Abstract OT3-31-01: The Amelia-1 Study: A phase 1b/2 trial of evexomostat (SDX-7320) plus fulvestrant (Faslodex®) and alpelisib (Piqray®) in patients with advanced breast cancer at risk for alpelisib (Piqray)-induced hyperglycemia
Authors: Cornelius Peter , Salomon Neal , Browning David , Gill Sakirat , Mayes Ben , Dufour Pierre , Shanahan James , Carver Bradley , Rugo Hope 
Published: March 2023

Abstract
Background: Breast cancer patients with mutation(s) in the PIK3CA gene have more aggressive disease and worse outcomes relative to patients without PIK3CA mutations. Alpelisib (Piqray), an inhibitor of PIK3CA, was approved for breast cancer patients with PIK3CA mutations. An on-target toxicity of alpelisib is hyperglycemia leading to hyperinsulinemia which may limit effectiveness of this drug. Patients with baseline metabolic dysfunction, insulin resistance, and/or elevated HbA1c are at greater risk of developing grade 3,4 hyperglycemia after receiving alpelisib (Piqray) than patients without metabolic dysfunction. Restoring insulin sensitivity and reducing systemic insulin levels improved the efficacy of alpelisib in preclinical models of breast cancer. Evexomostat is a polymer-drug conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor that in normal mice reduced alpelisib-induced hyperglycemia/hyperinsulinemia and in the MCF-7 model of HR+/PIK3CA-mutant breast cancer showed synergistic anti-tumor activity with alpelisib (Piqray). 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, among other metabolic and angiogenic markers. Methods: This is a phase 1b/2, open-label, single-arm pilot study (NCT05455619) in postmenopausal women with PIK3CA-mutated, HR+, HER2- metastatic breast cancer with disease progression following treatment with endocrine therapy plus a CDK4/6 inhibitor who are at risk for hyperglycemia, with risk factors defined as HbA1c between 5.7 and 6.4% and/or HOMA-IR ≥1.8. The primary objective is to determine the safety of evexomostat plus standard of care treatment alpelisib (Piqray) and fulvestrant (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 trial will begin with a dose-escalation cohort (n=6) 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 in accordance with their respective labels. Based on safety data from the first 6 patients (two cycles), the safety review committee may increase the evexomostat dose for the next cohort of six patients to 49 mg/m2 or may decrease the evexomostat dose to 27 mg/m2 and may adjust the dose of alpelisib if warranted. Once the MTD of the triplet therapy has been defined, additional enrollment will occur 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 safety profile and/or anti-tumor effect of the triplet therapy (total of up to 52 patients). This trial will open to accrual in August, 2022. Primary safety analysis consists of the type, frequency, and severity of treatment-emergent adverse events (TEAEs) per the NCI CTCAE, v5.0, the number of patients with grade 3 or 4 hyperglycemia during the first 2 cycles of therapy plus an estimate of the proportion and its exact upper one-sided 97.5% confidence bound will be analyzed. 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 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 or appropriate. 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, Neal Salomon, David Browning, Sakirat Gill, Ben Mayes, Pierre Dufour, James Shanahan, Bradley Carver, Hope Rugo. The Amelia-1 Study: A phase 1b/2 trial of evexomostat (SDX-7320) plus fulvestrant (Faslodex®) and alpelisib (Piqray®) in patients with advanced breast cancer at risk for alpelisib (Piqray)-induced hyperglycemia [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-31-01.