Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children
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)? - 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) Patients aged 1-21 years of age with relapsed or refractory high-risk neuroblastoma are randomised to one of six treatment arms: Temozolomide (T), irinotecan-temozolomide (IT), bevacizumab-T (BT), BIT (bevacizumab-IT), temozolomide-topotecan (TTo) or bevacizumab-temozolomide-topotecan (BTTo).
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
|Eligible Ages||1 Year - 21 Years|
- - 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 ≥7.5 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 ≥7.5 g/dL (transfusions allowed) - Renal function (within 72 hours of eligibility assessment): Absence of clinically significant proteinuria (early morning urine dipstick <2+).
- - 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).
- - 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.
- - Blood pressure below 95th centile for age and sex.
- - 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.
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 - Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) - Any ongoing arterial thrombo-embolic events - Patient <48 hours post bone marrow aspirate/trephine, <48 hours post central line insertion,
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 0: Exploratory study involving very limited human exposure to the drug to determine whether a drug is modulating its target.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|University of Birmingham|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
|Countries||Austria, Denmark, France, Ireland, Italy, Spain, Switzerland, United Kingdom|
The disease, disorder, syndrome, illness, or injury that is being studied.
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 six arms (approximately 30 patients per arm): T: Temozolomide BT: Bevacizumab + Temozolomide IT: Irinotecan + Temozolomide BIT: Bevacizumab + Irinotecan + Temozolomide TTo: Temozolomide + Topotecan BTTo: Bevacizumab + Temozolomide + Topotecan 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 1:1 ratio. Minimisation will be used to ensure balance across the arms for the important prognostic factors as described by London et al. : 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 18 or 24 weeks depending on the arm of the trial that they are randomised to. 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).
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The Royal Marsden NHS Foundation Trust and Institute of Cancer Research
Sutton, Surrey, SM2 5PT
Andrew DJ Pearson, MD