E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
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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
- To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide+topotecan) demonstrates activity 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 |
Inclusion criteria for dinutuximab beta and topotecan randomisations:
Disease specific
• Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition[1]
• 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 bone marrow detectable disease only (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 status 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)
• Bone marrow function (within 72 hours of randomisation):
o No bone marrow disease:
Platelets ≥75 x 109/L (unsupported for 72 hours)
ANC ≥ 0.75 x109/L (no G-CSF support for 72 hours)
Haemoglobin ≥ 8 g/dL (transfusions allowed)
o Bone marrow disease:
Platelets ≥ 50 x109/L (unsupported for 72 hours)
ANC ≥ 0.5 x 109/L (no G-CSF for 72 hours)
Haemoglobin ≥ 8 g/dL (transfusions allowed)
• Renal function (within 7 days of randomisation):
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 ≤ 3.0 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 by echocardiogram within 4 weeks of randomisation or within 12 weeks if the patient has not received anthracyclines or cardiotoxics in between. Shortening fraction ≥ 29% on echocardiogram
• Adequate lung function; no dyspnoea at rest and pulse oximetry > 94% in room air
• Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration.
• 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
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E.4 | Principal exclusion criteria |
Exclusion criteria for the dinutuximab beta and topotecan randomisations:
• Previous treatment with temozolomide
• Previous treatment with chemotherapy in combination with anti-GD2 directed therapy (“chemo-immunotherapy”) with any anti-GD2 antibody. Prior treatment with anti-GD2 directed therapy alone with/without cytokines is allowed provided a 4 week wash-out period is met
• Known hypersensitivity to:
o Any study drug or component of the formulation
o Patients with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but those with severe (or G4) hypersensitivity reactions to antiGD2 antibodies will be excluded
• Clinically significant neurological deficit, uncontrolled seizures or objective peripheral neuropathy (>grade 2). (Unresolved neurological deficits from previous spinal cord compression are acceptable)
• Uncontrolled infection
• Inadequate recovery from prior surgery with no ongoing ≥Grade 3 surgical complications. For core biopsies, no less than 24 hours; for open excisional biopsies, no less than 48 hours; for major surgery, no less than 2 weeks.
• Patient less than (at point of planned date of randomisation):
o Two weeks from prior chemotherapy. One week from prior oral metronomic chemotherapy (i.e. oral etoposide or oral cyclophosphamide).
o Six weeks from prior craniospinal radiotherapy or MIBG therapy and two weeks from radiotherapy to the tumour bed. No washout is required for palliative radiotherapy
o Eight weeks from prior high dose chemotherapy with autologous haematopoietic stem cell rescue
o Three months from prior allogeneic stem cell transplant, no ongoing treatment with immunosuppressive agents and no signs of ≥grade 2 acute graft versus host disease
o 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial.
o 14 days or 5 half-lives (whichever occurs later) from last administration of any other biological/targeted anticancer agent
• Bleeding metastases (Patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
• Pregnant or lactating patient
• Any uncontrolled medical condition that poses an additional risk to the patient
• Low probability of treatment compliance
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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. |
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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. |
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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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up until the last follow up |
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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 |
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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
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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. |
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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 |