Background: Multiple tumour suppressor proteins (TSPs) are altered in ovarian (OC), endometrial (EC) & cervical (CC) cancers, including p53, BRCA1/2, CDKN2A & pRB. Selinexor, an oral first in class, inhibitor of XPO1 mediated nuclear export, results in nuclear retention and activation of multiple TSPs. Selinexor has anti-cancer activity in preclinical models of CC & platinum-resistant OC & in a phase I clinical study. This phase II trial explores the efficacy & tolerability of Selinexor in patients (pts) with advanced/metastatic incurable OC, EC & CC. Methods: Pts with ≥ 1 line of prior therapy were treated with single agent oral S using Simons two-stage design (NCT02025985). The primary endpoint is disease-control-rate (DCR = PR+SD ≥ 12weeks [wk]). Other endpoints are ORR, PFS, safety, & tolerability. Three treatment schedules (50 mg/m² twice-weekly (BIW); 35 mg/m² BIW; & 50 mg/m² QW in 4-wk cycles) are evaluated. The three cohorts (OC, EC & CC) are evaluated independently for response by RECIST 1.1 after 6 & 12 wks, then every 8 wks. Results: All three cohorts have passed efficacy response rates for Simon analysis & proceeded to stage two. 30 OC (Median age [MA] 63, ECOG 0/1: 16/14, median 5.5 (1–11) prior treatment regimens [PTR]), 15 EC (MA 69, ECOG 0/1: 8/7, median 2 (1–5) PTR) & 18 CC (MA 55.5, ECOG 0/1: 13/5, median 3 (1–8) PTR) heavily pre-treated pts have been enrolled. No Grade 4 toxicities have been seen. Grade 3 drug related adverse events (AEs) include: Nausea (13%), Thrombocytopenia (13%), Vomiting (11%), & Fatigue (10%). Commonly reported Grade 1/2 drug related AEs for all three cohorts include: Nausea (54%), Vomiting (5%), Fatigue (32%), & Anorexia (25%). Dose reductions occurred in 30 % of pts. DCR in evaluable pts: OC: 36%; EC: 64%; CC: 28%. ORR in evaluable pts: OC: 9%; EC: 18%; CC 7%. Conclusions: The initial phase 2 data demonstrate meaningful single-agent anti-tumor activity of Selinexor in all three heavily pretreated gynaecological malignancies. Some pts required dose reduction of Selinexor due to fatigue & anorexia. The most tolerable dosing regimen will be selected for phase III trials. The trial continues to enrol pts. Updated data will be presented. Clinical trial information: NCT02025985