First-In-Class, First-In-Human Phase I Trial Of Kpt-330, A Selective Inhibitor Of Nuclear Export (Sine) In Patients (Pts) With Advanced Solid Tumors.

2537 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, dr...