A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL

Abstract

Background: KPT-9274 is an oral, small molecule modulator of PAK4 (p21 activated kinase) and NAMPT (nicotinamide phosphoribosyltransferase). PAK4 is a major player in cell morphology and WNT/β-catenin signaling. NAMPT is the rate-limiting enzyme in NAD biosynthesis. Co-inhibition of these targets leads to synergistic antitumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, and ultimately apoptosis. Cells can utilize niacin to make NAD through an alternative pathway using NAPRT1. NAPRT1 is often absent in tumors making it a potential response biomarker. KPT-9274 demonstrates potent anti-tumor activity pre-clinically and in patient dogs with cancer. Methods: This dose escalation study evaluates KPT-9274 as a single agent and co-dosed with niacin. KPT-9274 is given QoDx3/week (28-day cycle) at a starting dose of 10 mg. The objectives are to evaluate safety and tolerability of KPT-9274, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, early antitumor activities, pharmacokinetic (PK) and pharmacodynamic properties. Results: As of 02-Mar-17, 14 patients (pts: 9M/5F; median age 61) with advanced solid tumors were enrolled in 4 cohorts (10 - 40 mg). One DLT (G4 anemia) at 40 mg was reported. MTD is not yet reached. Drug-related adverse events (AEs) include G2-4 anemia (6 pts, 43%) and G3 fatigue (1 pt, 7%). The most common G2 AEs are arthralgia and myalgia (3 pts; 21% each) and influenza-like illness (2 pts; 14%). Stable disease (SD) was seen in 29% of the 14 pts. Preliminary PK analysis suggests plasma exposure was dose proportional on C1D1 increasing 4 to 5-fold by C1D24. On C1D24, the mean Cmax and AUC0-t observed in 20 - 30mg cohorts were 319 - 1,573 ng/mL and 10,456 - 59,152 ng∗hr/mL, respectively. Preliminary data indicate that treatment of KPT-9274 reduces NAD levels vs. baseline in circulating leukocytes and tumor biopsies. Analyses to correlate NAPRT1 status with response is ongoing (2 of 4 SD pts are NAPRT1-). Conclusions: Oral KPT-9274 is tolerated in pts with advanced solid malignancies. Anemia, arthralgias and myalgias are common AEs with one DLT (G4 anemia). PK is generally proportional and predictable.