E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent, progressive or newly diagnosed high risk neuroblastoma |
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E.1.1.1 | Medical condition in easily understood language |
neuroblastoma - childhood cancer |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029260 |
E.1.2 | Term | Neuroblastoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary trial objective is the safety and tolerability of the two immunotherapy regimens for patients with recurrent high risk neuroblastoma and of the standard immunotherapy regimen for newly diagnosed high risk neuroblastoma (three arm trial).
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E.2.2 | Secondary objectives of the trial |
Reduction of grade 2-4 key side effects in the experimental arm.
Neuralgia (with assessment of pain duration (days requiring morphin) and maximum grade of pain scores during first 2 antibody cycles)
Comparison of pharmacokinetics of antibody ch14.18 in both arms.
Comparison of immune response between treatment cycles, treatment arms and between recurrent and newly diagnosed patients.
Comparison of grade 2-4 toxicities between intravenously and subcutaneously administered IL-2.
2 year event free (EFS), progression free (PFS), and overall survival rates (OS) from time of randomization.
Tumor response at the end of treatment and time to progression (TTP)
Quality of Life (QoL)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Established diagnosis of neuroblastoma according to the international INSS criteria
High risk (HR): stage 4 over 18 months of age and MYCN amplified neuroblastoma of any stage and any age - Recurrent or progressive neuroblastoma: completed re-induction chemotherapy (Germany and The Netherlands) - Newly diagnosed neuroblastoma: Complete front-line treatment including induction chemotherapy, surgical removal and/ or local irradiation of the primary tumor and myeloablative chemotherapy with autologous stem cell reinfusion according to the actual guidelines of the GPOH/ DCOG (in The Netherlands only).
Achieved response status: stable disease or better (CR, VGPR, PR, SD) at the end of re-induction chemotherapy in recurrent disease and after ASCT in newly diagnosed disease
Written informed consent of parents or guardian and – if appropriate – of the patient.
For at least two weeks prior to start of trial medication - off any standard or experimental treatment (and fully recovered from short-term major toxic effects) - no tumour surgery (and fully recovered from any post-surgical complications) - no immediate requirements for palliative chemotherapy, radiotherapy or surgery
The patient may have had prior CNS metastases provided the following criteria are all met: - The patient’s CNS disease has been previously treated - The patient’s CNS disease has been clinically stable for four weeks prior to starting this study (assessed clinically and by MRI or CT) - The patient is off steroids for four weeks prior to starting the study and will not require them during the course of the study - A patient with seizure disorders may be enrolled if well controlled on anticonvulsants and if no seizures have occurred within a 6 week period prior to starting trial treatment
HIV sero-negative and neither active nor chronic-replicative hepatitis B infection
adequate functions of the cor, lung, bone marrow, liver, kidney |
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E.4 | Principal exclusion criteria |
Significant intercurrent illnesses and/or any of the following: - Symptoms of congestive heart failure or of uncontrolled cardiac arrhythmia - Significant psychiatric disabilities or psychological conditions preventing treatment realization - Uncontrolled seizure disorders - Active infections - Clinically significant neurologic deficit or objective peripheral neuropathy (> grade 2) - Significant, symptomatic pleural effusions
Requirement or likely requirement for corticosteroids or other immunosuppressive drugs (except the medications recommended for conditions mentioned in the protocol)
Platelet transfusion dependency
Concurrent treatment with any non-trial anticancer therapy or interventional study
Positive pregnancy test, lactation
Sexually active patients (male and female) at reproductive age not willing to use highly effective contraceptive methods according to the guidelines ICH M3
Neuroblastoma patients with actively progressing disease
Patients with HACA detected after previous antiGD2 immunotherapy
Known allergy or contraindications against one of the study drugs (IMP) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety (toxic deaths) and tolerability (grade 4 toxicities) for the three treatment arms. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
continously during treatment |
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E.5.2 | Secondary end point(s) |
Reduction of grade 2-4 key side effects in the experimental arm.
Neuralgia (with assessment of pain duration (days requiring morphin) and maximum grade of pain scores during first 2 antibody cycles)
Comparison of pharmacokinetics of antibody ch14.18 in both arms.
Comparison of immune response between treatment cycles, treatment arms and between recurrent and newly diagnosed patients.
Comparison of grade 2-4 toxicities between intravenously and subcutaneously administered IL-2.
2 year event free (EFS), progression free (PFS), and overall survival rates (OS) from time of randomization.
Tumor response at the end of treatment and time to progression (TTP)
Quality of Life (QoL) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
continously resp. at several time-points during treatment (side effects, neuralgia, pharmacokinetics, immune response)
at 2 years (EFS, PFS, OS)
at end of treamtent (tumor response)
at progression (TTP)
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immune response, Quality of life |
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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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
dose and route of application of interleukine 2 |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Last visit last subject (LVLS), 24 months after inclusion of the last patient |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |