The Amelia-1 study: A phase 1b/2 trial of evexomostat (SDX-7320) plus fulvestrant and alpelisib in patients with advanced breast cancer at risk for alpelisib-induced hyperglycemia.
Authors: Cornelius Peter , Salomon Neal , Browning David , Mayes Benjamin , Dufour Pierre , Fletcher Margaret S. , Shanahan James , Carver Bradley , Rugo Hope S. 
Published: June 2023

TPS1129 Background: Alpelisib, a selective PI3K p110a inhibitor, was approved for breast cancer patients with PIK3CA mutations. An on-target toxicity of alpelisib is hyperglycemia and patients with baseline insulin resistance/elevated HbA1c are at greater risk of developing grade 3,4 hyperglycemia after receiving alpelisib. Restoring insulin sensitivity and reducing systemic insulin levels improved the efficacy of alpelisib in animal models of breast cancer. Evexomostat is a polymer-drug conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor. In normal mice, it reduced alpelisib-induced hyperglycemia/hyperinsulinemia and in an animal model of breast cancer synergized with alpelisib to regress tumor growth. In a Phase 1 trial, evexomostat improved insulin resistance in patients with elevated baseline insulin, reduced angiogenic factors in patients with elevated baseline levels, increased the insulin-sensitizing adipokine adiponectin and showed anti-metastatic effects in patients with advanced solid tumors. Methods: This is a phase 1b/2, open-label, single-arm pilot study (NCT05455619) in postmenopausal women with HR+, HER2- metastatic breast cancer with a PIK3CA mutation who progressed following treatment with endocrine therapy plus a CDK4/6 inhibitor and who are at risk for hyperglycemia (HbA1c between 5.5 and 6.4%inclusive). The primary goal is to determine the safety of evexomostat plus alpelisib and fulvestrant (the ‘triplet therapy’), including the severity and number of hyperglycemic events, as well as anti-tumor benefit. The starting dose of evexomostat in the triplet therapy is 36 mg/m2 (n=6; one dose below the monotherapy MTD of 49 mg/m2). Once the MTD of evexomostat in the triplet therapy has been defined, up to 20 patients will be enrolled at that dose. An additional 20 patients may be enrolled to further characterize the safety and anti-tumor effect of the triplet therapy (up to 52 patients). This trial is open to accrual at multiple sites in the USA. Safety analysis includes the type, frequency, and severity of treatment-emergent adverse events (TEAEs) per NCI CTCAE, v5, and the number and proportion of patients with grade 3 or 4 hyperglycemia during the first 2 cycles of therapy, with an estimate of the exact upper one-sided 97.5% confidence bound. Efficacy analyses include objective response rate (ORR, consisting of complete response (CR) and partial response (PR)). The number of patients without disease progression six months from the start of the triplet therapy will be assessed. The CBR of CRs, PRs plus stable disease ≥24 weeks from C1D1 will be calculated. Overall survival data will be summarized as available. 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. Clinical trial information: NCT05455619 .