Article Text
Abstract
Introduction Dysregulation of mTOR signaling is implicated in the pathology of endometrial carcinoma (EC), particularly in endometrioid EC (EEC) in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Crosstalk between mTOR and estrogen signaling pathways is associated with endocrine therapy resistance, and mTOR inhibition combined with endocrine therapy has shown benefit in patients with recurrent EC in previous phase 2 studies. nab-Sirolimus, an intravenous nanoparticle albumin-bound mTOR inhibitor (mTORi), is approved in the US for adults with advanced malignant perivascular epithelioid cell tumors. Preclinical data demonstrated improved tumor accumulation, mTOR target inhibition, and tumor growth suppression of nab-sirolimus versus other mTORis. This trial will evaluate the antitumor activity of combined mTOR and estrogen signaling pathway inhibition with nab-sirolimus and letrozole, respectively, in patients with advanced or recurrent EEC.
Methods In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8, 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~30 planned, Simon’s 2-stage design) with clinically confirmed, advanced or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemotherapy-based regimen in the advanced, metastatic, or recurrent setting (prior adjuvant chemotherapy additionally permitted), ECOG performance status 0 or 1, mTORi-naïve, and measurable disease. The primary endpoint is best overall response rate (per RECIST v1.1). Key secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of biomarkers with clinical outcomes.
Current Trial Status The trial is currently open for enrollment.