Relapsed Neuroblastoma Cancer
Conditions
Interventions
Tier 1 Treatment Details:
Arm A: dbIT ? Dinutuximab beta 10 mg/m2/day iv days 1-7, Irinotecan 50 mg/m² iv days 1-5, Temozolomide 100 mg/m² po days 1-5.
3 weekly x12 cycles
Arm B: BIT ? Bevacizumab 1
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Disease specific 1. Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition 2. 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) 3. Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG scan with or without bone marrow histology), as per INRC. Participants with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study General 1. Age =1 year 2. Signed informed consent from participant, parent or guardian Performance and organ function 1. Performance Status: 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) 2. Life expectancy of =12 weeks 3. Bone marrow function (within 72 hours prior to randomisation): 3.1. Platelets = 50 x 10^9/L (unsupported for 72 hours) 3.2. ANC = 0.50 x 10^9/L (no G-CSF support for 72 hours) 3.3. Haemoglobin > 8 g/dL (transfusions allowed) 4. Renal function (within 72 hours prior to randomisation): 4.1. 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 4.2. 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 5. Liver function (within 72 hours prior to randomisation): 5.1. 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. 6. Coagulation: 6.1. Participants must not have an active uncontrolled coagulopathy. 6.2. 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. 7. 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 1. More than one relapse event. 2. 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): 2.1. bevacizumab, 2.2. any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) 2.3. previous treatment with temozolomide with irinotecan
Exclusion criteria
Exclusion criteria: Common to Tier 1 and Tier 2: 1. Known contraindication or hypersensitivity to: 1.1. Any study drug or component of the formulation 1.2. Chinese hamster ovary products or other recombinant human or humanised antibodies. 1.3. 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. 2. 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 3. Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) or any ongoing arterial thrombo-embolic events 4. A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis. 5. Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive prophylaxis for PJP 6. Uncontrolled infection 7. Inadequate recovery from prior surgery with ongoing =Grade 3 surgical complications. Grade =2 wound dehiscence. 8. 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: 8.1. Core biopsies within previous 24hr 8.2. Open excisional biopsies within previous 48hr 8.3. Major surgery within previous 2 weeks. 8.4. Bone marrow aspirates/trephines, within previous 48hr 8.5. Tunnelled central line insertion within previous 48hr 9. Washout from prior treatments (at start of trial treatment): 9.1. Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens) 9.2. Any anti-GD2 therapy within previous 2 weeks 9.3. Craniospinal radiotherapy or MIBG therapy within previous 6 weeks 9.4. Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy) 9.5. Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within previous 8 weeks 9.6. Allogeneic stem cell transplant within previous 12 weeks (with absence of active =G2 acute GVHD) 9.7. 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP- trial 10. 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 11. Use of enzyme inducing anticonvulsants within 72hr of randomisation 12. Conditions that increase the risk of bevacizumab-related toxicities: 12.1 History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation) 12.2 History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment 12.3 Current chronic intestinal inflammatory disease/bowel obstruction 13. Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose 14. Males or females of reproductive potential may not participate unless they agree to use an adequate method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Tier 1 (randomised comparison): Progression-Free Survival time (per the INRC 2017). In Tier 1, interim analyses will be conducted for each arm when 40 patients (stage 1) and 75 patients (stage 2) have been recruited and reached six months after randomisation. Tier 2 (dose expansion-confirmation cohorts): Definition of a safe and tolerable combination regimen. For Tier 2, an assessment will be made after recruitment of 10 patients of whether the toxicity is acceptable for the intervention to be incorporated into the main Tier 1 randomisation. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Best objective response (complete and partial response) per the INRC 2017 during trial treatment (12 cycles) 2. Clinical benefit (complete, partial and minor response and stable disease) per the INRC 2017, at treatment cycle 2, 4, 6, 9 and 12/end of treatment. 3. Time response to progression/Duration of Response for responders (the time from randomisation to progression). 4. Overall Survival time (the time from randomisation to death). 5. Quality of life of patients measured by Peds-QL questionnaires, at baseline and after treatment cycle 2, 4, 6, 9 and 12/end of treatment. 6. Incidence and Severity of AEs throughout the trial. The final analysis will be conducted when all patients have been followed up for at least 5 years. | — |
Countries
Australia, Austria, Belgium, Denmark, England, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, New Zealand, Northern Ireland, Norway, Poland, Scotland, Spain, Sweden, Switzerland, United Kingdom, Wales
Contacts
Public ContactRebecca Reid
Outcome results
None listed