Oral Presentation Advances in Neuroblastoma Research Congress 2016

Final results of the randomised short term infusion (STI) of ch14.18/CHOmAB immunotherapy in combination with Aldesleukin: a report on outcome and toxicities from the HR-NBL1/SIOPEN trial (#94)

Ruth Ladenstein 1 , Ulrike Pötschger 2 , Juliet Gray 3 , Domonique Valteau-Couanet 4 , Roberto Luksch 5 , Victoria Castel 6 , Isaac Yaniv 7 , Geneviève Laureys 8 , Martin Elliott 9 , JeanJ Michon 10 , Cormac Owens 11 , Toby Trahair 12 , Godfrey Chan 13 , Ellen Ruud 14 , Henrik Schroeder 15 , Maja Beck-Popovic 16 , Evgenia Glogova 2 , Guenter Schreier 17 , HansHans Loibner 18 , Holger Lode 19
  1. St. Anna Kinderkrebsforschung e.V. and St. Anna Kinderspital, Vienna, Austria
  2. St. Anna Kinderkrebsforschung e.V., Vienna, Austria
  3. University Hospital Southampton NHS Foundation Trust, Southampton, UK
  4. Institut Gustav Roussy, Villejuif, France
  5. Istituto Nazionale Tumori di Milano, Milan, Italy
  6. Hospital La Fe, Valencia, Spain
  7. Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  8. University Hospital Gent, Gent, Belgium
  9. Leeds Teaching Hospitals NHS Trust, Leeds , UK
  10. Institut Curie, Paris, France
  11. Our Lady's Children's Hospital, Crumlin, Ireland
  12. Sydney Children's Hospital, Randwick, Australia
  13. The University of Hong Kong, Pokfulam , Hong KOng
  14. Rikshospitalet, Oslo, Norway
  15. Hospital of Aarhus, Skejby, Denmark
  16. University Hospital Lausanne , Lausanne, Switzerland
  17. AIT Austrian Institute of Technology, Graz, Austria
  18. Apeiron Biologics AG, Vienna, Austria
  19. University of Greifswald, Greifswald, Germany

Aim

After the first important results of the antiGD2/SP02 combination immunotherapy (Alice Yu, NEJM, 2010), this trial investigated the potential and tolerance of ch14.18/CHO monoclonal antibody immunotherapy(IT)± subcutaneous interleukin 2(scIL2) in high-risk neuroblastoma (HRNBL1) front-line patients (pts).

Methods

Between 2009-2011,the HR-NBL1/SIOPEN Phase III trial (APN311-302)(EudraCT:2006-001489-17) randomized 406pts (all stage 4 but if <1yr only with MycN amplification (MNA) and MNA stages 2&3 all ages up to 21yrs). Pts were randomised for IT(R2) at start of maintenance. Eligibility included a COJEC induction ± 2TVD; enrolment on the HDC randomisation (R1, BUMEL vs CEM) with R1response criteria. Local treatments aimed at gross surgical resection and radiotherapy (21Gy). Pts receiver either 100mg/m² ch14.18/CHO (d8-12) as 5 daily 8-hour short-term infusion (STI) alone (STIA) or combined with 6x106IU/m2 scIL2 (d1-5;8-12) (STIB) for a total of 5 IT cycles; both had 6 cyles of oral 13-cis-RA (160mg/m2,d19-32). The median age at diagnosis was 3yrs(1month-19yrs) and the median observation time 3.1yrs. Outcomes are reported as 3-yrs event free/overall survival rates (EFS/OS).

Results

The EFS/OS for pts treated with ch14.18/CHO with and without scIL2 was 0.60±0.04/0.66±0.04(206pts) and 0.57±0.04/0.65±0.04/(200pts)(NS). The EFS for CR-pts (or VGPR/PRpts) on STIA was 0.68±0.05 (0.46±0.06) and with STIB 0.65±0.05 (0.53±0.06) indicating no benefit for scIL2. Early termination of IT occurred in 18% in STIA but in 44% in STIB (36% toxicity-related, 8% progressions). A Lansky performance status of ≤30% was found 17% STIA-pts but in of 39% STIB-pts (p<0.001). CTC-grade 3&4 allergic reactions was observed in 9% and 20% of STIA-pts and STIB-pts (<0.001). Incidence of capillary leak and CTC-grade 3&4 fever significantly lower without scIL2 STIA (1% and 14%) vs. STIB (9% and 40%).

Conclusion The EFS/OS rates at 3yrs show a clear improvement to previous SIOPEN experience. A markedly reduced toxicity without IL2 and equivalent outcome suggest a ch14.18/CHO only approach.