Early Phase 1 tirzepatide dual GIP/GLP-1 receptor agonist + LNG-IUD progestin in EIN/grade 1 endometrioid EC

This single-arm, window-of-opportunity pilot at Milton S. Hershey Medical Center evaluates feasibility, safety, and preliminary efficacy of adding tirzepatide (Eli Lilly’s dual GIP and GLP-1 receptor agonist that reduces appetite and improves insulin resistance) to standard levonorgestrel IUD therapy (a local progestin/progesterone receptor agonist that counteracts estrogen-driven endometrial proliferation). Adults with endometrial intraepithelial neoplasia or non-metastatic grade 1 endometrioid endometrial carcinoma are eligible if they also have obesity (BMI ≥30 kg/m²) and metabolic risk factors; the posting also highlights a dMMR-negative grade 1 subgroup. Participants receive weekly subcutaneous tirzepatide (starting 2.5 mg with protocol-guided escalation) while continuing clinician-directed LNG-IUD management, with pathologic response assessed at ~6 months plus metabolic, weight/BMI, quality-of-life, and adverse-event endpoints. The scientific angle is leveraging metabolic therapy to potentially increase progestin responsiveness and reduce “progesterone resistance” signals seen in some LNG-IUD–managed EIN/early cancers, a common fertility-sparing approach. Today, many patients with EIN/grade 1 disease are treated with hysterectomy; for those pursuing uterine preservation, care often uses progestin therapy (LNG-IUD and/or oral progestins) with close endometrial sampling surveillance, and this study tests whether modern incretin-based weight-loss pharmacology can augment that conservative pathway.