Atu-027

Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions.

Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST.

Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10.

Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.

Atu027 is a novel RNAi therapeutic agent based on cationic lipoplexes containing chem. stabilized siRNAs, which target Protein Kinase N3 (PKN3) gene expression in the vascular endothelium.Therefore, Atu027 is a novel, promising investigational therapeutic agent in anticancer therapy.The present study is the first in-human phase I study of Atu027 in patients with advanced solid tumors.Atu027 is well tolerated up to the current dose level 8 (0.180 mg/kg).So far no dose dependent toxicities have been observedTherefore, the maximum tolerated dose has not yet been reached and no pre-medication is required.Plasma samples of the patients show dose-dependent increase in siRNA antisense strand concentrations