Safety, Efficacy and Pharcacokinetics of Targeted Therapy with The Liposomal RNA Interference Therapeutic Atu027 Combined with Gemcitabine in Patients with Pancreatic Adenocarcinoma. A Randomized Phase Ib/IIa Study

Beate Schultheis, Dirk Strumberg, Jan Kuhlmann, Martin Wolf, Karin Link, Thomas Seufferlein, Joerg Kaufmann, Mathilde Feist, Frank Gebhardt, Mike Khan, Sebastian Stintzing, Uwe Pelzer, Beate Schultheis, Dirk Strumberg, Jan Kuhlmann, Martin Wolf, Karin Link, Thomas Seufferlein, Joerg Kaufmann, Mathilde Feist, Frank Gebhardt, Mike Khan, Sebastian Stintzing, Uwe Pelzer

Abstract

Background: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences the expression of protein kinase N3 (PKN3) in the vascular endothelium. This trial was designed to assess the safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC).

Methods: In total, 23 patients (pts) with inoperable APC were randomly assigned to gemcitabine combined with two different Atu027 schedules (0.235 mg/kg once weekly vs. 0.235 mg/kg twice weekly). ClinicalTrials.gov Identifier: NCT01808638.

Results: The treatment was well-tolerated. There were Grade 3 adverse events (AEs) in 9/11 pts (arm 1) and 11/12 pts (arm 2), while Grade 4 AEs were reported for two pts in each arm. The AEs were mainly laboratory abnormalities without clinical significance. The median progression-free survival reached statistical significance in patients who had metastatic disease (1.6 vs. 2.9 months, p = 0.025). Disease control during treatment was achieved in 4/11 pts (arm 1) and in 7/12 pts (arm 2). Pts in arm 1 experienced stable global health status while pts in arm 2 reported improvement.

Conclusions: Combining Atu027 with gemcitabine is safe and well tolerated. In pts with metastatic APC, twice-weekly Atu027 is associated with significantly improved outcomes. Our clinical results support the significant involvement of the vascular endothelium in the spread of cancer, and thus the further investigation of its target role.

Keywords: RNA interfering; pancreatic cancer; randomized trial; targeted therapy.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Subject disposition during the treatment period. FU-1=follow-up period 1.
Figure 2
Figure 2
Assessment cycle in Arms 1 and 2.
Figure 3
Figure 3
Kaplan–Meier survival curves for progression-free survival (A) and overall survival (B) (Safety analysis set, N = 23).
Figure 4
Figure 4
Absolute change from baseline in the global health status/quality of life and functional scales (EORTC) during the treatment period (Safety analysis set, N = 23). C = cycle; D = day; EoT = end of treatment; FU-1 = follow-up visit 1; PT = premature termination.
Figure 4
Figure 4
Absolute change from baseline in the global health status/quality of life and functional scales (EORTC) during the treatment period (Safety analysis set, N = 23). C = cycle; D = day; EoT = end of treatment; FU-1 = follow-up visit 1; PT = premature termination.

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