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Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children (BEACON)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02308527
Recruitment Status : Active, not recruiting
First Posted : December 4, 2014
Last Update Posted : February 15, 2022
Sponsor:
Collaborators:
Cancer Research UK
Roche Pharma AG
Imagine for Margo
EUSA Pharma, Inc.
Information provided by (Responsible Party):
University of Birmingham

Tracking Information
First Submitted Date  ICMJE September 10, 2014
First Posted Date  ICMJE December 4, 2014
Last Update Posted Date February 15, 2022
Actual Study Start Date  ICMJE July 2013
Actual Primary Completion Date August 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • 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. [ Time Frame: 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) [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Progression-free survival (PFS)
Original Primary Outcome Measures  ICMJE
 (submitted: December 3, 2014)
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. [ Time Frame: 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 or irinotecan-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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • To evaluate the toxicity of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Incidence and severity of Adverse Events (AE)s
  • To evaluate the safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Progression-free survival (PFS)
  • To evaluate the overall safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Overall survival (OS)
  • To evaluate the safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Event-free survival (EFS)
Original Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2014)
  • To evaluate the safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Incidence and severity of Adverse Events (AE)s
  • To evaluate the safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Progression-free survival (PFS)
  • To evaluate the safety of the regimens [ Time Frame: Assessment will be after 30 days after treatment or end of trial ]
    Safety of the regimens: Overall survival (OS)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children
Official Title  ICMJE A Randomised Phase IIb Trial of Bevacizumab Added to Temozolomide ± Irinotecan for Children With Refractory/Relapsed Neuroblastoma - BEACON-Neuroblastoma Trial
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neuroblastoma
Intervention  ICMJE
  • Drug: Bevacizumab
    10mg/kg IV (in the vein) on Days 1 and 15 of a 4 week cycle, for 6 cycles or until progression
    Other Name: Avastin
  • Drug: Temozolomide
    200mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression
    Other Name: Temodal
  • Drug: Temozolomide
    100mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 3 week cycle, for 6 cycles or until progression
    Other Name: Temodal
  • Drug: Irinotecan
    50mg/m2/d IV (in the vein) on Days 1 to 5 of a 3 week cycle, for 6 cycles or until progression
    Other Name: Campto
  • Drug: Bevacizumab
    15mg/kg IV (in the vein) on Day 1 of a 3 week cycle, for 6 cycles or until progression
    Other Name: Avastin
  • Drug: Topotecan
    0.75mg/m2/d IV (in the vein) on Days 1-5 of a 4 week cycle, for 6 cycles or until progression
  • Drug: Temozolomide
    150mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression
    Other Name: Temodal
  • Drug: Dinutuximab Beta
    10mg/m2/d IV (in the vein) on Days 1 to 7 of a 4 week cycle, for 6 cycles or until progression
    Other Name: Qarziba
  • Drug: Cyclophosphamide
    250mg/m2/d IV (in the vein) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression
Study Arms  ICMJE
  • Active Comparator: Temozolomide
    Temozolomide Days 1-5 every 4 weeks
    Intervention: Drug: Temozolomide
  • Experimental: Bevacizumab + Temozolomide
    Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks
    Interventions:
    • Drug: Bevacizumab
    • Drug: Temozolomide
  • Experimental: Irinotecan + Temozolomide
    Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks
    Interventions:
    • Drug: Temozolomide
    • Drug: Irinotecan
  • Experimental: Bevacizumab + Irinotecan + Temozolomide
    Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks
    Interventions:
    • Drug: Temozolomide
    • Drug: Irinotecan
    • Drug: Bevacizumab
  • Experimental: Temozolomide + Topotecan
    Temozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks
    Interventions:
    • Drug: Topotecan
    • Drug: Temozolomide
  • Experimental: Bevacizumab + Temozolomide + Topotecan
    Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks
    Interventions:
    • Drug: Bevacizumab
    • Drug: Topotecan
    • Drug: Temozolomide
  • Experimental: Dinutuximab beta + Temozolomide
    Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks
    Interventions:
    • Drug: Temozolomide
    • Drug: Dinutuximab Beta
  • Experimental: Dinutuximab beta + Temozolomide + Topotecan
    Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks
    Interventions:
    • Drug: Temozolomide
    • Drug: Topotecan
    • Drug: Dinutuximab Beta
  • Dinutuximab beta + Topotecan + Cyclophosphamide
    Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks
    Interventions:
    • Drug: Topotecan
    • Drug: Dinutuximab Beta
    • Drug: Cyclophosphamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 28, 2021)
225
Original Estimated Enrollment  ICMJE
 (submitted: December 3, 2014)
120
Estimated Study Completion Date  ICMJE December 2026
Actual Primary Completion Date August 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
  • Relapsed: any relapsed or progressed high-risk neuroblastoma
  • Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies
  • Measurable disease by cross sectional imaging (RECIST) or evaluable disease
  • Age ≥1 to ≤21 years
  • Informed consent from patient, parent or guardian
  • Performance Status:Lansky ≥ 50%, Karnofsky ≥ 50% or Eastern Cooperative Oncology Group ≤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)
  • Life expectancy of ≥12 weeks
  • No bone marrow disease: Platelets ≥75 x 10^9/L (unsupported for 72 hours), absolute neutrophil count ≥0.75 x10^9/L (no G-cerebrospinal fluid support for 72 hours), Haemoglobin ≥8 g/dL (transfusions allowed) Bone marrow disease: Platelets ≥50 x10^9/L (unsupported for 72 hours), absolute neutrophil count (ANC) ≥0.5 x 10^9/L (no granulocyte colony stimulating factor (G-CSF) for 72 hours), Haemoglobin ≥8 g/dL (transfusions allowed)
  • Renal function (within 72 hours of eligibility assessment): 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
  • Serum creatinine ≤ 1.5 upper limit of normal for age, if higher, a calculated glomerular filtration rate (radioisotope) must be ≥60 ml/min/1.73 m2
  • Liver function (within 72 hours of eligibility assessment): aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤2.5 ULN and Total bilirubin ≤1.5 upper limit of normal (ULN). In case of liver metastases, AST or ALT ≤5 ULN and Total bilirubin ≤2.5 ULN
  • Cardiac function, shortening fraction ≥29% on echocardiogram
  • Coagulation, patients not on anticoagulation must have an international normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 ULN for age. Anti-coagulation 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
  • 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
  • No dyspnoea at rest and pulse oximetry > 94% in room air
  • Availability and willingness to place a double central venous access if needed for trial treatment and supportive care in case of treatment with chemo-immunotherapy

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Denmark,   France,   Ireland,   Italy,   Netherlands,   Spain,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02308527
Other Study ID Numbers  ICMJE RG_11-087
2012-000072-42 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party University of Birmingham
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Birmingham
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Cancer Research UK
  • Roche Pharma AG
  • Imagine for Margo
  • EUSA Pharma, Inc.
Investigators  ICMJE
Principal Investigator: Lucas Moreno, MD University of Birmingham
PRS Account University of Birmingham
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP