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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
SIMPLE SUMMARY: Pancreatic cancer is still a challenging disease, as chemotherapeutic options are limited. We present the data of a new liposomally formulated short interfering RNA, Atu027, which has antimetastatic activity. In this randomized trial, pharmacokinetics and efficacy were assessed in tw...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693593/ https://www.ncbi.nlm.nih.gov/pubmed/33114652 http://dx.doi.org/10.3390/cancers12113130 |
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author | Schultheis, Beate Strumberg, Dirk Kuhlmann, Jan Wolf, Martin Link, Karin Seufferlein, Thomas Kaufmann, Joerg Feist, Mathilde Gebhardt, Frank Khan, Mike Stintzing, Sebastian Pelzer, Uwe |
author_facet | Schultheis, Beate Strumberg, Dirk Kuhlmann, Jan Wolf, Martin Link, Karin Seufferlein, Thomas Kaufmann, Joerg Feist, Mathilde Gebhardt, Frank Khan, Mike Stintzing, Sebastian Pelzer, Uwe |
author_sort | Schultheis, Beate |
collection | PubMed |
description | SIMPLE SUMMARY: Pancreatic cancer is still a challenging disease, as chemotherapeutic options are limited. We present the data of a new liposomally formulated short interfering RNA, Atu027, which has antimetastatic activity. In this randomized trial, pharmacokinetics and efficacy were assessed in two different treatment schedules. Both types of treatment were well-tolerated, with the side effects mainly being laboratory abnormalities without clinical importance. The twice-weekly regime compared patients with locally advanced to those with metastatic disease; in the latter group, a significant prolongation of survival without disease progression could be found. Therefore, as Atu027 influences the vascular endothelium, we suggest the further investigation of this compound as it seems to be able to prevent or delay metastases of pancreatic cancer. 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. |
format | Online Article Text |
id | pubmed-7693593 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76935932020-11-28 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 Schultheis, Beate Strumberg, Dirk Kuhlmann, Jan Wolf, Martin Link, Karin Seufferlein, Thomas Kaufmann, Joerg Feist, Mathilde Gebhardt, Frank Khan, Mike Stintzing, Sebastian Pelzer, Uwe Cancers (Basel) Article SIMPLE SUMMARY: Pancreatic cancer is still a challenging disease, as chemotherapeutic options are limited. We present the data of a new liposomally formulated short interfering RNA, Atu027, which has antimetastatic activity. In this randomized trial, pharmacokinetics and efficacy were assessed in two different treatment schedules. Both types of treatment were well-tolerated, with the side effects mainly being laboratory abnormalities without clinical importance. The twice-weekly regime compared patients with locally advanced to those with metastatic disease; in the latter group, a significant prolongation of survival without disease progression could be found. Therefore, as Atu027 influences the vascular endothelium, we suggest the further investigation of this compound as it seems to be able to prevent or delay metastases of pancreatic cancer. 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. MDPI 2020-10-26 /pmc/articles/PMC7693593/ /pubmed/33114652 http://dx.doi.org/10.3390/cancers12113130 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Schultheis, Beate Strumberg, Dirk Kuhlmann, Jan Wolf, Martin Link, Karin Seufferlein, Thomas Kaufmann, Joerg Feist, Mathilde Gebhardt, Frank Khan, Mike Stintzing, Sebastian Pelzer, Uwe 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693593/ https://www.ncbi.nlm.nih.gov/pubmed/33114652 http://dx.doi.org/10.3390/cancers12113130 |
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