Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial

Abstract

PurposeThis phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).MethodsFifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).ResultsThe hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29–1.08; P = 0.07) and 0.55 (95 % CI 0.3–1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26–0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31–1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3–1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation.ConclusionsMGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-014-1682-7) contains supplementary material, which is available to authorized users.

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

“…76 The Phase II clinical trial assessed MGN1703 maintenance treatment for metastatic colorectal carcinoma, and the results showed significantly improved progression-free survival. 77 MGN1703 also increased the IgG2 levels induced by Th1-biased responses in PBMCs. Conversely, it decreased the IgG1 and IgE levels induced by Th2-biased responses.…”

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

“…Following on from the promising phase I trial results, a double-blind phase II trial was performed to evaluate MGN1703 in the maintenance setting for patients who had achieved disease control of metastatic CRC after standard first-line induction therapy [64]. A total of 59 patients were randomized in a 2:1 ratio to receive subcutaneous MGN1703 at a dose of 60 mg or placebo, both given twice weekly until disease progression [64].…”

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

“…The phosphorothioate backbone that prevents nuclease-mediated degradation of CpG-ODN molecules has off-target immunostimulatory effects, which may increase and/or worsen adverse events (14). Because MGN1703's unique structure, comprising only natural DNA, obviates the need for such chemical modifications, MGN1703 has an excellent safety profile, which has been demonstrated during clinical testing (15,16).…”