Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer — Amelia-1  

Metastatic Breast Cancer Clinical Trial

Official title: Phase 1b/2 Study of the Safety and Efficacy of Evexomostat Plus Alpelisib and Fulvestrant in Postmenopausal Women at Risk for Hyperglycemia With Advanced Breast Cancer and a PIK3CA Mutation Following Endocrine Therapy and a CDK4/6 Inhibitor

Status Recruiting

Clinical Trial 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.

Clinical Trial Description

This is a Phase 1b/2, open-label, single-arm pilot study in post-menopausal women with HR+, HER2- advanced or metastatic breast cancer with a mutation of the PIK3CA gene at risk for hyperglycemia designed to determine the safety of the combination of evexomostat plus standard of care treatment alpelisib (PIQRAY®/BYL-719) and fulvestrant (combined, the 'triplet therapy'), to measure the severity and number of hyperglycemic events, and to assess the anti-tumor benefit of the triplet therapy. Up to 52 patients may be enrolled, starting with dose-escalation cohort(s) of 6 patients each. Once the maximum tolerated dose (MTD) of the triplet therapy has been defined, 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. If warranted, an additional 20 patients may be enrolled to further characterize the safety profile and/or anti-tumor effect of the 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 alpelisib and fulvestrant given at the marketed doses. Based on aggregate safety data from the first two cycles of the first 6 patients, in the absence of ≥ 2 dose-limiting toxicities (DLTs), 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 will decrease the evexomostat dose to 27 mg/m2 and may adjust the dose of alpelisib if warranted. The dose of fulvestrant will not be adjusted. If the evexomostat dose of 49 mg/m2 is determined not to be tolerable in combination with alpelisib and fulvestrant, then current and future patients will receive evexomostat at 36 mg/m2. In the event of significantly low drug exposure of the active moiety SDX-7539 (C24 < 200 pg/mL) at evexomostat 49 mg/m2, coupled with poor biomarker response (e.g., little/no change in insulin/leptin/adiponectin from baseline) and a favorable safety profile, the SRC in consultation with the Investigator(s) and Sponsor may elect to enroll an additional cohort at 65 mg/m2, which would become the future dose in the combination if tolerated. Subsequent cumulative safety data will be reviewed on a calendar quarterly basis Patients will remain on study for up to 7 cycles on the triplet therapy to characterize the safety and tolerability of the triplet therapy as well as to capture initial efficacy data (i.e., ORR and PFS following 6 months of the triplet therapy). Patients will be allowed to remain on the triplet therapy beyond the initial 7 cycles if they are receiving clinical benefit, including stable disease, as determined by their treating oncologist. The study will consist of a 14-day pre-treatment phase of evexomostat plus fulvestrant starting on Cycle 1, Day 1 (C1D1) before adding alpelisib on C1D15. ;

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