Evexomostat Plus PI3K or AKT Inhibitor and Fulvestrant in Women With a PI3K Alteration and HR+/Her2- Breast Cancer — Amelia-1  

Metastatic Breast Cancer Clinical Trial

Official title: Study to Assess the Safety and Efficacy of Evexomostat (SDX-7320) in Combination With A PI3K or Akt Inhibitor Plus Fulvestrant in Patients With HR+, HER2-, Metastatic Breast Cancer With PI3K Pathway Alteration(s)

Status Recruiting

Clinical Trial Summary

This is a Phase 1b/2, open-label, parallel-arms pilot study in 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.

Clinical Trial Description

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/ mammalian target of rapamycin (mTOR) pathway (André 2019, Turner 2023). However, hyperglycemia, a toxicity associated with PI3K and/or Akt inhibition, leads to hyperinsulinemia, re-activating the pathway and thereby limiting each drug's clinical efficacy. Management of hyperglycemia is important to ensure patients receive optimal anti-tumor therapy (Rugo 2020). Restoring insulin sensitivity and reducing levels of insulin have been suggested as ways to blunt the hyperglycemia associated with drugs that inhibit this pathway and have been reported to improve their efficacy (Hopkins 2018, Crouthamel 2009).

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.

This is a Phase 1b/2, open-label, parallel-arms pilot study in 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 study will consist of a 14-day pre-treatment phase of evexomostat plus fulvestrant starting on C1D1 before adding either alpelisib or capivasertib on C1D15. The Triple Therapy treatment schedule is summarized in the following table. Tumor assessments will be conducted as a function of when the triplet therapy starts.

Up to 52 patients for each combination arm may be enrolled, starting with dose-escalation cohorts of up to 6 patients for each combination arm. Once the maximum tolerated dose (MTD) of the triplet therapy has been defined for each combination, additional patients will be enrolled until a total of up to 20 patients have completed at least two cycles of the triplet therapy at that dose and combination. If warranted, up to an additional 20 patients may be enrolled to further characterize the safety profile and/or anti-tumor effect of each triplet therapy.

The planned escalation scheme starts at an evexomostat dose of 36 mg/m2 (one dose below the monotherapy MTD of 49 mg/m2) in combination with either alpelisib or capivasertib and fulvestrant given at the marketed doses. Based on aggregate safety data from the first two cycles of the first 6 patients across each triplet combination, and in the absence of ≥ 2 dose-limiting toxicities (DLTs as defined herein), the Safety Review Committee (SRC), in consultation with the Sponsor and the Investigator(s), may increase the evexomostat dose for the next cohort to 49 mg/m2. In the presence of ≥2 DLTs, the SRC may decrease the evexomostat dose to 27 mg/m2 and may adjust the dose of either alpelisib or capivasertib if warranted. The dose of fulvestrant will not be adjusted. If the evexomostat dose of 49 mg/m2 is determined by the SRC not to be tolerable in combination with either alpelisib or capivasertib and fulvestrant, then current and future patients for only their respective combination treatment will receive evexomostat at 36 mg/m2.

Patients will remain on study for up to 7 cycles to characterize the safety and tolerability of the triplet therapy as well as to capture initial efficacy data (e.g., progression-free survival [PFS] following 6 months of the triplet therapy). Patients will be allowed to continue on the triplet therapy if they are receiving clinical benefit, including stable disease, as determined by their treating oncologist. ;

Related Conditions & MeSH terms

• Breast Neoplasms
• HR+/HER2-negative Breast Cancer
• Metastatic Breast Cancer

• NCT number: NCT05455619
• Study type: Interventional
• Source: SynDevRx, Inc.
• Contact: David Browning
• Phone: +1-615-975-7776
• Email: dbrowning@syndevrx.com
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 26, 2022
• Completion date: September 2026