Vanderbilt Clinical Trials

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion:

1. Patient is an adult 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 dose escalation 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 postmenopausal. 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 (i.e., no ERS1 mutation).

11. Patient is allowed prior PI3K treatment for patients otherwise eligible for
capivasertib treatment. Likewise, patient is allowed prior 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 received prior mammalian target of rapamycin (mTOR) inhibitor.

4. Patient has a known hypersensitivity to evexomostat, fulvestrant, alpelisib, or
capivasertib, or to any of their excipients.

5. Patient has an established diagnosis of type 1 diabetes mellitus or uncontrolled
(based on fasting plasma glucose [FPG] >140mg/dL or HbA1c ≥6.5%) type 2 diabetes or
has taken insulin in the 4 weeks prior to C1D1.

6. 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.

7. Patient has ongoing toxicities related to prior anti-cancer therapies that have not
resolved to ≤Grade 1, per National Cancer Institute Common Terminology Criteria for
Adverse Events, Version 5.0 (NCI CTCAE v.5.0), with the exception of alopecia.

8. Patient has a Child Pugh score of B or C.

9. Patient has uncontrolled human immunodeficiency virus (HIV) infection.

10. 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.

11. 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.

12. 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.

13. 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).

14. 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)

- Sulfonylureas

15. Patient has a history of acute pancreatitis within 1 year of screening or past
medical history of chronic pancreatitis.

16. 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).

17. 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).

18. Patient is currently receiving or has received systemic corticosteroids ≤4 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).