Oral Presentation Advances in Neuroblastoma Research Congress 2016

Phase II clinical trial with long-term infusion of anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 (IL2) showed clinical efficacy and improved toxicity in patients with high risk neuroblastoma. (#102)

Holger N Lode 1 , Domonique Valteau-Couanet 2 , Sascha Troschke-Meurer 1 , Alberto Garaventa 3 , Roberto Luksch 4 , Juliet Gray 5 , Victoria Castel 6 , Isaac Yaniv 7 , Geneviève Laureys 8 , Martin Elliott 9 , Jean Michon 10 , Cormac Owens 11 , Toby Trahair 12 , Godfrey Chan 13 , Ellen Ruud 14 , Henrik Schroeder 15 , Maja Beck-Popovic 16 , Guenter Schreier 17 , Hans Loibner 18 , Nikolai Siebert 1 , Evgenia Glogova 19 , Ulrike Pötschger 19 , Ruth Ladenstein 19
  1. University Medicine Greifswald, Greifswald, Germany
  2. Institut Gustave Roussy, Villejuif, France
  3. Gaslini Instutite, Genova, Italy
  4. S.C. Pediatria, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Itlay
  5. University Hospital Southampton, Southampton, United Kingdom
  6. University Hospital La Fe, Valencia, Spain
  7. Schneider Children’s Medical Centre of Israel, , Petach Tikvah, Israel
  8. University Hospital Ghent, Ghent, Belgium
  9. Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
  10. Institut Curie, Paris, France
  11. Our Lady's Children's Hospital, Dublin, Ireland
  12. Center for Chidlren’s Cancer & Blood Disorders, Sydney, Australia
  13. University of Hong Kong, Hong Kong, China
  14. Oslo University Hospital, Oslo, Norway
  15. Aarhus Universitetshospital Skejby, Aarhus, Denmark
  16. Pediatric Hematology and Oncology, University Hospital Lausanne, Lausanne, Switzerland
  17. AIT Austrian Institute of Technology, Graz, Austria
  18. Apeiron Biologics, Vienna, Austria
  19. Children's Cancer Research Institute, Vienna, Austria

Background: A new delivery method of anti-GD2 antibody ch14.18/CHO by long term infusion (LTI) may improve the toxicity profile but maintain effective immune modulation and clinical activity in patients (pts) with high risk relapsed/refractory neuroblastoma (NB).
Methods: 124 pts were enrolled into an open label Phase II clinical trial (EudraCT 2009-018077-31) to receive up to 5 cycles of 6x106 IU/m2 sc IL2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2 oral 13-cis-RA (d19-32)(APN311-202). Primary efficacy endpoints were antibody (>1µg/ml) and NK-cell levels. Toxicity endpoint was i.v. morphine free antibody delivery after 5 days of cycle 1 in >80% patients. Secondary endpoints were increased ADCC levels over baseline, Fc gamma receptor (FCGR) polymorphisms, objective clinical responses and progression as well as overall survival.

Results:

All per protocol treated patients met primary efficacy endpoints. This translated into an increase in ADCC in all evaluable patients. Toxicity observed in this trial was improved compared to standard delivery methods of anti-GD2 antibodies. Objective clinical response rate observed in this trial was 40%. The survival update of the cohort revealed a 2-y OS of 64±6% (mean OS 2.7± 0.2 y, median EFS 3.7 y (95% CI: 2.0-3.7 y)) and a 2-y EFS of 53 ± 6% (mean EFS 2.0 ± 0.2 y, median EFS 2.3 y (95% CI: 1.2-3.3 y)). This result is clearly superior to historical controls not treated with ch14.18/CHO (p<0.001), indicating clinical efficacy of the treatment.

In this cohort, we found 63/124 pts with low affinity FCGR alleles (FCGR2A-H131R/R and/or FCGRA3A-V158 F/F). These patients showed lower EFS and OS rates compared to 59/124 patients with high affinity FCGR polymorphisms (p<0.05). These findings underline FCGR mediated ADCC as mechanism of action of this treatment modality.

Conclusion: Results of this Phase II study show efficacy, clinical activity and improved toxicity profile of a new delivery method of ch14.18/CHO and underline ADCC as the mechanism of action.