Contact information
Type
Scientific
Contact name
Dr Lucas Moreno
ORCID ID
Contact details
Paediatric Oncology & Haematology
Hospital Universitari Vall d’Hebron
Vall d’Hebron Barcelona Hospital Campus
Passeig de la Vall d’Hebron
119-129
Barcelona
08035
Spain
34 93 489 30 00, ext 3093
lucas.moreno@vhebron.net
Additional identifiers
EudraCT/CTIS number
2012-000072-42
IRAS number
ClinicalTrials.gov number
NCT02308527
Protocol/serial number
RG_11-087
Study information
Scientific title
A randomised phase IIb trial of BEvACizumab added to temozolomide +/- irinOtecan for children with refractory/relapsed Neuroblastoma
Acronym
BEACON-Neuroblastoma
Study hypothesis
Current study hypothesis as of 25/03/2019:
Primary objectives:
1. To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide or irinotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma
2. To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma
3. To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma
4. To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma.
Secondary objectives:
1. To evaluate the safety of the regimens
Previous study hypothesis:
Primary objectives:
1. To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide or irinotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma
2. To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma
Secondary objectives:
1. To evaluate the safety of the regimens
Ethics approval(s)
The NRES Commitee West Midlands - Coventry & Warwickshire, 06/02/2013, ref: 13/WM/0023
Study design
Interventional phase II randomised open label international multicentre 2x2 factorial trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Study setting(s)
Hospital
Study type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Neuroblastoma in children aged ≥1 to ≤21 years
Intervention
Current intervention as of 25/03/2019:
Investigational medicinal products: bevacizumab, irinotecan, temozolomide, topotecan, dinutuximab beta, cyclophosphamide
Arm T:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Arm BT:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks
Arm IT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Duration of intervention: 18 weeks
Arm BIT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Bevacizumab 15 mg/kg intravenous on day 1 every 3 weeks
Duration of intervention: 18 weeks
Arm TTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Arm BTTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks
Arm dBT
Dinutuximab beta 10 mg/m2/day 24-h infusion on days 1-7 every 4 weeks
Temozolomide 200 mg/m2/day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Arm dBTTo
Dinutuximab beta 10 mg/m2/day 24-h infusion on days 1-7 every 4 weeks
Temozolomide 200 mg/m2/day oral on days 1-5 every 4 weeks
Topotecan 0.75mg/m2/day intravenous on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Previous intervention:
Investigational Medicinal Products: Bevacizumab, Irinotecan, Temozolomide
Arm T:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Arm BT:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks
Arm IT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Duration of intervention: 18 weeks
Arm BIT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Bevacizumab 15mg/kg intravenous on day 1 every 3 weeks
Duration of intervention: 18 weeks
Added 28/08/2018:
Arm TTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks
Arm BTTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks
Intervention type
Drug
Pharmaceutical study type(s)
Phase
Phase II
Drug/device/biological/vaccine name(s)
Bevacizumab, temozolomide, irinotecan, topotecan, dinutuximab beta, cyclophosphamide
Primary outcome measure
Best response (Complete Response [CR], or Partial Response [PR][1] at any time during the first 6 cycles of trial treatment
Secondary outcome measures
1. Safety of the regimens: Incidence and severity of Adverse Events (AEs)
2. Progression-free survival (PFS)
3. Overall survival (OS)
Overall study start date
01/04/2013
Overall study end date
30/06/2026
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Disease specific
1. Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) [1] definition
2. Relapsed or refractory neuroblastoma
2.1. Relapsed: any relapsed or progressed high-risk neuroblastoma
2.2. Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g myeloablative chemotherapy)
3. Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study
General
1. Age ≥1 to ≤21 years
2. Informed consent from patient, parent or guardian
Performance and organ function
1. Performance Status:
1.1. Lansky ≥ 50%, Karnofsky ≥ 50% or ECOG ≤3
(Patients 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 of eligibility assessment):
No bone marrow disease:
1. Platelets ≥ 75 x 109/L (unsupported for 72 hours)
2. ANC ≥ 0.75 x 109/L (no G-CSF support for 72 hours)
3. Haemoglobin > 7.5 g/dL (transfusions allowed)
Bone marrow disease:
1. Platelets ≥ 50 x109/L (unsupported for 72 hours)
2. ANC ≥0.5 x 109/L (no G-CSF for 72 hours)
3. Haemoglobin > 7.5 g/dL (transfusions allowed)
4. Renal function (within 72 hours of eligibility assessment):
4.1. Absence of clinically significant proteinuria (early morning urine dipstick ≤2+). When the dipstick urinalysis shows a proteinuria > 2+, a 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 calculated GFR (radioisotope) must be ≥ 60 ml/min/1.73 m2
5. Liver function (within 72 hours of eligibility assessment): AST and ALT ≤2.5 ULN and total bilirubin ≤1.5 ULN. In case of liver metastases, AST and ALT ≤5 ULN and total bilirubin ≤2.5 ULN
6. Cardiac function, shortening fraction ≥29% on echocardiogram
7. Coagulation, patients not on anticoagulation must have an INR ≤1.5 and APTT ≤1.5 ULN for age. Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the patient 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. Use of antihypertensive medication is permitted
8. Males or females of reproductive potential may not participate unless they agree to use an effective contraceptive method, for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche
Participant type(s)
Patient
Age group
Child
Lower age limit
1 Year
Upper age limit
21 Years
Sex
Both
Target number of participants
224
Participant exclusion criteria
1. Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
2. Known hypersensitivity to:
2.1. Any study drug or component of the formulation
2.2. Chinese hamster ovary products or other recombinant human or humanised antibodies
3. Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis)
4. Any ongoing arterial thrombo-embolic events
5. Patient less than (at point of eligibility assessment):
5.1. 48 hours post bone marrow aspirate/trephine
5.2. 48 hours post central line insertion
5.3. Four weeks post major surgery
5.4. One week post core biopsy
5.5. Two weeks from prior chemotherapy
5.6. Six weeks from prior craniospinal or MIBG therapy and two weeks from radiotherapy to the tumour bed
5.7. Eight weeks from prior myeloablative therapy with haematopoeitic stem cell rescue (autologous stem cell transplant)
5.8. Three months from prior allogeneic stem cell transplant
5.9. Two weeks from last administration of an IMP in an IMP-trial
6. Bleeding metastases (patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
7. Invasion of major blood vessels
8. Use of enzyme inducing anticonvulsants within 72 hours of eligibility assessment
9. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)
10. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment
11. Pregnant or lactating patient
12. Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
13. Low probability of treatment compliance
14. Planned immunisation with live vaccine
Recruitment start date
01/04/2013
Recruitment end date
30/06/2021
Locations
Countries of recruitment
Austria, Belgium, Denmark, England, France, Germany, Ireland, Italy, Netherlands, Spain, Switzerland, United Kingdom
Study participating centre
The Royal Marsden NHS Foundation Trust & Institute of Cancer Research
15 Cotswold Rd
Sutton
Surrey
SM2 5PT
United Kingdom
Sponsor information
Organisation
University of Birmingham
Sponsor details
c/o Dr Birgit Whitman
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
Sponsor type
University/education
Website
ROR
Funders
Funder type
Charity
Funder name
Cancer Research UK (UK) - Clinical Trials Awards & Advisory Committee: C1536/A14426
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit organizations
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
Intention to publish date
30/06/2027
Individual participant data (IPD) sharing plan
The current data sharing plans for this study are unknown and will be available at a later date
IPD sharing plan summary
Data sharing statement to be made available at a later date
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |