PMID- 25403217 OWN - NLM STAT- MEDLINE DCOM- 20150223 LR - 20190111 IS - 1527-7755 (Electronic) IS - 0732-183X (Linking) VI - 32 IP - 36 DP - 2014 Dec 20 TI - First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. PG - 4141-8 LID - 10.1200/JCO.2013.55.0376 [doi] AB - PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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. CI - (c) 2014 by American Society of Clinical Oncology. FAU - Schultheis, Beate AU - Schultheis B AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Strumberg, Dirk AU - Strumberg D AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. dirk.strumberg@marienhospital-herne.de. FAU - Santel, Ansgar AU - Santel A AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Vank, Christiane AU - Vank C AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Gebhardt, Frank AU - Gebhardt F AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Keil, Oliver AU - Keil O AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Lange, Christian AU - Lange C AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Giese, Klaus AU - Giese K AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Kaufmann, Jorg AU - Kaufmann J AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Khan, Michael AU - Khan M AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. FAU - Drevs, Joachim AU - Drevs J AD - Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jorg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tubingen, Germany. LA - eng SI - ClinicalTrials.gov/NCT00938574 PT - Clinical Trial, Phase I PT - Journal Article DEP - 20141117 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Cytokines) RN - 0 (Liposomes) RN - 0 (RNA, Small Interfering) RN - 9007-36-7 (Complement System Proteins) RN - EC 2.7.1.- (protein kinase N) RN - EC 2.7.11.13 (Protein Kinase C) RN - IFJ2SAK127 (Atu027) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Complement System Proteins/analysis MH - Cytokines/blood MH - Female MH - Humans MH - Liposomes MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy MH - Prospective Studies MH - Protein Kinase C/*antagonists & inhibitors/genetics MH - RNA, Small Interfering/adverse effects/pharmacokinetics/*therapeutic use EDAT- 2014/11/19 06:00 MHDA- 2015/02/24 06:00 CRDT- 2014/11/19 06:00 PHST- 2014/11/19 06:00 [entrez] PHST- 2014/11/19 06:00 [pubmed] PHST- 2015/02/24 06:00 [medline] AID - JCO.2013.55.0376 [pii] AID - 10.1200/JCO.2013.55.0376 [doi] PST - ppublish SO - J Clin Oncol. 2014 Dec 20;32(36):4141-8. doi: 10.1200/JCO.2013.55.0376. Epub 2014 Nov 17.