| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Neuroblastoma is a cancer of specialised nerve cells called neural crest cells. These cells are involved in the development of the nervous system and other tissues. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029261 |
| E.1.2 | Term | Neuroblastoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- 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
- To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety of the above therapy regimens and to compare how the combinations influence the frequency of relapsing and prolong the survival of treated patients. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease specific
• Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
• Relapsed or refractory neuroblastoma
o Relapsed: any relapsed or progressed high-risk neuroblastoma
o Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g. myeloablative chemotherapy)
• Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study
General
• Age ≥1 to ≤21 years
• Informed consent from patient, parent or guardian
Performance and organ function
• Performance Status:
o Lansky ≥ 50%, Karnofsky ≥ 50% or ECOG ≤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
• Bone marrow function (within 72 hours of randomisation):
o No bone marrow disease:
Platelets ≥75 x 10^9/L (unsupported for 72 hours)
ANC ≥ 0.75 x10^9/L (no G-CSF support for 72 hours)
Haemoglobin ≥ 7.5 g/dL (transfusions allowed)
o Bone marrow disease:
Platelets ≥ 50 x10^9/L (unsupported for 72 hours)
ANC ≥ 0.5 x 10^9/L (no G-CSF for 72 hours)
Haemoglobin ≥ 7.5 g/dL (transfusions allowed)
• Renal function (within 7 days of randomisation):
o 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
o Serum creatinine ≤ 1.5 ULN for age, if higher, a calculated GFR (radioisotope or 24 hour urine calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2
• Liver function (within 72 hours of randomisation): AST or ALT ≤ 2.5 ULN and Total bilirubin ≤1.5 ULN. In case of liver metastases, AST or ALT ≤ 5 ULN and Total bilirubin ≤ 2.5 ULN
• Cardiac function, measured using echocardiogram within 4 weeks of randomisation or 12 weeks if patient has not received anthracyclines or cardiotoxics. Shortening fraction ≥ 29% on echocardiogram
• Coagulation, patients not on anticoagulation must have an INR ≤1.5 and 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 adequate method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine (preferred) or serum pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche
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|
| E.4 | Principal exclusion criteria |
• Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
• Known hypersensitivity to:
o Any study drug or component of the formulation
o Chinese hamster ovary products or other recombinant human or humanised antibodies
o 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):
o 48 hours post bone marrow aspirate/trephine
o 48 hours post central line insertion
o Four weeks post major surgery
o One week post core biopsy
o Two weeks from prior chemotherapy
o Six weeks from prior craniospinal radiotherapy or MIBG therapy and two weeks from radiotherapy to the tumour bed
o Eight weeks from prior myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant)
o Three months from prior allogeneic stem cell transplant
o 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial
o Six 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
• Planned immunisation with live vaccine |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Best response (Complete Response [CR], or Partial Response [PR]) at any time during the 6 cycles of trial treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response will be assessed after 2, 4 and 6 cycles of trial treatment. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
- Safety of the regimens: Incidence and severity of Adverse Events (AE)s
- Progression-free survival (PFS)
- Overall survival (OS)
Exploratory/Tertiary Endpoints:
- Changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2*
- Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples
- Pilot descriptive study of angiogenesis and neuroblastoma markers that may include:
o O6-methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up until the last follow up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| For the purposes of the Competent Authorities, the end of trial will be 6 months after the last patient has completed treatment. This will allow sufficient time for the completion of protocol procedures, data collection and data input. For the purposes of the main REC approval, the trial end date is deemed to be 12 months after the last data capture following 5 years of long-term follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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