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Clinical Trial
. 2014 Sep;140(9):1615-24.
doi: 10.1007/s00432-014-1682-7. Epub 2014 May 10.

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

Hans-Joachim Schmoll  1 , Burghardt Wittig, Dirk Arnold, Jorge Riera-Knorrenschild, Dieter Nitsche, Hendrik Kroening, Frank Mayer, Johannes Andel, Reinhard Ziebermayr, Werner Scheithauer
Affiliations
Clinical Trial

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

Hans-Joachim Schmoll et al. J Cancer Res Clin Oncol. 2014 Sep.

Abstract

Purpose: This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).

Methods: Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).

Results: The 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.

Conclusions: MGN1703 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.

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Figures

Fig. 1
Fig. 1
Mechanism of action of MGN1703. ADCC antibody-dependent cell-mediated cytotoxicity, BCR B-cell receptor, IFN interferon, IL interleukin, mDC myeloid dendritic cells, MHC major histocompatibility complex, NK cell natural killer cell, NKT cell natural killer T cell, pDC plasmacytoid dendritic cells, TAA tumour-associated antigens, TCR T-cell receptor, TLR9 Toll-like receptor 9
Fig. 2
Fig. 2
Trial profile. ITT intent to treat
Fig. 3
Fig. 3
PFS by treatment group from a randomisation and b start of induction therapy (investigator assessmenta). CI confidence interval, HR hazard ratio, mPFS median progression-free survival, PFS progression-free survival
Fig. 4
Fig. 4
PFS from randomisation by treatment group for patients with NKT cell counts ≥3.08 % (a) or <3.08 % (b). CI confidence interval, HR hazard ratio, NKT natural killer T, PFS progression-free survival
See this image and copyright information in PMC

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