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 the most common extracranial solid cancer in childhood and the most common cancer in infancy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 the hypothesis that the addition of subcutaneous aldesleukin (IL-2, (Proleukin®)) to immunotherapy with Dinutuximab beta given as continuous infusion in addition to differentiation therapy with isotretinoin (13-cis-RA) following myeloablative therapy (MAT) and autologous stem cell rescue, will improve EFS in patients with high-risk neuroblastoma (stage 4 disease or stages 2 and 3 with MYCN amplification, all over the age of one, or infants with MYCN amplification) (R4 randomisation). -To correlate molecular biological features with metastatic and primary tumour response, event free and overall survival (EFS, OS) as well as with respective treatment elements and phases
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E.2.2 | Secondary objectives of the trial |
- To test the molecular-biological profile of disseminating tumour cells (DTCs) obtained via liquid biopsies in comparison with profiles in BM and primary tumour at diagnosis and respective follow up time points to validate the value of liquid biopsies and correlate with EFS and OS - To evaluate BM response to Rapid COJEC (after the fourth and eight cycles) - To determine the effect of response of metastatic disease to induction therapy on EFS and OS with mIBG/SPECT SIOPEN stand scoring of skeletal response - To investigate the relationship between complete surgical resection of the primary tumour on EFS and OS within the scope of established standard treatments. - To collect data on selected, validated biological features and to determine the effect of these on EFS, the incidence of relapse/progression and OS. - To compare the toxicity, in particular episodes of febrile neutropenia and grade 3-4 infection, associated with induction therapy with Rapid COJEC and modified N7. |
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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 Neuroblastoma Staging System (INSS) - Age below 21 years. - High-risk neuroblastoma, defined as either: a) INSS stages 2, 3, 4 and 4s with MYCN amplification, or b) INSS stage 4 without MYCN amplification aged ≥ 12 months - Patients who have received no previous chemotherapy except for 1 cycle of etoposide and carboplatin (Vp/Carbo). In this situation patients will receive Rapid COJEC induction and the first COJEC cycle may be replaced by the first cycle of Vp/Carbo. - Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met. - Tumour cell material available for determination of biological prognostic factors. - Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis. - Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding. - Provisional follow up of 5 years. - National and local ethical committee approval.
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E.4 | Principal exclusion criteria |
Any negative answer concerning the inclusion criteria of the study, R3 and R4 will render the patient ineligible for the corresponding therapy phase. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Randomisation 4: Trial Design R4 is a randomised Phase II trial. Patients will be randomised to ch14.18/CHO alone or ch14.18/CHO + IL-2 to evaluate whether the addition of IL-2 is sufficiently active in combination with long-term infusion of ch14.18/CHO to warrant further study in future MRD-studies A likelihood based Bayesian approach with a non-informative prior will be used for the primary presentation of the data.
Primary Endpoint The primary endpoint is Event Free Survival calculated from the date of the R4- randomisation. The following will be considered as events: - disease progression or relapse, - death from any cause - second neoplasm.
Patients lost to follow-up without event will be censored at the date of their last follow-up evaluation.
Sample Size The randomised phase II study R4 will be open until the randomisation for the induction question is closed. The anticipated closure date of R3 is September 2016. When all participating centres have opened R4, 120 randomisation/year are expected (R2-experience). Thus, it is anticipated that until R3-closure a total of 100 to 180 patients will be randomised for R4. R4 will remain open until R3 is closed. If a minimum sample size of 140 patients is not reached at R3-closure, R4 will remain open until 140 patients have been randomised.
Assuming a baseline 1-year EFS of 65% (without IL-2) and a sample size of 140 patients an increase in 1-year EFS to 79% with IL-2 , i.e. a hazard ratio of 0.55, can be shown with alpha and beta of approximately 0.2. (A relaxed alpha has been used as this is a Phase II trial with the aim of obtaining sufficient evidence of activity, not definitive results). With a total size of 180 patients hazard ratios of 0.66 can be shown with these type I and II errors. These calculations are based on baseline EFS rates similar as our experience with the original HR-NBL1 scheme. The calculation is based on a 1.5 year recruitment and a minimum follow-up of 1 year.
Interim Analyses Given the long-term endpoint and the short recruitment period, the trial will not include any formal interim analysis for efficacy. An interim report will be sent to the DMC after approximately 100 patients to assess compliance, safety and conditional power during the recruitment phase of the study. At this interim-analysis, the conditional power, i.e. the probability of a significant result at the end of the study (i.e. after a final simple size of 180 patients) given the interim-data and given a HR of 0.6 for the future data will be calculated. This evaluation will not be used for any formal and binding stopping rule for futility. However, if the conditional power is very small (e.g. below 20%), it gives some guidance together with other factors – such as toxicity and evidence from other studies - of whether early stopping for futility is warranted.
Main Analysis The final analysis will be performed 1 year after the closure of the randomisation. All analyses will be intention to treat, i.e. with all patients analysed in the arm to which they were randomised.
Randomisation 3: Two co-primary endpoints will be investigated: 1) Metastatic response after induction - No skeletal uptake on MIBG -Negative Bone marrow aspirates and trephines - Absence of other metastatic sites 2) Event Free Survival - disease progression or relapse - death from any cause - second neoplasm Patients lost to follow-up without event will be censored at the date of their last follow-up evaluation.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be performed 6 months for R3 after the inclusion of the last patient. The final analysis will be performed 1 year for R4 after the inclusion of the last patient. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints of the main trial - Overall survival Calculated from date of randomisation to death from any cause. Patients lost to follow-up without an event will be censored at the date of their last follow-up evaluation. - Cumulative incidence of relapse/progression and deaths without relapse/progression - The cumulative incidence of treatment related mortality and of disease related mortality - Response Overall response (incl. primary tumour after induction), skeletal response on MIBG, BM-response, - Toxicity in particular comparison of the frequency of episodes of febrile neutropenia and grade 3-4 infections during induction (modified N7 vs. Cojec) - Response rates, survival, EFS and the cumulative incidence of relapse/progressions will be related to potential prognostic factors including: - Biological factors (MYCN amplification, SCAs, expression signature) of neuroblastoma cells in the bone marrow and/or the primary tumour. - Serological factors (serum concentrations at diagnosis of LDH, ferritin, neuron specific enolase). - Urinary catecholamines at diagnosis (VMA, HVA, Dopamine)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be performed 18 months for R1 and R2 and 6 months for R3 after the inclusion of the last patient. |
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 |
Australia |
China |
Israel |
Switzerland |
Serbia |
Austria |
Belgium |
Czechia |
Denmark |
Finland |
France |
Greece |
Hungary |
Ireland |
Italy |
Norway |
Poland |
Portugal |
Slovakia |
Slovenia |
Spain |
Sweden |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 15 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 15 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |