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

About this study

This is a Phase 1b/2, open-label, parallel-arms pilot study in men and post-menopausal women with hormone receptor positive (HR+), HER2- advanced or metastatic breast cancer with an alteration in the PI3K pathway, including a mutation of the PIK3CA gene, PTEN loss, or AKT1 mutation, designed to determine the safety of evexomostat (SDX-7320) plus standard of care treatment alpelisib (BYL-719) or capivasertib and fulvestrant (each combined, the 'triplet therapy'), to measure the severity and number of hyperglycemic events, and to assess clinical, anti-tumor benefit of the triplet therapy. The purpose of this study is: * to characterize the safety of the triplet drug combination consisting of either alpelisib or capivasertib (per the treating oncologist's choice) and fulvestrant plus evexomostat, * to test whether evexomostat, when given in combination with either alpelisib or capivasertib and fulvestrant will reduce the number and severity of hyperglycemic events and/or reduce the number or dose of anti-diabetic medications needed to control the hyperglycemia for metabolically normal patients and those deemed at risk for capivasertib and alpelisib-induced hyperglycemia (insulin resistance, as measured by HOMA-IR, baseline elevated HbA1c or well-controlled type 2 diabetes), and * to assess preliminary anti-tumor efficacy for each combination and changes in key biomarkers and quality of life in this patient population.

Phosphoinositide 3-kinase (PI3K) pathway alterations frequently occur in breast cancer, conferring growth advantages to cancer cells via increased catalytic activity of various related proteins, such as protein kinase B (AKT) or via the loss of function of the negative regulator phosphatase and tensin homolog (PTEN) (He 2021). Of these alterations, the PIK3CA gene is most frequently mutated, leading to disease aggressiveness and patient mortality. Currently approved treatments targeting this pathway include alpelisib, a small molecule that inhibits the activity of the PIK3CA gene product PI3Kα, and capivasertib, a small molecule that targets the AKT protein. Both molecules have demonstrated similar clinical benefit in cancer patients with genetic alterations that activate the PI3K/Akt/ mam…

• Hoag Memorial Hospital Presbyterian

  Newport, California

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• Loma Linda University Cancer Center

  Loma Linda, California

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• Miami Cancer Institute at Baptist Health

  Miami, Florida

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• Penn State Milton S Hershey Medical Center

  Hershey, Pennsylvania

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• Vanderbilt University Medical Center

  Nashville, Tennessee

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