Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma

Inclusion Criteria

• •At study entry patients must be \> 1 year
• •Relapsed or refractory high risk neuroblastoma (as defined by International Neuroblastoma Risk Group (INRG) criteria)
• •MIBG avid disease on imaging within 4 weeks to study entry.
• •≥ 3 months since any myeloablative chemotherapy / stem cell rescue
• •≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy.
• •Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky)
• •Estimated life expectancy ≥ 12 weeks
• •Adequate bone marrow function: Absolute Neutrophil Count (ANC) \>1.0 x 10/L, platelets, 20 x 10/L and haemoglobin \> 8.0 g/dL.
• •Adequate renal function: serum creatinine \<1.5 mg/dL or a estimated creatinine clearance or radioisotope Glomerular Filtration Rate Study (GFR) of \> 60 mL/minute/1.73m2.
• •Adequate cardiac function: shortening fraction of 28 % by echocardiogram.
• •Adequate hepatic function: Alanine transaminase (ALT) or Aspartate transaminase (AST) \< 5 x ULN and a total bilirubin \< 1.5 x Upper Limit of Normal (ULN)
• •Adequate lung function: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) \>60% of the predicted by pulmonary function tests. Children unable to do Pulmonary Function Tests (PFTs) should have no dyspnea at rest and a pulse oximetry \>94% on room air.
• •Adequate pancreatic function: serum lipase \< 1.5 x upper limit normal
• •Patients may have had prior Central Nervous System (CNS) metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable prior for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema.
• •Patients must consent to the placement of a central venous line, if one has not already been placed.
• •Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery.
• •Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• •Patients with seizure disorders may be enrolled if seizures are well controlled.
• •All patients and/or their parents or legal guardians must sign a written informed consent
• •All institutional and national requirements for clinical trials must be met.
• •Expression of PD-L1 by tumour is not a pre-requisite
• •Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration.
• •Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy