Randomized Phase IIb Study with Bevacizumab as Add-on Therapy to Temozolomide ± Irinotecan in Children with a Neuroblastoma that has Recurred (recurrent Neuroblastoma) or is Resistant to Current Therapies (therapy-refractory Neuroblastoma) – Medications after Study Modification: Temozolomide, Topotecan, and Dinutuximab beta.
Zusammenfassung der Studie
BEACON is an international study in which children and adolescents from many European countries are treated for recurrent or therapy-refractory neuroblastoma, i.e., a neuroblastoma that has reappeared after treatment (recurrence) or has not responded to the initially applied therapy (therapy-refractory neuroblastoma). Currently, there is no standard treatment for this situation. Many different combination therapies are currently being used. Commonly used chemotherapy drugs include Temozolomide alone or in combination with Topotecan. Dinutuximab beta is an anti-GD2 antibody used to treat high-risk neuroblastomas. Studies with other anti-GD2 antibodies have provided initial evidence that combined use with chemotherapy may lead to improved responses with an acceptable toxicity profile. The study has four main objectives: First, to assess whether the addition of Irinotecan to Temozolomide improves treatment outcomes in children with neuroblastoma that has recurred or is resistant to the initially applied therapies. (This part of the study has now been completed). Second, to determine whether the addition of Topotecan to Temozolomide improves treatment outcomes. (This part of the study has been closed). Third, to determine whether the addition of Bevacizumab to chemotherapy (Temozolomide, Irinotecan+Temozolomide, or Temozolomide+Topotecan) improves treatment outcomes. (This part of the study has now been completed). Fourth, to determine whether the addition of Dinutuximab beta to chemotherapy (Temozolomide+Topotecan) improves treatment outcomes. (This part of the study is open).
(BASEC)
Untersuchte Intervention
It is not always known which type of treatment is best for patients. To find this out, different treatments must be compared. Patients are therefore divided into groups, and each group receives a different treatment. The results are then compared to see if one is better than the other. To ensure that the groups are equal at the start, each patient is randomly assigned to a group. In this study, there were initially six treatment groups:
• Treatment group T receives only Temozolomide
• Treatment group BT receives Bevacizumab and Temozolomide
• Treatment group IT receives Irinotecan and Temozolomide
• Treatment group BIT receives Bevacizumab, Irinotecan, and Temozolomide
• Treatment group TTo receives Temozolomide and Topotecan
• Treatment group BTTo receives Bevacizumab, Temozolomide, and Topotecan
In June 2018, the assignment to Irinotecan treatment groups was removed, as the recruitment target of 120 patients in these treatment groups was reached.
In February 2019, the assignment to Bevacizumab treatment groups was also completed (recruitment target of 160 patients reached).
Two new treatment groups with Dinutuximab beta were added. The probability that a patient will be assigned to the Dinutuximab beta treatment group is 2:1. It is therefore twice as likely that a patient will be assigned to a treatment group with Dinutuximab beta than to a group without Dinutuximab beta.
There will therefore be four treatment groups:
• Treatment group T receives only Temozolomide
• Treatment group DbT receives Dinutuximab beta and Temozolomide
• Treatment group TTo receives Temozolomide and Topotecan
• Treatment group DbTTo receives Dinutuximab beta, Temozolomide, and Topotecan
In February 2020, the assignment to treatment groups T and DbT was removed.
There is the possibility of treatment crossover if the patient was not initially assigned to the Dinutuximab beta treatment group and the disease progresses or returns within 30 months of study entry. In this case, the patient may receive 6 cycles of Dinutuximab beta combined with chemotherapy (Topotecan – Cyclophosphamide).
As part of this study, blood, bone marrow, imaging studies, and, if available, tumor samples will be used to better understand:
• how Bevacizumab / Dinutuximab beta works in the body
• why some patients with neuroblastoma respond better to Bevacizumab / Dinutuximab beta
• why some patients experience side effects from Bevacizumab / Dinutuximab beta
• what factors influence how a patient's neuroblastoma progresses
Overall, the treatment is expected to last 24 weeks, depending on which treatment group the patient is assigned to. Assignment is done randomly (randomization). In case of good efficacy, an extension of treatment for up to 24 weeks may also be possible. (If the patient is assigned to the treatment group with Dinutuximab beta, treatment with Dinutuximab beta will be completed after 24 weeks. Further treatment will consist of chemotherapy alone).
(BASEC)
Untersuchte Krankheit(en)
Neuroblastoma (malignant tumor) that has recurred or is resistant to current therapies.
(BASEC)
- Neuroblastoma that has recurred or is resistant to previously used therapies. - Age ≥1 to ≤21 years - etc. (BASEC)
Ausschlusskriterien
- Previous treatment with Temozolomide or a combination of Dinutuximab beta (or another antibody with the same mechanism of action) and chemotherapy - Bleeding metastases - Pregnant or breastfeeding patients - etc. (BASEC)
Studienstandort
Lausanne, Zürich
(BASEC)
Sponsor
University of Birmingham SPOG (Schweizer Pädiatrische Onkologie Gruppe)
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
PD Dr. med. Nicolas Gerber
+41 44 249 63 50
Nicolas.Gerber@clutterkispi.uzh.chUniversitäts-Kinderspital Zürich
(BASEC)
Allgemeine Auskünfte
University of Birmingham
(ICTRP)
Wissenschaftliche Auskünfte
University of Birmingham
(ICTRP)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Zürich
(BASEC)
Datum der Bewilligung durch die Ethikkommission
17.06.2016
(BASEC)
ICTRP Studien-ID
NCT02308527 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
BEACON - A randomised phase IIb trial of BEvACizumab added to Temozolomide ± IrinOtecan for children with refractory/relapsed Neuroblastoma (BASEC)
Wissenschaftlicher Titel
A Randomised Phase IIb Trial of Bevacizumab Added to Temozolomide ? Irinotecan for Children With Refractory/Relapsed Neuroblastoma - BEACON-Neuroblastoma Trial (ICTRP)
Öffentlicher Titel
Activity Study of Bevacizumab With Temozolomide ? Irinotecan for Neuroblastoma in Children (ICTRP)
Untersuchte Krankheit(en)
Neuroblastoma (ICTRP)
Untersuchte Intervention
Drug: Bevacizumab;Drug: Temozolomide;Drug: Temozolomide;Drug: Irinotecan;Drug: Bevacizumab;Drug: Topotecan;Drug: Temozolomide;Drug: Dinutuximab Beta;Drug: Cyclophosphamide (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Randomized. Intervention model: Factorial Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Ein-/Ausschlusskriterien
Gender: All
Maximum age: 21 Years
Minimum age: 1 Year
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
(ICTRP)
nicht verfügbar
Primäre und sekundäre Endpunkte
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.;For the bevacizumab part 2 only; Progression-free survival (PFS) (ICTRP)
To evaluate the toxicity of the regimens;To evaluate the safety of the regimens;To evaluate the overall safety of the regimens;To evaluate the safety of the regimens (ICTRP)
Registrierungsdatum
nicht verfügbar
Einschluss des ersten Teilnehmers
nicht verfügbar
Sekundäre Sponsoren
Cancer Research UK;Roche Pharma AG;Imagine for Margo;EUSA Pharma, Inc. (ICTRP)
Weitere Kontakte
Lucas Moreno, MD, University of Birmingham (ICTRP)
Sekundäre IDs
2012-000072-42, RG_11-087 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://clinicaltrials.gov/ct2/show/NCT02308527 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar