Study of Tucatinib and Doxil in Participants with Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Metastatic Breast Cancer

Inclusion Criteria:

• Written informed consent, according to local guidelines, signed and dated by thepatient or by a legal guardian prior to the performance of any study-specificprocedures, sampling, or analyses

• At least 18 years-of-age at the time of signature of the informed consent form (ICF)

• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1

• Have a confirmed diagnosis of locally advanced/metastatic HER2+ breast cancer (basedon local laboratory testing per American Society of Clinical Oncology (ASCO)/Collegeof American Pathologists (CAP) guidelines immunohistochemistry 3+ (IHC3+) orfluorescence in situ hybridization + (FISH+))

• Have had prior treatment with at least 1 line of anti-HER2 therapy for locallyadvanced/metastatic disease or relapsed within 6 months of completion of adjuvantanti-HER2 therapy. Prior treatment with tucatinib in the metastatic setting isallowed

• Measurable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

• Females of child-bearing potential should be using adequate contraceptive measuresfrom the time of screening until 6 months following the last dose of study drug(s),should not be breast feeding and must have a negative pregnancy test prior to startof dosing, or must have evidence of non-child-bearing potential by fulfilling one ofthe following criteria at screening:

• Post-menopausal: defined as aged more than 50 years and amenorrheic for atleast 12 months following cessation of all exogenous hormonal treatments

• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy, but not tubal ligation

• Women under 50 years-of-age will be considered postmenopausal if they have beenamenorrheic for at least 12 months following the cessation of exogenoushormonal treatments, and have serum follicle-stimulating hormone andluteinizing hormone levels in the postmenopausal range for the institution.

• Male patients with female partners of childbearing potential and female patients ofchildbearing potential are required to use two forms of acceptable contraception,including one barrier method, during their participation in the study and for 6months following last dose. Male patients must also refrain from donating spermduring their participation in the study.

• Adequate hematologic function

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelet count ≥100,000/µL (no transfusions allowed to meet this requirement)

• Hemoglobin ≥9 g/dL (at least 2-week washout from any transfusion)

• Adequate hepatic function

• Total bilirubin ≤1.5 × upper limit of normal (ULN). Exception: participantswith known history of Gilbert's Syndrome who have a direct bilirubin ≤1.5 × ULNin addition to a normal aspartate aminotransferase (AST) and alanineaminotransferase (ALT) are eligible.

• AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present)

• Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2

• Left ventricular ejection fraction (LVEF) ≥50% based on screening echocardiogram (ECHO)/multigated acquisition (MUGA)

• Central nervous system (CNS) Inclusion - Based on screening contrast brain magneticresonance imaging (MRI), patients must have one of the following:

• No evidence of brain metastases

• Untreated brain metastases not needing immediate local therapy. For patientswith untreated CNS lesions >2.0 cm on screening contrast brain MRI, discussionwith and approval from the Medical Monitor is required prior to enrollment.

• Relevant records of any CNS treatment must be available to allow forclassification of target and non-target lesions.

• Previously treated brain metastases:

• Brain metastases previously treated with local therapy may either be stable sincetreatment or may have progressed since prior local CNS therapy, provided that thereis no clinical indication for immediate re-treatment with local therapy in theopinion of the Investigator.

• Patients treated with CNS local therapy for newly identified lesions found oncontrast brain MRI performed during screening for this study may be eligible toenroll if all of the following criteria are met:

• Time since whole brain radiotherapy (WBRT) is ≥14 days prior to first dose oftreatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to first doseof treatment, or time since surgical resection is ≥28 days

• Other sites of disease assessable by RECIST 1.1 are present

Exclusion Criteria:

• Treatment with any of the following:

• Any systemic anti-cancer chemotherapy or small molecule, biologic, or hormonalagent from a previous treatment regimen or clinical study within 21 days or 5half-lives (whichever is longer) prior to the first dose of study drugs. Atleast 10 days must have elapsed between the last dose of such agent and thefirst dose of study drugs.

• Prior treatment with anthracycline in any setting

• Major surgery (excluding placement of vascular access) within 28 days of firstdose of study drugs

• Palliative radiation therapy within 14 days of first dose of study drugs

• Based on screening brain MRI, patients must not have any of the following:

• Any untreated brain lesions >2.0 cm in size, unless discussed with the MedicalMonitor and approval for enrollment is granted

• Ongoing use of systemic corticosteroids for control of symptoms of brainmetastases at a total daily dose of >2 mg of dexamethasone (or equivalent).However, patients on a chronic stable dose of ≤2 mg total daily ofdexamethasone (or equivalent) may be eligible with discussion and approval bythe Medical Monitor

• Any brain lesion thought to require immediate local therapy, including (but notlimited to) a lesion in an anatomic site where increase in size or possibletreatment-related edema may pose risk to patient (e.g., brain stem lesions).Patients who undergo local treatment for such lesions identified by screeningcontrast brain MRI may still be eligible for the study based on criteriadescribed under CNS inclusion criteria 14c

• Known or suspected leptomeningeal disease (LMD) as documented by theInvestigator

• Have poorly controlled (>1 week) generalized or complex partial seizures, ormanifest neurologic progression due to brain metastases, notwithstandingCNS-directed therapy.

• Use of a strong cytochrome P450 (CYP)2C8-inhibitor or use of a strong CYP3A4 or useof a CYP2C8 inducer within 5 days prior to the first dose of study treatment

• With the exception of alopecia, any unresolved toxicities from prior therapy greaterthan CTCAE Grade 1 at the time of starting study treatment. Note: patients withchronic Grade 2 toxicities who are asymptomatic or adequately managed with stablemedication may be eligible with approval by the Medical Monitor.

• Women who are pregnant or nursing or plan to become pregnant while in the study andfor at least 6 months after the last administration of study treatment

• Men who plan to father a child while in the study and for at least 6 months afterthe last administration of study treatment

• Presence of active gastrointestinal disease or other condition that will interferesignificantly with the absorption, distribution, metabolism, or excretion oftucatinib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, malabsorption syndrome)

• Any of the following cardiac criteria:

• Mean resting QT interval with QT corrected for heart rate by Fridericia'sformula [QTcF]) prolongation to >480 msec for females and >460 msec for malesin three successive screening measures

• Any clinically important abnormalities (as assessed by the Investigator) inrhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g.,complete left bundle branch block, third-degree heart block

• Congestive heart failure (New York Heart Association ≥ Grade 2 within past 6months)

• Patients with a left ventricular ejection fraction (LVEF) <50% or the lowerlimit of normal of the institutional standard

• As judged by the Investigator, any evidence of severe or uncontrolled systemicdiseases, including uncontrolled hypertension, uncontrolled diabetes mellitus,active bleeding diatheses, or active infection, including hepatitis B and hepatitisC. Screening for chronic conditions is not required.

• Known human immunodeficiency virus (HIV) infection or positivity on immunoassay.Testing for seropositive status during screening will be at the discretion of theInvestigator for subjects without previously reported results.

• Presence of other active invasive cancers other than the one treated in this studywithin 3 years prior to screening, except appropriately treated basal cell carcinomaof the skin, in situ carcinoma of uterine cervix, or other local tumors consideredcured by local treatment

• Psychological, familial, sociological, or geographical conditions that do not permitcompliance with the protocol and/or follow-up procedures outlined in the protocol.