Clinical Trial of Alpelisb and Tucatinib in Patients With PIK3CA-Mutant HER2+ Metastatic Breast Cancer.

Criteria: Inclusion criteria:

1. Women and men ≥ 18 years old are eligible to enroll
2. ECOG performance status 0-1
3. Life expectancy of more than 6 months, in the opinion of the investigator
4. Histologically confirmed diagnosis of HER2+ locally advanced unresectable ormetastatic breast cancer. HER2 positivity is defined by fluorescence in situhybridization (FISH) and/or 3+ staining by IHC according to the latest ASCO/CAPguidelines.
5. Documented presence of activating mutation in PIK3CA in the tumor, based on theanalysis of solid or liquid biopsy by an assay approved for clinical decision makingbyan FDA-approved test (examples include FoundationOne Liquid®; Guardant360®,Therrascreen® PIK3CA).
6. Known ER and PR status of the tumor defined by IHC according to the latest ASCO/CAPguidelines
7. Patients with HR-/HER2+ or HR+/HER2+ breast cancer may enroll
8. HR+/HER2+ patients should be men or post-menopausal women; premenopausal women withHR+/HER2+ breast cancer are eligible if on ovarian suppression, or agreeable tomandatory ovarian suppression
9. HR+/HER2+ patients should be agreeable to concomitant treatment with fulvestrant perstudy protocol. Prior therapy with fulvestrant is allowed.
10. Patients should have received at least two FDA-approved HER2-targeted agents at anytime in the course of their disease. Note: 1 line of therapy containing EGFR orHER2-tyrosine kinase inhibitors (for example, neratinib, tucatinib, lapatinib,afatinib, pyrotinib, etc.) in the metastatic setting is allowed
11. Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria (appendix C). Bone only disease is allowed.
12. CNS inclusion criteria: Based on screening contrast brain MRI, patients must have one of the following:
13. No evidence of brain metastases 2. Untreated brain metastases not needing immediatelocal therapy. For patients with untreated CNS lesions > 2.0 cm on screening contrast brainMRI, discussion with and approval from the medical monitor is required prior to enrollment
14. Previously treated brain metastases a. Brain metastases previously treated with local therapy may either be stable sincetreatment or may have progressed since prior local CNS therapy, provided that there is noclinical indication for immediate re-treatment with local therapy in the opinion of theinvestigator b. Patients treated with CNS local therapy for newly identified lesions foundon contrast brain MRI performed during screening for this study may be eligible to enrollif all of the following criteria are met: i. Time since WBRT is ≥ 21 days prior to firstdose of treatment, time since surgical resection of CNS metastases is ≥ 14 days prior tothe first dose of study treatment, or time since SRS is ≥ 7 days prior to first dose oftreatment. ii. Other sites of disease evaluable by RECIST 1.1 or RANO-BM are present c. Relevantrecords of any CNS treatment must be available to allow for classification of target andnon-target lesions. 13. Adequate organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1,500/mm3
• Platelets ≥ 75,000/mm3
• Hemoglobin ≥ 9.0 mg/dL without red blood cell transfusion ≤ 7 days prior to Cycle 1Day 1 of therapy
• Total serum bilirubin ≤ 1.5 X upper limit of normal (ULN) except for subjects withknown Gilbert's disease, who may enroll if the conjugated bilirubin is ≤ 1.5 ULN
• AST (SGOT)/ALT (SGPT) ≤2.5 X ULN;
• Serum creatinine Estimated creatinine clearance ≥50 mL/min as calculated byCockroft-Gault formula; actual body weight must be used for creatinine clearancecalculations unless BMI > 30 kg/m2 then lean body weight must be used;≤ 1.5 mg/dL
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT
• Fasting blood glucose ≤140 mg/dL
• HbA1C≤6.4%
• Left ventricular ejection fraction (LVEF) ≥ 50% (as assessed by ECHO or MUGA)documented within 4 weeks prior to first dose of study treatment
• Serum or urine pregnancy test (for women of childbearing potential, defined aspremenopausal women who are not permanently sterile due to hysterectomy, bilateraloophorectomy, bilateral tubal ligation, or bilateral tubal occlusion) negative ≤ 7days of starting treatment 14. Patients with body mass index >25, or FBG 110-140mg/dL,or HbA1C 5.7 - 6.4% should be agreeable for low glycemic diet and lifestylemodifications, and consulted by nutritionist prior to initiation of the study drugs.Ability to understand and the willingness to sign a written informed consent andcomply with the study scheduled visits, treatment plans, laboratory tests and otherprocedures.

Exclusion criteria:

1. Patients with contraindications to undergo contrast MRI imaging of the brain areexcluded from the study
2. Pregnancy or breast feeding
3. Any systemic anti-cancer therapy (including hormonal therapy or investigationalagents) or surgery in <14 days prior to the first dose of study treatment WBRT in <21days, SBRT for CNS disease in <7 days, or palliative radiation to extracranial sitesin <14 days prior to the first dose of study treatment5.
4. Based on screening brain MRI, patients must not have any of the following:
5. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor andapproval for enrollment is given 2. Ongoing use of systemic corticosteroids for control ofsymptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (orequivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily ofdexamethasone (or equivalent) may be eligible with discussion and approval by the medicalmonitor 3. 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 whoundergo local treatment for such lesions identified by screening contrast brain MRI maystill be eligible for the study based on criteria described under CNS inclusion criteria 3b
6. Known or suspected leptomeningeal disease as documented by the investigator 5. Havepoorly controlled (> 1/week) generalized or complex partial seizures, or manifestneurologic progression due to brain metastases notwithstanding CNS-directed therapy 5. Anytoxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with theexception of peripheral neuropathy, which must have resolved to ≤ Grade 2, and alopecia 6.More than 1 line of therapy containing tucatinib, lapatinib, neratinib, afatinib,pyrotinib, or other EGFR or HER2 tyrosine kinase inhibitor in the metastatic setting. Note:receiving the above medications for <30 days is not considered to be a "line of therapy".Adjuvant treatment with EGFR or HER2 tyrosine kinase inhibitors does not count.
7. Previous treatment with alpelisib or other PI3K, mTOR or AKT inhibitor of more than 30days duration.
8. An established diagnosis of diabetes mellitus type I, or uncontrolled diabetes mellitustype II 9. History of acute pancreatitis within 1 year of screening, or a past medicalhistory of chronic pancreatitis 10. History of severe cutaneous hypersensitivity reactions (Steven Johnson syndrome, erythema multiforme or toxic epidermal necrolysis) 11. Activebacterial, fungal or viral infections requiring treatment with IV antibiotic, IVanti-fungal, or IV anti-viral drugs 12. Known active hepatitis B (HBV) or, active hepatitisC (HCV) or human immunodeficiency virus (HIV) infections. Note: pretesting is not required.Patients with history of treated and cured HCV infection may enroll if they have documentedundetectable viral load.
9. Known HIV infection with CD4+ T-cell (CD4+) counts < 350 cells/μL. Note: pretesting isnot required. Patients with known HIV infection and CD4+ T-cell (CD4+) counts ≥ 350cells/μL may enroll.
10. Inability to swallow pills or any significant gastrointestinal disease which wouldpreclude the adequate oral absorption of medications 15. Use of prohibited medicationslisted in the Appendix D (strong CYP3A4 inducers or inhibitors, and strong CYP2C8 inducersor inhibitors) within 3 elimination half-lives prior to initiation of study treatments 16.Myocardial infarction, severe/unstable angina, percutaneous transluminal coronaryangioplasty/stenting (PTCA), or coronary artery bypass graft (CABG) within 6 month of thefirst dose of the study treatment 17. Clinically significant cardio-vascular disease, suchas ventricular arrhythmia requiring therapy, uncontrolled hypertension (defined aspersistent systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hgon antihypertensive medications), or any history of symptomatic congestive heart failure (CHF) 18. Other severe acute or chronic medical or psychiatric conditions or laboratoryabnormalities that may increase the risk associated with study participation or study drugadministration, or may interfere with the interpretation of study results, or in thejudgment of the investigator would make the subject inappropriate for entry into the study.