A trial of BEvACizumab added to temozolomide +/- irinOtecan for children with refractory/relapsed Neuroblastoma
| ISRCTN | ISRCTN40708286 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN40708286 |
| EudraCT/CTIS number | 2012-000072-42 |
| ClinicalTrials.gov number | NCT02308527 |
| Secondary identifying numbers | RG_11-087 |
- Submission date
- 22/02/2013
- Registration date
- 24/04/2013
- Last edited
- 08/03/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Contact information
Dr Lucas Moreno
Scientific
Scientific
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
| Phone | 34 93 489 30 00, ext 3093 |
|---|---|
| lucas.moreno@vhebron.net |
Study information
| 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 |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | A randomised phase IIb trial of BEvACizumab added to temozolomide +/- irinOtecan for children with refractory/relapsed Neuroblastoma |
| Study 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 |
| 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 |
Eligibility
| 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 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 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
Sutton
Surrey
SM2 5PT
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
c/o Dr Birgit Whitman
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Website | http://www.birmingham.ac.uk |
|---|---|
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
Cancer Research UK (UK) - Clinical Trials Awards & Advisory Committee: C1536/A14426
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/06/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be 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 |
Editorial Notes
08/03/2024: Cancer Research UK plain English summary link was amended.
10/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2020 to 30/06/2021.
2. The overall end date was changed from 31/12/2025 to 30/06/2026.
3. The intention to publish date was changed from 31/12/2026 to 30/06/2027.
4. The trial website was added.
5. The publication and dissemination plan was added.
6. The participant level data was changed from 'Not provided at time of registration' to 'To be made available at a later date'.
25/03/2020: The trial contact has been updated.
27/08/2019: ClinicalTrials.gov number added.
25/03/2019: The following changes have been made:
1. The recruitment end date has been changed from 01/02/2019 to 31/12/2020.
2. The overall trial end date has been changed from 01/06/2020 to 31/12/2025.
3. The intention to publish date date has been added.
4. The study hypothesis has been changed.
5. The intervention has been changed.
6. Topotecan, dinutuximab beta and cyclophosphamide have been added to the drug names.
7. The target number of participants has been changed from 160 to 224.
8. Denmark, Ireland, Switzerland and Belgium have been added to the countries of recruitment.
9. The sponsor contact has been changed from Dr Sean Jennings to Dr Birgit Whitman.
15/01/2019: The recruitment end date has been changed from 31/12/2018 to 01/02/2019.
28/08/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/03/2015 to 31/12/2018.
2. The overall trial end date was changed from 31/03/2015 to 01/06/2020.
3. The target number of participants was changed from 120 to 160.
4. The interventions were updated.
12/01/2017: No publications found in PubMed, verifying study status with principal investigator.
