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 |
With all substudies having randomisation question closed, the main objective of the HRNBL1 trial is to correlate clinical, therapeutic and molecular biological features with Event Free Survival (EFS).
Secondarily, the metastatic and primary tumour response and long-term Overall Survival (OS) and toxcicity or sequelae will be investigated.
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Mit der Schließung aller Randomisierungsfragen, ist die Hauptobjektive der HRNBL1 Studie die Korrelation der klinischen, therapeutischen und molekular biologischen Eigenschaften in Bezug auf EFS.
Zweitens werden das Vorkommen von Metastasen, Ansprechen des primären Tumors und Langzeit OS, Toxizität und Folgerscheinungen untersucht.
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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 molecular - biological profiles in BM and primary tumour at diagnosis and respective specified response and follow up time points to validate the value of liquid biopsies for future follow up and to correlate above parameters with EFS and OS. •To evaluate BM response to Rapid COJEC (after the fourth and eight cycles with ICH-GD2, AIPF and QRT-PCR. •To determine the effect of response of metastatic disease to induction therapy on EFS and overall survival (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.
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•Untersuchung des molekularbiologischen Profils von disseminierenden Tumorzellen (DTCs) mittels Flüssigbiopsien im Vergleich zu molekularbiologischen Profilen im Knochenmark und Primärtumor bei Diagnosestellung und jeweils spezifizierten Ansprech- und Nachbeobachtungszeitpunkten zur Validierung des Wertes von Flüssigbiopsien für zukünftige Weiterverfolgung und Korrelation der obigen Parameter mit EFS und OS •Bewertung der Response im Knochenmark auf Rapid COJEC (nach dem vierten und achten Zyklus mit ICH-GD2, AIPF und QRT-PCR). •Untersuchung der Reaktion der metastasierten Erkrankung auf die Induktionstherapie auf EFS und Gesamtüberleben (OS) mit mIBG / SPECT SIOPEN Stand Scoring des Responses im Skelett •Untersuchung der Beziehung zwischen vollständiger chirurgischer Resektion des Primärtumors auf EFS und OS im Rahmen etablierter Standardbehandlungen |
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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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-Etablierte Diagnose eines Neuroblastoms nach dem International Neuroblastoma Staging System (INSS) - Alter unter 21 Jahren. - Hochrisiko-Neuroblastom, definiert als: a) INSS-Stufen 2, 3, 4 und 4s mit MYCN-Amplifikation oder b) INSS-Stadium 4 ohne MYCN-Amplifikation im Alter von ≥ 12 Monaten - Patienten, die bis auf 1 Zyklus Etoposid und Carboplatin (Vp / Carbo) keine vorherige Chemotherapie erhalten haben. In dieser Situation erhalten die Patienten eine rasche COJEC-Induktion und der erste COJEC-Zyklus kann durch den ersten Zyklus von Vp / Carbo ersetzt werden. - schriftliche Einverständniserklärung, einschließlich der Zustimmung von Eltern oder Erziehungsberechtigten für Minderjährige, in eine randomisierte Studie einzutreten, wenn die Randomisierungskriterien erfüllt sind. - Tumorzellmaterial zur Bestimmung biologischer prognostischer Faktoren. - Registrierung aller Zulassungskriterien innerhalb von 6 Wochen nach der Diagnose beim Datenzentrum. - Frauen im gebärfähigen Alter müssen einen negativen Schwangerschaftstest haben. Patienten im gebärfähigen Alter müssen sich verpflichten, eine wirksame Verhütungsmethode anzuwenden. Weibliche Patienten, die stillen, müssen sich verpflichten, das Stillen zu beenden. - Vorläufige Follow-up von 5 Jahren. - Nationale und lokale Ethikkommission. |
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E.4 | Principal exclusion criteria |
Any negative answer concerning the inclusion criteria of the study will render the patient ineligible for the corresponding therapy phase. |
Jede negative Antwort bezüglich der Einschlusskriterien der Studie macht den Patienten für die entsprechende Therapiephase unzulässig |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is event free survival (EFS) calculated form the date of start of induction. Events are: •disease progression or relapse •death from any cause •second neoplasm
Patients without event are censored at the date of last follow-up evaluation.
Sample Size : All randomised questions below have been closed by March 2018. Thereof no further sample size definition is set.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be performed at End of trial |
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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 non-relapse mortality and of disease related mortality -The cumulative incidence of secondary malignancies -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. Rapid COJEC) -Rate of patients that discontinued therapy -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 at End of trial |
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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 |
Switzerland |
Hong Kong |
Australia |
China |
Israel |
Serbia |
United Kingdom |
Austria |
Belgium |
Czechia |
Denmark |
Finland |
France |
Greece |
Hungary |
Ireland |
Italy |
Norway |
Poland |
Portugal |
Slovakia |
Slovenia |
Spain |
Sweden |
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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 | 26 |
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 | 26 |
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 |