title: 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: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine IV, Oncology/Hematology, University Clinic Halle (Saale), Center for Cell and Gene Therapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Germany, hans-joachim.schmoll@medizin.uni-halle.de.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: Burghardt
authors.initials: B
authors.lastname: Wittig
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.forename: Jorge
authors.initials: J
authors.lastname: Riera-Knorrenschild
authors.forename: Dieter
authors.initials: D
authors.lastname: Nitsche
authors.forename: Hendrik
authors.initials: H
authors.lastname: Kroening
authors.forename: Frank
authors.initials: F
authors.lastname: Mayer
authors.forename: Johannes
authors.initials: J
authors.lastname: Andel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ziebermayr
authors.forename: Werner
authors.initials: W
authors.lastname: Scheithauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D051217:Toll-Like Receptor 9 / Q000819:agonists*
chemical_list: D007155:Immunologic Factors; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9