Evexomostat Plus Alpelisib and Fulvestrant in Postmenopausal Women at Risk for Hyperglycemia With Breast Cancer

• Status: Not yet recruiting
• Trial end date: 2026-09-01
• Target enrollment: 0
• Participant gender: All

Summary

The PIK3CA gene is frequently mutated in breast cancer, leading to disease aggressiveness and patient mortality. Alpelisib, a small molecule that inhibits the activity of the PIK3CA gene product PI3Kα, has demonstrated clinical benefit in cancer patients with this gene mutation. However, hyperglycemia, an on-target toxicity associated with alpelisib that leads to hyperinsulinemia, limits the drug's clinical efficacy and induces high grade hyperglycemia in patients with baseline metabolic dysfunction, insulin resistance and/or elevated HbA1c. Restoring insulin sensitivity and reduction in circulating concentrations of insulin have been reported to improve the activity of alpelisib.

Evexomostat (SDX-7320) is a polymer-conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor that has demonstrated the ability to reduce alpelisib-induced hyperglycemia in multiple animal experiments and has demonstrated synergistic anti-tumor activity independent of changes in glucose or insulin. Evexomostat was well tolerated in a Phase 1 safety study in late-stage cancer patients and showed improvements in insulin resistance for patients that presented with baseline elevated insulin. Overall, the most common treatment-emergent adverse events with evexomostat (TEAEs) were fatigue (44%), decreased appetite (38%), constipation and nausea (each 28%), and diarrhea (22%). All other TEAEs occurred at an incidence <20%.

The purpose of this study is to characterize the safety of the triplet drug combination (alpelisib, fulvestrant plus evexomostat), to test whether evexomostat, when given in combination with alpelisib and fulvestrant will reduce the number and severity of hyperglycemic events and/or reduce the number of anti-diabetic medications needed to control the hyperglycemia for patients deemed at risk for alpelisib-induced hyperglycemia (baseline elevated HbA1c or well-controlled type 2 diabetes), and to assess preliminary anti-tumor efficacy and changes in key biomarkers and quality of life in this patient population.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: SynDevRx, Inc.

Criteria

Inclusion:

1. Patient is an adult ≥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 PIK3CA mutation status using a FDA-approved test, as determined either during Screening or was previously determined to have the mutation as evidenced by written documentation.

4. Patient has advanced (local regionally recurrent not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories:

Relapsed disease, with documented evidence of progressive disease (PD) more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently progressed, with documented evidence of PD while receiving or after one line of endocrine therapy plus a CDK 4/6 inhibitor for at least 12 months for their metastatic disease.

Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after only one line of endocrine therapy plus a CDK 4/6 inhibitor for at least 12 months.

Recurrent disease or PD while receiving or after aromatase inhibitor (AI) therapy (i.e., letrozole, anastrozole, exemestane) with co-treatment with a CDK 4/6 inhibitor for at least 12 months.

5. Patient has either measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or at least one evaluable predominantly lytic bone lesion

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 at least one of the following ADDITIONAL criteria must be met:

1. An HbA1c of ≥5.7 and ≤6.4% (39 and 47 mmol/mol), or

2. An HOMA-IR ≥1.8

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 agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (>8 hours) on designated fasting days.

11. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility):

Platelet count ≥140×10^9/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

Hemoglobin ≥ 9 g/dl

Absolute neutrophil count [ANC]) ≥1500/mL

Creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation

Albumin > 3.5 gm/dL

Exclusion:

1. Patient has inflammatory breast cancer at screening

2. Patient has known primary brain malignancy, brain metastasis or active central nervous system pathology, any of which as determined by the Investigator

3. Patient has received prior PI3K/Akt/mTOR inhibitor or fulvestrant treatment

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

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