Clinical Trials /

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

NCT02308527

Description:

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.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children
  • Official Title: A Randomised Phase IIb Trial of Bevacizumab Added to Temozolomide ± Irinotecan for Children With Refractory/Relapsed Neuroblastoma - BEACON-Neuroblastoma Trial

Clinical Trial IDs

  • ORG STUDY ID: RG_11-087
  • SECONDARY ID: 2012-000072-42
  • NCT ID: NCT02308527

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
BevacizumabAvastinBevacizumab + Temozolomide
TemozolomideTemodalBevacizumab + Temozolomide
TemozolomideTemodalBevacizumab + Irinotecan + Temozolomide
IrinotecanCamptoBevacizumab + Irinotecan + Temozolomide
BevacizumabAvastinBevacizumab + Irinotecan + Temozolomide
TopotecanBevacizumab + Temozolomide + Topotecan
TemozolomideTemodalBevacizumab + Temozolomide + Topotecan
Dinutuximab BetaQarzibaDinutuximab beta + Temozolomide
CyclophosphamideDinutuximab beta + Topotecan + Cyclophosphamide

Purpose

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).
    

Trial Arms

NameTypeDescriptionInterventions
TemozolomideActive ComparatorTemozolomide Days 1-5 every 4 weeks
  • Temozolomide
Bevacizumab + TemozolomideExperimentalBevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks
  • Bevacizumab
  • Temozolomide
Irinotecan + TemozolomideExperimentalIrinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks
  • Temozolomide
  • Irinotecan
Bevacizumab + Irinotecan + TemozolomideExperimentalBevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks
  • Temozolomide
  • Irinotecan
  • Bevacizumab
Temozolomide + TopotecanExperimentalTemozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks
  • Topotecan
  • Temozolomide
Bevacizumab + Temozolomide + TopotecanExperimentalBevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks
  • Bevacizumab
  • Topotecan
  • Temozolomide
Dinutuximab beta + TemozolomideExperimentalDinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks
  • Temozolomide
  • Dinutuximab Beta
Dinutuximab beta + Temozolomide + TopotecanExperimentalDinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks
  • Temozolomide
  • Topotecan
  • Dinutuximab Beta
Dinutuximab beta + Topotecan + CyclophosphamideOtherDinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks
  • Topotecan
  • Dinutuximab Beta
  • Cyclophosphamide

Eligibility Criteria

        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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:To evaluate the toxicity of the regimens
Time Frame:Assessment will be after 30 days after treatment or end of trial
Safety Issue:
Description:Safety of the regimens: Incidence and severity of Adverse Events (AE)s
Measure:To evaluate the safety of the regimens
Time Frame:Assessment will be after 30 days after treatment or end of trial
Safety Issue:
Description:Safety of the regimens: Progression-free survival (PFS)
Measure:To evaluate the overall safety of the regimens
Time Frame:Assessment will be after 30 days after treatment or end of trial
Safety Issue:
Description:Safety of the regimens: Overall survival (OS)
Measure:To evaluate the safety of the regimens
Time Frame:Assessment will be after 30 days after treatment or end of trial
Safety Issue:
Description:Safety of the regimens: Event-free survival (EFS)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Birmingham

Trial Keywords

  • Children
  • Young adults

Last Updated

March 24, 2020