• Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC)

• Have received previous treatment with trastuzumab, a taxane and trastuzumab deruxtecan in the metastatic setting or have recurred within 6 months of receiving these treatments in the adjuvant or neoadjuvant setting. Prior capecitabine and T-DM1 is not required. Prior tucatinib therapy is allowed. Patients for whom Trastuzumab is contraindicated are not permitted. Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by site investigator),or be intolerant of last systemic therapy.

• Have measurable or non-measurable disease assessable by RECIST 1.1

• Be at least 18 years of age at time of consent.

• Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0,1 or 2

• Have a life expectancy of at least 6 months, in the opinion of the site investigator.

• Have adequate hepatic function as defined by the following:

∙ 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

‣ 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)

• Have adequate baseline hematologic parameters as defined by:

∙ Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL

‣ 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,

‣ Hemoglobin ≥ 9 g/dL

‣ 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,

• 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,

⁃ 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.)

⁃ 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.

⁃ 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.

⁃ NOTE: 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

⁃ 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.

⁃ 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.

⁃ Patients must be willing and able to comply with study procedures.

• CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), patients must have one of the following:

• No evidence of brain metastases

• 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,

• 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 site 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, iii. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions