Gemcitabine plus selinexor in selective advanced sarcomas: a phase I of the Spanish group for research on sarcoma study.

Exportin-1 (XPO-1) is related to drug resistance and poor prognosis in solid tumors. Selinexor, an XPO-1 inhibitor, has shown preclinical and clinical activity in sarcomas. This Phase I study explores the combination of gemcitabine and selinexor in a classic 3 + 3 design. Adult patients with selected advanced sarcomas receive gemcitabine and weekly selinexor in 21-day cycles. The main endpoint is to determine the recommended phase 2 dose (RP2D). Secondary end-points include safety, overall response rate (ORR), overall survival (OS), and quality of life. Seventeen patients are included in this study. One dose-limiting toxicity (grade 4 thrombocytopenia) is detected in dose-level +3, but the R2PD is established at dose-level +2 (gemcitabine at 1200 mg/m² at 10 mg/m²/min followed by 60 mg weekly selinexor) based on its better tolerability. The most frequent adverse events are neutropenia (82.4%) and thrombocytopenia (76.5%). The ORR is 31.25 %, and the median OS (mOS) is 39.5 months (95% CI, 12.4-67) with a 36-month OS rate of 50.2%. A phase II is currently exploring this combination in leiomyosarcoma and malignant peripheral nerve sheath tumors. Trial registration: NCT04595994.