Background: KPT-330 is an inhibitor of Exportin 1 (XPO1) that forces the nuclear retention and activation of over 10 Tumor Suppressor Proteins (TSPs) resulting in tumor cell death in preclinical models. Methods: KPT-330 was administered orally for 8-10 doses in a 28-day cycles. Cycle 1 was the DLT period. Pharmacokinetic (PK) analyses were performed. XPO1 mRNA, a pharmacodynamic (PDn) marker of XP01 inhibition, was assessed in blood. Tumor biopsies were performed. Response was evaluated every 2 cycles (RECIST 1.1). All pts had to have documented progressive disease on study entry. Results: 103 pts (59/44 M/F; median age 61 yrs; median treatment regimens: 3; ECOG PS 0/1: 24/79) received KPT-330 across 12 dose levels (3 to 65 mg/m²) in dose escalation and expansion cohorts. 2 DLTs (fatigue, dehydration) at 40mg/m² on the 10-doses/cycle regimen; 1 DLT (nausea) at 35mg/m² on the 8-doses/cycle (twice weekly, BIW) regimen were noted. Dosing at 65mg/m² BIW is ongoing (MTD not reached). Grade 3/4 non-DLT, drug related, adverse events (AEs) in cycle 1 in >2 pts: hyponatremia (9%), fatigue (6%), thrombocytopenia (5%), vomiting (4%), anemia (3%), nausea (3%). The most common grade 1/2 AEs in cycle 1: nausea (63%), fatigue (52%), anorexia (42%) and vomiting (37%). The PK and PDn showed dose-dependent increases in C_max / AUC_0-inf and XPO1 mRNA increases. Tumor biopsies showed nuclear localization of TSPs (p53, FOXO3A, IkB) and apoptosis induction. Of 87 response evaluable pts, 3 partial responses were observed in colorectal cancer (KRAS mutant), melanoma (BRAFwt) and ovarian adenocarcinoma (OvCa) pts. Stable disease (SD) was noted in 39 pts, with 12 pts for ≥6 months. Five of 5 evaluable pts with hormone and chemotherapy refractory prostate cancer (HRPC) achieved SD; all pts still on study 70-240+ days. Nine of 13 evaluable pts with squamous head and neck cancer (HNCa) achieved SD with 7 on study 75-290+ days. Conclusions: Oral KPT-330 has a manageable toxicity profile and prolonged dosing is feasible. Preliminary signals of durable antitumor activity were observed. The recommended dose for phase 2 is ≥50mg/m² BIW. Phase 2 studies in HNCa, OvCa, and HRPC are planned. Clinical trial information: NCT01607905.