the long-term 
follow-up portion of the study. Patients will be contacted at 90-day intervals until death, 
withdrawal of consent, or study closure. Patients will be contacted or have an in-person 
assessment of OS and/or disease recurrence, and collection of any additional anti-cancer 
therapies administered after completion of study treatment. Review of medical records, 
public records, or public platforms may be used to obtain this information if reasonable 
efforts for contact or in-person assessment are unsuccessful.  
 


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8 
TRIAL PROCEDURES 
8.1 Double-blind Phase 
The schedule of events is summarized in Appendix A.1. Study activities are listed by visit 
in this section and descriptions of study assessments are presented in Section 9. All 
assessments performed on Day 1 of all treatment cycles should be performed prior to 
administration of study drugs with the exception of AE documentation, concomitant 
medication documentation, and post-dose PK in Cycle 3 only. Study assessments will 
continue regardless of any dose holds or delays. 
8.1.1 
Screening/Baseline (Days -28 to 1) 
Optional prescreening to confirm HER2 positivity by central review is permitted at any 
time prior to study screening, after signing a separate pre-screening consent form. 
The following will be obtained or confirmed: 
• Informed consent* 
• Study eligibility per inclusion/exclusion criteria 
• Confirmatory central HER2+ testing, with biopsy showing HER2+ by ISH or 
FISH (or centrally confirmed HER2+ by ISH, FISH or 3+ staining by IHC in a 
previous study as approved by the medical monitor).*  
o Confirmatory HER2 testing may be obtained greater than 28 days prior to 
randomization if separate prescreening consent for confirmatory HER2 
testing is signed. 
• Documentation of concomitant medications 
• Documentation of baseline medical conditions 
• Documentation of disease history  
• Physical examination  
• Vital signs (height, weight, blood pressure, heart rate, temperature, and respiration 
rate) 
• ECG 
• ECHO, or MUGA to include at a minimum LVEF; note that whichever testing 
modality is chosen in screening should be used for all subsequent cardiac 
assessments throughout the study for comparison* 
• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function tests 
including all lab tests listed in Section 9.4.2 


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• Blood samples for coagulation panel that include all tests listed in Section 9.4.2 
• Blood samples for hepatitis screening: Hepatitis B surface antigen (HBsAg), 
antibodies to Hepatitis B core (anti-HBc), and antibodies to Hepatitis C 
(anti-HCV). (If positive, additional confirmatory testing may be required after 
discussion with medical monitor.)* 
• Blood sample for assessment of potential biomarkers of response* 
• Urine sample for urinalysis  
• For females of childbearing potential (have not had a hysterectomy and/or 
bilateral oophorectomy, or ≥ 12 months of amenorrhea) serum or urine pregnancy 
test within 7 days of first study treatment 
• Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as 
appropriate to document sites of extracranial disease and assessment of tumor 
burden. At minimum, scans must include chest, abdomen, and pelvis, as well as 
appropriate imaging of any other known sites of disease (e.g., skin lesion 
photography, bone imaging). 
• Contrast MRI of the brain for all patients for assessment of brain tumor burden; 
CT of the brain will not be allowed, and patients with known contraindications to 
undergoing contrast MRI imaging will be excluded from the study.* 
• For patients with brain metastases discovered during screening or a history of 
brain metastases, confirm relevant MRI brain reports and CNS treatment records 
can be obtained. 
• Documentation of AEs 
• Randomization MUST occur on or before Cycle 1 Day 1, such that dosing should 
commence within 5 days after randomization 
*For patients who have unsuspected brain metastases discovered at screening and go on 
to receive immediate local therapy to the CNS, certain screening evaluations may not 
need to be repeated outside the 28 day screening window with medical monitor approval. 
This includes the following: Informed consent, ECHO/MUGA, hepatitis screening, 
biomarker sampling, and confirmatory HER2 testing. All other safety labs and 
assessments will need to be repeated if outside the 28 day window for these patients. In 
addition, an additional contrast MRI brain following local therapy will not be required 
prior to starting study treatment if radiation treatment was given. A postoperative contrast 
MRI brain scan is required prior to starting study treatment if surgical resection was 
performed. 


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8.1.2 
Cycle 1 Day 1 
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination† 
• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS† 
• Blood samples for hematology and clinical chemistry (Results must be reviewed 
and eligibility confirmed prior to first dose)† 
• Blood samples for liver function tests (Results must be reviewed and eligibility 
confirmed prior to first dose)† 
• Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to dose administration) 
• Dispense tucatinib or placebo and administer the morning dose of tucatinib or 
placebo ‡  
• Administer morning dose of capecitabine at 1000 mg/m2‡  
• Administer trastuzumab at 8 mg/kg given IV, unless patient has received 
trastuzumab within 4 weeks of first dose of trastuzumab on study. In this case, 
patient will not receive loading dose, and will instead receive trastuzumab 
6 mg/kg. Alternatively, if subcutaneous trastuzumab is used (in countries where 
approved), 600 mg given as a fixed dose, once every 3 weeks.‡ 
†These assessments do not need to be repeated if performed within 96 hours of C1D1. 
‡Study drugs may be administered in any order and can be given simultaneously. 
8.1.3 
Cycle 1 Day 12 (± 3 days) 
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination  
• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS  
• Blood samples for hematology, clinical chemistry, and liver function tests 
8.1.4 
Cycle 2 Day 1 and Day 1 of All Subsequent Cycles (- 1 day to +3 
days) 
• Documentation of AEs 


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• Documentation of concomitant medications including review of number of day(s) 
anti-diarrheals were taken from previous cycle 
• Physical examination 
• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECG (through Cycle 4 only) 
• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function test 
• For females of child-bearing potential only: serum or urine pregnancy test for 
each cycle; a positive urine test must be confirmed with a serum pregnancy test 
prior to each cycle of therapy 
• Pre-tucatinib/placebo blood samples (up to 2 hours pre-dose) for PK analysis 
(through Cycle 6 only)  
• Post-tucatinib/placebo blood sample (1-4 hours) for PK Analysis (Cycle 3 only) 
• Completion of the EQ-5D-5L quality of life questionnaire (to be completed prior 
to dose administration) every 2 cycles regardless of treatment delays from Cycle 
3-9 and every 3 cycles starting at Cycle 12 
• Review tucatinib or placebo and capecitabine drug compliance from previous 
cycle and dispense tucatinib or placebo for next cycle‡ 
• Administer trastuzumab at 6 mg/kg IV or subcutaneously ‡ 
‡Study drugs may be administered in any order and can be given simultaneously 
8.1.5 
Cycle 2 Day 12 (± 3 days) 
• Blood samples for liver function tests (total bilirubin, AST and ALT) (may be 
obtained at a laboratory outside the clinical site if normal ranges are made 
available) 
8.1.6 
Every Six Weeks as Determined by Cycle 1 Day 1, Through Week 24 
(- 7 days) 
• Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as 
appropriate to document site of extracranial disease and assessment of tumor 
burden. At minimum, scans must include chest, abdomen, and pelvis, as well as 
appropriate imaging of any other known sites of disease (e.g., skin lesion 
photography, bone imaging) 
• Contrast MRI of the brain (only in patients with presence or history of brain 
metastases) and assessment of CNS lesions (brain or dura) 


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• If cycles are delayed for any reason continue with initial scan schedule as 
determined by the date of Cycle 1 Day 1 
• 
If an interim unscheduled assessment is performed, scans should continue to be 
done on schedule. In cases of medical contraindication for repeat scans, please 
contact the 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 
8.1.7 
Every 12 Weeks as Determined by Screening Exam (-7 days) 
• ECHO or MUGA, using the same cardiac testing modality performed in 
screening/baseline 
• If there is an interim assessment, subsequent cardiac ECHO or MUGA should be 
performed every 12 weeks as determined by the date of the most recent interim 
assessment  
8.1.8 
Beginning Week 24, Every 9 Weeks Through End of Treatment 
(- 7 Days) 
• Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as 
appropriate to document all known sites of disease and assessment of tumor 
burden. At minimum, scans must include chest, abdomen, and pelvis, as well as 
appropriate imaging of any other known sites of disease (e.g., skin lesion 
photography, bone imaging) 
• Contrast MRI of the brain (only in patients with presence or history of brain 
metastases) and assessment of CNS lesions (brain or dura) 
• If cycles are delayed for any reason, then perform scans every 9 weeks beginning 
Week 24 as determined by the date of Cycle 1 Day 1 
• If an interim unscheduled assessment is performed, scans should continue to be 
done on schedule. In cases of medical contraindication for repeat scans, please 
contact the 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 
8.1.9 
30-Day Follow-up Visit (30 days, + 7 days, after last dose of study 
treatment) 
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination  
• Vital signs 


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• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function tests 
• Blood sample for coagulation panel 
• Serum or urine pregnancy test; a positive urine test must be confirmed with a 
serum pregnancy test. (If not done within the last 60 days; not required for 
females of non-child-bearing potential) 
• Blood sample for biomarker analysis 
• Contrast CT, PET/CT (if high quality CT scan included) and/or non-brain MRI 
scan only in patients having ended study treatment for reasons other than 
radiographic disease progression. Imaging is to be performed within 30 days of 
ending study treatment. At minimum, contrast scans must include chest, abdomen, 
and pelvis, as well as appropriate imaging of any other known sites of disease 
(e.g., skin lesion photography, bone imaging) 
• Contrast MRI of the brain for all patients and assessment of CNS lesions (unless 
brain MRI performed within 30 days of ending study treatment or with prior 
documentation of progression in brain while on study) 
• ECHO or MUGA, as appropriate, if not done within previous 12 weeks 
• Completion of the EQ-5D-5L quality of life questionnaire 
8.1.10 Long-Term Follow-up  
• Starting 90 days (± 7 days) from the 30-Day Follow-Up Visit and continuing 
every 90 days (± 7 days) until death, withdrawal of consent, or study closure, the 
following must be performed.  If a 30-Day Follow-Up Visit was not done, the 
long-term follow-up should begin every 90 days (± 7 days) starting from the date 
of the last dose of study treatment.   
o Patient contact or in-person assessment of OS and/or disease recurrence, 
as well as collection of information regarding any additional anti-cancer 
therapies administered after completion of study treatment. Review of 
medical records, public records, or other public platforms may be used to 
obtain this information if reasonable efforts to contact patient are 
unsuccessful. 
o More frequent long-term follow-up may be conducted as needed for OS 
event tracking 
• If study treatment is discontinued for reasons other than disease progression 
(per RECIST 1.1) or death – Every 9 weeks (± 1 week) starting from the date of 
the last study treatment until disease progression (per RECIST 1.1), death, 


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withdrawal of consent, or study closure, in an effort to document a PFS event 
date: 
o Every effort should be made to collect contrast CT, PET/CT (if high 
quality CT scan included) and/or MRI scans (e.g., skin lesion 
photography, bone imaging). 
8.2 Unblinded Phase 
8.2.1 
Experimental Arm Continuing on Treatment 
At the time of unblinding, patients who were randomized to the experimental arm 
(tucatinib + trastuzumab + capecitabine) and are on study treatment will remain on that 
treatment arm. Starting with the next normally scheduled cycle, the patient will continue 
treatment with a modified schedule of events beginning at the Day 1 of All Subsequent 
Cycles visit (See Section 8.2.9 and Appendix A.2). Treatment cycle counting will 
continue from prior to the crossover, and patients will continue study treatment at the 
same doses they were given in the double-blind phase of the study. 
Study activities are listed by visit in this section and descriptions of study assessments are 
presented in Section 9. All assessments performed on Day 1 of all treatment cycles 
should be performed prior to administration of study drugs except for AE and 
concomitant medication documentation. Study assessments will continue regardless of 
any dose holds or delays. 
8.2.2 
Experimental Arm in the Long-term Follow-up 
Patients who were randomized to the experimental arm (tucatinib + trastuzumab + 
capecitabine), ended study treatment and are in the long-term follow-up are not eligible 
for additional treatment on the experimental arm in this study and will remain in long-
term follow-up. 
8.2.3 
Control Arm Continuing on Treatment or in Long-term Follow-up  
At the time of unblinding, patients who were randomized to the control arm (placebo + 
trastuzumab + capecitabine) may crossover to the experimental arm if crossover criteria 
are met (Section 8.2.4). Patients who crossover to the experimental arm will restart their 
cycle number as Cycle 1 at Cycle 1, Day 1, per Section 8.2.5, and Appendix A.3 
The schedule of events is summarized in Appendix A.3. Study activities are listed by visit 
in this section and descriptions of study assessments are presented in Section 9. All 
assessments performed on Day 1 of all treatment cycles should be performed prior to 
administration of study drugs except for AE and concomitant medication documentation. 
Study assessments will continue regardless of any dose holds or delays. 


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8.2.3.1 
Control Arm Patients who do not meet Crossover Criteria  
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) 
and were receiving study treatment at the time of unblinding who do not meet crossover 
criteria will continue trastuzumab + capecitabine therapy. At the start of the next 
scheduled cycle, the patient will continue trastuzumab + capecitabine therapy with a 
modified schedule of events beginning at the Day 1 of All Subsequent Cycles visit (See 
Section 8.2.9 and Appendix A.3). These patients will continue trastuzumab + 
capecitabine therapy at the same doses they were given in the double-blind phase of the 
study. 
Patients who were randomized to the control arm (placebo + trastuzumab + capecitabine) 
and are in long-term follow-up at the time of unblinding who do not meet crossover 
criteria will remain in long-term follow-up. 
8.2.4 
Screening for Crossover Criteria  
There will be a crossover screening period of up to 28 days after patients sign revised 
informed consent. Patients currently receiving treatment on the control arm (placebo + 
trastuzumab + capecitabine) will continue to receive study treatment during this 
crossover screening period at the same doses they were given in the double-blind phase 
of the study. 
During crossover screening period, the following will be obtained or confirmed: 
• Sign Revised Informed Consent 
• Documentation of AEs 
• Document crossover eligibility 
• Document newly developed baseline medical conditions since discontinuation of 
control arm treatment (for patients who were in long-term follow-up at the time of 
unblinding)  
• Document recent disease history (for patients who were in long-term follow-up at 
the time of unblinding), specifically all anti-cancer treatment regimens, 
radiation/surgery for disease since entering long-term follow-up 
• Documentation of concomitant medications 
• Physical examination  
• Vital signs (height, weight, blood pressure, heart rate, temperature, and respiration 
rate) 
• ECG 


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• ECHO or MUGA, as appropriate, if not done within 6 weeks prior to the time of 
crossover consent * 
• ECOG PS 
• Laboratory assessments for hematology, clinical chemistry, and liver function 
tests, including all lab tests listed in Section 9.4.2 
• For females of childbearing potential (have not had a hysterectomy and/or 
bilateral oophorectomy, or ≥ 12 months of amenorrhea) serum or urine pregnancy 
test within 7 days prior to start of crossover (tucatinib) treatment 
• Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as 
appropriate to document sites of extracranial disease and assessment of tumor 
burden, if not done within 6 weeks prior to the time of crossover consent. At 
minimum, scans must include chest, abdomen, and pelvis, as well as appropriate 
imaging of any other known sites of disease (e.g., skin lesion photography, bone 
imaging) 
o New baseline RECIST lesions will be selected based on the results of 
these assessments of tumor burden 
• Contrast MRI of the brain for all patients for assessment of brain tumor burden, if 
not done within previous 6 weeks; CT of the brain will not be allowed, and 
patients with known contraindications to undergoing contrast MRI imaging will 
be excluded from the study.* 
*For patients who have unsuspected brain metastases discovered at crossover screening 
and go on to receive immediate local therapy to the CNS, certain screening evaluations 
may not need to be repeated outside the 28-day screening window with medical monitor 
approval. This includes the following: Informed consent and ECHO/MUGA. All other 
safety labs and assessments will need to be repeated if outside the 28-day window for 
these patients. In addition, an additional contrast MRI brain following local therapy will 
not be required prior to starting study treatment if radiation treatment was given. A 
postoperative contrast MRI brain scan is required prior to starting study treatment if 
surgical resection was performed. 
8.2.5 
Crossover to the Experimental Arm, Cycle 1 Day 1 
For patients who were receiving study treatment at the time of unblinding, the Cycle 1, 
Day 1 crossover visit should be scheduled to synch with the patients’ current cycle, 
occurring at the next Day 1.  
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination† 


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• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS† 
• Blood samples for hematology and clinical chemistry (Results must be reviewed 
and eligibility confirmed prior to start of crossover [tucatinib] treatment)† 
• Blood samples for liver function tests (Results must be reviewed and eligibility 
confirmed prior to start of crossover [tucatinib] treatment)† 
• Dispense tucatinib and administer the first dose of tucatinib ‡  
• Administer the first dose of capecitabine ‡  
o Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of each 
21-day cycle. For patients who required dose reductions of capecitabine, 
capecitabine must be given at the same reduced dose most recently given 
in the double-blind phase of the study. 
• Administer loading dose of trastuzumab at 8 mg/kg given IV, unless patient has 
received trastuzumab within 4 weeks. In this case, patient will not receive loading 
dose, and will instead receive trastuzumab 6 mg/kg. Alternatively, if 
subcutaneous trastuzumab is used (in countries where approved), 600 mg given as 
a fixed dose, once every 3 weeks‡ 
†These assessments do not need to be repeated if performed within the previous 96 hours. 
‡Study drugs may be administered in any order and can be given simultaneously. 
8.2.6 
Crossover to the Experimental Arm, Cycle 1 Day 12 (± 3 days) 
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination  
• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS  
• Blood samples for hematology, clinical chemistry, and liver function tests 
(samples may be collected up to 2 days prior to this visit) 
8.2.7 
Crossover to the Experimental Arm, Cycle 2 Day 1 (- 1 day to +3 
days) 
• Documentation of AEs 
• Documentation of concomitant medications including review of number of day(s) 
anti-diarrheals were taken from previous cycle 
• Physical examination 


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• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function test (samples 
may be collected up to 2 days prior to this visit) 
• For females of child-bearing potential only: serum or urine pregnancy test for 
each cycle; a positive urine test must be confirmed with a serum pregnancy test 
prior to each cycle of therapy 
• Review tucatinib and capecitabine drug compliance from previous cycle and 
dispense tucatinib for next cycle‡ 
• Administer trastuzumab at 6 mg/kg IV or subcutaneously ‡ 
‡Study drugs may be administered in any order and can be given simultaneously 
8.2.8 
Crossover to the Experimental Arm, Cycle 2 Day 12 (± 3 days) 
• Blood samples for liver function tests (total bilirubin, AST and ALT) and serum 
creatinine (may be obtained at a laboratory outside the clinical site if normal 
ranges are made available) 
8.2.9 
Day 1 of All Subsequent Cycles (- 1 day to +3 days) 
At the first visit after unblinding, patients who were randomized to the experimental arm 
[tucatinib + trastuzumab + capecitabine] and are continuing treatment must sign the 
revised informed consent.  
The remainder of this section applies to all patients who are continuing to receive study 
treatments in the Unblinded Phase.  
• Documentation of AEs 
• Documentation of concomitant medications including review of number of day(s) 
anti-diarrheals were taken from previous cycle 
• Physical examination 
• Vital signs (weight, blood pressure, heart rate, temperature, and respiration rate) 
• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function test (samples 
may be collected up to 2 days prior to this visit) 
• For females of child-bearing potential only: serum or urine pregnancy test for 
each cycle; a positive urine test must be confirmed with a serum pregnancy test 
prior to each cycle of therapy 


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• Review tucatinib and capecitabine drug compliance from previous cycle and 
dispense tucatinib for next cycle‡ 
• Administer trastuzumab at 6 mg/kg IV or subcutaneously ‡ 
‡Study drugs may be administered in any order and can be given simultaneously 
8.2.10 Every 12 Weeks as Determined by Crossover Screening Exam or 
Most Recent Exam (-7 days) 
This section applies to all patients who are continuing to receive study treatments in the 
Unblinded Phase 
• ECHO or MUGA, using the same cardiac testing modality performed in 
screening/baseline 
• If there is an interim assessment, subsequent cardiac ECHO or MUGA should be 
performed every 12 weeks as determined by the date of the most recent interim 
assessment  
8.2.11 Tumor Assessments after Crossover Screening Through End of 
Treatment  
This section applies to all patients who are continuing to receive study treatments in the 
Unblinded Phase 
The investigator will determine the frequency and method of tumor assessments 
performed for patient care decisions according to routine clinical practice, with a 
maximum interval of 12 weeks between tumor assessments. Investigators should 
continue to use RECIST 1.1 for tumor assessments and for patient care decisions. 
• Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as 
appropriate to document all known sites of disease and assessment of tumor 
burden at intervals as per standard clinical practice as determined by the 
investigator 
• Contrast MRI of the brain, if appropriate, at intervals as per standard clinical 
practice as determined by the investigator 
8.2.12 After Last Dose of Study Treatment - 30-Day Follow-up Visit 
(30 days, + 7 days) 
• Documentation of AEs 
• Documentation of concomitant medications 
• Physical examination  
• Vital signs 
• ECHO or MUGA, as appropriate, if not done within previous 12 weeks 


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• ECOG PS 
• Blood samples for hematology, clinical chemistry, and liver function tests 
• Serum or urine pregnancy test; a positive urine test must be confirmed with a 
serum pregnancy test. (If not done within the last 60 days; not required for 
females of non-child-bearing potential) 
8.2.13 Long-Term Follow-up  
• Starting 90 days (± 7 days) from the 30-day Follow-Up Visit and continuing 
every 90 days (± 7 days) until death, withdrawal of consent, or study closure, the 
following must be performed. If a 30-day Follow-Up Visit was not done, the 
long-term follow-up should begin every 90 days (± 7 days) starting from the date 
of the last dose of study treatment.   
o Patient contact or in-person assessment of survival status and/or disease 
recurrence, as well as collection of information regarding any additional 
anti-cancer therapies administered after completion of study treatment. 
Review of medical records, public records, or other public platforms may 
be used to obtain this information if reasonable efforts to contact patient 
are unsuccessful. 
o More frequent long-term follow-up may be conducted as needed for OS 
event tracking 
 


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9 
STUDY ASSESSMENTS 
9.1 Efficacy Assessments 
9.1.1 
Double-blind Phase 
Following initiation of study treatment, measurement of all known sites of metastatic or 
locally advanced unresectable disease (including at a minimum the chest, abdomen, and 
pelvis) by high quality spiral contrast CT, PET/CT (if high quality CT scan included) 
and/or contrast MRI scan as appropriate, as well as appropriate imaging of any other 
known sites of disease (e.g., skin lesion photography, bone imaging) will be obtained at 
the end of every 6 weeks for 24 weeks, then every 9 weeks while on study treatment.  
These scans will remain on this schedule irrespective of dose interruptions. Additional 
imaging, such as nuclear bone scans, may be done as appropriate at the discretion of the 
investigator. All body contrast CT or MRI scans, bone imaging, and skin lesion 
photographs, including baseline scans and scans done during long-term follow-up will be 
collected for retrospective BICR. All treatment decisions will be made on the basis of 
local investigator assessment. Results of centralized review will not be available to 
investigators for clinical decision making. If study treatment is discontinued for reasons 
other than disease progression (per RECIST 1.1) or death, patients will continue to have 
long-term follow-up for disease progression and every effort should be made to collect 
scans and clinical data approximately every 9 weeks until disease progression or other 
criteria for patient withdrawal from the study are met in an effort to document a PFS 
event date.  
All brain contrast MRI images will be performed locally and collected prospectively for 
centralized independent review. However, all treatment decisions will be made on the 
basis of local review of radiologic imaging. Patients with any history of brain metastases, 
any brain metastases at baseline, or brain lesions of equivocal significance at baseline 
will continue to have follow-up brain contrast MRIs on the same schedule as non-CNS 
disease re-staging. In patients with baseline brain lesions, at least one brain lesion should 
be included in the baseline RECIST lesion selection as either a target or non-target lesion. 
Patients without brain metastases at baseline will not require follow-up brain contrast 
MRIs while on treatment unless clinically indicated, but will be asked to have an 
additional brain contrast MRI at the 30-Day Follow-up Visit, unless a brain contrast MRI 
has been performed within 30 days or the reason for going off treatment was progression 
in the brain. If study treatment is discontinued for reasons other than disease progression 
(per RECIST 1.1) or death, patients will continue to have long-term follow-up for disease 
progression and every effort should be made to collect scans and clinical data 
approximately every 9 weeks until disease progression or other criteria for patient 
withdrawal from the study are met in an effort to document a PFS event date. Brain 
contrast MRIs will be used to determine the incidence and time to progression in brain, as 
well as the brain response rate.  


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In the event of equivocal progression for example a new lesion ≤ 5 mm in maximum 
diameter (defined as an equivocal new lesion) and no imminent threat to patient safety, 
all efforts should be made to continue the patient until unequivocal radiologic progression 
or clinical progression is documented. An unequivocal new lesion is defined as any new 
lesion > 5 mm in maximum diameter, as defined in the response assessment manual. 
Demonstration of an unequivocal new lesion constitutes disease progression.  
All scans will be assessed per RECIST 1.1. Refer to Appendix B and study binder for 
further details.  
9.1.2 
Unblinded Phase 
Patients in the unblinded phase of the study will have the frequency and method of tumor 
assessments done according to routine clinical practice as determined by the investigator 
with a maximum interval of 12 weeks between tumor assessments. Investigators should 
continue to use RECIST 1.1 for tumor assessments and for patient care decisions.  
9.2 Health Economic Assessments 
9.2.1 
Double-blind Phase 
A quality of life assessment using the EQ-5D-5L questionnaire is to be completed at 
Cycle 1 Day 1 prior to the start of treatment then every 2 cycles regardless of treatment 
delays from Cycle 3-9 and every 3 cycles starting at Cycle 12. Additionally, a post-
treatment assessment will occur approximately 30 days post-end of treatment. Detailed 
medical resource utilization data are captured in the eCRF. 
9.2.2 
Unblinded Phase 
Health economic assessments will not be performed in the unblinded phase of the study. 
9.3 Pharmacokinetic Assessments 
9.3.1 
Double-blind Phase 
The steady state PK of tucatinib and its metabolite will be assessed through the sparse 
sampling of the peak and trough levels from Cycle 2 to Cycle 6. PK assessment of trough 
levels will be performed on all patients on Day 1 of Cycles 2–6 prior to drug 
administration and peak level assessment will be on Cycle 3 Day 1 within 1-4 h after 
drug administration. PK samples should continue to be collected on schedule regardless 
of dose holds or interruptions. 
Table 9-1 Pharmacokinetic Sampling 
Cycle 
Day 
Time point 
Tucatinib Sampling 
2 
1 
0 h (-2 h) prior to administration of tucatinib/placebo 
1 x 5 mL 
3 
1 
0 h (-2 h) prior to administration of tucatinib/placebo 
1 x 5 mL 
1 – 4 h following administration of tucatinib/placebo 
1 x 5 mL 
4-6 
1 
0 h (-2 h) prior to administration of tucatinib/placebo 
1 x 5 mL 


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9.3.2 
Unblinded Phase 
Pharmacokinetic and biomarker assessments of tucatinib will not be performed in the 
unblinded phase of the study. 
9.4 Safety Assessments 
Safety assessments will consist of monitoring and recording AEs and SAEs; physical 
examination and vital signs; and measurement of protocol-specified clinical laboratory 
tests, and either ECHO or MUGA scans deemed critical to the safety evaluation of the 
study drug(s). Clinically significant changes in these parameters may be captured as AEs.  
The investigator is responsible for the appropriate medical care and the safety of patients 
who have entered this study. The investigator must document all AEs and notify the 
sponsor of any SAE experienced by patients who have entered this study. Contact 
information for the sponsor’s medical expert is provided on the protocol cover page. 
9.4.1 
Data Monitoring Committee 
9.4.1.1 
Double-blind Phase  
The independent DMC will be responsible for monitoring the safety of patients in the 
study at regular intervals. The DMC will look at blinded and unblinded data including 
deaths, discontinuations, dose reductions, AEs, and SAEs on a regular basis. The DMC 
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. A separate DMC Charter will outline the committee’s 
composition, members’ roles and responsibilities, and describe DMC procedures. 
Sponsor will provide a copy of each DMC recommendation to the investigators.  
9.4.1.2 
Unblinded Phase 
The monitoring responsibility of the independent DMC will be considered completed and 
no more DMC reviews will occur. 
9.4.2 
Clinical Laboratory Evaluation 
All safety labs will be analyzed by the site’s local laboratory(ies). A central laboratory 
will be used for confirmatory HER2 testing during pre-screening and screening in the 
double-blind phase. Repeat confirmatory HER2 testing will not be required for the 
unblinded phase. 
The chemistry panel is to include the following tests: calcium, magnesium, inorganic 
phosphorus, total protein, albumin, blood urea nitrogen (BUN), creatinine, bicarbonate, 
glucose, potassium, chloride, and sodium. 
Liver function tests (LFT) are to include the following: AST/SGOT, ALT/SGPT, total 
bilirubin, and alkaline phosphatase. 


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The hematology panel is to include the following tests: complete blood count (CBC) with 
differential, hemoglobin, hematocrit (Hct), and platelets. 
9.4.3 
Safety Plan for Cardiotoxicity 
Trastuzumab and other HER2-targeted therapies are known to increase the risk of the 
development of asymptomatic and symptomatic declines in LVEF. There have been rare 
reports of asymptomatic left ventricular ejection fraction decline in patients taking 
tucatinib in combination with trastuzumab alone or with capecitabine. Cardiac function 
will therefore be monitored closely.  
Patients will be closely monitored throughout the study for the occurrence of any other 
expected and/or unexpected toxicities. Assessment of cardiac ejection fraction will be 
performed by MUGA or ECHO at screening and at least once every 12 weeks thereafter 
until study discontinuation, and 30 days after the last treatment dose (unless done within 
12 weeks prior to 30-day follow-up visit).  
9.4.4 
Safety Plan for Hepatotoxicity 
While not among the most common adverse reactions reported in patients taking 
tucatinib, Grade 3 and 4 elevation of LFTs have been seen in some patients on tucatinib 
studies. Monitoring of liver function tests is required for any patient taking tucatinib. 
Refer to the Investigator’s Brochure for additional information on LFT elevations. 
Patients will have LFTs (ALT, AST, total bilirubin, alkaline phosphatase) monitored 
closely. Measurement of conjugated and unconjugated bilirubin should be considered in 
cases of hyperbilirubinemia to assist in determination of its etiology. Tucatinib should be 
held according to protocol if liver functions tests are elevated, and monitored for 
normalization to the appropriate level per protocol before restarting study drugs. Other 
contributing factors (e.g., concomitant use of hepatotoxic agents) should also be 
considered and modified as clinically appropriate. 
The identification of liver enzyme abnormalities as potential adverse reactions to 
tucatinib does not impact upon the anticipated favorable benefit-risk profile of tucatinib, 
and is thus far in line with the types and severity of AEs that may be seen with other 
cancer therapies for patients with metastatic breast cancer. 
9.4.5 
Safety Plan for Patients with Brain Metastases 
Patients with brain metastases are at risk for occurrence of AEs due to the presence of 
CNS lesions, progression of disease and toxicities potentially related to study treatment. 
On occasion, treatment of brain metastases with systemic or radiation therapy has been 
associated with localized edema thought to be due to treatment effect and not tumor 
progression. A patient in study ONT-380-005 with known brain metastases was found to 
have cerebral edema in an area surrounding a known metastasis in the thalamus shortly 
after starting treatment with tucatinib, capecitabine and trastuzumab. The patient’s 


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symptoms responded rapidly and completely to systemic corticosteroids. It was not 
known if this patient’s symptoms were due to local progression or treatment-related 
toxicity. Similarly, a patient treated with tucatinib and trastuzumab alone experienced 
enlargement of a previously irradiated CNS lesion during study treatment. The patient 
was taken for surgical resection, and found to have no viable tumor. The resected lesion 
was thought to represent treatment-related necrosis.  
In order to minimize the risk of symptomatic cerebral edema in patients with brain 
metastases in this study, patients with high-risk metastases, including those requiring 
immediate local therapy, those with rapidly progressing lesions, those requiring 
corticosteroids at the start of the study (> 2 mg of dexamethasone or equivalent per day) 
for control of CNS symptoms, and those with larger untreated lesions, are excluded from 
the trial. However, if these patients are amenable to immediate CNS-directed therapy 
with either surgery or radiation, they may undergo local therapy and then be eligible for 
the trial. Under select circumstances patients may receive corticosteroid therapy for acute 
management of symptomatic local edema, as long as contrast brain MRI does not show 
clear evidence of CNS progression. All such instances require approval from the study 
medical monitor.  
9.4.6 
Safety Plan for Prevention of Pregnancy 
Due to the potential effect on embryo-fetal development, women of childbearing 
potential (who have not undergone surgical sterilization with a hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy; or, are not postmenopausal, as defined as 
≥ 12 months of amenorrhea) must agree to use a highly effective birth control method. 
Highly effective methods of birth control include intrauterine device, bilateral tubal 
occlusion/ligation, vasectomized partner, or sexual abstinence when it is the preferred 
and usual lifestyle choice of the subject. 
Male patients with partners of childbearing potential must use barrier contraception. All 
study patients should practice effective method of contraception, as described above, 
starting from the signing of informed consent until 7 months after the last dose of study 
medication or investigational medicinal product. 
Patients of child-bearing potential are to have serum or urine pregnancy tests performed 
on Day 1 of each treatment cycle. 
9.4.7 
Adverse Events 
9.4.7.1 
Definitions  
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  


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An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product 
(International Conference on Harmonisation (ICH) E2A guideline; Definitions and 
Standards for Expedited Reporting; 21 CFR 312.32 IND Safety Reporting.) 
The following should be considered when determining whether or not to record a test 
result or medical condition as an AE: 
• Any new undesirable medical occurrence or unfavorable or unintended change of 
a pre-existing condition that occurs during or after treatment with study drugs 
should be recorded as an AE. 
• Complications that occur as a result of protocol-mandated interventions (e.g. 
invasive procedures such as biopsies) should be recorded as an AE. 
• Elective procedures or routinely scheduled treatment are not considered AEs. 
However, an untoward medical event occurring during the pre-scheduled elective 
procedure should be recorded as an AE.  
• Baseline conditions are not considered AEs unless the condition worsens 
following study drug administration. Any change assessed as clinically significant 
worsening of the disease from baseline must be documented as an AE. Baseline 
conditions present prior to consent will be recorded as medical history. 
• Clinically significant laboratory abnormalities or vital signs (e.g. requiring 
intervention, meeting serious criteria, resulting in study termination or 
interruption of study treatment, or associated with signs and symptoms) should be 
recorded as AEs. If possible, abnormal laboratory results that meet the definition 
of an AE should be reported as a clinical diagnosis rather than the abnormal value 
itself (e.g., “anemia” rather than “decreased blood count”). 
Serious Adverse Event 
An AE should be classified as an SAE if it meets one of the following criteria:  
 
Fatal: 
The AE resulted in death.  
 
Life Threatening: 
The AE placed the patient at immediate risk of death. This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe. 
 


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Hospitalization: 
The AE required 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: 
Resulted in a substantial and permanent disruption of the patient’s 
ability to carry out activities of daily living. 
 
Congenital Anomaly or Birth 
Defect: 
An adverse outcome in a child or fetus of a patient exposed to the 
study drug or study treatment regimen before conception or during 
pregnancy. 
 
Important medical event: 
The AE did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or 
surgical intervention to prevent one of the outcomes listed above. 
Overdose, Medication Error, Misuse and Abuse 
Overdose is defined as the administration of a quantity of investigational medicinal 
product given per administration or cumulatively which is above the maximum dose, 
according to the protocol. 
Medication error refers to an unintentional error in dispensing or administration of the 
investigational medicinal product not in accordance with the protocol. 
Misuse is defined as any situation where the investigational medicinal product is 
intentionally and inappropriately used not in accordance with the protocol. 
Abuse is defined as the persistent or sporadic intentional excessive use of the 
investigational medicinal product, which is accompanied by harmful physical or 
psychological effects.  
Overdoses, medication errors, abuse or misuse will be collected as part of investigational 
medicinal product dosing information and/or as a protocol violation, as required. 
Any AE associated with an overdose, medication error, misuse or abuse of study drug 
should be recorded on the AE eCRF with the diagnosis of the AE. 
Adverse Event of Special Interest 
An AE of special interest 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 following AEs of special interest will need to be reported to the sponsor irrespective 
of regulatory seriousness criteria or causality within 24 hours (Section 9.4.7.4). 


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Potential drug-induced liver injury 
Any potential case of drug-induced liver injury as assessed by laboratory criteria for Hy’s 
Law will be considered as a protocol-defined event of special interest. The following 
laboratory abnormalities define potential Hy’s Law cases: 
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 the ULN, except in patients with 
documented Gilbert’s syndrome. Measurement of conjugated and unconjugated bilirubin 
should be considered in cases of hyperbilirubinemia to assist in determination of its 
etiology. 
Asymptomatic left ventricular systolic dysfunction 
In general, asymptomatic declines in LVEF should not be reported as AEs since LVEF 
data are collected separately in the eCRF. However, an asymptomatic decline in LVEF 
leading to a change in study treatment or discontinuation of study treatment is considered 
an event of special interest and a serious adverse event, and must be reported to the 
sponsor.  
Cerebral Edema 
Any event of cerebral edema not clearly attributable to progression of disease should be 
reported as an Event of Special Interest. 
Adverse Event Severity 
AE severity should be graded using the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. These criteria are 
provided in Appendix F. 
AE severity and seriousness are assessed independently. Severity characterizes the 
intensity of an AE. Seriousness is a regulatory definition and serves as a guide to the 
sponsor for defining regulatory reporting requirements (see definition of SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of an AE to all study drugs (tucatinib/placebo, capecitabine, and 
trastuzumab) should be assessed using the guidelines presented below. An AE for which 
there has been no causal relationship reported will require follow-up to determine 
causality. 
 


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Is the AE/SAE suspected to be caused by the investigational product on the basis of 
facts, evidence, science-based rationales, and clinical judgment?  
Related 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship possible AND other drugs, 
therapeutic interventions or underlying conditions do not provide 
sufficient explanation for the AE/SAE. 
Not related  The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship unlikely OR other drugs, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the AE/SAE. 
9.4.7.2 
Procedures for Eliciting and Recording of Adverse Events Eliciting 
Adverse Events 
The investigator will assess patients for the occurrence of AEs at all scheduled and 
unscheduled visits. The occurrence of AEs should be sought by non-direct questioning of 
the patient at each visit. AEs may also be detected when they are volunteered by the 
patient during and between visits or through physical examination, or other assessments.  
All AEs reported by the patient will be reviewed by the investigator and must be recorded 
on the source documents and AE eCRFs provided. 
Recording Adverse Events 
Regardless of relationship to study drug, all serious and nonserious AEs that occur during 
the protocol-defined reporting period are to be recorded on the eCRF. SAEs occurring 
between pre-screening consent and main consent do not need to be documented, unless 
they are caused by a study procedure (for example, biopsy). 
The following information will be assessed and recorded on the eCRF for each AE: 
• Description of the AE including onset and resolution dates 
• Severity (see Definitions) 
• Relationship to each study drug (see Definitions) 
• Outcome of each event 
• Seriousness (see Definitions) 
• Action taken regarding each study drug 
Diagnosis vs. Signs or Symptoms 
Whenever possible, the investigator should group signs or symptoms that constitute a 
single diagnosis under a single event term. For example, cough, rhinitis and sneezing 
might be grouped together as “upper respiratory tract infection”. Grouping of symptoms 


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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 event. 
Progression of Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
will not be reported as an AE or SAE. Symptomatic clinical deterioration due to disease 
progression as determined by the investigator will not be reported as 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.  
9.4.7.3 
Reporting Periods and Follow-up of Adverse Events and Serious 
Adverse Events 
Report all AEs identified during the clinical study from the time the patient signs 
informed consent through the 30-day follow-up visit (tucatinib/placebo, capecitabine, or 
trastuzumab). For subjects who previously had a 30-day follow-up visit and are now 
crossing over to the experimental arm, report all AEs through the Unblinded 30-day 
follow-up visit (Section 8.2.12), or 30 days after the last dose of protocol administered 
study drug. 
Any SAE that occurs after the patient discontinues study treatment considered by the 
investigator to be related to any study drug should be reported to the sponsor.  
All SAEs and AEs of special interest will be followed until the acute event has resolved 
or stabilized, even if the patient discontinues study treatment prior to SAE resolution. 
Non-serious AEs will be followed per the reporting period as noted above. 
If a non-serious AE is ongoing at the 30-Day Follow-up Visit, the AE will be recorded as 
ongoing.  
9.4.7.4 
Serious Adverse Event and Event of Special Interest Reporting 
Procedures 
All SAEs/EOIs regardless of relationship to study drug that occur after the first 
administration of study drug must be reported to the sponsor on a SAE/EOI form within 
24 hours of discovery of the event. An SAE occurring after informed consent but before 
administration of study drug and possibly related to a protocol procedure must also be 
reported to the sponsor within 24 hours of discovery of the event. Any new information 


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or follow-up information pertaining to previously reported SAEs/EOIs should be reported 
to the sponsor within 24 hours of becoming aware of the new or follow-up information. 
For initial SAE/EOI reports, available case details are to be recorded on a SAE/EOI form. 
At a minimum, the following should be included: 
• Patient number 
• AE term(s), including serious criteria and onset date 
• Study treatment 
• Causality assessment 
The processes for reporting and documenting SAEs and EOIs are provided in the study 
binder. Investigators are responsible for reporting these events to their IRB and/or IEC in 
accordance with federal and local institutional laws and regulations.  
New or follow-up information should be faxed or emailed to the sponsor’s clinical safety 
department. The fax number and email address can be found on the SAE/EOI form and in 
the study binder. Medical concerns or questions regarding safety should be directed to the 
medical monitor. 
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/EOI form and the eCRF 
• 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 
9.4.7.5 
Sponsor Safety Reporting to Regulatory Authorities  
Investigators are required to report all SAEs to the sponsor (Section 9.4.7.4). 
The sponsor will conduct safety reporting to regulatory authorities, IRBs, and IECs as 
required per local regulatory reporting requirements. SAEs assessed as related and 
unexpected (as per IB) to tucatinib/placebo will be unblinded by the sponsor to identify 
study treatment and will be reported in accordance with local regulatory reporting 
requirements. In the double-blind phase, investigators will receive all expedited reports in 
a blinded manner. In the unblinded phase, investigators will receive all expedited reports 
in an unblinded manner. 
9.4.7.6 
Pregnancy Reporting 
Cases of pregnancy must be reported through 7 months after the last dose of study drug 
(tucatinib, capecitabine, or trastuzumab, whichever is latest). If a patient or the female 
partner of a male patient becomes pregnant during participation in the study, the sponsor 


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must be notified. If a study participant becomes pregnant during administration of the 
drug, treatment must be discontinued.  
The investigator should report all pregnancies within 24 hours to the sponsor including 
the partners of male patients. The sponsor will ask for follow up evaluation of the 
pregnancy, fetus, and child.  
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as a SAE. 
Congenital anomaly or birth defects should also be reported as a SAE as described in 
Section 9.4.7.1. 
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.  
Pregnancy should be reported to the sponsor’s clinical safety department on a Pregnancy 
Report Form. 


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10 DATA QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Site Monitoring and Training 
The following are required of the sponsor or its representatives to ensure accurate, 
complete and reliable data: 
• Provide instructional material to the study sites, as appropriate 
• Conduct an initiation/start-up training session to instruct the investigators and 
study personnel on the protocol, completion of the eCRFs, study procedures, and 
GCP 
• Make periodic monitoring visits to the study site 
• Be available for consultation and stay in contact with the study-site personnel by 
mail, telephone, and/or fax  
• Monitor the patient data recorded in the eCRF against source documents at the 
study site 
• Review and evaluate eCRF data and use standard computer edits to detect errors 
in data collection 
10.2 Data Management 
Web-based eCRFs will be used to collect patient data in this study. This system, provided 
by a contract research organization, also includes electronic queries to resolve any 
questions or data discrepancies. All eCRFs and resulting data will be developed and 
maintained in a manner consistent with currently available regulations and guidances 
pertinent to the use of computerized systems in clinical trials. All sponsor, sponsor 
designees, and study-site users of the eCRF system will be trained prior to the use of the 
system. 
10.3 Quality Assurance Audits 
The study site may be audited by the sponsor or its representatives and/or regulatory 
agencies at any time. The sponsor must be notified immediately if an investigator is 
contacted by a regulatory agency to schedule an audit in relation to this study.  
Sponsor audits may be conducted to verify data, protocol compliance and overall 
adherence to GCP. The investigator and/or clinical staff must agree to allow the auditor 
direct access to all trial-related documents (i.e., source medical records), and must 
allocate time to meet with the auditor when applicable. Contact information for the 
sponsor is provided in the study binder. 


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11 STATISTICS  
11.1 Double-blind Phase  
This randomized, international, multi-center, double-blind study is designed to assess the 
efficacy and safety of tucatinib vs. placebo (in combination with capecitabine and 
trastuzumab) in patients with progressive unresectable locally advanced or metastatic 
HER2+ breast carcinoma who have previously received treatment with trastuzumab, 
pertuzumab and T-DM1. Tumor efficacy, both in extracranial and intracranial locations, 
will be evaluated.  
11.1.1 Statistical Methods 
This section outlines the statistical and analytical methods to be used in the study. 
Exploratory analyses of the data not described in the following subsections may be 
conducted as deemed appropriate. Additional details will be provided in the Statistical 
Analysis Plan (SAP), which will be finalized before study unblinding. 
11.1.1.1 General Considerations 
Data collected in this study will be presented using summary tables, patient data listings, 
and figures. Continuous variables will be summarized using descriptive statistics, 
specifically the mean, median, standard deviation, minimum, and maximum. Categorical 
variables will be summarized by frequencies and percentages.  
11.1.1.1.1 Analysis Populations 
The intent-to-treat (ITT) population will include all randomized patients and will be used 
for efficacy analyses. In all efficacy analyses, patients will be allocated to the treatment 
group to which they were randomized. 
Safety analyses will include all randomized patients who received at least one dose of 
study treatment (tucatinib/placebo, capecitabine or trastuzumab), with patients allocated 
to the treatment group associated with the regimen actually received. 
Pharmacokinetic analyses will include all randomized patients who received at least one 
dose of tucatinib and who had at least one evaluable PK assessment. 
11.1.1.1.2 Adjustments for Covariates 
The dynamic hierarchical randomization scheme will include the following stratification 
factors: known history of treated or untreated brain metastases (yes/no); ECOG PS (0 vs. 
1); and region of world (US vs. Canada vs. Rest of World). The primary PFS analysis, 
brain metastases subgroup PFS analysis and the analysis for OS will use 
re-randomization to reflect the dynamic randomization. For simplicity, descriptive 
analyses conducted for all other efficacy endpoints will be conducted without 
stratification. 


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11.1.1.1.3 Timing of Analyses 
First Analysis: 
The primary analysis of PFS will occur when: at least 288 PFS events determined by 
BICR have occurred in the first 480 randomized patients in the ITT population; and 
enrollment has been completed for the study. An interim analysis for the key secondary 
endpoints PFSBM and OS in the ITT population will also be performed at this time if PFS 
is statistically significant (see Section 11.1.1.8 for details).  
Second Analysis:  
• If PFSBM is not statistically significant at the time of the primary analysis of PFS, 
the final analysis of PFSBM will be performed when approximately 220 PFS 
events based on BICR have occurred in the subgroup of patients with a history of 
brain metastases and/or brain metastases or brain lesions of equivocal significance 
at baseline. If OS is not statistically significant at the time of the primary analysis 
of PFS, a second interim analysis for OS will be performed at this time. Update of 
PFS will also be provided at the time of final analysis for PFSBM.  
or 
• If PFSBM is statistically significant at the time of the primary analysis of PFS, no 
further formal testing of PFSBM will be conducted. A second interim analysis for 
OS will be performed when approximately 75% (271) of the total required 
361 OS events have occurred in the ITT population, if OS is not statistically 
significant at the time of the primary analysis of PFS. 
Third Analysis: 
If OS is not statistically significant at the first or second analysis, the final analysis of OS 
will be performed after 361 OS events have occurred in the ITT population.  
11.1.1.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated by treatment group. The 
number of patients in each analysis population will likewise be tabulated by treatment 
group. Patients who discontinue study drug will be summarized and listed, with the 
reason for drug or study discontinuation. 
Protocol violations will be summarized by treatment group. All non-protocol specified 
anti-cancer therapies will be listed and summarized by treatment group. 
11.1.1.3 Baseline Characteristics 
The following baseline characteristics will be summarized 
• Patient demographics  


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• Disease history  
• Prior disease-related therapies; and 
• Baseline disease characteristics 
Concomitant medications, separately for medications taken prior to enrollment and while 
on study, will be listed and summarized by treatment group.  
11.1.1.4 Efficacy Analyses 
11.1.1.4.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS, defined as the time from randomization to 
documented disease progression as determined by BICR per RECIST 1.1 or death from 
any cause, whichever occurs earlier.  
The analysis of the primary endpoint will be performed using the first 480 randomized 
patients in the ITT population. For the primary endpoint of centrally-reviewed PFS, the 
two treatment groups will be compared using a stratified log-rank test. The p-value for 
this test will be calculated using a re-randomization procedure (Rosenberger 2015)  to 
reflect the dynamic allocation used in randomization: known history of treated or 
untreated brain metastases (yes/no); ECOG PS (0 vs. 1); and region of world.  Patients 
who are alive and have not progressed at the time of the analysis will be censored at the 
time of their last tumor assessment that was a CR, PR, non-CR/non-PD or SD. Details of 
the censoring scheme for the primary analysis of PFS are described in the SAP. 
Kaplan-Meier methodology will be used to estimate the PFS time curves. The median 
PFS and its 95% confidence interval (CI) will be provided for two treatment arms. A Cox 
proportional-hazards model taking into account the stratification factors, will be used to 
estimate the hazard ratio (HR) and its 95% CI. 
For patients who receive non-protocol specified anti-cancer therapy (NPT) prior to 
documented PD, details of the censoring scheme and sensitivity analyses to be performed 
for the primary endpoint will be described in the statistical analysis plan for this study. 
11.1.1.4.2 Key Secondary Efficacy Endpoints 
11.1.1.4.2.1 Progression-Free Survival in Patients With Brain Metastases 
If the overall test of PFS is statistically significant at the 0.05 level (2-sided), PFS for the 
subgroup of patients with brain metastases at baseline (PFSBM), defined as patients with a 
history of brain metastases, current brain metastases, or equivocal brain lesions at 
baseline, will be evaluated using the same statistical methods used for the primary 
analysis of PFS. The multiplicity adjustment is described in Section 11.1.1.9. 


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11.1.1.4.2.2 Overall Survival 
Duration of OS is defined as the time from randomization to death from any cause. The 
same statistical methods for the primary analysis of PFS will be used for OS. The 
multiplicity adjustment is described in Section 11.1.1.9. For a patient who is not known 
to have died by the data cutoff date, OS will be censored on the date the patient was last 
known to be alive (i.e., date of last contact).   
11.1.1.4.3 Other Secondary Efficacy Endpoints 
11.1.1.4.3.1 Investigator-Assessed PFS 
PFS will also be assessed based solely on investigator assessments, namely: the time 
from randomization to investigator-assessed documented disease progression per 
RECIST 1.1 or death from any cause, whichever occurs earlier. 
11.1.1.4.3.2 Response Rates – Objective Response Rate and Clinical Benefit 
Rate 
Data summaries for ORR will be provided for patients with measurable disease at 
baseline, as well as for all patients in the ITT population. For the First Analysis (the 
primary analysis of PFS), the first 480 randomized patients in the ITT population will be 
used for this analysis. The 95% CI will be estimated for each treatment group. 
Additionally, the difference in incidence between the two treatment groups will be 
provided with its corresponding 95% CI. 
A similar approach will be used for the clinical benefit rate (CBR) analysis, but the 
analysis for CBR will include all patients in the ITT population. 
Duration of Response 
Only patients with a response will be included in the analysis of duration of response. 
Duration of response is defined as the time from first documented response to 
documented disease progression or death from any cause, whichever occurs earlier. 
Duration of responses will be graphically described using Kaplan-Meier methodology. 
The median DOR and its 95% confidence interval (CI) will be provided for two treatment 
arms. 
11.1.1.4.4 Exploratory Efficacy Endpoints 
ORR and DOR in brain per RANO-BM will be summarized in patients who had brain 
metastasis at baseline. Time to progression in brain per RANO-BM, defined as the time 
from the date of randomization to the date of documented disease progression in brain 
will be summarized using cumulative incidence curves by treatment group (i.e., 
competing risk methodology) treating non-brain progression and death as competing 
events. 


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HER2 and other mutations will be explored as possible predictive biomarkers though the 
use of descriptive subgroup analyses of the primary and secondary endpoints. 
11.1.1.4.5 Health-Related Quality of Life 
Health-related quality of life will be evaluated using the EQ-5D-5L questionnaire. The 
recall time frame for the descriptive system is the day in which the questionnaire is 
administered. The instrument is in paper format and is completed by the patient prior to 
being seen by her care providers in clinic. 
Responses to the descriptive system form a 5-digit number describing the respondent’s 
health, with 11111 representing the best possible health state and 55555 representing the 
worst health state.  Each health state will be converted into a single number called an 
index value or health utility. The index value ranges from less than zero (worse than 
death) to 1 (perfect health) according to the preferences of the general population. This 
conversion will occur through mapping the EQ-5D-5L responses to the appropriate value 
sets recommended by EuroQol (van Reenen 2019). 
The EQ-5D-5L questionnaire also includes a 20-cm vertical visual analog scale (VAS) 
with 100 on the top representing the “best imaginable health state” and 0 at the bottom 
representing the “worst imaginable health state.” The recall time frame for the VAS is the 
day in which it is administered. The treatment and placebo group will be compared using 
a t-test if the VAS scores are normally distributed and a Mann-Whitney test if the data are 
non-parametric. A difference of 7 in VAS score will be considered to be clinically 
important (Pickard 2007). 
The treatment and placebo group index values changes will be summarized. Longitudinal 
and descriptive data analysis will be used to evaluate patient-reported outcomes. 
11.1.1.4.6 Health Care Resource Utilization 
Health care resource utilization data collected from the eCRF and will include procedures 
that occur on study, length of stay and procedure time, hospitalizations, ED visits, 
planned and unplanned provider visits, medication use, radiology, and other treatments 
and procedures. Analysis by resource utilization category will rely primarily on 
descriptive summary statistics and confidence intervals.  
11.1.1.5 Pharmacokinetic Analyses 
Individual (patient) plasma tucatinib and ONT-993 concentrations at each sampling time 
will be listed; corresponding summary statistics at each sampling time will also be 
calculated. Additional exploratory pharmacokinetic analyses may be conducted. 
Exploratory analyses investigating the relationship between tucatinib exposure and 
efficacy and safety endpoints may be conducted.  


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11.1.1.6 Safety Analyses 
Safety is assessed through summaries of AEs, changes in laboratory test results, changes 
in vital signs, physical examination findings, changes in ECOG PS, and changes in 
cardiac ejection fraction results. AEs will be classified by system organ class (SOC) and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA); AE 
severities will be classified using the CTCAE criteria. 
11.1.1.6.1 Extent of Exposure 
Study drug administration data will be listed by treatment group, study site, patient 
number, and cycle; any dose modifications or dose holdings will be flagged. For each of 
the regimen components (tucatinib/placebo, trastuzumab, capecitabine), duration of 
exposure and number of treated cycles will be summarized by treatment group.  
For each of the regimen components (tucatinib/placebo, trastuzumab, capecitabine), 
tolerability will be assessed by tabulating the frequency of study drug interruption and 
discontinuations due to AE by treatment group. In addition, for tucatinib/placebo and 
capecitabine, tolerability will be further assessed by tabulating the frequency of dose 
reductions by treatment group. Treatment compliance (percent of actual to planned 
dosing) will likewise be summarized for tucatinib/placebo and capecitabine by treatment 
group. 
The summary of trastuzumab and capecitabine exposure will only include the period 
when patients are on study treatment, i.e., before tucatinib/placebo is discontinued. 
11.1.1.6.2 Adverse Events 
All collected AE data will be listed by treatment group, study site, patient number, and 
cycle. Separately, all serious AEs and AEs of special interest (e.g., any drug-induced liver 
injury, asymptomatic left ventricular systolic dysfunction, and/or cerebral edema) will be 
analogously listed. 
All TEAEs will be summarized by treatment group, as follows: 
• All AEs (regardless of grade) 
• All Grade 3/4/5 AEs 
• All drug-related AEs (regardless of grade) 
• All AEs leading to study drug discontinuations 
• All serious AEs, including deaths 
• All AEs of special interest (regardless of grade) 
In the event of multiple occurrences of the same AE with the same preferred term in one 
patient, the AE will be counted once as the occurrence.  


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A separate listing of all on-study deaths will be presented. 
11.1.1.6.3 Clinical Laboratory Results 
Laboratory values (hematology, chemistry, and liver function) will be summarized by 
treatment group. Abnormal laboratory values (relative to respective normal ranges) will 
be flagged in listings. 
Additional analytical methods for a more thorough investigation of LFTs (including 
temporal/simultaneous summaries and figures) will be specified in the SAP. 
11.1.1.6.4 Vital Signs and Physical Examination Findings 
The frequency and percentage of patients with post-baseline clinically significant vital 
signs will be summarized. Abnormal physical examination findings may be collected as 
AEs. 
11.1.1.6.5 Cardiac Ejection Fraction 
Cardiac ejection fraction data will be summarized by treatment group. Corresponding 
shift tables will also be provided by treatment group. 
11.1.1.7 Handling of Missing Data 
For the analysis of PFS, data for patients without disease progression (per RECIST 1.1) 
or death will be censored at the time of last tumor assessment that was CR, PR, non-
CR/non-PD or SD (or, if no tumor assessment was performed after the baseline visit, at 
the time of randomization). Further details describing the censoring scheme for PFS will 
be described in the SAP. 
For the analysis of ORR and CBR, patients without a post baseline tumor assessment will 
be considered non-responders/non-clinical benefiters. 
For the analysis of OS, patients who are alive at the time of analysis will be censored at 
the last date they were known to be alive. Patients with no post baseline information will 
be censored at the date of randomization. Further details describing the censoring scheme 
for OS will be described in the SAP. 
11.1.1.8 Interim Analyses 
One formal interim analysis for superiority is planned for PFSBM and two formal interim 
analyses for superiority are planned for OS if the primary analysis for PFS is statistically 
significant. The interim analyses will be conducted at the timing described in Section 
11.1.1.1.3. The stopping boundaries will be determined using Lan-DeMets spending 
functions for the O'Brien and Fleming boundaries. See Section 11.1.1.9 for control of 
multiplicity. Further details will be provided in the SAP. 


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11.1.1.9 Multiple Comparison and Multiplicity 
To maintain strong control of the family-wise type I error rate at 0.05, the PFS will be 
tested using the first 480 randomized patients in the ITT population at 0.05 level first, and 
if it is significant, then the key secondary endpoints will be tested using the group 
sequential Holm variable (GSHv) procedure (Ye 2013).  
 
Figure 11-1 
Type I Error Reallocation Strategy Following Closed Testing Principle 
As illustrated in Figure 11-1, the sequence of testing will begin with the evaluation of 
PFS. If PFS is statistically significant, then the key secondary endpoints PFSBM and OS 
will be tested using group sequential boundaries: PFSBM will be tested using a total alpha 
of 0.03 and OS will be tested using a total alpha of 0.02. If only one of the two key 
secondary endpoints is statistical significant, the unused alpha can be passed to the other 
one following the GSHv procedure. A Lan-DeMets O’Brien-Fleming approximation 
spending function will be used for the calculation of efficacy boundaries for PFSBM and 
OS. 
11.1.2 Determination of Sample Size 
The sample size for this study was calculated based on maintaining 90% power for the 
primary endpoint PFS with an alpha of 0.05 and 80% power for OS with an alpha of 0.02. 
For PFS, 288 events are required with 90% power to detect a hazard ratio of 0.67 (4.5 
months median PFS in the control arm versus 6.75 months in the experimental arm) using 
a 2-sided log-rank test and alpha of 0.05.  
For OS, 361 events are required with 80% power to detect a hazard ratio of 0.70 (15 
months median OS in the control arm vs. 21.4 months in the experimental arm) using a 2-


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sided log-rank test and alpha of 0.02, taking into account two interim analyses. With 361 
OS events, it will provide 88% power using a 2-sided log-rank test with an alpha of 0.05. 
For PFSBM, 220 events are required with 80% power to detect a hazard ratio of 0.67 (4.5 
months median PFSBM in the control arm versus 6.75 months in the experimental arm) 
using a 2-sided log-rank test at alpha of 0.05, taking into account one interim analysis. 
The power will be 74% at 2-sided alpha of 0.03. 
Approximately, 600 patients will be randomized in a 2:1 ratio to either the experimental 
arm or the control arm. Assuming an accrual period of 48 months and a 5% yearly drop-
out rate, it is expected that 361 OS events will be observed approximately 59 months 
after first patient is randomized. 
11.2 Unblinded Phase 
Safety data will be summarized for the patients who receive study treatment in the 
unblinded phase. Progression-free survival per RECIST 1.1 by investigator and overall 
survival will be summarized at approximately 2 years after the last patient was 
randomized in this study. 
 


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12 INFORMED CONSENT, ETHICAL REVIEW, AND ADMINISTRATIVE AND 
REGULATORY CONSIDERATIONS 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual. The study must fully adhere to the principles outlined in the “Guideline for 
Good Clinical Practice” ICH Tripartite Guideline or with local law if it affords greater 
protection to the patient. For studies conducted in the EU/EEA countries, the investigator 
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC) or applicable 
European local regulations. For studies conducted in the United States or under U.S. 
IND, the investigator will additionally adhere to the basic principles of “Good Clinical 
Practice” as outlined in the current version of 21 CFR subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators,” part 50, “Protection of Human 
Patients,” and part 56 “Institutional Review Boards.” 
In other countries where “Guidelines for Good Clinical Practice” exist, Seagen and the 
investigators will strictly ensure adherence to the stated provisions. 
12.1 Informed Consent 
It is the responsibility of the investigator or a person designated by the investigator (if 
acceptable by local regulations) to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, anticipated 
benefits, objectives, and potential hazards of the study. Appropriate forms for obtaining 
written informed consent will be provided by the investigator or by Seagen/designee and 
must be approved by an IRB/IEC. For patients not qualified to give or incapable of giving 
legal consent, written consent must be obtained from the legally acceptable 
representative. 
If new safety information results in significant changes in the risk/benefit assessment, the 
informed consent form (ICF) should be reviewed and updated if necessary. All patients, 
including those already being treated, should be informed of the new information, given a 
copy of the revised form, and give their consent to continue in the study. 
12.2 Ethical Review 
Prior to enrollment of patients into the study, as required by the FDA, applicable 
European guidelines, and other regulatory authorities, the protocol and informed consent 
document will be reviewed and approved by an appropriate IRB/IEC. By signing the 
Statement of Investigator Form (FDA Form 1572), the investigator assures that approval 
of the study protocol will be obtained from the IRB/IEC and that all aspects of the 
IRB/IEC review will be conducted in accordance with current regulations. Amendments 
to the protocol will be subject to the same IRB/IEC review requirements as the original 


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protocol. Only changes necessary to eliminate apparent immediate hazards to the patients 
may be initiated prior to IRB/IEC approval. In that event, the investigator must notify the 
IRB/IEC and Seagen in writing within 5 working days after implementation. The 
investigator will also promptly notify the IRB/IEC of any serious, unexpected AEs, or 
any other information that may affect the safe use of the investigational product. A letter 
documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members or federal wide assurance number must be received by Seagen prior to the 
initiation of the study. All correspondence with the IRB/IEC should be retained in the 
investigator’s study file. The investigator shall submit a progress report, at least once 
yearly, to the IRB/IEC, and must provide a copy to Seagen. As soon as possible after 
completion or termination of the study, the investigator will submit a final report to the 
IRB/IEC and to Seagen. This report should include the dates of initiation and completion 
of the study, a description of any changes in study procedures or amendments to the 
protocol, any deviations from the protocol, the number and type of patients evaluated, the 
number of patients who discontinued (and the reasons for discontinuation), the number of 
patients who completed the study, and the results of the study, including a description of 
any AEs. Seagen will assist the investigator in the preparation of this report, as needed. 
The name and address of the reviewing committee are provided in the investigator file. 
The investigator must provide the following documentation to the sponsor or its designee: 
• The IRB/IEC approvals of the protocol and informed consent document, and any 
amendments or revisions  
• The IRB/IEC periodic re-approval of the protocol where applicable 
• Submission to IRB or IEC of safety and SAE reports, as appropriate 
12.3 Administrative and Regulatory Considerations 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that Seagen and investigators abide 
by GCP as described in the ICH Harmonised Tripartite Guideline E6 GCP: Consolidated 
Guideline, and for US Investigators, 21 CFR Parts 50, 54, 56, and 312. Compliance with 
these regulations also constitutes compliance with the ethical principles described the 
current revision of the Declaration of Helsinki. The study will also be carried out in 
keeping with local legal and regulatory requirements. 
12.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and 
subinvestigators and the name and address of the research facilities are included in the 
trial master files. After reading the protocol, each principal investigator will sign the 
protocol signature page and return it to the sponsor or the sponsor’s designee. 


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12.3.2 Protocol Amendments and Study Termination 
The sponsor may periodically and officially amend the protocol to address safety issues 
or other developing issues.  
The sponsor may terminate the study at any time. The IRB/IEC must be advised in 
writing of study completion or early termination. 
12.3.3 Payments, Insurance, and Publications 
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 described in the Clinical Trial Agreement. 
12.4 Study Documentation, Privacy, and Records Retention 
As described in the ICH GCP Guidelines, ‘essential documents’, including eCRFs, source 
documents, ICFs, laboratory test results and the investigational product inventory 
records, should be retained by the investigator until at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
These documents should be retained for a longer period however if required by the 
applicable regulatory requirements or by an agreement with Seagen.  
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial be retained by the investigator until notified by 
the sponsor in writing that retention is no longer necessary. These records must be made 
available at reasonable times for inspection and duplication, if required, by a properly 
authorized representative of the US FDA, European Competent Authorities, and Health 
Canada (HC) in accordance with regulatory requirements. 
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 
patient medical records in the patient files as original source documents. If requested, the 
investigator will provide the sponsor, applicable regulatory agencies and applicable 
IRB/IEC with direct access to original source documents. The investigator will also 
provide appropriate facilities for periodic monitoring by the sponsor or designee. 
Records containing patient medical information must be handled by the investigator in 
accordance with the required privacy policies and consistent with the terms of the patient 
authorization contained in the informed consent document for the study. 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, eCRFs and other documents to be 
transferred to the sponsor or sponsor designee should be completed in strict accordance 


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with the instructions provided by the sponsor, including the instructions regarding the 
coding of patient identities. 
No study document should be destroyed without prior written agreement between the 
sponsor and the investigator. Should the investigator wish to assign the study records to 
another party or move them to another location, written approval must be obtained from 
the sponsor. 
The investigator must keep these documents on file according to local regulations after 
completion or discontinuation of the study. After that period of time the documents may 
be destroyed, subject to local regulations. Should the investigator wish to assign the study 
records to another party or move them to another location, Seagen must be notified in 
advance. 
If the investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
investigator and Seagen to store these in a sealed container(s) outside of the site so that 
they can be returned sealed to the investigator, in case of a regulatory audit. Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made before storing outside of the site. 
 


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Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with 
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Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of 
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Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive 
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Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for 
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Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or 
in combination with trastuzumab in women with ErbB2-positive, trastuzumab-
refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-30. 
 
Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in 
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Bray F, Colombet M, Mery L, et al. Cancer Incidence in Five Continents, Vol. XI 
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Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines 
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Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated 
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Curigliano G, Mueller V, Borges VF, et al. Updated results of tucatinib versus placebo 
added to trastuzumab and capecitabine for patients with pretreated HER2+ 
metastatic breast cancer with and without brain metastases (HER2CLIMB)  J Clin 
Oncol. 2021;39(15 Suppl):Abstract 1043. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-
47. 
 
Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE. Capecitabine therapy of 
central nervous system metastases from breast cancer. J Neurooncol. 
2007;85(2):223-7. 
 
Freedman RA, Anders CK. Treatment of breast cancer brain metastases. Curr Breast 
Cancer Rep. 2012;4(1):1-9. 
 
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advanced breast cancer. N Engl J Med. 2006;355(26):2733-43. 
 
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and trastuzumab in women with locally advanced, inflammatory, or early HER2-
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human epidermal growth factor receptor 2-positive breast cancer: American 
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the treatment of women with brain metastases from HER2-positive breast cancer. 
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Appendix A.1 
Schedule of Events – Double-blind Phase 
 
Screening 
Cycle 1 
Cycle 2 
Study Procedure and Day 
Day -28 to 1 
Day 1 
Day 12 
(± 3 days) 
Day 1 
(- 1 day to +3 
days) 
Day 12 
(± 3 days) 
 CT/MRI 
Schedule 
Assessments 
Informed consent 
X 
 
 
 
 
 
Document AEs 
X 
X 
X 
X 
 
 
Document study eligibility 
X 
 
 
 
 
 
Confirmatory HER2+ testingl 
X 
 
 
 
 
 
Document concomitant medsm 
X 
X 
X 
X 
 
 
Document baseline medical conditions 
X 
 
 
 
 
 
Document disease history 
X 
 
 
 
 
 
Physical exam 
X 
Xh 
X 
X 
 
 
Height 
X 
 
 
 
 
 
Vital signs (weight, BP, heart rate, 
temp, resp rate) 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
X 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
ECOG PS 
X 
Xh 
X 
X 
 
 
Labsa 
X 
Xh 
X 
X 
Xj 
 
Coagulation 
X 
 
 
 
 
 
Hepatitis B and C screeningb 
X 
 
 
 
 
 
Blood sample for biomarker evaluation 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Pregnancy testo 
Xc 
 
 
X 
 
 
CT, PET/CT, or MRId 
X 
 
 
 
 
X 
Contrast MRI Brain 
X 
 
 
 
 
Xk 
EQ-5D-5L Questionnaire 
 
Xn 
 
 
 
 
Study Drug Treatment 
Tucatinib/placeboe 
 
X 
 
X 
 
 
Capecitabinef 
 
X 
 
X 
 
 
Trastuzumabg 
 
X 
 
X 
 
 
PK 
Blood samples 
 
 
 
Xi 
 
 
a. Blood samples for hematology, clinical chemistry and liver function tests.  
b. Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B core (anti-HBc), and antibodies to Hepatitis C (anti-HCV). If positive, contact medical 
monitor. 
c. Serum or urine pregnancy test within 7 days prior to treatment (required only for females of child-bearing potential) 
d. Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate to document sites of extracranial disease and assessment of tumor burden. At minimum, 
scans must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease such as skin lesion photography, bone imaging. Scans should 


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be performed every six weeks (based on Cycle 1 Day 1) through Week 24 then every nine weeks through end of study drug 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 as described in Section 8.6 and Section 8.8. Use the same 
modality performed at screening/baseline. If bone imaging is collected, any RECIST appropriate imaging modality may be used. 
e. Tucatinib/placebo is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib/placebo for next cycle. 
f. Capecitabine is administered PO BID, on Day 1 through Day 14. On day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for next cycle. 
g. Trastuzumab is administered intravenously or subcutaneously, once every 21 days. 
h. These evaluations do not need to be repeated if obtained within 96 hours of scheduled first dose of study drug on Cycle 1 Day 1. All lab results must be reviewed and eligibility 
confirmed prior to first dose. 
i. 
Pre-dose  
j. 
Only total bilirubin, AST and ALT are required at this visit.  
k. MRI of the brain and assessment of brain lesions; only in patients with known brain metastases. 
l. 
Confirmatory HER2 testing may be obtained greater than 28 days prior to randomization if separate consent for confirmatory HER2 pre-testing is signed. 
m. Including concomitant procedures, hospitalization, and review of number of day(s) anti-diarrheals were taken from previous cycle. 
n. To be completed prior to administration of any study drug treatment 
o. Urine or serum pregnancy test, not required for females of non-child-bearing potential; a positive urine test must be confirmed with a serum pregnancy test. 
 
 


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Cycle 3 and Beyond 
30-Day Follow-Up Visit 
Long-Term Follow-Up 
Study Procedure and Day 
Day 1 
(- 1 day 
to + 3 
days) 
 CT/MRI and 
ECHO/MUGA 
Schedule  
30 days (+ 7 days) after last dose of 
study treatment  
90 days following 30-Day 
Follow-Up Visit and 
continuing every 90 dayst 
Assessments 
Document AEs 
X 
 
X 
 
Document concomitant medsq 
X 
 
X 
 
Physical exam 
X 
 
X 
 
Vital signs (BP, heart rate, temp, and 
resp rate) 
X 
 
X 
 
ECG 
Xi 
 
 
 
ECOG PS 
X 
 
X 
 
Labsa 
X 
 
X 
 
Coagulation 
 
 
X 
 
Pregnancy testb 
Xj 
 
Xm 
 
Blood sample for biomarker 
evaluation 
 
 
X 
 
ECHO/MUGAc 
 
Xl 
Xn 
 
CT, PET/CT, or MRId 
 
X 
Xo 
Xs 
Contrast MRI Braine 
 
X 
Xo 
Xs 
EQ-5D-5L Questionnaire 
Xr 
 
X 
 
Patient contact/clinic visitP 
X 
 
X 
X 
Study Drug 
Treatment 
Tucatinib/placebof 
X 
 
 
 
Capecitabineg 
X 
 
 
 
Trastuzumabh 
X 
 
 
 
PK  
Blood samples 
Xk 
 
 
 
a. Blood samples for hematology, clinical chemistry and liver functions tests. 
b. Urine or serum pregnancy test not required for females of non-child-bearing potential; a positive urine test must be confirmed with a serum pregnancy test. 
c. Use the same modality performed at screening/baseline. 
d. Contrast CT, PET/CT (if high quality CT scan included) or non-brain MRI scan only in patients having ended study treatment for reasons other than radiographic disease 
progression. At minimum, contrast scans must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease such as skin lesion 
photography, bone imaging. Use the same modality performed at screening/baseline. If bone imaging is collected, any RECIST appropriate imaging modality may be used. 
Scans should be performed every six weeks through Week 24 then every nine weeks through end of study drug 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 as described in Section 8.6 and Section 8.8.  
e. Contrast MRI of the brain and assessment of brain lesions per RECIST; only in patients with known brain metastases except at the 30-day follow-up visit where all patients 
should have an MRI of the brain done (unless already done within 30 days of ending study treatment or brain progression has already been documented while on study). 
f. Tucatinib/placebo is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib/placebo for next cycle. 
g. Capecitabine is administered PO BID, on Day 1 through Day 14. On day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for next cycle. 
h. Trastuzumab is administered intravenously or subcutaneously, once every 21 days. 
i. 
ECG should be performed through cycle 4 only. 


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j. 
Performed for each cycle. 
k. Through Cycle 6 only: Pre-dose at Cycles 3 – 6 and 1-4 hour post-dose at Cycle 3 only.  
l. 
Every 12 weeks as determined by the date of the screening exam.  
m. If not done within the last 60 days. 
n. If not done within the previous 12 weeks. 
o. If not done within the previous 30 ± 7 days. NOTE: If study treatment is discontinued for reasons other than  disease progression (per RECIST 1.1) or death, patients will 
continue to have follow-up for disease progression and  scan data should be collected approximately every 9 weeks until disease progression, death, withdrawal of consent, or 
study closure. 
p. Review of medical records, public records, or other public platforms may be used to obtain this information if reasonable efforts to make phone/personal contact are 
unsuccessful. 
q. Including concurrent procedures, hospitalizations, and review of number of day(s) anti-diarrheals were taken from previous cycle. 
r. To be completed prior to administration of any study drug treatment every 2 cycles from Cycle 3-9 and every 3 cycles starting at Cycle 12 
s. If study treatment is discontinued for reasons other than disease progression (per RECIST 1.1) or death, patients will continue to have follow-up for disease progression and 
scan data should be collected approximately every 9 weeks until disease progression, death, withdrawal of consent, or study closure.  
t. 
More frequent long-term follow-up may be requested for OS event tracking. If a 30-Day Follow-Up Visit was not done, the long-term follow-up should begin every 90 days 
(± 7 days) starting from the date of the last dose of study treatment. 
 
 


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Appendix A.2 
Schedule of Events – Experimental Arm Continuing on Treatment in the Unblinded Phase 
Subsequent Cyclesg 
30-Day Follow-Up Visit 
Long-Term Follow-Up 
Assessments 
Day 1 
(- 1 day to + 3 days) 
CT/MRI and 
ECHO/MUGA Schedule 
30 days (+ 7 days) after 
last dose of study 
treatment 
90 days (+7 days) following 
30-Day Follow-Up Visit and 
continuing every 90 days k 
Sign Revised Informed Consent 
X a 
 
 
 
Document AEs 
X 
 
X 
 
Document concomitant meds h 
X 
 
X 
 
Physical exam 
X 
 
X 
 
Vital signs (weight, BP, heart rate, 
temp, resp rate) 
X 
 
X 
 
ECOG PS 
X 
 
X 
 
Labs b 
X 
 
X 
 
Pregnancy test i 
X 
 
X 
 
ECHO/MUGA 
 
X c 
X l 
 
CT, PET/CT or MRI 
 
X c 
 
 
Contrast MRI Brain 
 
X c 
 
 
Patient contact/clinic visit  
X 
 
X 
X j 
Study Drug Treatment 
 
 
 
 
Tucatinib d 
X 
 
 
 
Capecitabine e 
X 
 
 
 
Trastuzumab f 
X 
 
 
 
a. For the first visit after unblinding only. 
b. Blood samples for hematology, clinical chemistry and liver function tests. Samples may be collected up to 2 days prior to visits. 
c.  Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate to document sites of extracranial disease and assessment of tumor burden. At minimum, 
scans must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of disease such as skin lesion photography, bone imaging.  While on 
treatment, scans should be performed at intervals as per standard clinical practice as determined by investigator with a maximum interval of 12 weeks between tumor 
assessments. Investigators should continue to use RECIST 1.1 for tumor assessments and for patient care decisions. 
d. Tucatinib is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib for next cycle. 
e. Capecitabine is administered PO BID, on Day 1 through Day 14. On day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for next cycle. 
f. Trastuzumab is administered intravenously or subcutaneously, once every 21 days. 
g. Patients will continue treatment cycle counting from prior to unblinding. 
h. Including concomitant procedures, hospitalization, and review of number of day(s) anti-diarrheals were taken from previous cycle. 
i. 
Urine or serum pregnancy test not required for males or females of non-child-bearing potential; a positive urine test must be confirmed with a serum pregnancy test prior to 
each cycle of therapy. 
j. 
Review of medical records, public records, or other public platforms may be used to obtain this information if reasonable efforts to make phone/personal contact are 
unsuccessful. 
k. More frequent long-term follow-up may be requested for OS event tracking. If a 30-day Follow-Up Visit was not done, the long-term follow-up should begin every 90 days 
(± 7 days) starting from the date of the last dose of study treatment. 
l. 
ECHO or MUGA, as appropriate, if not done within previous 12 weeks 


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Appendix A.3 
Schedule of Events – Control Arm Continuing on Treatment in the Unblinded Phase 
Crossover 
Screening  
Crossover to the 
Experimental 
Arm, Cycle 1 
Crossover to the 
Experimental 
Arm, Cycle 2 
Cycle 3 and Subsequent 
Cycles 
30-Day 
Follow-Up 
Visit 
Long-Term 
Follow-Up 
Assessments 
Day -28 to 1 
Day 1 
Day 12 
(± 3 
days) 
Day 1 
Day 12 
(± 3 
days) 
Day 1 
(- 1 day to + 3 
days) 
CT/MRI and 
ECHO/MUGA 
Schedule 
30 days (+ 7 
days) after 
last dose of 
study 
treatment 
90 days (+ 7 days) 
following 30-Day 
Follow-Up Visit 
and continuing 
every 90 days l 
Sign Revised Informed Consent 
X 
 
 
 
 
 
 
 
 
Document AEs 
X 
X 
X 
X 
 
X 
 
X 
 
Document crossover eligibility 
X 
 
 
 
 
 
 
 
 
Document concomitant meds i 
X 
X 
X 
X 
 
X 
 
X 
 
Document newly developed baseline 
medical conditions 
X 
 
 
 
 
 
 
 
 
Document recent disease history  
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
X g 
X 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Vital signs (weight, BP, heart rate, 
temp, resp rate) 
X 
X 
X 
X 
 
X 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
ECHO/MUGA 
X c 
 
 
 
 
 
X m 
X n 
 
CT, PET/CT or MRI 
X c 
 
 
 
 
 
X m 
 
 
Contrast MRI Brain 
X c 
 
 
 
 
 
X m 
 
 
ECOG PS 
X 
X g 
X 
X 
 
X 
 
X 
 
Labs a 
X 
X g 
X 
X 
X h 
X 
 
X 
 
Pregnancy test j 
X b 
X 
 
X 
 
X 
 
X 
 
Patient contact/clinic visit  
X 
X 
X 
X 
 
X 
 
X 
X k 
Study Drug Treatment 
 
 
 
 
 
 
 
 
 
Tucatinib d 
 
X 
 
X 
 
X 
 
 
 
Capecitabine e 
 
X 
 
X 
 
X 
 
 
 
Trastuzumab f 
 
X 
 
X 
 
X 
 
 
 
a. Blood samples for hematology, clinical chemistry and liver function tests. Samples may be collected up to 2 days prior to visits 
b. Serum or urine pregnancy test within 7 days prior to start of crossover (tucatinib) treatment (required for only females of child-bearing potential only) 
c.  Screening imaging not required if performed in the previous 6 weeks; Contrast CT, PET/CT (if high quality CT scan included) or MRI scan as appropriate to document sites of 
extracranial disease and assessment of tumor burden. At minimum, scans must include chest, abdomen, and pelvis, as well as appropriate imaging of any other known sites of 
disease such as skin lesion photography, bone imaging.  While on treatment, scans should be performed at intervals as per standard clinical practice as determined by 
investigator.  Contrast MRI of the brain should also be done at intervals as per standard clinical practice after screening. 


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d. Tucatinib is administered PO BID, on a 21-day cycle. On day 1 of each cycle, review compliance from previous cycle and dispense tucatinib for next cycle. Patients who were 
randomized to the control arm (placebo + trastuzumab + capecitabine) and were receiving study treatment at the time of unblinding who do not meet crossover criteria will 
continue trastuzumab + capecitabine therapy without tucatinib. 
e. Capecitabine is administered PO BID, on Day 1 through Day 14. On day 1 of each cycle, review compliance from previous cycle and dispense capecitabine for next cycle. 
f. Trastuzumab is administered intravenously or subcutaneously, once every 21 days. 
g. These evaluations do not need to be repeated if obtained within the prior 96 hours. All lab results must be reviewed, and crossover eligibility confirmed prior to start of 
crossover (tucatinib) treatment. 
h. Only total bilirubin, AST, ALT, and serum creatinine are required at this visit. 
i. 
Including concomitant procedures, hospitalization, and review of number of day(s) anti-diarrheals were taken from previous cycle. 
j. 
Urine or serum pregnancy test not required for males or females of non-child-bearing potential; a positive urine test must be confirmed with a serum pregnancy test. 
k. Review of medical records, public records, or other public platforms may be used to obtain this information if reasonable efforts to make phone/personal contact are 
unsuccessful. 
l. 
More frequent long-term follow-up may be requested for OS event tracking. If a 30-Day Follow-Up Visit was not done, the long-term follow-up should begin every 90 days 
(± 7 days) starting from the date of the last dose of study treatment. 
m. A maximum interval of 12 weeks between tumor assessments. Investigators should continue to use RECIST 1.1 for tumor assessments and for patient care decisions.  
n. ECHO or MUGA, as appropriate, if not done within previous 12 weeks 
 
 


 
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Appendix B RECIST 1.1 Criteria 
RECIST 1.1 is to be used to assess all sites of disease. Selected sections from RECIST 
1.1. criteria are provided below. For detailed guidelines, see study binder and/or 
published guideline (Eisenhauer 2009).  
Measurability of Tumor Lesions at Baseline 
Definitions 
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be 
accurately measured in at least one dimension [longest diameter to be recorded] with a 
minimum size of 10 mm with spiral contrast CT scan with slice thickness no greater than 
5 mm or if CT scan with slice thickness > 5 mm, the minimum lesion size must have a 
longest diameter twice the actual slice thickness or nonmeasurable (all other lesions, 
including small lesions [longest diameter < 10 mm with spiral CT scan] and truly 
nonmeasurable lesions). 
The term "evaluable" in reference to measurability is not recommended and will not be 
used because it does not provide additional meaning or accuracy. 
All measurements should be recorded in metric notation by use of a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks (approximately 30 days) before the beginning of 
treatment. 
Lesions considered to be truly nonmeasurable include the following: blastic bone lesions, 
LMD, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging 
techniques. Lytic bone lesions and cystic lesions must meet criteria detailed in the study 
binder and RECIST 1.1. 
 
Specifications by Methods of Measurements 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the anti-tumor effect of a treatment. 
• Clinical Examination – Clinically detected lesions will be considered measurable 
only when they are superficial (e.g., skin nodules and palpable lymph nodes). For 
the case of skin lesions, documentation by color photography—including a ruler 
to estimate the size of the lesion—is required. 


 
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• Contrast CT and MRI – CT and MRI are the best currently available and most 
reproducible methods for measuring target lesions selected for response 
assessment. Conventional contrast CT and MRI should be performed with 
contiguous cuts of 10 mm or less in slice thickness. Spiral contrast CT should be 
performed by use of a 5-mm or less contiguous reconstruction algorithm; this 
specification applies to the tumors of the chest, abdomen, and pelvis, whereas 
head and neck tumors and those of the extremities usually require specific 
protocols. 
Tumor Response Evaluation 
Baseline Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease – To assess objective 
response, it is necessary to estimate the overall tumor burden at baseline to which 
subsequent measurements will be compared. Measurable disease is defined by the 
presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
Baseline Documentation of “Target” and “Nontarget” Lesions – All measurable lesions 
up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at 
baseline (this means in instances where patients have only one or two organ sites 
involved a maximum of two and four lesions respectively will be recorded). Lymph 
nodes are considered one organ.  Only two lymph nodes should be measured as target 
lesions (Schwartz 2016). Target lesions should be selected on the basis of their size 
(those with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically). A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum of diameters. The baseline sum of diameters will be used as 
the reference by which to characterize the objective tumor response. All other lesions (or 
sites of disease) should be identified as non-target lesions and should be recorded at 
baseline. Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up. 
New Lesions 
If a new lesion is equivocal (for example because of its small size [< 5 mm in diameter] 
or due to differences in scanning technique) therapy should be continued, and follow-up 
assessment performed will confirm whether it represents truly new disease.  
Lesions identified in anatomic locations not scanned at baseline and > 5mm in diameter 
are considered new.  
New lesions identified on ultrasound should be confirmed on contrast CT/MRI. 


 
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Treatment Effect or Pseudoprogression or Equivocal Progression 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or treatment effects in existing lesions) in clinically stable patients, treatment 
may continue until the next scheduled assessment or until unequivocal progression is 
confirmed.  
Response Criteria 
Evaluation of Target Lesions – This section provides the definitions of the criteria used to 
determine objective tumor response for target lesions. The criteria have been adapted 
from the original WHO Handbook, taking into account the measurement of the longest 
diameter only for all target lesions: CR—the disappearance of all target lesions; PR—at 
least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum of diameters; PD—at least a 20% increase in the sum of the of diameters of 
target lesions, taking as reference the smallest sum of diameter recorded since the 
treatment started or the appearance of one or more new lesions; SD—neither sufficient 
shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference 
the smallest sum of diameter since the treatment started. 
Evaluation of Non-target Lesions – This section provides the definitions of the criteria 
used to determine the objective tumor response for nontarget lesions: CR—the 
disappearance of all non-target lesions and normalization of tumor marker level; 
incomplete response/SD—the persistence of one or more non-target lesion(s) and/or the 
maintenance of tumor marker level above the normal limits; and PD—the appearance of 
one or more new lesions and/or unequivocal progression of existing non-target lesions.  
Evaluation of Best Overall Response – The best overall response is the best response 
recorded from the start of treatment until disease progression/recurrence (taking as 
reference for PD the smallest measurements recorded since the treatment started). In 
general, the patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. The table below provides overall responses for all 
possible combinations of tumor responses in target and nontarget lesions with or without 
the appearance of new lesions. 


 
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Overall Responses for All Possible Combinations of Tumor Responses in Target 
and Non-Target Lesions With or Without the Appearance of New Lesionsa, b 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
a. Conditions that may define early progression, early death, and inevaluability are study specific and should be 
clearly defined in each protocol (depending on treatment duration and treatment periodicity). 
b. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation 
of CR depends on this determination, it is recommended that the residual lesion be investigated (fine-needle 
aspiration/biopsy) before confirming the CR status). 
Frequency of Tumor Re-Evaluation – Frequency of tumor re-evaluation while on 
treatment should be protocol specific and adapted to the type and schedule of treatment.  
 


 
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Appendix C Selected Strong Inhibitors and Inducer of CYP2C8 and Their 
Elimination Half-Lives 
Druga, b 
Elimination Half-lifec 
(hours) 
Strong Inhibitors 
Clopidogrel 
Gemfibrozil 
6 hours 
1–2 hours 
Montelukast 
3–6 hours 
Strong Inducer 
Rifampin 
3–5 hours 
a. FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664 htm#potency). 
b. EMA. “Guideline on the investigation of drug interactions” 
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2012/07/WC500129606.pdf  
c. Drug package insert 
 
 
Note: This table is prepared to provide examples and is not intended to be an exhaustive list. 


 
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Appendix D Selected Strong Inhibitors or Inducers of CYP3A4 and Their 
Elimination Half-Lives 
Druga, b, c 
Elimination Half-lifed  
(hours) 
Strong Inhibitors 
Macrolide Antibiotics 
 
Clarithromycin,  
Troleandomycin 
3–7 hours 
2 hours 
Azole Antifungals 
Itraconazole 
 
16-28 hours (single dose), 34-42 hours (repeat 
dose) 
Ketoconazole (systemic) 
Voriconazole 
Posoconazole 
Other 
2–8 hours 
Dose dependent 
27–35 hours 
 
Nefazodone 
Diltiazem 
White grapefruit juice 
2–4 hours 
3-4 hours 
~ 4-5 hourse 
 
 
 
 
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 hoursf 
a. FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664 htm#potency). 
b. EMA. “Guideline on the investigation of drug interactions” 
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2012/07/WC500129606.pdf 
c. Strong CYP3A inhibitors are defined as those drugs that increase the AUC of oral midazolam or other CYP3A 
substrates ≥ 5-fold. Ritonavir, indinavir, nelfinavir, atazanivir, and saquinavir are also strong CYP3A3 
inhibitors, but would not be used in this study as patients with known HIV are excluded. 
d. Drug package insert 
e. Bailey et al., Br J Clin Pharmacol 1998; 46: 101-110 
f. Kerb et al., Antimicrob Agent & Chemother 1996, 40(9): 2087-2093 
Note: This table is prepared to provide examples and is not intended to be an exhaustive list. 
 
 
 


 
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Appendix E Examples of Clinical Substrates for CYP3A-Mediated 
Metabolism 
 
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
c, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin
d, midazolam, naloxegol, nisoldipine, 
saquinavir
c, simvastatin
d, sirolimus, tacrolimus, 
tipranavir
c, triazolam, vardenafil 
 
alprazolam, aprepitant, atorvastatin
a, 
colchicine, eliglustat
b, pimozide, rilpivirine, 
rivaroxaban, tadalafil 
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir
c, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a 
given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase 
in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive 
substrates of CYP3A with ≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above 
the dashed line. Other elimination pathways may also contribute to the elimination of the substrates listed in the table 
above and should be considered when assessing the drug interaction potential. 
Abbreviations: AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; 
OATP1B1: organic anion transporting polypeptide 1B1.  
a. Listed based on pharmacogenetic studies. 
b. Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
c. Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
d. Acid form is an OATP1B1 substrate 
This table is prepared to provide examples of clinical substrates and not intended to be an exhaustive list. 
DDI data were collected based on a search of the University of Washington Metabolism and Transport 
Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61]. 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeli
ng/ucm093664.htm#table3-1 
Note: This table is prepared to provide examples and is not intended to be an exhaustive list. 
 


 
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Appendix F Adverse Event Severity Grading Scale (CTCAE Version 4.03) 
Severity 
Grade 
Description 
Mild  
1 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
Moderate  
2 
Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
Instrumental ADL refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, 
etc. 
Severe 
3 
Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. Self-care ADL refer to 
bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.  
Life-threatening  
4 
Life-threatening consequences; urgent intervention indicated  
Death 
5 
Death related to adverse event. 


 
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Appendix G List of Selected Substrates or Inhibitors of P-gp and 
Substrates of BCRP Oral Drugs  
Druga 
Class 
Druga 
Class 
P-gp Substrates or Inhibitorsb, c 
BCRP Substratesd, e, f 
Captopril 
angiotensin-converting 
enzyme (ACE) inhibitor 
Nitrofurantoin 
antibiotic 
Erythromycin 
antibiotic 
Ciprofloxacin 
antibiotic 
Azithromycin 
antibiotic 
Norfloxacin 
antibiotic 
Conivaptan 
anti-diuretic hormone 
Ofloxacin 
antibiotic 
Itraconazole 
anti-fungal 
Glyburide 
antidiabetic 
Ketoconazole 
anti-fungal 
Methotrexate 
anti-metabolite 
Ivermectin 
anti-parasitic 
Prazosin 
MT3 receptor antagonist  
(anti high blood pressure) 
Digoxin  
atrial fibrillation 
Sulfasalazine 
RA 
Carvedilol 
beta-blocker 
Cerivastatin 
Statin 
Cyclosporin A 
calcineurin inhibitors 
Pitastatin 
Statin 
Tacrolimus 
calcineurin inhibitors 
Pravastatin 
Statin 
Amlodipine 
calcium channel blocker 
Rosuvastatin 
Statin 
Diltiazem 
calcium channel blocker 
 
 
Felodipine 
calcium channel blocker 
 
 
Verapamil 
calcium channel blocker 
 
 
Domperidone 
dopamine antagonist 
 
 
Cimetidine 
H2-receptor antagonist 
 
 
Ranitidine 
H2-receptor antagonist 
 
 
Clarithromycin 
macrolide antibiotics 
 
 
Morphine 
pain 
 
 
Aldosterone 
steroid 
 
 
Cortisol 
steroid 
 
 
Dexamethasone 
steroid 
 
 
Methylprednisolone 
steroid 
 
 
a. FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664 htm#potency). 
b. Marchetti, S., R. Mazzanti, J. H. Beijnen and J. H. Schellens (2007). "Concise review: Clinical relevance of 
drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein)." 
Oncologist 12(8): 927-941. 
c. Kim, R. B. (2002). "Drugs as P-glycoprotein substrates, inhibitors, and inducers." Drug Metab Rev 34(1-2): 
47-54. 
d. Ni, Z., Z. Bikadi, M. F. Rosenberg and Q. Mao (2010). "Structure and function of the human breast cancer 
resistance protein (BCRP/ABCG2)." Curr Drug Metab 11(7): 603-617. 
e. Poirier, A., R. Portmann, A. C. Cascais, U. Bader, I. Walter, M. Ullah and C. Funk (2014). "The need for 
human breast cancer resistance protein substrate and inhibition evaluation in drug discovery and development: 
why, when, and how?" Drug Metab Dispos 42(9): 1466-1477. 
f. Lee, C. A., M. A. O'Connor, T. K. Ritchie, A. Galetin, J. A. Cook, I. Ragueneau-Majlessi, H. Ellens, B. Feng, 
M. E. Taub, M. F. Paine, J. W. Polli, J. A. Ware and M. J. Zamek-Gliszczynski (2015). "Breast cancer 
resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for 
clinical victim and perpetrator drug-drug interaction study design." Drug Metab Dispos 43(4): 490-509. 
Note: This table is prepared to provide examples and is not intended to be an exhaustive list. 
 
 


 
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Appendix H Drugs Accepted or Possibly Associated with Risk of QT Prolongation or Torsade de Pointes 
 
Anti-
infectives 
Anti-
psychotics 
Opioid 
analgesics 
Antihistamines 
Antidepressants 
Anti-emetics/  
Gastric 
motility drugs 
Anti-
cancer 
Anti-
arrythmics 
Accepted 
association 
Clarithromycin 
Erythromycin 
Chloroquine 
Pentamidine 
Haloperidol 
Chlorpromazine 
Methadone 
Terfaenadine 
 
Domperidone 
Cisapride 
 
Amiodarone 
Sotalol 
Disopyramide 
Dofetilide 
Procainamide 
Quinidine 
Possibly 
associated 
Azithromycin 
Roxithromycin 
Telithromycin 
Moxifloxacin 
Amantadine 
Resperidone 
Quetiapine 
Sertinodole 
Zisprasidone 
Lithium 
Clozapine 
 
 
Escitalopram 
Venlafaxine 
Ondansetron 
Dolasteron 
Granisetron 
Tamoxifen 
Nilotinib 
Lapatinib 
 
Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) October 2005, ICH. 
Geoffrey K Isbister and Colin B Page. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. Br J Clin Pharmacol. 2013 Jul; 
76(1): 48–57. 
 
Note: This table is prepared to provide examples and is not intended to be an exhaustive list. 
 
 
 
 
 
 
 
 

SAP_003.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 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
Phase 2 Randomized, Double-Blinded, Controlled 
Study of Tucatinib vs. Placebo in Combination with 
Capecitabine and Trastuzumab in Patients with 
Pretreated Unresectable Locally Advanced or 
Metastatic HER2+ Breast Carcinoma  
(HER2CLIMB) 
Protocol Number: 
ONT-380-206 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Version: 
1.0, 7-Aug-2019 
 




 
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TABLE OF CONTENTS 
SPONSOR APPROVAL PAGE ............................................................................................................................. 2 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objective ................................................................................................................................. 6 
2.2 
Secondary Objectives ........................................................................................................................... 6 
2.2.1 
Key Secondary Objectives ....................................................................................................... 6 
2.2.2 
Other Secondary Objectives ..................................................................................................... 6 
2.2.3 
Exploratory Objectives ............................................................................................................. 7 
3 
STUDY DESIGN ............................................................................................................................................ 7 
3.1 
Description ........................................................................................................................................... 7 
3.2 
Method of Assigning Subjects to Treatment Arms ............................................................................... 7 
3.3 
Endpoints .............................................................................................................................................. 8 
3.3.1 
Primary Endpoint ..................................................................................................................... 8 
3.3.2 
Secondary Endpoints ................................................................................................................ 8 
3.3.3 
Exploratory Endpoints .............................................................................................................. 9 
3.4 
Data Monitoring Committee ................................................................................................................. 9 
3.5 
Blinding .............................................................................................................................................. 10 
4 
GENERAL STATISTICAL CONSIDERATIONS ....................................................................................... 10 
4.1 
Analysis Sets ...................................................................................................................................... 10 
4.2 
Subgroups ........................................................................................................................................... 11 
4.3 
Handling of Missing Data ................................................................................................................... 11 
4.3.1 
Efficacy .................................................................................................................................. 11 
4.3.2 
Safety ...................................................................................................................................... 12 
4.3.3 
Pharmacokinetics .................................................................................................................... 13 
4.4 
Multicenter Studies ............................................................................................................................. 13 
4.5 
Determination of Sample Size ............................................................................................................ 13 
4.6 
Timing of Analyses ............................................................................................................................ 13 
4.7 
Multiple Comparison/Multiplicity ...................................................................................................... 14 
4.8 
Data Conventions, Definitions, and Formulas .................................................................................... 16 
5 
STATISTICAL METHODOLOGY .............................................................................................................. 18 
5.1 
Trial Details ........................................................................................................................................ 18 
5.1.1 
Subject Disposition ................................................................................................................. 18 
5.1.2 
Protocol Deviations ................................................................................................................ 18 
5.1.3 
Baseline Characteristics and Disease History ......................................................................... 18 
5.1.4 
Concomitant Therapy ............................................................................................................. 19 
5.1.5 
Extent of Exposure ................................................................................................................. 19 
5.1.6 
Subsequent anticancer treatment ............................................................................................ 20 
5.2 
Analysis of Efficacy ........................................................................................................................... 20 
5.2.1 
Primary Endpoint ................................................................................................................... 21 
5.2.2 
Key Secondary Endpoints ...................................................................................................... 25 
5.2.3 
Other Secondary Endpoints .................................................................................................... 26 
5.2.4 
Exploratory Efficacy Endpoints ............................................................................................. 28 
5.3 
Analysis of Safety ............................................................................................................................... 30 
5.3.1 
Adverse Events ....................................................................................................................... 30 
5.3.2 
Serious Adverse Events .......................................................................................................... 31 
5.3.3 
Adverse Events of Special Interest ......................................................................................... 31 
5.3.4 
Clinical Laboratory Results .................................................................................................... 32 
5.3.5 
Ejection Fraction .................................................................................................................... 32 
5.3.6 
Vital Signs .............................................................................................................................. 32 
5.3.7 
Deaths ..................................................................................................................................... 32 


 
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5.4 
Pharmacokinetic Analyses .................................................................................................................. 33 
5.5 
Health Economics and Outcomes ....................................................................................................... 33 
5.5.1 
Health Care Resource Utilization ........................................................................................... 33 
5.5.2 
Health-Related Quality of Life ............................................................................................... 33 
5.6 
Interim Analyses ................................................................................................................................. 33 
5.7 
Changes in the Planned Analysis ........................................................................................................ 33 
6 
REFERENCES .............................................................................................................................................. 34 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Initial LD (OF) boundaries for PFSBM (2 analyses) and OS (3 analyses) ...................................... 14 
Table 2: 
LD (OF) boundaries for PFSBM (2 lo analyses) and OS (3 analyses) at α=0.05 level.................... 15 
Table 3: 
Initial LD (OF) boundaries for PFSBM (2 analyses) and OS (2 analyses) ...................................... 15 
Table 4: 
LD (OF) boundaries for PFSBM (2 analyses) and OS (2 analyses) at α=0.05 level ........................ 16 
Table 5: 
Analysis population and re-randomization procedure for efficacy endpoints ............................... 21 
Table 6: 
Censoring Scheme for Primary Analysis of PFS ........................................................................... 22 
Table 7: 
Analysis Data Set Structure based on Alternative Randomizations .............................................. 23 
Table 8: 
Censoring Scheme for the Primary Analysis of OS ....................................................................... 26 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Illustration of Timing of Analyses ................................................................................................. 14 
 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event(s) 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BICR 
Blinded Independent Central Review  
CBR 
Clinical Benefit Rate 
CDISC 
Clinical Data Interchange Standards Consortium 
CDS 
Clinical Drug Safety 
CMH 
Cochran Mantel Haenszel 
CNS 
Central Nervous System 
CR 
Complete Response 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
ECHO 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
HER2 
Human Epidermal Growth Factor Receptor 2 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
LFT 
liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
multiple-gated acquisition scan 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics  
PR 
Partial Response 
PT 
Preferred Term 
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
T-DM1 
ado-trastuzumab emtansine or trastuzumab emtansine 
ULN 
Upper Limit of Normal 
WHODRUG 
World Health Organization Drug Dictionary 
 


 
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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol ONT-380-206, entitled “Phase 2 Randomized, Double-Blinded, Controlled Study of 
Tucatinib vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with 
Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma 
(HER2CLIMB)”.  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 analyses will 
proceed.  All planned analyses specified in this document will be performed.  Any changes 
will either be reflected in amendments to this plan before the database lock or specifically 
documented in the clinical study report.  Any changes to this plan, in the form of “post hoc” 
or “data driven” analyses will be identified as such in the clinical study report.   
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
● 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on progression-free survival (PFS) per RECIST 1.1 based on blinded 
independent central review (BICR) 
2.2 Secondary Objectives 
2.2.1 Key Secondary Objectives 
● 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on PFS in patients with a history of brain metastases or brain metastases 
at baseline or equivocal brain lesions at baseline using RECIST 1.1 based on BICR 
● 
To assess the effects of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on overall survival (OS) 
2.2.2 Other Secondary Objectives 
● 
To assess the effects of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on objective response rate (ORR) per RECIST 1.1 based on BICR and 
investigator 
● 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on PFS per RECIST 1.1 based on investigator assessment 
● 
To assess the duration of response (DOR) of tucatinib in combination with 
capecitabine and trastuzumab per RECIST 1.1 based on BICR and investigator 
● 
To assess the clinical benefit rate (CBR) [stable disease (SD) or non-CR/non-PD for 
≥ 6 months, or best response of complete response (CR) or partial response (PR)] of 
tucatinib vs. placebo in combination with capecitabine and trastuzumab per RECIST 
1.1 based on BICR and investigator 


 
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● 
To assess health-related quality of life and health economics associated with tucatinib 
vs. placebo in combination with capecitabine and trastuzumab based on patient health 
status collected using the EQ-5D-5L instrument and health care resources utilized in 
patient care 
● 
To assess the safety and tolerability of tucatinib in combination with capecitabine and 
trastuzumab 
● 
To evaluate the pharmacokinetics of tucatinib and metabolite ONT-993 when 
administered in combination with capecitabine and trastuzumab 
2.2.3 Exploratory Objectives 
● 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab using RANO-BM by BICR in the subgroup of patients with brain 
metastases at baseline 
● 
To assess the effect of tucatinib vs. placebo in combination with capecitabine and 
trastuzumab on progression in brain in the subgroup of patients with brain metastases 
at baseline. 
● 
To identify potential biomarkers of response, including human epidermal growth 
factor receptor 2 (HER2) mutations and other mutations by DNA sequence analyses 
of ctDNA isolated from plasma samples 
3 
STUDY DESIGN 
3.1 Description 
This is a randomized, international, multi-center, double-blinded study of tucatinib or 
placebo in combination with capecitabine and trastuzumab in patients with unresectable 
locally advanced or metastatic HER2+ breast cancer who have had prior treatment with 
trastuzumab, pertuzumab and T-DM1 (ado-trastuzumab emtansine or trastuzumab 
emtansine). After signing informed consent and meeting all eligibility criteria, patients will 
be randomized to receive tucatinib or placebo in combination with capecitabine and 
trastuzumab. 
Treatment will be administered in cycles of 21 days each. Tucatinib or placebo will be given 
PO BID. Capecitabine will be given at 1000 mg/m2 PO BID on Days 1–14 of each 21-day 
cycle. Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once 
every 21 days (or as 600 mg of trastuzumab given subcutaneously once every 3 weeks), 
except in specific circumstances where it may be given weekly to compensate for 
modifications in treatment schedule. 
3.2 Method of Assigning Subjects to Treatment Arms 
Subjects will be assigned to the tucatinib or placebo arms (in combination with capecitabine 
and trastuzumab) in a 2:1 ratio using a dynamic hierarchical randomization scheme. The 
randomization scheme will control for the stratification factors: 


 
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● 
Presence or history of treated or untreated brain metastases (Yes, No), 
● 
Eastern Cooperative Oncology Group Performance Status (0, 1) 
● 
Region of world (US, Canada, Rest of World) 
The presence or history of brain metastases will be determined based upon investigator 
assessment of screening MRI and clinical history. Patients who have a documented history of 
prior brain metastases or unequivocal presence of brain lesions on screening MRI will be 
considered a “Yes” for stratification purposes, and subsequent efficacy assessments. Patients 
with brain lesions of equivocal significance on screening MRI will also be considered a 
“Yes” for purposes of stratification and follow-up. 
The dynamic hierarchical randomization scheme includes specifications for a biased-coin 
assignment when the imbalance at a given hierarchical level (overall treatment group 
balance, then treatment group balance within each of the listed stratification factors) has 
exceeded a specified threshold. 
3.3 Endpoints 
3.3.1 Primary Endpoint 
The primary endpoint is progression-free survival (PFS) time defined as the time from the 
date of randomization to the date of documented disease progression (as determined by BICR 
assessment using RECIST 1.1) or death from any cause, whichever occurs first. 
3.3.2 Secondary Endpoints 
Key secondary endpoints 
● 
Progression-free survival (PFSBM) time in the subgroup of patients with a history of 
brain metastases or brain metastases at baseline, or with brain lesions of equivocal 
significance on screening MRI, defined as the time from the date of randomization to 
the date of documented disease progression (as determined by BICR assessment 
using RECIST 1.1) or death from any cause, whichever occurs first. 
● 
Overall survival (OS) time defined as the time from the date of randomization to the 
date of death from any cause.  
Other Secondary Efficacy Endpoints 
● 
Objective response rate (ORR). Objective response is defined as achieving a best 
overall response of complete (CR) or partial response (PR) as determined by BICR 
and by investigator using RECIST 1.1. 
● 
Progression-free survival (PFSINV) time defined as the time from the date of 
randomization to the date of documented disease progression (as determined by the 
investigator using RECIST 1.1) or death from any cause, whichever occurs first. 


 
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● 
Duration of response (DOR) defined as the time from the first objective response (CR 
or PR) to documented disease progression (PD) (as determined by BICR and by 
investigator using RECIST 1.1) or death from any cause, whichever occurs first. 
● 
Clinical benefit rate (CBR). Clinical benefit is defined as achieving stable disease 
(SD) or non-CR/non-PD for ≥ 6 months or a best overall response of complete (CR) 
or partial response (PR) as determined by BICR and by investigator using RECIST 
1.1. 
Safety Endpoints 
● 
Adverse events (AEs) 
● 
Clinical laboratory assessments 
● 
Vital signs and other relevant safety variables 
● 
Frequency of dose holding, dose reductions, and discontinuations of capecitabine 
● 
Frequency of dose holding, dose reductions, and discontinuations of tucatinib 
● 
Frequency of dose holding and discontinuations of trastuzumab 
Pharmacokinetic Endpoints 
● 
Plasma concentrations of tucatinib and metabolite ONT-993 
Heath Economics and Outcomes 
● 
Cumulative incidence of health resource utilization, including length of stay, 
hospitalizations, and emergency department (ED) visits. 
● 
Health-related quality of life / health status, assessed using the EQ-5D-5L instrument.  
3.3.3 Exploratory Endpoints 
• Presence of HER2 mutations or other potential biomarkers of response 
• In the subgroup of patients with a history of brain metastases or brain metastases at 
baseline, the following exploratory endpoints will be evaluated, as assessed by BICR 
using RANO-BM for brain metastases. 
○ 
Objective response rate (ORRBC) in brain 
○ 
Duration of response (DORBC) in brain 
○ 
Time to progression in brain (excluding body) 
 
3.4 Data Monitoring Committee 
An independent data monitoring committee (DMC) will monitor the safety of subjects and 
provide an ongoing clinical assessment of the study treatment’s evolving safety profile as the 


 
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trial progresses. The DMC will review blinded and unblinded data that include deaths, 
discontinuations, dose reductions, adverse events, events of special interest, and serious 
adverse events. The DMC will meet on a regular basis and make recommendations to the 
sponsor regarding the conduct of the trial. Further details regarding the DMC’s roles, 
responsibilities, and operating procedures are described in a separate DMC charter. 
3.5 Blinding 
This is a double-blinded trial. Patients, site investigators and personnel, the sponsor (except 
for designated Clinical Drug Safety (CDS) personnel), and all other individuals involved in 
the monitoring, data management, and/or conduct of the trial will be blinded. Designated 
CDS personnel may request the treatment assignment of an individual subject in the event of 
a Suspected Unexpected Serious Adverse Reaction (SUSAR) but will not have access to the 
overall randomization scheme. 
Unblinded data including deaths, discontinuations, dose reductions, adverse events (serious 
and non-serious) will be monitored regularly by an independent DMC. The independent data 
coordinating center preparing this output for the DMC will be unblinded and have access to 
the overall randomization scheme.  
At the time of the primary analysis for the primary endpoint (PFS), specific sponsor 
personnel will be unblinded, however sponsor personnel directly involved in the conduct of 
the study will remain blinded to individual subject treatment assignments (tucatinib/placebo) 
until the final analysis for the key secondary endpoint of PFSBM. 
 
4 
GENERAL STATISTICAL CONSIDERATIONS 
4.1 Analysis Sets 
Intent-to-Treat  
The intent-to-treat (ITT) analysis set will include all randomized subjects.  
Specifically, the primary analyses for the primary endpoint of PFS per BICR will be 
conducted using the first 480 randomized subjects in the ITT analysis set (henceforth referred 
to as ITT-PFS set). The analyses of the key secondary endpoint OS will be conducted on all 
the randomized subjects in the ITT analysis set (henceforth referred to as ITT-OS set). The 
analysis of the key secondary endpoint PFSBM will be conducted using all the randomized 
subjects in the BM subgroup (as defined in section 4.2) in the ITT analysis set (henceforth 
referred to as ITT-PFSBrainMets set).  
Subjects will be evaluated by their randomized treatment assignment. 
Safety 
The safety analysis set will include all randomized subjects who received at least one dose of 
study treatment (tucatinib/placebo, capecitabine or trastuzumab). Subjects will be evaluated 
by the study treatment actually received. 


 
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Pharmacokinetics 
The pharmacokinetic analysis set will include all randomized subjects who received at least 
one dose of tucatinib and who have at least one evaluable PK assessment. Subjects will be 
evaluated by the treatment actually received. 
4.2 Subgroups 
The following subgroup variables will be evaluated for primary and key secondary efficacy 
endpoints when applicable, as supportive analyses. If the total number of subjects in a 
subgroup is less than 10% of the total population, the subgroup analysis will not be 
performed. Subgroup analyses will be conducted using conventional stratified log rank 
statistical methods (i.e., rerandomization methods will not be used), as well as stratified Cox 
proportional hazards regression model. If the subgroup is a stratification factor, then the 
stratified models will use all the other stratification factors. 
● 
History of parenchymal brain metastases or brain metastases at baseline (Yes, No): 
Patients with target and/or non-target parenchymal brain lesions (per RECIST 1.1) at 
baseline or who have a history of brain metastases, or with brain lesions of equivocal 
significance on screening MRI based on screening data collected in eCRF will be 
assigned to the ‘Yes’ subgroup. This group will henceforth be referred to as “BM 
subgroup” in this document. Patients not meeting the above criteria will be assigned 
to the ‘No’ subgroup for this variable. Patients with dural lesions only, i.e. no 
parenchymal brain lesions, will be assigned to the ‘No’ subgroup. Patients with 
incomplete screening data and not meeting the criteria for BM subgroup will be not 
evaluable (NE) for this subgroup determination. 
● 
Geographic Region: North America, Rest of World 
● 
ECOG: 0 vs. 1 as recorded in eCRF at baseline 
● 
Age : <65 vs. ≥65 years 
● 
Race: White, African-American, others 
● 
Hormone Receptor Status (Negative, Positive): Patients ‘positive’ for either or both 
estrogen receptor and progesterone receptor will be assigned to the ‘positive’ 
subgroup. Patients not meeting the above criteria will be assigned to the ‘negative’ 
subgroup. 
4.3 Handling of Missing Data 
4.3.1 Efficacy 
Partial dates of start of post study treatment anti-cancer therapy and dates of concomitant 
medication or procedure, will be imputed as follows: 
● 
Missing day only: For partial dates with only the day of the month missing, the day 
will be imputed as the 15th day of the month, provided that a preceding or succeeding 


 
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date of interest does not occur in the same month. If the preceding date does occur in 
the same month, then the missing day will be imputed as half the distance between 
the preceding date and the end of the month. If the succeeding date does occur in the 
same month, then the missing day will be imputed as half the distance between the 
beginning of the month and the succeeding date. 
● 
Missing month and day: For partial dates with the month and day missing, the month 
and day will be imputed as July 1st, provided that a preceding or succeeding date of 
interest does not occur in the same year. If the preceding date occurs in the same year, 
then the month and day will be imputed as half the distance from the preceding date 
to the end of the known year. If the succeeding date does occur in the same year, then 
the missing day will be imputed as half the distance between the beginning of the 
year and the succeeding date. 
The date of death, tumor assessment dates, dates of last contact, hospitalization, date of initial 
diagnosis and first date of metastases will be imputed if only day is missing, following the 
“Missing day only” rule as above. 
4.3.2 Safety 
For AEs where the date of onset is during or after administration of the first dose of study 
treatment, missing or partial start dates will be imputed as the earliest possible date that is on 
or after the date of the first dose of study treatment (tucatinib/placebo, capecitabine or 
trastuzumab) and before the AE end date.  
● 
Missing day only: If the start date and date of first dose share the same month and 
year, the missing start day will be imputed as the day of first dose. If the start date 
month is after the month of first dose, day will be imputed as the 1st 
(i.e., 01-MMM-YY). 
● 
Missing month and day: If the start date and date of first dose share the same year, 
day and month will be imputed as the day and month of first dose. If the start date 
year is after the year of first dose, the month and day will be imputed as January 1st 
(i.e., 01-JAN-YY). 
● 
Missing month, day, and year: Missing start dates will be imputed as the date of first 
dose. 
For AEs where the end date is a partial date, the end date will be imputed as: 
• Missing day only: AE end date will be imputed as the minimum of (death date, data 
cutoff date, last day of the end date month/year) 
• Missing month and day: AE end date will be imputed as the minimum of (death date, 
data cutoff date, December 31st of the end date year) 
• Missing month, day and year: not imputed. 


 
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4.3.3 Pharmacokinetics 
Missing values for PK measurements will be listed as missing and excluded from the 
calculation of summary statistics. 
4.4  Multicenter Studies 
Approximately 600 subjects will be randomized to the study from approximately 200 sites 
worldwide. 
4.5 Determination of Sample Size 
The sample size for this study was calculated based on maintaining 90% power for the 
primary endpoint PFS and 80% power for OS with an alpha level of 0.02.  
For PFS, 288 events are required with 90% power to detect a hazard ratio of 0.67 (4.5 months 
median PFS in the control arm versus 6.75 months in the experimental arm) using a 2-sided 
log-rank test and alpha of 0.05. 
For OS, 361 events are required with 80% power to detect a hazard ratio of 0.70 (15 months 
median OS in the control arm vs. 21.4 months in the experimental arm) using a 2-sided 
log-rank test and alpha of 0.02, taking into account of two interim analyses. With 361 OS 
events, it will provide 88% power using a 2-sided log-rank test with an alpha of 0.05. 
For PFSBM, 220 events are required with 80% power to detect a hazard ratio of 0.67 
(4.5 months median PFSBM in the control arm versus 6.75 months in the experimental arm) 
using a 2-sided log-rank test at alpha of 0.05, taking into account of one interim analysis. The 
power will be 74% at 2-sided alpha of 0.03. 
Approximately 600 subjects will be randomized in a 2:1 ratio to either the experimental arm 
or the control arm. Assuming an accrual period of 48 months and a 5% yearly drop-out rate, 
it is expected that 361 OS events will be observed approximately 59 months after first subject 
randomized. 
Sample size and power were calculated using EAST® version 6.4, by Cytel Inc. 
4.6 Timing of Analyses 
The primary analysis of PFS will occur when approximately 288 PFS events determined by 
BICR have occurred in the ITT-PFS set and enrollment has been completed for the study. An 
interim analysis for the key secondary endpoints PFSBM and OS will also be performed at 
this time if PFS is statistically significant (see Section 5.6 for details). 
If PFSBM is statistically significant at the first interim analysis, no further formal testing of 
PFSBM will be conducted. The second interim analysis for OS will be performed when 
approximately 75% (271) of total OS events have occurred in the ITT-OS set, and the final 
OS analysis will be conducted after approximately 361 OS events have occurred in the ITT-
OS set. 


 
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If PFSBM is not statistically significant at the first interim analysis, a second analysis of the 
key secondary endpoints will be performed when (a) approximately 220 PFSBM events have 
occured in the ITT-PFSBrainMets set or the PFSBM events are sufficiently mature (e.g. 
approximately less than 6 events are expected with 3 months additional follow up) and (b) at 
least 3 months before the projected OS final analysis. If both of the above conditions (a and 
b) are not met, this analysis of PFSBM and OS will not be conducted, and the OS final 
analysis at 361 OS events will also be the timing of the final PFSBM analysis. 
The timing of analyses for the primary and key secondary endpoints are illustrated in 
Figure 1. 
Figure 1: 
Timing of Primary and Key Secondary Endpoints Analyses  
 
4.7 Multiple Comparison/Multiplicity 
To maintain strong control of the family-wise type I error rate at 0.05, the PFS will be tested 
at 0.05 level first in the ITT-PFS set, if it is significant, then the key secondary endpoints will 
be tested using the group sequential Holm variable (GSHv) procedure (Ye et.al. 2013). 
The α split between PFSBM and OS is α=0.03 and α=0.02, respectively, and each one will be 
tested at the interim analysis(s) and again at the final analysis, if not rejected at the interim 
analysis. The information fraction t is the ratio between number of events at interim analysis 
and number of events at final analysis. For illustration purpose, we assume t=0.812 for 
PFSBM and t1=0.626, t2=0.779 for the two interim analyses for OS. 
The boundary at interim analysis is determined according to the Lan-DeMets O’Brien-
Fleming (LD(OF)) approximation spending function LD(OF): 𝛼𝛼(𝑡𝑡) = 4 −4Φ(
𝑧𝑧𝛼𝛼/4
√𝑡𝑡) for two-
sided tests, where 𝑧𝑧𝛼𝛼/4is the upper 
𝛼𝛼
4 critical point of the standard normal distribution. 
The GSHv procedure operates as follows. 
● 
Begin with a 0.03-level group sequential boundary for PFSBM and a 0.02-level group 
sequential boundary for OS. The corresponding boundaries for the two endpoints are 
given in Table 1. 
Table 1: 
Initial LD (OF) boundaries for PFSBM (2 analyses) and OS (3 analyses) 
Analysis 
PFSBM (α=0.03, t=0.812) 
OS (α=0.02, t1=0.626, t2=0.779 ) 


 
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1 
0.0139 
0.0023 
2 
0.0259 
0.0069 
3 
 
0.0176 
 
If both of the endpoints are found significant at analysis 1 (primary analysis), then no 
more formal statistical testing for PFSBM and OS will be conducted. 
● 
If only one endpoint is found significant at the analysis 1 (primary analysis) then the 
α can be recycled to the other endpoint: If PFSBM is significant at interim but OS is 
not then the α will be recycled from PFSBM to OS and use a 0.05-level LD(OF) 
boundary for OS. On the other hand, if OS is significant at analysis 1 (primary 
analysis) but PFSBM is not then the α will be recycled from OS to PFSBM and use a 
0.05-level LD(OF) boundary for PFSBM. The corresponding 0.05-level LD(OF) 
boundaries are given in Table 2. The unrejected hypothesis can be re-tested at the 
current and future analysis using the modified boundaries. 
Table 2: 
LD (OF) boundaries for PFSBM (2 lo analyses) and OS (3 analyses) at α=0.05 
level 
Analysis 
PFSBM (α=0.05, t=0.812) 
OS (α=0.05, t1=0.626, t2=0.779) 
1 
0.0258 
0.0092 
2 
0.0425 
0.0194 
3 
 
0.0429 
 
● 
If neither of the endpoints is found significant at analysis 1 (primary analysis), then 
both endpoints will be tested again at analysis 2. The initial boundaries for final 
analysis follow Table 1 (analysis 2). If only one endpoint is found significant by these 
initial boundaries, then the other one can be tested again using the modified boundary 
as shown in Table 2 (analysis 2). For example, if PFSBM was found significant at final 
analysis at α=0.0259 level, but OS was not significant at α=0.0069 level, then OS can 
be tested again at the α=0.0194 level. 
● 
If PFSBM is significant at analysis 1 or 2, the boundary of OS analysis at analysis 3 is 
0.0429; otherwise, the boundary for OS analysis at analysis 3 is 0.0176. 
● 
Note that the boundaries presented in the tables will be adjusted with the actual 
information fraction. 
As detailed in Section 4.6, the second interim analysis for OS may not be conducted, which 
means both PFSBM and OS will have at most 2 analyses. In that case, LD(OF) boundaries at 
each analysis will be modified as illustrated in Table 3 and Table 4. Similar to Table 1 and 
Table 2, the information fraction (t) in Table 3 and Table 4 are for illustration purpose only. 
Table 3: 
Initial LD (OF) boundaries for PFSBM (2 analyses) and OS (2 analyses) 
Analysis 
PFSBM (α=0.03, t=0.812) 
OS (α=0.02, t=0.626) 
1 
0.0139 
0.0023 
2 
0.0259 
0.0193 
 


 
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Table 4: 
LD (OF) boundaries for PFSBM (2 analyses) and OS (2 analyses) at α=0.05 level 
Analysis 
PFSBM (α=0.05, t=0.812) 
OS (α=0.05, t=0.626) 
1 
0.0258 
0.0092 
2 
0.0425 
0.0471 
 
If both PFSBM and OS are statistically significant, the secondary endpoint of ORR by BICR 
in the ITT-OS set will be formally tested between two treatment arms at the two sided α=0.05 
level. 
4.8 Data Conventions, Definitions, and Formulas 
The following data conventions will be used for the tables, listings, and figures. 
● 
Study treatment: tucatinib/placebo, capecitabine or trastuzumab. Subjects who 
discontinued tucatinib/placebo and only continued with capecitabine and/or 
trastuzumab are not considered to be receiving study treatment anymore. 
● 
Baseline: The last non-missing observation prior to or on the first dose of study 
treatment (tucatinib/placebo, capecitabine or trastuzumab), unless otherwise 
specified. If more than one assessment meet the above criteria and were collected on 
the same date, the value of the assessment indicating better status will be used as 
baseline to be conservative, for instance, lower vs. higher lab grade, ECOG 0 vs. 1, 
ECG normal vs. abnormal. If there are no directional difference (for instance, lab 
values of the same grade) of observation on the same date, the last record in database 
(identified by sequence number or visit number) will be marked as baseline. For 
patients who were randomized but not treated, the observation on screening visit will 
be marked as baseline. 
● 
Pre-treatment Period: Prior to first dose of study treatment (tucatinib/placebo, 
capecitabine or trastuzumab) 
● 
Study Treatment Period: Period of time that begins on the date of the first dose of 
study treatment (tucatinib/placebo, capecitabine or trastuzumab) through 30 days after 
the date of the final dose of study treatment (tucatinib/placebo, capecitabine or 
trastuzumab) as recorded in the End of Treatment eCRF page. 
● 
Study Day: 
○ 
Safety: Study day will be calculated for safety endpoints relative to the first dose 
of study treatment (tucatinib/placebo, capecitabine or trastuzumab). The first dose 
of study treatment will be Day 1, and the date preceding Day 1 will be Day –1 
which is consistent with the Submission Data Standards (Version 3.1) from 
Clinical Data Interchange Standards Consortium (CDISC). 
○ 
Efficacy: Study day will be calculated for efficacy endpoints relative to the date 
of randomization. The day of randomization will be Day 1. 


 
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● 
Duration of Exposure: 
○ 
For tucatinib/placebo, duration of exposure (days) = date of last dose – date of 
first dose + 1 
○ 
For capecitabine, duration of exposure (days) = (date of last dose +7) – date of 
first dose) + 1 
○ 
For trastuzumab, duration of exposure (days) = (date of last dose +20) – date of 
first dose) + 1 
Note that for each study drug, the date of last dose is as recorded in the End of Treatment 
eCRF page. 
● 
Total Dose of tucatinib/placebo (mg), capecitabine (mg/m2), and trastuzumab 
(mg/kg): 
Total dose (units) = ∑
(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖)
𝑛𝑛
𝑖𝑖=1
 
where i = dose number, dosei = ith dose received (units), n = total number of doses 
received 
● 
Intended dose intensity (IDI): the intended dose of drug per unit of time (day). 
For example, tucatinib/placebo: IDI = 300mg BID =600 (mg/day);  
capecitabine: IDI = 2000 mg/m2/day * (14 dosing day/21 days in a cycle) =1333.3 
mg/m2/day 
● 
Absolute dose intensity (ADI): the actual dose per unit of time that the subject 
received over the duration of exposure for that study drug. 
ADI = Total dose / Duration of exposure (days) 
● 
Relative dose intensity (RDI): the percent of the intended dose intensity over the 
entire treatment period: 
RDI = ADI/IDI * 100% 
● 
Response assessment date 
For efficacy assessments, the date of response assessment of CR, PR or non-CR/non-
PD, SD will be the latest of all radiologic scan dates for the given response 
assessment. The date of equivocal progression or progression will be the earliest of all 
radiologic scan dates that showed evidence of PD for the given response assessment. 


 
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5 
STATISTICAL METHODOLOGY 
5.1 Trial Details 
5.1.1 Subject Disposition 
Patient enrollment and disposition will be summarized by treatment group and total. The 
table will present the number and percentage of patients who were randomized in each 
stratum, received study drug, received treatment per randomization assignment, and 
participated in follow-up visits. The number and percentage of patients who discontinued 
treatment will be summarized by the reason for treatment discontinuation. The number and 
percentage of patients who discontinued the study will be summarized by the primary reason 
for study discontinuation. The summary of disposition will be conducted for ITT-PFS, ITT-
OS and ITT-PFSBrainMets sets. 
Number of patients who signed informed consent and number of patients 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 also be 
produced, with reasons for screen failure and available demographic information. 
The number of patients enrolled in each country and at each site will be summarized by 
treatment group and total. 
5.1.2 Protocol Deviations 
Protocol deviations (as defined in the ONT-380-206 Global Clinical Monitoring Plan) will be 
identified by site monitors, the medical monitor and by checks of the clinical database. 
Important deviations will be summarized for each treatment arm by type of deviation. All 
protocol deviations will be listed. 
5.1.3 Baseline Characteristics and Disease History 
Baseline characteristics will be summarized for each treatment arm 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: 
● 
Demographic variables: age, sex, race, and ethnicity 
● 
ECOG performance status 
● 
Disease history:  
○ 
Time (months) from diagnosis of breast cancer to randomization 
○ 
Time (months) from metastatic diagnosis to randomization 
○ 
Unresectable locally advanced breast cancer (yes, no) 


 
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○ 
Stage at diagnosis 
○ 
History of brain metastases or brain metastases at study entry 
○ 
Estrogen/progesterone receptor status 
○ 
Non-CNS metastatic disease sites 
○ 
Brain metastases treatment status at baseline (treated stable, treated progressive 
and untreated) 
○ 
Time (months) from date of first diagnosis of brain metastases to randomization 
in subject previously diagnosed with brain metastases 
○ 
Prior surgery and/or radiotherapy for brain metastases (yes, no) 
○ 
Type of prior radiotherapy for brain metastases (whole brain vs. targeted 
radiation) 
○ 
Prior systemic therapies  
The summary of demography and baseline disease characteristics will be conducted for ITT-
OS, ITT-PFS and ITT-PFSBrainMets sets. 
5.1.4 Concomitant Therapy 
Concomitant medications will be listed and coded using the World Health Organization Drug 
Dictionary (WHODRUG) Version 2009Q3 or higher and summarized for each treatment arm 
by preferred term and treatment arm using counts and percentages. Multiple occurrences of 
the same medication within a subject will be summarized only once. 
Concomitant systemic corticosteroids, antidiarrheals as well as concomitant procedures will 
be summarized and listed. 
5.1.5 Extent of Exposure 
Exposure will be summarized by treatment arm 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 separately for capecitabine, trastuzumab, and 
tucatinib/placebo: 
● 
Total number of treatment cycles per subject 
● 
Duration of exposure 
● 
Total cumulative dose 
● 
Percentage of subjects with interrupted, missed, reduced and discontinued 
infusions/doses overall and by reason 


 
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● 
Absolute dose intensity (ADI) and relative dose intensity (RDI). 
Dose reduction and ADI/RDI will only be summarized for tucatinib/placebo and 
capecitabine. 
For tucatinib/placebo, the type, reason and time to first dose modification will be 
summarized. The total number of dose modifications and reasons will also be summarized. 
The summary of trastuzumab and capecitabine exposure will only include the period when 
patients are on study treatment, i.e., before tucatinib/placebo is discontinued. 
The extent of exposure will be summarized both for the safety set within first 480 
randomized subjects and the safety set in all randomized subjects. 
5.1.6 Subsequent anticancer treatment 
The type and regimen of subsequent anticancer treatment after discontinuation from study 
treatment will be summarized by treatment arm.  
5.2 Analysis of Efficacy 
Table 5 summarizes the analysis population at the time of primary analysis for PFS, as well 
as whether the re-randomization procedure needs to be used to calculate p-value. Subjects 
will be analyzed based on their randomized treatment arm (‘intent-to-treat’ analysis). 


 
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Table 5: 
Analysis population and re-randomization procedure for efficacy endpoints 
Analysis 
Population for primary 
analyses 
Use of re-
randomization 
procedure 
Primary endpoint: PFS per BICRa 
ITT-PFS 
Yes 
Sensitivity analysis for primary endpoint 
ITT-PFS 
Yes 
Subgroup analysis for primary endpoint 
ITT-PFS 
No 
Key secondary endpoints: PFSBM 
ITT-PFSBrainMets 
Yes 
Sensitivity analysis for PFSBM 
ITT-PFSBrainMets 
Yes 
Subgroup analysis for PFSBM 
ITT-PFSBrainMets 
No 
Key secondary endpoints: OS 
ITT-OS 
Yes 
Sensitivity analysis for OS 
ITT-OS 
Yes 
Subgroup analysis for OS 
ITT-OS 
No 
PFS per INVa 
ITT-PFS 
No 
PFSBM per INV 
ITT-PFSBrainMets 
No 
ORR, CBR and DORb 
ITT-OS 
No 
Exploratory efficacy endpoints 
ITT-OS 
No 
a exploratory analyses will also be conducted using ITT-OS analysis set. 
b exploratory analyses will also be conducted using ITT-PFS analysis set. 
 
For the primary analysis of PFS and OS, the stratification factors per Interactive Response 
Technology (IRT) system will be used as strata in stratified analysis. For a stratification 
factor with two strata, if one of the two strata has a sample size too small (e.g., less than 
20%), the statistical analysis will not include this randomization stratification factor in the 
analysis. For a stratification factor with more than two strata, if one of the strata has a sample 
size too small (e.g., less than 20%), this stratum will be combined with some other strata of 
this stratification factor. For example, for the region stratification factor, if the stratum 
Canada has a small sample size of less than 20% per the pooled blinded data, the stratum 
Canada will be combined with the stratum US in the statistical analysis. 
For the primary analysis of PFSBM, the actual stratification factor (brain metastasis as 
recorded in eCRF) will be used to define the population; the stratification factors per 
Interactive Response Technology (IRT) system (ECOG and region) will be used as strata in 
stratified analysis. 
Sensitivity analyses using the eCRF values for the actual stratification factors as strata may 
be performed for the primary endpoint and the two key secondary endpoints if the percentage 
of mis-stratification exceeds five percent. 
5.2.1 Primary Endpoint 
5.2.1.1 Primary Analysis 
Progression-free survival (PFS) time is defined as the time from the date of randomization to 
the date of documented disease progression (as determined by BICR assessment using 
RECIST 1.1) or death from any cause, whichever occurs first. Subjects who are alive and 
have not progressed at the time of the analysis will be censored at the time of their last tumor 


 
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assessment that was a CR, PR, non-CR/non-PD or SD. Details of the censoring scheme for 
the primary analysis of PFS are described below in Table 6.  
Table 6: 
Censoring Scheme for Primary Analysis of PFS 
Scenario 
Progression/Censor Date 
Outcome 
No post-baseline tumor assessments  
Date of randomization  
Censored 
No documented disease progression or death 
Date of last tumor assessment of CR, PR, SD, or 
non-CR/non-PD 
Censored 
New anti-cancer treatment (systemic, 
radiation, or surgery) started before PD or 
death observed 
Date of last CR, PR, SD, or non-CR/non-PD 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 
consecutive missed tumor assessments 
Date of last tumor assessment of CR, PR, SD, or 
non-CR/non-PD 
Censored 
Note: CT, PET/CT scans are performed every 6 weeks starting at Cycle 1 Day1 through Week 24 and every 9 weeks starting 
at Week 24 until documented PD or death. 
 
Partial or missing dates of death, dates of last contact, and tumor assessment dates will be 
imputed as described in Section 4.3. 
The two treatment arms will be compared for PFS using a stratified, log-rank test controlling 
for the randomization stratification factors [i.e., history of brain metastases or presence of 
brain metastases or lesions of equivocal significance on screening MRI (yes, no), ECOG 
status (0, 1), and region of the world (US, Canada, Rest of world)]. The p-value for this test 
will be calculated using a re-randomization based procedure (Rosenberger and Lachin, 2002) 
to reflect the dynamic, hierarchical allocation scheme (Section 3.2) used for the study 
randomization. The null hypothesis for this comparison is that the assignment of subjects to 
the two treatment arms had no effect on response for the subjects randomized to treatment. 
The procedure for performing the comparison and calculating the p-value are described 
below. Details of the specific significance level to be used for the treatment arm comparison 
are described in Section 4.7. 
Using the randomized treatment assignments for the trial, a stratified, log-rank test chi-square 
statistic will be computed for the comparison of the two treatment arms for PFS. This test 
statistic will be referred to as X0 and will be calculated based on the following sample SAS 
code: 
** Pfstime = PFS time; 
** Censor = Censor variable (1 = censored); 
** Trt = treatment arm; 
** BM = presence or history of treated or untreated brain metastases at baseline or 
lesions of equivocal significance (Yes, No) 
** ECOG (0,1) 
** Region (US, Canada, Rest of World) 
ODS OUTPUT HomTests=chisq; 
 


 
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PROC LIFETEST DATA = pfsdata; 
 
TIME pfstime*censor(1); 
 
STRATA bm ecog region / GROUP=armcd TEST=logrank; 
RUN; 
DATA x0(keep=x0); 
SET chisq; 
 
where test = 'Log-Rank'; 
 
X0=ChiSq; 
RUN; 
Utilizing the dynamic randomization algorithm used to create the original randomization 
scheme for the trial, 10,000 alternative subject randomizations will then be generated. Each 
subject randomization will then be merged with each subject’s observed PFS time, censoring 
status, and values for each stratification variable to produce an analysis data set with the 
basic structure shown in Table 7. 
Table 7: 
Analysis Data Set Structure based on Alternative Randomizations 
Randomization ID 
Number (i) 
Subject 
ID 
Baseline Stratification Variables 
PFS 
Time 
Censor 
Treatment 
Arm 
Prescence/History 
of Brain 
Metatases or 
lesions of 
equivocal 
significance 
ECOG 
Region 
1 
1 
Y 
0 
US 
T1 
0 
A 
1 
2 
N 
1 
Canada 
T2 
1 
B 
- 
- 
- 
- 
- 
- 
- 
- 
1 
600 
Y 
1 
US 
T600 
1 
A 
- 
- 
- 
- 
- 
- 
- 
- 
10,000 
1 
Y 
0 
US 
T1 
0 
B 
10,000 
2 
N 
1 
Canada 
T2 
1 
A 
- 
- 
- 
- 
- 
- 
- 
- 
10,000 
600 
Y 
1 
US 
T600 
1 
B 
 
For each alternative randomization, a stratified, log-rank test chi-square statistic will then be 
computed (using the same SAS code above used to calculate X0) for the comparison of the 
two treatment arms for PFS. The test statistic for the i-th randomization and comparison will 
be referred to as Xi where i = 1 to 10,000. 
The two-sided p-value (based on the rerandomization procedure), will then be calculated as 
the number of times Xi ≥ X0 divided by 10,000. 
𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 = ෎
𝐼𝐼(∙)
10,000 , 𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 
10,000
𝑖𝑖=1
𝐼𝐼(∙) = ൜1 𝑖𝑖𝑖𝑖 𝑋𝑋𝑖𝑖≥ 𝑋𝑋0
0 𝑖𝑖𝑖𝑖 𝑋𝑋𝑖𝑖< 𝑋𝑋0 
The critical value (Xc) for a 0.05 significance level test using the rerandomization 
reference distribution will correspond to the 5th percentile of the Xi’s. 


 
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For the purpose of describing the treatment effect, the treatment arm hazard ratio and 95% 
confidence interval will be estimated using a stratified Cox proportional hazards regression 
model controlling for the study stratification factors. This analysis will be implemented using 
the following SAS sample code. 
PROC PHREG DATA = pfsdata; 
 
CLASS armcd(ref=’B’); 
 
 STRATA stratvar1 stratvar2 stratvar3; 
 
 MODEL pfstime*censor(1) = armcd / TIES=BRESLOW RL; 
 
 HAZARDRATIO armcd; 
RUN; 
Kaplan-Meier curve will be generated by treatment arms. Kaplan-Meier estimates of the 
median and quartiles (corresponding 95% confidence intervals), as well as probability of PFS 
at different timepoints (for instance, 3, 6, 9 months) will be computed for each treatment arm.  
In addition to the primary efficacy analysis (i.e., re-randomization model analysis), an 
analysis of PFS time will also be performed using a stratified, log-rank test based on the 
randomized treatment assignments. The analysis will be implemented using the following 
sample SAS code. 
PROC LIFETEST DATA = pfsdata; 
TIME pfstime*censor(1); 
STRATA bm ecog region / GROUP=armcd TEST=logrank; 
RUN; 
5.2.1.2 Sensitivity Analyses 
● 
Non-proportional hazard: In the case that the proportional hazard assumption is 
violated (by plotting the “log-negative-log” of the Kaplan Meier estimator vs time by 
treatment group, and the Schoenfeld residuals by treatment group), a restricted mean 
survival time (RMST) analysis up to 18 months will be performed to compare the 
mean survival time of the two treatment arms. In addition, the Max-Combo test 
(Losorok and Lin, 1999; Karrision et al., 2016) will be performed to compare the two 
treatment arms.  
If the primary analysis of PFS is significant, the following analyses may be performed for 
PFS, using the same rerandomization procedure as for the primary analysis. 
● 
Missing Assessments of Disease Response: To explore the potential impact of 
missing assessments of disease response on the primary analysis of PFS, two 
sensitivity analyses will be performed 
○ 
(1) Ignoring the missing assessments, i.e., subjects who missed two or more 
consecutive scheduled assessments before death or PD are considered to have had 
an event on the date of death or progression. 


 
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○ 
(2) Imputing the missing assessment, i.e., subjects who missed two or more 
consecutive scheduled assessments before death or PD are considered to have 
events at the time of the next scheduled assessment after the last non-missing 
assessment. 
● 
Stratification: In the case of stratification errors >5% between what is recorded in 
IRT and eCRF, the hazard ratio and its 95% CI will be estimated using a stratified 
Cox proportional hazards regression model controlling for the eCRF stratification 
factors. 
● 
New therapy before PD/death: For subjects who received new anti-cancer therapy 
before PD or death, two sensitivity analyses will be conducted: 
○ 
(1) Not to consider any anti-cancer therapies (whether systemic, radiation, or 
surgery) as a censoring reason, 
○ 
(2) Not to consider radiation therapies as a censoring reason. 
5.2.2 Key Secondary Endpoints 
5.2.2.1 Progression-Free Survival in BM subgroup  
BM subgroup is defined as subjects with target and/or non-target parenchymal brain lesions 
per RECIST 1.1) at baseline or who have a history of brain metastases, or with brain lesions 
of equivocal significance on screening MRI based on screening data collected in eCRF. 
Progression-free survival time (as defined for the primary efficacy endpoint) in the BM 
subgroup will be tested if the test of the primary endpoint of PFS is statistically significant 
(Section 4.7). This analysis will be performed using the same statistical methods and set of 
alternative subject randomizations used to evaluate the primary endpoint overall PFS. This 
will be accomplished by selecting only subjects in the BM subgroup from the set of 10,000 
randomizations and calculating the stratified log-rank statistics (using stratification factors of 
ECOG and region) and rerandomization procedure p-value as described for primary analysis 
of PFS in Section 5.2.1.1. Details of the specific significance level to be used for the 
treatment arm comparison are described in Section 4.7. 
The hazard ratio and 95% confidence interval will be estimated using a stratified Cox 
proportional hazards regression model controlling for the study stratification factors of 
ECOG and region. 
The sensitivity analyses described in Section 5.2.1.2 for the primary endpoint may be 
performed if appropriate. 
As an exploratory analysis, the Kaplan Meier curve and summary for PFS in the non-BM 
subgroup among all randomized subjects will also be presented. 


 
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5.2.2.2 Overall Survival 
Overall survival time (OS) is defined as the number of days from the date of randomization 
until the date of death from any cause. Subjects who did not achieve the event (death) at the 
time of the analysis or are lost to follow-up will be censored at the date they were last known 
to be alive (i.e., right censored). Partial or missing dates of death or last contact will be 
imputed as described in Section 4.3. Details of the censoring scheme for the primary analysis 
of OS are described below in Table 8. 
Table 8: 
Censoring Scheme for the Primary Analysis of OS 
Scenario 
Death/Censor Date 
Outcome 
Not known to have died by data cutoff date  
Date last known alive 
Censored 
Death 
Death date  
Death 
 
This analysis will be performed using the same statistical methods and set of alternative 
subject randomizations used to evaluate the primary endpoint PFS. This will be 
accomplished by merging each subject’s observed survival time and censoring status to each 
subject randomization to produce an analysis data set. The stratified log-rank statistics and 
rerandomization procedure p-value will then be calculated as described for the primary 
efficacy analysis of PFS as described in Section 5.2.1.1. Details of the specific significance 
level to be used for the treatment arm comparison are described in Section 4.7. 
The hazard ratio and 95% confidence interval will be estimated using a stratified Cox 
proportional hazards regression model controlling for the study stratification factors. 
The sensitivity analyses for non-proportional hazard and stratification described in Section 
5.2.1.2 for the primary endpoint may be performed if appropriate. 
5.2.3 Other Secondary Endpoints 
Analyses of the following secondary endpoints will not be subject to formal type I error 
control and will be analyzed using conventional log rank statistical methods (i.e., 
rerandomization methods will not be used). 
5.2.3.1 Objective Response Rate 
Objective response is defined as achieving a best overall response of confirmed complete 
(CR) or confirmed partial response (PR) per RECIST 1.1. Only response assessments before 
first documented PD or new anti-cancer therapies will be considered. The proportion of 
subjects with objective response will be calculated by treatment arm. Comparison of the two 
treatment arms will be performed using a 2-sided Cochran-Mantel-Haenszel (CMH) test 
controlling for the study stratification factors. ORR determined by BICR will be summarized 
for subjects who had at least one measurable target lesion at baseline as assessed by BICR 
among ITT-OS set. If both of the key secondary endpoints (OS and PFSBM) are statistically 
significant, then the ORR by BICR will be formally tested between two treatment arms (see 
Section 4.7), the p-value from the stratified CMH test will be reported. 


 
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ORR determined by investigator assessment will be summarized for subjects who had at least 
one measurable target lesion at baseline as assessed by investigator among ITT-OS set. As 
exploratory analyses, the same analyses for ORR will also be conducted using ITT-PFS set. 
The nominal p-value from the stratified CMH tests will be reported for ORR determined by 
investigator in ITT-OS and ITT-PFS sets and ORR determined by BICR in ITT-PFS set. 
5.2.3.2 Investigator Assessed Progression-Free Survival 
Progression-free survival (PFSINV) time is defined as the time from the date of randomization 
to the date of documented disease progression (as determined by the investigator using 
RECIST 1.1) or death from any cause, whichever occurs first. Subjects who are alive and 
have not progressed at the time of the analysis will be censored at the time of their last tumor 
assessment that was a CR, PR, non-CR/non-PD, SD or equivocal progression. Details of the 
censoring scheme for the analysis of PFSINV are described above in Table 6. The primary 
analysis of PFSINV will be performed based on ITT-PFS set. PFSINV will also be summarized 
based on ITT-OS set as an exploratory analysis. 
In the cases where an equivocal new lesion was later confirmed to be a truly new disease 
lesion, or a non-target lesion assessed as equivocal progression changed to unequivocal 
progression in consecutive later assessment, the PD date should be backdated to the visit 
when the equivocal new lesion or non-target lesion with equivocal progression was first 
identified. Note: in cases where PD occurs at a date after an equivocal new lesion or 
equivocal progression of non-target lesion is identified, but the progression is not due to a 
change of the same equivocal new lesion or equivocal non-target lesion progression to an 
unequivocal lesion or unequivocal non-target lesion progression, but rather from progression 
of other lesions, the PD date will not be backdated, but will be the date when definitive PD is 
recorded. 
The treatment arm hazard ratio and 95% confidence interval will be estimated using a 
stratified Cox proportional hazards regression model controlling for the study stratification 
factors. Comparison of the two treatment arms will be performed using a stratified log-rank 
test controlling for the study stratification factors. The nominal p-value from the stratified 
log-rank test will be provided. Kaplan-Meier estimates of the median (corresponding 95% 
confidence intervals) will also be computed for each treatment arm. 
To explore the potential impact of clinical progression on the analysis of PFS, a sensitivity 
analysis will be performed using the same censoring scheme and methods described for the 
primary analysis of PFS with the exception that subjects who discontinued any study 
treatment due to clinical progression will be counted as ‘progressed’ in the analysis. 
PFSINV will also be summarized based on ITT-PFSBrainMets set as exploratory analyses. 
In addition, the concordance between BICR and investigator assessed PFS event will be 
summarized. 


 
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5.2.3.3 Clinical Benefit Rate 
Clinical benefit is defined as achieving stable disease (SD) or non-CR/non-PD for ≥6 months 
(i.e., subject has been followed for at least 6 months and no documented PD or death within 6 
months from date of randomization) or a best overall response of confirmed complete (CR) 
or confirmed partial response (PR) per RECIST 1.1. A subject will have a best response of 
SD or non-CR/non-PD if there is at least one SD or non-CR/non-PD assessment ≥5 weeks 
after the date of randomization and the subject does not qualify for CR or PR. The duration 
of SD or non-CR/non-PD will be calculated for subjects who had a best response of SD or 
non-CR/non-PD, and is defined as the duration from the date of randomization to 
documented PD or death. Only response assessments before first documented PD or new anti 
cancer therapies will be considered. The same derivation of PD date and censoring rules as 
for primary PFS analysis will apply for duration of SD or non-CR/non-PD.  
The proportion of subjects with clinical benefit determined by BICR will be calculated by 
treatment arm. Comparison of the two treatment arms will be performed using a 2-sided 
CMH test controlling for the study stratification factors. The nominal p-value from the 
stratified CMH test will be reported. Similar analysis will be performed for CBR determined 
by investigator assessment. For investigator assessed CBR, the same algorithm for 
backdating equivocal progression will be applied as in Section 5.2.3.1. CBR will be 
summarized for the ITT-OS set. As exploratory analyses, the same analyses for CBR will 
also be conducted using ITT-PFS set.  
5.2.3.4 Duration of Response 
Duration of response (DOR) is defined as the time from the first objective response (CR or 
PR that is subsequently confirmed) to documented disease progression (PD) per RECIST 1.1 
or death from any cause, whichever occurs first. Only those who achieve a confirmed 
response among the ITT-OS set will be included in the analysis. Kaplan-Meier estimates of 
the median (corresponding 95% confidence intervals) will be computed for each treatment 
arm. The nominal p-value from the stratified log-rank test will be reported. The same 
derivation of PD date and censoring rules as for primary PFS analysis will apply for DOR. 
The analysis of DOR will be repeated based on BICR assessment and investigator 
assessment. For DOR per investigator assessment, the same algorithm for backdating 
equivocal progression will be applied as in Section 5.2.3.1. As exploratory analyses, the same 
analyses for DOR will also be conducted using ITT-PFS set.  
5.2.4 Exploratory Efficacy Endpoints 
Analyses of the following exploratory endpoints will not be subject to formal type I error 
control and will be analyzed using conventional log rank statistical methods (i.e., 
rerandomization methods will not be used). Analyses for the exploratory endpoints may not 
be performed at time of primary analysis for PFS, depending on data availability. 


 
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5.2.4.1 Incidence of HER2 and Other Mutations 
The incidence of HER2 mutations and other tumor-related mutations will be summarized by 
treatment arm using counts and percentages. Cox proportional hazards regressions will be 
performed for the primary efficacy endpoint and the two key secondary endpoints. Each 
model will include treatment arm and type of mutation as independent variables and the time-
to-event variable as the dependent variable. Hazard ratios and 95% confidence intervals will 
be estimated. 
5.2.4.2 RANO-BM assessment for BM subgroup 
In the BM subgroup (as defined in Section 4.2) from the ITT analysis set, disease status in 
brain will be assessed by BICR using RANO-BM for brain metastases. The following 
exploratory endpoints will be evaluated for the BM subgroup. 
Objective Response Rate in Brain 
Objective response in brain is defined as achieving a best overall response of confirmed 
complete (CR) or confirmed partial response (PR) in brain. The proportion of subjects with 
objective response in brain (ORRBrain) will be calculated by treatment arm. ORRBrain will be 
summarized for subjects who had at least one measurable target lesion in brain at baseline as 
assessed by BICR. 
Duration of response in Brain 
Duration of response in brain (DORBrain) is defined as the time from the first objective 
response (CR or PR that is subsequently confirmed) in brain to documented disease 
progression (PD) in brain or death from any cause, whichever occurs first. Only subjects who 
achieve a confirmed response in brain will be included in the analysis. Kaplan-Meier 
estimates of the median (corresponding 95% confidence intervals) will be computed for each 
treatment arm. The same censoring rules as for primary PFS analysis will apply. 
Time to Progression in Brain 
Time to progression in brain is defined as the time from the date of randomization to the date 
of documented disease progression in brain. This endpoint will be evaluated using 
cumulative incidence methodology for competing risks treating non-brain progression and 
death as competing events. The treatment arm hazard ratio and 95% confidence interval will 
be estimated using a Cox proportional hazards regression model based on the following SAS 
sample code. 
** tte = Time to event; 
** Status (0=censored, 1=brain progression, 2=death or non-brain progression); 
** Trt = treatment arm; 
PROC PHREG DATA = ttedata; 
 
CLASS armcd(ref=’B’) param=glm; 
 
MODEL tte*status(0) = armcd / TIES=BRESLOW EVENTCODE=1; 


 
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HAZARDRATIO armcd; 
RUN; 
To designate brain progression (Status = 1) in the model, EVENTCODE = 1 is specified in 
the MODEL statement. 
5.3 Analysis of Safety 
All analyses of safety will be produced for the safety analysis set.  
5.3.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical or investigational product, in this case, tucatinib/placebo, capecitabine or 
trastuzumab. Per the study protocol all adverse events (AE) occurring during the study, 
whether or not attributable to study treatment, will be recorded in the subject’s source 
documents and eCRF. AE severity will be assessed and graded by the Investigator using 
Version 4.03 of the National Cancer Institute’s Common Toxicity Criteria for Adverse 
Events (CTCAE). In addition, the Investigator will also assess the relationship (related, not 
related) of each AE to capecitabine, trastuzumab, and tucatinib/placebo. All AEs will be 
coded by the Sponsor to standard “preferred terms” (PT) and system organ classifications 
(SOC) using MedDRA Version 22.0 or higher. 
Definitions 
Treatment-emergent adverse events (TEAE): Treatment-emergent AEs are defined as 
events that are new or worsened on or after receiving the first dose of study treatment 
(tucatinib/placebo, capecitabine or trastuzumab) and up through 30 days after the last dose of 
study treatment. 
Treatment-related adverse events: Adverse events assessed by the Investigator as ‘related’ 
to capecitabine, trastuzumab, or tucatinib/placebo. 
Summaries 
Adverse events will be summarized by PT or by SOC and PT for each treatment arm using 
counts and percentages. Multiple occurrences of the same adverse event within a subject will 
be summarized only once at the most severe grade level for the time frame under 
consideration. For summaries by severity, only the worst grade for an AE will be counted for 
a particular subject. 
Summaries to be produced include: 
● 
Incidence of TEAE by SOC and preferred term 
● 
Incidence of TEAE by decreasing frequency of preferred term 
● 
Incidence of TEAE by toxicity grade, SOC and preferred term 
● 
Incidence of grade 3 or higher of TEAE by decreasing frequency of preferred term 


 
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● 
Incidence of TEAEs which lead to premature discontinuation of study treatment by 
decreasing frequency of preferred term 
● 
Incidence of TEAEs which lead to dose interruption or dose reduction of study 
treatment by decreasing frequency of preferred term 
● 
Incidence of treatment related TEAEs by decreasing frequency of preferred term 
In addition to summary tables, the following listings will be produced. 
● 
All AEs 
● 
AEs which resulted in Death 
● 
AEs which lead to discontinuation of study treatment 
● 
Grade 3 or higher AEs 
5.3.2 Serious Adverse Events 
Serious adverse events (SAEs) will be summarized by preferred term and SOC for each 
treatment arm using counts and percentages. The following summaries of SAEs will be 
produced. 
● 
Incidence of treatment emergent SAEs (TESAEs) by decreasing frequency of 
preferred term 
● 
Incidence of TESAEs by decreasing frequency of SOC and preferred term 
● 
Incidence of treatment related TESAEs by decreasing frequency of preferred term 
In addition to summary tables, listings of SAEs will be produced. 
5.3.3 Adverse Events of Special Interest 
The incidence of treatment emergent adverse events of special interest will be summarized 
by treatment arm and preferred term or lab values and listings also produced. Adverse events 
of special interest to be summarized are described in the protocol Section 9.4.7.1 and are the 
following: 
AE of Special Interest 
Search Strategy 
Potential drug-induced liver injury 
• 
Laboratory abnormalities: LFTs meeting 
the following criteria - AST/ALT 
>3xULN and Bilirubin >2xULN occurring 
within 21 days 
Cerebral edema not clearly attributable to progression of disease  
• 
Brain oedema (PT) 
• 
Cytotoxic oedema (PT) 
• 
Vasogenic cerebral oedema (PT) 
Left ventricular systolic dysfunction leading to a change in study 
treatment or discontinuation of study treatment 
• 
Cardiomyopathy SMQ (Narrow) 
• 
Cardiac failure SMQ (Narrow) 
• 
Left Ventricular Ejection Fraction 
measurements by ECHO/MUGA 


 
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5.3.4 Clinical Laboratory Results 
Serum chemistry and hematology samples will be collected per protocol specified schedules. 
All laboratory results will be converted into Système International (SI) units for analysis and 
graded using the laboratory reference ranges and the criteria from NCI CTCAE (Common 
Terminology Criteria for Adverse Events, Version 4.03) by the Sponsor. For lab parameters 
ALT, AST, BILI, ALP, APTT and INR, the reference ranges from individual laboratories 
will be used if available; for other lab parameters, the Sponsor’s standard normal range will 
be used to perform toxicity grading. 
Incidence of Laboratory Toxicities 
The incidence of laboratory toxicities by grade will be summarized by treatment arm. For 
each test, only the worst (i.e., highest) toxicity grade will be counted for subjects with 
multiple toxicities within a time period (including scheduled and unscheduled assessments). 
The change of toxicity grade from baseline to worst baseline grade (shift table) will also be 
summarized. In addition to summary tables, listings of laboratory test results will be 
provided. 
Incidence of Liver Abnormalities 
The incidence of liver abnormalities will be summarized by treatment arm. A liver 
abnormality is defined as AST or ALT elevations that are >3 x ULN with concurrent 
elevation (same day or within 21 days following AST and/or ALT elevations) of total 
bilirubin >2 x the ULN. 
5.3.5 Ejection Fraction 
The minimal post baseline ejection fraction and the maximum decrease from baseline will be 
summarized for each treatment group. Time to minimal post baseline ejection fraction may 
also be tabulated. 
5.3.6 Vital Signs 
Vital signs (weight, body temperature, respiratory rate, heart rate, and systolic and diastolic 
blood pressure) will be listed. The frequency and percentage of patients with post baseline 
clinically significant vital signs will be summarized. The clinically significant vital signs are 
defined as:; heart rate >100 bpm; Temperature >38.0 degrees C (100.4 F) and respiratory rate 
>20 breaths per min. Blood pressure will be summarized both for subjects with systolic blood 
pressure >120 mmHg or diastolic blood pressure >80 mmHg, as well as for subjects with 
systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. 
For weight, the maximum decrease from baseline will also be summarized. 
5.3.7 Deaths 
Death information will be listed by subject. 


 
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5.4 Pharmacokinetic Analyses 
The analyses described in this section will be produced for the pharmacokinetics analysis set. 
Tucatinib and metabolite drug levels will be summarized with descriptive statistics at each 
PK sampling time point. The primary efficacy endpoint and the adverse events of special 
interest will be summarized by the quartiles of tucatinib trough concentration. Additional PK 
and PK/PD analyses may be performed and described in a separate pharmacometric analysis 
plan. 
5.5 Health Economics and Outcomes 
5.5.1 Health Care Resource Utilization 
Cumulative incidence of health resource utilization, including length of stay, hospitalizations, 
and ED visits will be summarized by treatment group in safety analysis set. 
5.5.2 Health-Related Quality of Life 
Health-related quality of life/health status using the EQ-5D-5L instrument will be analyzed 
for ITT-OS set. Figures may be produced for utility score and compliance with PRO 
completion (the number of completed surveys at each measure divided by number expected) 
over time by treatment group for ITT-OS analysis set. 
5.6 Interim Analyses 
No interim analyses for efficacy are planned for the primary endpoint. One formal interim 
analysis for superiority is planned for the key secondary endpoint of PFSBM and two formal 
interim analyses for superiority are planned for the key secondary endpoint of OS if the 
primary analysis for PFS is statistically significant. The second interim analysis for OS may 
not be conducted as described in Section 4.6. The interim analyses will be conducted at the 
timing described in Section 4.6. The stopping boundaries will be determined using Lan-
DeMets spending functions for the O'Brien and Fleming boundaries. See Section 4.7 for 
control of multiplicity. 
5.7 Changes in the Planned Analysis 
There are no changes from the planned analysis outlined in the protocol for this trial. 
 


 
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6 
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