Randomisierte Phase IIb Studie mit Bevacizumab als Zusatztherapie zu Temolozomid ± Irinotecan bei Kindern mit einem Neuroblastom, das wieder aufgetreten ist (rezidiviertes Neuroblastom, Neuroblastom-Rezidiv) oder gegen die heutigen Therapien resistent ist (therapierefraktäres Neuroblastom) – Medikamente nach Modifikation der Studie: Temozolomid, Topotecan und Dinutuximab beta.

Drug: Bevacizumab;Drug: Temozolomide;Drug: Irinotecan;Drug: Topotecan;Drug: Dinutuximab Beta;Drug: Cyclophosphamide

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