A phase I/II study of TKM-080301, a PLK1-targeted RNAi in patients with adrenocortical cancer (ACC).

2547 Background: Polo-like kinase 1 (PLK1) regulates critical aspects of tumor progression. High expression levels correlate with poor survival in ACC. TKM-080301 is a lipid nanoparticle formulation of a siRNA against PLK1. Methods: TKM-080301 was evaluated in an open-label study with dose escalation and expansion phases in patients with refractory ACC. TKM-080301 was infused IV over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Primary study objectives included assessment of safety and anti-tumor activity by RECIST 1.1 after every 2 cycles. Results: Sixteen patients were treated at 0.6 or 0.75 mg/kg/week for up to 18 cycles. Eight received at least 2 cycles of study treatment and were evaluable for tumor response. Four had a best response of stable disease including one with a 13% reduction of target tumor diameter. One 51 yo man with metastatic intraperitoneal non-functional ACC had a partial response (target tumor reduction of 19% after cycle 2 and 49% after cycle 14). Residual tumor was resected and histopathology showed near-complete necrosis. Paired tumor/normal whole exome sequencing of this tumor revealed key somatic alterations including a missense mutation (Q331H) in TP53’s DNA binding domain, an NF1 nonsense mutation (S365*), and a missense ARID1A mutation (A438V). RNA sequencing showed elevated expression of PLK1 (FPKM = 13.5) in this tumor compared to a normal adrenal RNA control (FPKM = 0.95). Two subjects completed at least 6 cycles. Subjects were discontinued for progressive disease (7); infusion reactions (2); acute respiratory failure (1); elevated LFTs (1); or bowel obstruction (1). Most common AEs related to TKM-080301 were pyrexia (56%); chills (50%); back pain (31%); infusion reaction (31%); and nausea (25%). Serious AEs related to TKM-080301 were ECG T-wave inversion and musculoskeletal pain (1) and infusion reaction (1). Conclusions: TKM-080301 has been tolerated at a dose of 0.6 - 0.75 mg/kg for up to 18 cycles. Preliminary anti-tumor efficacy has been observed. A potential molecular therapeutic context of increased PLK1 expression with inactivation of p53 or NF1 was observed in a remarkable responder. Further evaluation of PLK1 as a therapeutic target of TKM-080301 in ACC is warranted. Clinical trial information: NCT01262235.