| 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 the most common extracranial solid cancer in childhood and the most common cancer in infancy |
|
| 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 modified N7 induction regimen will
improve the metastatic response rates or event free survival (EFS) as
compared to Rapid COJEC (R3 randomisation).
- To test the hypothesis that the addition of subcutaneous aldesleukin
(IL-2, (Proleukin®)) to immunotherapy with chimeric 14.18 anti-GD2
monoclonal antibody produced in Chinese hamster ovary (CHO) cells
(ch14.18/CHO) given as continuous infusion in addition to
differentiation therapy with isotretinoin (13-cis-RA) following
myeloablative therapy (MAT) and autologous SCR, 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). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate BM response to Rapid COJEC (after the fourth and eight
cycles) and modified N7 (after the third and fifth cycles) with ICH-GD2,
AIPF and QRT-PCR.
- To evaluate response to Rapid COJEC and modified N7 induction
therapies with mIBG for standardised scoring of skeletal response.
- To determine the effect of response of metastatic disease to induction
therapy on EFS and overall survival (OS).
- To investigate the relationship between complete surgical resection of
the primary tumour and OS.
- 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. |
|
| 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.
• Provisional follow up of 5 years.
• National and local ethical committee approval.
The date of eligibility is defined as the date at which all criteria for entry into the study have been checked by the co-ordinating centre along with the referring physician. The date of diagnosis will be the starting point for subsequent follow up.
|
|
| 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. |
|
| 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
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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.
|
|
| 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. |
|
| 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)
|
|
| 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. |
|
| 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 | No |
| E.8.2.3.1 | Comparator description |
| Rapid COJEC induction scheme |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 |
| Austria |
| Belgium |
| China |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Norway |
| Poland |
| Portugal |
| Serbia |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
|
| 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
|
The final analysis will be performed 18 months after the inclusion of the last patient.
To evaluate the difference of EFS between the randomised arms all randomised patients will be analysed and the comparison of treatment regimens will be performed according to intention to treat.
The 3-year EFS will be estimated by the Kaplan-Meier method. The standard errors of these estimates will be calculated according to the method described by Peto et al.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
| 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 |
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