Universität zu Köln

Weihrauch, Martin R., Richly, Heike, von Bergwelt-Baildon, Michael S., Becker, Hans Jiro, Schmidt, Manuel, Hacker, Ulrich T., Shimabukuro-Vornhagen, Alexander ORCID: 0000-0002-2351-7294, Holtick, Udo, Nokay, Bahar, Schroff, Matthias, Wittig, Burghardt and Scheulen, Max E. (2015). Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours. Eur. J. Cancer, 51 (2). S. 146 - 157. OXFORD: ELSEVIER SCI LTD. ISSN 1879-0852

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Abstract

Purpose: This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. Methods: The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. Results: 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade 62. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naive B cells during therapy. Conclusion: Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients. (C) 2014 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weihrauch, Martin R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richly, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bergwelt-Baildon, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Hans Jiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hacker, Ulrich T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shimabukuro-Vornhagen, Alexander UNSPECIFIED orcid.org/0000-0002-2351-7294 UNSPECIFIED Holtick, Udo UNSPECIFIED UNSPECIFIED UNSPECIFIED Nokay, Bahar UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroff, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittig, Burghardt UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheulen, Max E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-418061
DOI:	10.1016/j.ejca.2014.11.002
Journal or Publication Title:	Eur. J. Cancer
Volume:	51
Number:	2
Page Range:	S. 146 - 157
Date:	2015
Publisher:	ELSEVIER SCI LTD
Place of Publication:	OXFORD
ISSN:	1879-0852
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NON-HODGKIN-LYMPHOMA; CELL LUNG-CANCER; CPG OLIGODEOXYNUCLEOTIDE; 1ST-LINE TREATMENT; TLR9 AGONIST; TRIAL; DNA; PF-3512676; MELANOMA; OLIGONUCLEOTIDE Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41806