Tucatinib, Trastuzumab, and Capecitabine With SRS for Brain Metastases From HER-2 Positive Breast Cancer

Inclusion Criteria:

1. Histologically confirmed HER-2 -positive breast cancer with newly-diagnosed brainmetastases.

2. ECOG Performance Status (PS) of 0, 1, 2

3. Patients with 1-10 brain metastases will be candidates for tucatinib, capecitabine,and trastuzumab with SRS at the discretion of the treating radiation oncologist.Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension

4. Age 18 years or greater and being willing and able to sign a written informedconsent. A signed informed consent must be obtained prior to any study specificprocedures

5. Life expectancy at least 12 weeks

6. Any number of prior systemic therapies will be allowed, except tucatinib andcapecitabine.

7. Hemoglobin ≥ 9g/dL, White blood count ≥3.0 × 10^9/ L , Absolute Granulocyte count ≥1.5x 10^9/ L and platelet count ≥100 × 10^9/ L.

8. Serum bilirubin ≤ 1.5 × ULN

9. AST and / or ALT <= 2 × ULN (≤ 5 × ULN when clearly attributable to the presence ofliver metastases)

10. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance > 60mL/min

11. Ability to comply with study procedures and monitoring

12. For women of childbearing potential, a negative pregnancy test should be obtainedwithin one week prior to the start of therapy

13. Male or female patients of reproductive potential need to employ two highlyeffective and acceptable forms of contraception throughout their participation inthe study and for 7 months after last dose of tucatinib, capecitabine andtrastuzumab.

Highly effective and acceptable forms of contraception are:

• Male condom plus spermicide

• Cap plus spermicide

• Diaphragm plus spermicide

• Copper T

• Progesterone T

• Levonorgestrel-releasing intrauterine system (e.g., Mirena®)

• Implants

• Hormone shot or injection

• Combined pill

• Mini-pill

• Patch

Postmenopausal woman on the study (that will not need contraception) is defined as:

• Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments

• LH and FSH levels in the postmenopausal range for women under 50

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with >1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy).

Men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

1. Patients with leptomeningeal metastases documented by MRI or CSF evaluation

2. Evidence of intra-tumoral or peri-tumoral hemorrhage deemed significant by thetreating physician

3. Brain metastases within 5 mm of the optic chiasm or optic nerve

4. Significant or recent acute gastrointestinal disorders with diarrhea as a majorsymptom, e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of anyetiology at baseline

5. History of clinically significant or uncontrolled cardiac disease, includingcongestive heart failure, angina, myocardial infarction, arrhythmia, New York HeartAssociation (NYHA) functional classification of 3 or 4

6. Unable to undergo brain MRI

7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C

8. All toxicities from prior therapies must have resolved to CTCAE v 5.0 grade 1 orbetter by the time of study enrollment

9. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,active or uncontrolled infection, uncontrolled diabetes, second active malignancy)that could cause unacceptable safety risks or compromise compliance with theprotocol

10. Currently receiving other investigational cancer therapy within 4 weeks prior tostart of study treatment with the exception of continuing therapy with GnRHanalogues

11. Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3electrocardiograms using Frediricia's Correction

12. Left ventricular ejection fraction (LVEF) <50%

13. Concomitant use of strong cytochrome P450 (CYP)3A inhibitors including macrolideantibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., ritonavir), and Nefazodone

14. Concomitant use of strong CYP2C8 inhibitor within 5 half-lives of the inhibitor

15. Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin,carbamazepine, St. John's Wort) within 5 days prior to the first dose of studytreatment

16. Concomitant use of a strong CYP2C8 inducer within 5 days prior to the first dose ofstudy treatment

17. History of hypersensitivity to tucatinib, capecitabine, and trastuzumab, or any ofits excipients

18. History and/or confirmed corneal ulceration

19. Pregnant or breast feeding

20. Use of anthracyline will be prohibited on the protocol