P-0268 - The randomized phase 3 IMPALA study: Immunomodulatory maintenance therapy with TLR-9 agonist MGN1703 in patients with metastatic colorectal carcinoma

Date 28 June 2014
Event World GI 2014
Session Poster Session
Topics Colon Cancer
Cancer Immunology and Immunotherapy
Rectal Cancer
Presenter David Cunningham
Citation Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165
Authors A. Zurlo1, T. Waddell2, A. Stein3, C. Tournigand4, A. Sobrero5
  • 1Mologen AG, Berlin/DE
  • 2Royal Marsden Hospital, London/UK
  • 3University Medical Center Hamburg, Hamburg/DE
  • 4Hôpital Henri Mondor, Créteil/FR
  • 5IRCCS AOU San Martino IST, Genoa/IT

Abstract

Introduction

The synthetic DNA-based immunomodulatory agent MGN1703 is a potent Toll Like Receptor 9 (TLR-9) agonist, which showed a good safety profile, activation of the immune system and proof of efficacy in advanced cancer patients in a phase 1 study. In the phase 2 IMPACT trial MGN1703 was compared to placebo in mCRC patients with disease control after 4.5 to 6 months of standard induction chemotherapy +/- bevacizumab. MGN1703 showed a superior effect compared to placebo with a hazard ratio for the primary endpoint PFS on maintenance of 0.55 (p = 0.041) by local investigator assessment and 0.56 (p = 0.070) by independent radiological review. Three objective responses were observed in the MGN1703 arm, two of them appearing as late as 9 months after the start of treatment, thus showing a pattern similar to other immunological active agents currently under investigation. At time of study closure 4 MGN1703 patients were still without progressive disease and continued treatment in a compassionate use setting. Exploratory Cox regression and ROC analyses suggested a potential predictive role at baseline for normal CEA, objective response to prior chemotherapy and presence of activated NKT-cells. The confirmation of these promising data is the rationale for the design of the IMPALA study.

Methods

Trial design: The evidence from the IMPACT study has been used to identify the CRC patients more likely to benefit from immunomodulation with MGN1703 treatment. Analysis of pre-treatment characteristics in IMPACT suggests that patients with smaller tumor burden and with a good response to chemotherapy may be the best candidates to receive immunotherapy; similar evidence is increasingly being reported for other immunotherapeutic approaches. The IMPALA study is a randomized, international, multicenter, open-label phase 3 trial, with the participation of the AIO, TTD, and Gercor cooperative groups. In the IMPALA trial mCRC patients having achieved an objective tumor response following any first line induction therapy +/- biological agents will be randomized to MGN1703 monotherapy maintenance in the experimental arm or local standard of care in the control arm. At time of initial relapse, patients in both arms will reintroduce the initial induction treatment whenever feasible, with patients in the experimental arm continuing to receive MGN1703 therapy in the weeks without chemotherapy administration. Patients will also be stratified by CEA level and activated NKT at baseline. Approximately 540 patients from 120 centers in Germany, Austria, Spain, Italy, France, UK, Belgium and Estonia will be randomized. The primary endpoint of the study will be overall survival. Secondary endpoints include PFS, response rates, safety, and QoL in selected centers. All randomized patients will take part in a comprehensive immune monitoring plan evaluating cytokines and chemokines in serum and the activation status of various immune cell populations. Additional Translational Research programs will be reviewed and discussed by the Study Steering Committee and will be implemented in subgroups of patients.