BEACON Immuno (anti-GD2 amendment) The prognosis for relapsed and refractory patients is poor. Five-year overall survival for relapsed neuroblastoma is 8% for Stage 4, and 4% for MYCN amplified. Similarly, patients that do not achieve complete remission or very good partial remission after induction have three-year event-free survival of just 15%. Currently, there is no standard treatment for these patients, and clinicians will treat with various chemotherapy combinations. BEACON study aims to find the best chemotherapy and to improve its efficacy through the addition of novel agents. Investigators: Dr Lucas Moreno (Vall d'Hebron Barcelona Hospital Campus), Dr Juliet Gray (University of Southampton) Project partners: Imagine For Margo Total project award: £500,000 Our project grant: £150,000 Date of award: May 2018 Rationale The current BEACON study completed its evaluation of Bevacizumab in late 2018. An amendment to keep the study open to investigate the combination of the anti-GD2 monoclonal antibody dinutuximab beta in combination with chemotherapy (chemoimmunotherapy) was proposed in light of recently published studies from America. In relapse: Mody, R. et al. Lancet Oncol 2017, Temozolomide-irinotecan + dinutuximab anti-GD2 + GM-CSF (9/17) 53% response rate (CR+PR) compared to 6% for temozolomide-irinotecan + temsirolimus. In frontline: Furman, W.L. et al. ASCO 2016 and ASCO 2017 2 cycles of topotecan-cyclophosphamide + hu14.18K322A anti-GD2: 76% ≥ objective response rate compared to 40% from historical controls. Dinutuximab beta (ch14.18/CHO) the chimeric anti-GD2 monoclonal antibody manufactured by EUSA Pharma has not yet been evaluated in combination with chemotherapy. Further, the administration of anti-GD2 antibodies as a ten-day continuous infusion (so-called LTI) in combination with chemotherapy has also not been evaluated. Study Objectives To test whether dinutuximab beta added to a backbone chemotherapy regimen demonstrates activity in children with relapsed or refractory neuroblastoma. Primary endpoint: Assessment of response rate for chemotherapy + dinutuximab beta vs. chemotherapy alone. Secondary endpoints: Progression free survival (PFS). Overall survival (OS). Safety & tolerability. Description of Study The study will enrol 64 patients over 2 years (based on current recruitment to BEACON). Patients will be randomised to receive chemotherapy alone or chemotherapy plus dinutuximab beta (chemoimmunotherapy). This trial has two very noteworthy features. Patients will be randomised on a 2:1 basis in favour of chemoimmunotherapy. That is for every three patients enrolled on the trial, two will receive chemotherapy plus dinutuximab beta, and one will receive chemotherapy alone. This trial design maximises the number of patients who can receive chemoimmunotherapy, whilst still preserving the scientific validity of the study. This is extremely important if the ultimate aim of a successful trial is to provide an evidence base for the combination of chemotherapy plus dinutuximab beta to become an approved therapy that clinicians can simply prescribe in future. Patients who are randomised to receive chemotherapy alone will be allowed to cross-over to receive chemotherapy plus dinutuximab beta if their disease progresses within two and a half years of enrolment. This is an important concept, as it means that for most children chemotherapy plus anti-GD2 antibody will be available as either a first-line or second-line relapse therapy. The study amendment will open in 40 institutions across Europe and is operated under the auspices of the Innovative Therapies for Children with Cancer in Europe (ITCC) collaborative research group. The study sponsor, responsible for running the trial, is Cancer Research Clinical Trials Unit (CRCTU) at the University of Birmingham who have a long-established track record of delivering high-class clinical trials. Solving Kids’ Cancer is funding a dedicated Senior Trials Coordinator (STC) post within the CRCTU to manage the delivery of all neuroblastoma projects with the aim of delivering more trials more quickly for children with neuroblastoma. Summary of Impact This will be the first study in Europe to combine chemotherapy with anti-GD2 antibody therapy for the treatment of neuroblastoma. With published results of small studies in North America, larger studies either completed and awaiting reporting of results, or still ongoing, this treatment could represent an important advance in improving outcomes for children. The prognosis for children with relapsed or refractory neuroblastoma remains dismal and the need for more effective treatments is pressing. This study will determine if dinutuximab beta given alongside conventional chemotherapy can improve survival for this group of patients. If so, it would not only help the children now who receive it, but also represent the first step towards chemoimmunotherapy becoming standard for children with recurrent disease or disease that is resistant to frontline therapy.