Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children
- Conditions
- Neuroblastoma
- Interventions
- Registration Number
- NCT02308527
- Lead Sponsor
- University of Birmingham
- Brief Summary
The purpose of this study is to investigate whether Bevacizumab (an anti-VEGF monoclonal antibody) added to a backbone chemotherapy regimen (Temozolomide, Irinotecan-Temozolomide or Topotecan-Temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma. Also, to investigate whether the addition of Irinotecan or Topotecan to Temozolomide increases the activity of chemotherapy.The primary objective of the study is the best response (Complete Response or Partial Response) while trial treatment, within 18 or 24 weeks depending on the arm of the trial the participant is randomised to. Secondary endpoints are assessing the side effects, the length of time before progression (Progression Free Survival) and overall survival (OS).
This trial will address two important questions:
* does targeting blood vessel development using bevacizumab, (a monoclonal antibody against the Vascular Endothelial Growth Factor (VEGF)), add to the effect on a tumour when used with existing chemotherapy, compared to the effect of the existing chemotherapy alone (temozolomide)? NOTE- This question has been completed.
* does the addition of a second chemotherapy drug (irinotecan or topotecan) increase the effect on a tumour compared to the effect of one alone (temozolomide) NOTE - This question has been completed.
* does the addition of dinutuximab beta added to a backbone chemotherapy (temozolomide or temozolomide + topotecan) increase the effect of backbone alone.
Patients aged 1-21 years of age with relapsed or refractory high-risk neuroblastoma are randomised to one of two treatment arms: temozolomide-topotecan (TTo) or dinutuximab beta-temozolomide-topotecan (dBTTo). Temozolomide (T), irinotecan-temozolomide (IT), bevacizumab-T (BT), BIT (bevacizumab-IT), bevacizumab-temozolomide-topotecan (BTTo) and dinutuximab beta-temozolomide (dBT) are now closed to recruitment.
- Detailed Description
This is an international open-label, randomised, multicentre phase II trial of temozolomide ± irinotecan, with or without bevacizumab, for the treatment of patients with relapsed or refractory neuroblastoma. The study will evaluate the safety and activity of these combinations.
Patients will be registered into the trial and randomised at the same time to one of the following two arms (approximately 30 patients per arm):
TTo: Temozolomide + Topotecan dBTTo: Dinuximab beta + Temozolomide + Topotecan
Arms which have now closed to recruitment:
dBT: Dinutuximab beat + Temozolomide Closed 28 \]Jan 2020 T: Temozolomide - Closed 28 Jan 2020 BT: Bevacizumab + Temozolomide - Closed 7 Feb 2019 IT: Irinotecan + Temozolomide - Closed 21 June 2018 BIT: Bevacizumab + Irinotecan + Temozolomide - Closed 21 June 2018 BTTo: Bevacizumab + Temozolomide + Topotecan - Closed 7 Feb 2019
Randomisation will be via a secure on-line computer-based system at the Cancer Research Clinical Trial Unit (CRCTU), University of Birmingham, United Kingdom (UK) and patients will be allocated in a 2:1 ratio. Minimisation will be used to ensure balance across the arms for the important prognostic factors as described by London et al. \[10\]: a) relapsed, refractory disease, b) early (\< 18 months), late relapse (≥18 months) and c) measurable versus evaluable disease (i.e. disease evaluated according to RECIST versus disease detectable only by MIBG scanning with or without bone marrow involvement as detected by local morphology) Patients will receive treatment for 6 courses, lasting 24 weeks.
Patients with a response (CR, PR) or stable disease (SD) while on the BEACON-Neuroblastoma trial will receive 6 cycles of trial treatment. If the patient has achieved a satisfactory response (i.e. CR, PR or SD) with acceptable toxicity, treatment may be extended beyond 6 cycles (up to 12 cycles) after discussion with the Sponsor and the Chief Investigator (CI).
In addition, patients randomised to TTo may recieve an optional regimen of dinutuximab beta + topotecan + cyclophosphamide (up to 6 cycles).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 225
Not provided
- Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
- Known hypersensitivity to: Any study drug or component of the formulation, Chinese hamster ovary products or other recombinant human or humanised antibodies, Dacarbazine
- Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis)
- Any ongoing arterial thrombo-embolic events
- Patient less than (at point of planned date of randomisation): 48 hours post bone marrow aspirate/trephine, 48 hours post central line insertion, Four weeks post major surgery, One week post core biopsy, Two weeks from prior chemotherapy, Six weeks from prior craniospinal radiotherapy or MIBG therapy and two weeks from radiotherapy to the tumour bed, Eight weeks from prior myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant), Three months from prior allogeneic stem cell transplant, 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial, 6 months from presentation of lung haemorrhage/haemoptysis
- Bleeding metastases (patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
- Invasion of major blood vessels
- Use of enzyme inducing anticonvulsants within 72 hours of randomisation
- 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
- Pregnant or lactating patient
- Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
- Low probability of treatment compliance
- Any uncontrolled medical condition that poses an additional risk to the patient
- Planned immunisation with live vaccine
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Bevacizumab + Irinotecan + Temozolomide Irinotecan Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks Bevacizumab + Temozolomide + Topotecan Bevacizumab Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Bevacizumab + Temozolomide Temozolomide Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks Irinotecan + Temozolomide Irinotecan Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks Dinutuximab beta + Topotecan + Cyclophosphamide Dinutuximab Beta Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks Dinutuximab beta + Topotecan + Cyclophosphamide Cyclophosphamide Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks Temozolomide Temozolomide Temozolomide Days 1-5 every 4 weeks Bevacizumab + Temozolomide Bevacizumab Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks Irinotecan + Temozolomide Temozolomide Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks Bevacizumab + Irinotecan + Temozolomide Bevacizumab Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks Bevacizumab + Irinotecan + Temozolomide Temozolomide Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks Temozolomide + Topotecan Topotecan Temozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks Bevacizumab + Temozolomide + Topotecan Topotecan Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Temozolomide + Topotecan Temozolomide Temozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks Dinutuximab beta + Temozolomide Temozolomide Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks Bevacizumab + Temozolomide + Topotecan Temozolomide Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Dinutuximab beta + Temozolomide Dinutuximab Beta Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks Dinutuximab beta + Temozolomide + Topotecan Temozolomide Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Dinutuximab beta + Temozolomide + Topotecan Topotecan Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Dinutuximab beta + Temozolomide + Topotecan Dinutuximab Beta Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks Dinutuximab beta + Topotecan + Cyclophosphamide Topotecan Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks
- Primary Outcome Measures
Name Time Method Best response (Complete Response or Partial Response) while on trial treatment, within 18 or 24 weeks depending on the arm of the trial participant is randomised to. Within 18 or 24 weeks depending on the arm of the trial the participant is randomised to. To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan-temozolomide or topotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma
For the bevacizumab part 2 only; Progression-free survival (PFS) Assessment will be after 30 days after treatment or end of trial Progression-free survival (PFS)
- Secondary Outcome Measures
Name Time Method To evaluate the safety of the regimens Assessment will be after 30 days after treatment or end of trial Safety of the regimens: Event-free survival (EFS)
To evaluate the overall safety of the regimens Assessment will be after 30 days after treatment or end of trial Safety of the regimens: Overall survival (OS)
To evaluate the toxicity of the regimens Assessment will be after 30 days after treatment or end of trial Safety of the regimens: Incidence and severity of Adverse Events (AE)s
Trial Locations
- Locations (10)
St Anna Children's Hospital and CCRI/Studies and Statistics
🇦🇹Vienna, Austria
University Hospital Rigshospitalet
🇩🇰Copenhagen, Denmark
Ospedale Pediatrico Bambino Gseu
🇮🇹Rome, Italy
University Hospital
🇧🇪Gent, Belgium
Hopital des Enfants
🇫🇷Toulouse, France
Our Ladys Children's Hospital Dublin
🇮🇪Dublin, Ireland
Natasha van Eijkelenburg
🇳🇱Utrecht, Netherlands
Swiss Paediatric Oncology Group
🇨🇭Bern, Switzerland
The Royal Marsden NHS Foundation Trust and Institute of Cancer Research
🇬🇧Sutton, Surrey, United Kingdom
Instituto de Investigacion Sanitaria
🇪🇸Valencia, Spain