Introduction Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative treatment options for advanced or recurrent endometrial carcinoma (EC) remain necessary. Dysregulation of mTOR signaling is implicated in the pathology of EC, particularly in endometrioid EC (EEC) in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORi) and endocrine therapy provides clinical benefit in patients with EC. nab-Sirolimus is a nanoparticle injectable form of mTORi approved for malignant perivascular epithelioid cell tumor. Preclinical data with nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORi. We hypothesize that nab-sirolimus in combination with letrozole may produce synergistic antitumor activity in patients with recurrent EEC.
Methods In this phase 2, open-label, single-arm, multi-center study (NCT05997017), nab-sirolimus (100 mg/m2, IV, days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned) with clinically confirmed, advanced or recurrent EEC. Eligibility criteria include age ≥18 years, 0–1 prior chemo-based regimens, ECOG 0–1, mTORi naïve, and RECIST-measurable disease. The primary endpoint is best ORR by RECIST v1.1; key secondary endpoints include duration of response, PFS, OS, and safety. The relationship between biomarkers and response outcomes is an exploratory endpoint.
Current Trial Status Open for enrollment.
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