Abstract OT2-17-02: The ARETHA Study: A phase 2 randomized control trial of Eribulin with Evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer and metabolic dysfunction

Background: The prognosis for advanced/metastatic triple negative breast cancer (TNBC) remains poor and novel therapeutic strategies are urgently needed to improve outcomes. Insulin resistance and obesity contribute to cancer progression and are independent predictors of worse survival after TNBC diagnosis. Chemotherapy worsens insulin resistance, body mass index, and multiple other metabolic parameters which can paradoxically limit treatment efficacy and survival. Methionine aminopeptidase 2 (MetAP2/p67) is overexpressed in many tumor types and MetAP2 inhibitors exhibit broad anti-tumor activity. Additionally, MetAP2 inhibitors improve insulin resistance, reduce adiposity, and normalize levels of adipokines, attenuating the effects of metabolic dysfunction on tumor growth. Evexomostat (SDX-7320) is a second-generation MetAP2 inhibitor designed to improve drug-like properties and minimize central nervous system toxicities. Evexomostat improved insulin sensitivity, reduced fat mass and normalized adipokine levels in preclinical models of obesity, and reduced tumor growth in preclinical models of TNBC. In phase 1 trials, MetAP2 inhibition combined with chemotherapy was safe and well tolerated, while evexomostat monotherapy partially restored insulin sensitivity, reduced angiogenic factors as well as adipokines and showed anti-metastatic effects in patients with advanced solid tumors. The goal of this phase 2 study is to test whether evexomostat in combination with eribulin chemotherapy prevents worsening of insulin resistance and augments tumor response in patients with metastatic TNBC and concomitant metabolic dysfunction. Methods: This is a single-center, placebo-controlled phase 2 randomized control trial of evexomostat, a MetAP2 inhibitor, in combination with eribulin chemotherapy. Eligible patients must have histologically confirmed metastatic TNBC, measurable disease or ≥1 predominantly lytic bone lesion, baseline metabolic dysfunction defined as hemoglobin A1c >5.5% and/or BMI ≥30 kg/m2, have received ≤2 prior lines of therapy in the advanced/metastatic setting, have ECOG performance status ≤1, and adequate organ function. Patients with uncontrolled or insulin-dependent type II diabetes, or who require combination antihyperglycemic therapy are excluded. During the safety run-in period, 15 patients will be assigned to receive evexomostat 49 mg/m2 every 2 weeks in combination with eribulin 1.4 mg/m2 administered on days 1 and 8 of a 21-day cycle. Upon safety confirmation, an additional 40 patients will be randomized 2:1 to receive evexomostat or placebo in combination with eribulin. The primary endpoint is metabolic efficacy assessed by change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Secondary endpoints include objective response rate, progression-free survival, duration of response, safety and tolerability, patient-reported outcomes, changes in metabolic markers, and changes in body composition parameters. Historically, HOMA-IR scores double during chemotherapy, and this trial will test whether evexomostat will attenuate the expected rise in HOMA-IR. Specifically, the trial will have >90% power to detect a difference between a 1.5-fold change in HOMA-IR in the control arm versus no change in the investigational arm while controlling the Type I error at 5%. This trial opened to accrual in July 2022. A total accrual of 61 patients is planned with a goal of 55 evaluable patients. For any inquiries/questions, please contact Sherry Shen at shens1@mskcc.org. Clinical trial registry number: pending Funding, study drug evexomostat and other support provided by: SynDevRx, Inc. Citation Format: Sherry Shen, Anna Whalen, Mark E. Robson, Larry Norton, Tiffany A. Traina, Neil M. Iyengar. The ARETHA Study: A phase 2 randomized control trial of Eribulin with Evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer and metabolic dysfunction [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 OT2-17-02.