First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Beate
B
Schultheis
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany. dirk.strumberg@marienhospital-herne.de.
Dirk
D
Strumberg
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Ansgar
A
Santel
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Christiane
C
Vank
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Frank
F
Gebhardt
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Oliver
O
Keil
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Christian
C
Lange
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Klaus
K
Giese
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Jörg
J
Kaufmann
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Michael
M
Khan
Beate Schultheis and Dirk Strumberg, Marienhospital Herne/University of Bochum, Herne; Ansgar Santel, Christiane Vank, Frank Gebhardt, Oliver Keil, Christian Lange, Klaus Giese, Jörg Kaufmann, and Michael Khan, Silence Therapeutics, Berlin; and Joachim Drevs, UniFontis Clinic, Tübingen, Germany.
Joachim
J
Drevs
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003165:Complement System Proteins / Q000032:analysis; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D016207:Cytokines; D008081:Liposomes; D034741:RNA, Small Interfering; D003165:Complement System Proteins; C061570:protein kinase N; D011493:Protein Kinase C; C561746:Atu027