Inclusion Criteria:

• Disease specific

  • Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS)[1] definition

  • High risk relapsed neuroblastoma (relapsed or progressed after being defined as High Risk at any time following diagnosis or progressed/relapsed as high-risk neuroblastoma)

  • Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG scan with or without bone marrow histology), as per INRC [2, 3]. Participants with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study General

  • Age ≥1 year

  • Signed informed consent from participant, parent or guardian Performance and organ function

  • Performance Status

    o Lansky (for patients ≤12 years of age) or Karnofsky (for those >12) ≥ 50%, (Participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score)

  • Life expectancy of ≥12 weeks

  • Bone marrow function (within 72 hours prior to randomisation):

    • Platelets ≥ 50 x 109/L (unsupported for 72 hours)
    • ANC ≥ 0.50 x 109/L (no G-CSF support for 72 hours)
    • Haemoglobin > 8 g/dL (transfusions allowed)

  • Renal function (within 72 hours prior to randomisation):

    • Absence of clinically significant proteinuria (either early morning urine dipstick ≤ 2+) or if dipstick urinalysis shows > 2+ proteinuria, protein: creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein excretion must be < 0.5g
    • Serum creatinine ≤ 1.5 ULN for age, if higher, a measured GFR (radioisotope or 24 hour urine calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2

  • Liver function (within 72 hours prior to randomisation):

    o Absence of clinically significant signs of liver dysfunction. AST or ALT ≤ 3.0 ULN and total bilirubin ≤ 1.5 ULN. In patients with liver metastases, AST or ALT ≤ 5 ULN and total bilirubin ≤ 2.5 ULN is allowed.

  • Coagulation:

    • Participants must not have an active uncontrolled coagulopathy.
    • Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the participant has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment.

  • Blood pressure below 95th centile for age and sex. Participants ≥18 years of age should have a blood pressure ≤150/90 mmHg (within 72 hours prior to randomisation). Use of antihypertensive medication is permitted.

Tier 2 Specific Inclusion Criteria

• More than one relapse event or ineligible for Tier 1.

NB- The following previous treatments are allowed provided that the principal investigator expects a favourable benefit/risk assessment (e.g. patients could derive potential benefit from the Tier 2 combination):

• bevacizumab,
• any anti-GD2 antibody given with chemotherapy ('chemo-immunotherapy')
• previous treatment with temozolomide with irinotecan

Exclusion Criteria:

• • Known contraindication or hypersensitivity to:

  • Any study drug or component of the formulation

  • Chinese hamster ovary products or other recombinant human or humanised antibodies.

  • Participants with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but those with severe (or G4) hypersensitivity reactions to anti-GD2 antibodies will be excluded.

    • Clinically significant neurological toxicity, uncontrolled seizures or objective peripheral neuropathy (> grade 2). (Unresolved neurological deficits from previous spinal cord compression or surgeries are acceptable). Participants with previous ≥ Grade 3 motor neurotoxicity secondary to anti-GD2 are excluded, even if recovered
    • Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) or any ongoing arterial thrombo-embolic events
    • A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis.
    • Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive prophylaxis for PJP
    • Uncontrolled infection
    • Inadequate recovery from prior surgery with ongoing ≥ Grade 3 surgical complications. Grade ≥ 2 wound dehiscence.
    • Recent surgical procedures (at start of trial treatment). Patient can be randomised up to 48hr prior to these periods being completed provided that trial treatment only starts after complying with all of them:

  • Core biopsies within previous 24hr

  • Open excisional biopsies within previous 48hr

  • Major surgery within previous 2 weeks

  • Bone marrow aspirates/trephines, within previous 48hr

  • Tunnelled central line insertion within previous 48hr

    • Washout from prior treatments (at start of trial treatment):

  • Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens)

  • Any anti-GD2 therapy within previous 2 weeks

  • Craniospinal radiotherapy or MIBG therapy within previous 6 weeks

  • Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy)

  • Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within previous 8 weeks

  • Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥ G2 acute GVHD)

  • 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial

    • Bleeding metastases (participants with CNS metastases can be enrolled as long as the metastases are not bleeding). At least 6 months from any ≥ G3 haemoptysis or pulmonary haemorrhage
    • Use of enzyme inducing anticonvulsants within 72hr of start of trial treatment
    • Conditions that increase the risk of bevacizumab-related toxicities:

  • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)

  • History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment

  • Current chronic intestinal inflammatory disease/bowel obstruction

    • Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose
    • Males or females of reproductive potential may not participate unless they agree to use a highly effective method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine or serum pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche.
    • Pregnant or lactating participant
    • Live or live-attenuated vaccines given within previous 28 days prior to study enrolment
    • Any uncontrolled medical condition that poses an additional risk to the participant

Tier 1 Specific Exclusion Criteria

• More than one relapse/progression event after the start of high risk neuroblastoma therapy

• Previous treatments that are not allowed

  • Bevacizumab for relapsed neuroblastoma. Patients who have received BIT for refractory disease are not excluded, providing no progression of disease during this treatment occurred
  • Treatment with any anti-GD2 antibody given with chemotherapy ('chemo-immunotherapy') for treatment of relapsed neuroblastoma. Prior treatment with chemo-immunotherapy for refractory disease is allowed, provided no disease progression during this therapy.