Abstract P3-08-18: The AmeliaTM-1 study: A phase 1b/2 study assessing the safety and efficacy of evexomostat (SDX-7320) plus a PI3K/Akt inhibitor and fulvestrant in patients with advanced HR+/Her2- breast cancer

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Abstract Clinical Rationale: Breast cancer patients with alterations in the PI3K pathway (eg, mutations in PIK3CA, Akt or loss of PTEN) have more aggressive disease and worse outcomes relative to patients without these alterations. Agents approved or in late-stage development for treating this patient population (alpelisib, capivasertib, inavolisib) can cause on-target hyperglycemia leading to hyperinsulinemia which may limit effectiveness of these drugs by overcoming pathway inhibition and/or secondary to reduced dose-density. Restoring insulin sensitivity (which reduces systemic levels of insulin) has been shown to improve the efficacy of PI3K inhibitors in preclinical models of breast cancer. Evexomostat is a polymer-drug conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor that in a xenograft model of HR+/Her2-/PIK3CA-mutant breast cancer showed synergistic anti-tumor activity with alpelisib, and in a xenograft model of HR+/Her2+ breast cancer enhanced the efficacy of capivasertib. Studies conducted in normal mice demonstrated that evexomostat significantly reduced hyperglycemia and hyperinsulinemia induced by these PI3K/Akt pathway inhibitors. Evexomostat was well-tolerated in a phase 1 monotherapy safety study in late-stage cancer patients and improved insulin resistance in patients with elevated insulin at baseline, along with improvements in other metabolic and angiogenic markers, Study Design: This is a phase 1b/2, open-label, single-arm proof-of-concept study in postmenopausal women with HR+, HER2- metastatic breast cancer harboring alterations in the PI3K pathway who progressed following endocrine therapy plus a CDK4/6 inhibitor (www.amelia1.com; NCT05455619). The primary objective is to determine the safety of evexomostat plus standard of care treatment (physician’s choice of alpelisib or capivasertib) and fulvestrant (combined, the ‘triplet therapy’), to measure the severity and number of hyperglycemic events, and to assess anti-tumor benefit of the triplet therapy. The trial consists of a dose-escalation cohort (n=6) with evexomostat dosed at 36 mg/m2 (one dose below the phase I monotherapy MTD of 49 mg/m2) in combination with either alpelisib or capivasertib and fulvestrant dosed in accordance with their respective labels. Based on safety data from the first 6 patients in each triplet combination to complete two cycles, the safety review committee may alter the evexomostat dose for the next safety cohort of six patients. Once the MTD of the triplet therapy is defined, additional patients will be enrolled until a total of up to 20 patients have completed at least two cycles of triplet therapy at that dose. If warranted, an additional 20 patients may be enrolled to further characterize the efficacy and safety of the triplet therapy. To date, eight patients have been enrolled. Planned Analyses: Primary safety analysis consists of the number of patients with grade 3 or 4 hyperglycemia during the first 2 cycles of triplet therapy plus the type, frequency, and severity of treatment-emergent adverse events (TEAEs) per the NCI CTCAE, v5.0. Efficacy analyses include calculation of the ORR, consisting of complete response (CR) and partial response (PR). The number of patients alive without disease progression six months from the start of evexomostat and fulvestrant dosing will also be assessed. The CBR of CRs, PRs plus stable disease ≥24 weeks from C1D1 will be calculated. QoL will be analyzed according to functional scores and recommendations in the EORTC scoring manual. ECOG performance status and change from baseline will be summarized. Citation Format: Peter Cornelius, David Browning, Benjamin Mayes, Pierre Dufour, James Shanahan, Bradley Carver, Margaret Fletcher, Hope S. Rugo, Srilata Gundala, Chaitali S. Nangia, Brent N. Rexer. The AmeliaTM-1 study: A phase 1b/2 study assessing the safety and efficacy of evexomostat (SDX-7320) plus a PI3K/Akt inhibitor and fulvestrant in patients with advanced HR+/Her2- breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-18.

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