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

NCT02308527 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: RG_11-0872012-000072-42
• Study Type: interventional
• Target: 225
• Locations: 10 countries
• Sites: 10

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.

Conditions

Neuroblastoma

Keywords

Children; Young adults

Outcome Measures

Primary Outcomes (2)

• 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.

  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

  Within 18 or 24 weeks depending on the arm of the trial the participant is randomised to.

• For the bevacizumab part 2 only; Progression-free survival (PFS)

  Progression-free survival (PFS)

  Assessment will be after 30 days after treatment or end of trial

Secondary Outcomes (4)

• To evaluate the toxicity of the regimens

  Assessment will be after 30 days after treatment or end of trial

• To evaluate the safety of the regimens

  Assessment will be after 30 days after treatment or end of trial

• To evaluate the overall safety of the regimens

  Assessment will be after 30 days after treatment or end of trial

• To evaluate the safety of the regimens

  Assessment will be after 30 days after treatment or end of trial

Study Arms (9)

Temozolomide

ACTIVE COMPARATOR

Temozolomide Days 1-5 every 4 weeks

Drug: Temozolomide

Bevacizumab + Temozolomide

EXPERIMENTAL

Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks

Drug: Bevacizumab; Drug: Temozolomide

Irinotecan + Temozolomide

EXPERIMENTAL

Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks

Drug: Temozolomide; Drug: Irinotecan

Bevacizumab + Irinotecan + Temozolomide

EXPERIMENTAL

Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks

Drug: Temozolomide; Drug: Irinotecan; Drug: Bevacizumab

Temozolomide + Topotecan

EXPERIMENTAL

Temozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks

Drug: Topotecan; Drug: Temozolomide

Bevacizumab + Temozolomide + Topotecan

EXPERIMENTAL

Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks

Drug: Bevacizumab; Drug: Topotecan; Drug: Temozolomide

Dinutuximab beta + Temozolomide

EXPERIMENTAL

Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks

Drug: Temozolomide; Drug: Dinutuximab Beta

Dinutuximab beta + Temozolomide + Topotecan

EXPERIMENTAL

Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks

Drug: Temozolomide; Drug: Topotecan; Drug: Dinutuximab Beta

Dinutuximab beta + Topotecan + Cyclophosphamide

OTHER

Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks

Drug: Topotecan; Drug: Dinutuximab Beta; Drug: Cyclophosphamide

Interventions

Bevacizumab DRUG

10mg/kg IV (in the vein) on Days 1 and 15 of a 4 week cycle, for 6 cycles or until progression

Also known as: Avastin

Bevacizumab + Temozolomide; Bevacizumab + Temozolomide + Topotecan

Temozolomide DRUG

200mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression

Also known as: Temodal

Bevacizumab + Temozolomide; Dinutuximab beta + Temozolomide; Dinutuximab beta + Temozolomide + Topotecan; Temozolomide

Irinotecan DRUG

50mg/m2/d IV (in the vein) on Days 1 to 5 of a 3 week cycle, for 6 cycles or until progression

Also known as: Campto

Bevacizumab + Irinotecan + Temozolomide; Irinotecan + Temozolomide

Topotecan DRUG

0.75mg/m2/d IV (in the vein) on Days 1-5 of a 4 week cycle, for 6 cycles or until progression

Bevacizumab + Temozolomide + Topotecan; Dinutuximab beta + Temozolomide + Topotecan; Dinutuximab beta + Topotecan + Cyclophosphamide; Temozolomide + Topotecan

Dinutuximab Beta DRUG

10mg/m2/d IV (in the vein) on Days 1 to 7 of a 4 week cycle, for 6 cycles or until progression

Also known as: Qarziba

Dinutuximab beta + Temozolomide; Dinutuximab beta + Temozolomide + Topotecan; Dinutuximab beta + Topotecan + Cyclophosphamide

Cyclophosphamide DRUG

250mg/m2/d IV (in the vein) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression

Dinutuximab beta + Topotecan + Cyclophosphamide

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Birmingham: lead
• Cancer Research UK: collaborator
• Roche Pharma AG: collaborator
• Imagine for Margo: collaborator
• EUSA Pharma, Inc.: collaborator

Study Sites (10)

St Anna Children's Hospital and CCRI/Studies and Statistics

Vienna, A-1090, Austria

Location

University Hospital

Ghent, Belgium

Location

University Hospital Rigshospitalet

Copenhagen, DK-2100, Denmark

Location

Hopital des Enfants

Toulouse, 31059, France

Location

Our Ladys Children's Hospital Dublin

Dublin, Dublin 12, Ireland

Location

Ospedale Pediatrico Bambino Gseu

Rome, 00165, Italy

Location

Natasha van Eijkelenburg

Utrecht, Netherlands

Location

Instituto de Investigacion Sanitaria

Valencia, 46026, Spain

Location

Swiss Paediatric Oncology Group

Bern, 3008, Switzerland

Location

The Royal Marsden NHS Foundation Trust and Institute of Cancer Research

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Moreno L, Weston R, Owens C, Valteau-Couanet D, Gambart M, Castel V, Zwaan CM, Nysom K, Gerber N, Castellano A, Laureys G, Ladenstein R, Rossler J, Makin G, Murphy D, Morland B, Vaidya S, Thebaud E, van Eijkelenburg N, Tweddle DA, Barone G, Tandonnet J, Corradini N, Chastagner P, Paillard C, Bautista FJ, Gallego Melcon S, De Wilde B, Marshall L, Gray J, Burchill SA, Schleiermacher G, Chesler L, Peet A, Leach MO, McHugh K, Hayes R, Jerome N, Caron H, Laidler J, Fenwick N, Holt G, Moroz V, Kearns P, Gates S, Pearson ADJ, Wheatley K; Innovative Therapies for Children with Cancer (ITCC) and European Association for Neuroblastoma Research (SIOPEN). Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial. J Clin Oncol. 2024 Apr 1;42(10):1135-1145. doi: 10.1200/JCO.23.00458. Epub 2024 Jan 8.

  PMID: 38190578 DERIVED

MeSH Terms

Conditions

Neuroblastoma

Interventions

Bevacizumab; Temozolomide; Irinotecan; Topotecan; dinutuximab; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Camptothecin; Alkaloids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds

Study Officials

• Lucas Moreno, MD

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2014
• First Posted: December 4, 2014
• Study Start: July 1, 2013
• Primary Completion: August 1, 2021
• Study Completion: February 1, 2026
• Last Updated: May 14, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1); GB (1); IE (1); AU (1); NL (1); CH (1); IT (1); FR (1); ES (1); BE (1)