Evexomostat Plus PI3K or AKT Inhibitor and Fulvestrant in Patients With a PI3K Alteration and HR+/Her2- Breast Cancer

Inclusion: 1. Patient is an adult male or postmenopausal female ≥18 years old at the time of informed consent(s) and has signed informed consent(s) before any trial related activities and according to local guidelines. 2. Patient with histologically and/or cytologically confirmed diagnosis of HR+, HER2- breast cancer, as determined by the local laboratory. 3. Patient has identified PI3K pathway alteration, defined as a PIK3CA mutation or PTEN loss or an AKT1 mutation using a Food and Drug Administration (FDA)-approved test, as determined either during Screening or was previously determined to have the alteration as evidenced by written documentation. 4. Patient has locally advanced (not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories: * Relapsed disease, not amenable to curative therapy, with documented evidence of progressive disease (PD) following receipt of both (neo) adjuvant endocrine therapy and a CDK 4/6 inhibitor therapy (either alone or in combination with endocrine therapy) in the early stage or metastatic setting. * Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after endocrine therapy plus a CDK 4/6 inhibitor. 5. Patient has measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. For bone lesions, lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) can be considered as measurable lesions if the soft tissue component meets the definition of measurability per RECIST 1.1. Blastic bone lesions are non-measurable. For bone metastases only (without measurable lesions), patients may be accrued to the safety Cohorts only. 6. Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1 7. Patient has a Screening fasting plasma glucose (FPG) level ≤140 mg/dL (7.7 mmol/L) and an HbA1c ≤6.4% (47 mmol/mol) for those taking alpelisib, or an HbA1c \<8% (64 mmol/mol) for those taking capivasertib. 8. Patient has a body mass index (BMI) ≥ 20 kg/m2. 9. Patient is male or postmenopausal female. Postmenopausal is defined as any of the following: * ≥45 years of age and has not had menses for \>2 years. * Amenorrheic for \>2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation. * Post hysterectomy with oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. In case of oophorectomy alone, hormone level assessment (follicle-stimulating hormone, estradiol) will be done locally at Screening to confirm postmenopausal status. Patients who are on ovarian function suppression also qualify. 10. Patient is allowed prior fulvestrant treatment, provided they remain eligible for fulvestrant treatment. Patients whose disease progressed while receiving fulvestrant monotherapy are not allowed. 11. Patient is allowed prior mTOR or PI3K inhibitor treatment for patients otherwise eligible for capivasertib treatment. Likewise, patient is allowed prior mTOR or AKT treatment if they are otherwise eligible for alpelisib treatment. 12. Patient is allowed up to one (1) prior chemotherapy for their metastatic disease. 13. Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (\>8 hours) on designated fasting days. 14. Patient has adequate bone marrow and organ function as defined by the following laboratory values: * Platelet count ≥140×109/L * In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST ≤5×ULN. * Total bilirubin ≤1.5×ULN except for patient with Gilbert's syndrome who may only be included if the total bilirubin is ≤3.0×ULN or direct bilirubin ≤1.5×ULN. * Fasting serum amylase ≤2×ULN. * Fasting serum lipase ≤1.5×ULN. * Hemoglobin ≥ 9 g/dL. * Absolute neutrophil count (ANC) ≥1500/mL. * Creatinine clearance ≥ 50 mL/min using either the Cockcroft-Gault equation or the CKD-EPI formula for calculation of eGFR, or has chronic kidney disease (CKD) grade ≤1 as evidenced by a treating nephrologist. Alternatively, a 24-hour urine test can be performed to confirm renal sufficiency. * Albumin ≥ 3.5 gm/dL. 15. Patient is able to take oral medications. Exclusion: 1. Patient has inflammatory breast cancer at screening. 2. Patient has known primary brain malignancy, active brain metastasis or active central nervous system pathology or is considered by the Investigator to be neurologically unstable. Furthermore, patients must not have received corticosteroids within 4 weeks of study entry and must have unchanged brain CT or MRI findings for at least two months prior to screening. 3. Patient has a known hypersensitivity to evexomostat, fulvestrant, alpelisib, or capivasertib, or to any of their excipients. 4. Patient has an established diagnosis of type 1 diabetes mellitus or uncontrolled (based on fasting plasma glucose \[FPG\] \>140mg/dL or HbA1c ≥6.5% for patients assigned alpelisib) or HbA1c for patients assigned to capivasertib, type 2 diabetes or has taken insulin in the 4 weeks prior to C1D1. 5. Patient has had major surgery within 30 days or minor surgery within 14 days prior to the first study drug dose, or has not recovered from major side effects from prior surgery. 6. Patient has ongoing toxicities related to prior anti-cancer therapies that have not resolved to Grade 0 for bone marrow toxicities or ≤Grade 1 for other toxicities, per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v.5.0), with the exception of alopecia. 7. Patient has a Child Pugh score of B or C. 8. Patient has uncontrolled human immunodeficiency virus (HIV) infection. 9. Patient has received radio therapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to enrollment, and who has not recovered to ≤Grade 1 from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥25 percentage of bone marrow was irradiated. 10. Patient has a concurrent malignancy other than breast cancer or had a malignancy other than breast cancer within 2 years of enrollment, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. 11. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the drug alpelisib or capivasertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, gastric bypass or small bowel resection) based on Investigator discretion. 12. Patient has currently documented or unresolved pneumonitis/interstitial lung disease (the chest computed tomography \[CT\] scan performed before start of study treatment for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present). 13. Patient is currently receiving any of the following medications and cannot be discontinued at least 7 days prior to the start of the treatment: * Strong cytochrome P450 3A4 (CYP3A4) inducers * Inhibitors of breast cancer resistance protein (BCRP) * Sulfonylurea-based anti-diabetic drugs (e.g., glipizide, glyburide, etc.) 14. Patient has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis. 15. Patient has unresolved osteonecrosis of the jaw (unless they are being considered for treated with capivasertib - i.e., this exclusion is only for patients being considered for alpelisib). 16. Patient has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS). 17. Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses (PO or IV), topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular). 18. Patient is nursing (lactating) or pregnant confirmed by a positive serum (hCG) test prior to initiating study treatment. 19. Patient participated in a prior investigational study within 21 days prior to the start of study treatment or within 5 half-lives of the investigational product, whichever is longer. 20. Patient has any other concurrent, severe and/or uncontrolled medical condition that would, in the Investigator's judgement, contra-indicate patient participation in the clinical study (e.g., chronic active hepatitis, severe hepatic impairment, recent cardiac events, uncontrolled heart disease) 21. Patient is not able to understand nor to comply with study instructions and requirements, including fasting requirements.