High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
ConditionNeuroblastoma
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age1-21
SponsorSt. Anna Kinderkrebsforschung
About this trial
This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified \> 12 months at diagnosis).
The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3 randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion as standard of care outside of controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba ®).
In the induction phase, all patients receive Rapid COJEC following the result of the R3 randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned.
Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and complete excision of the primary tumour will be attempted.
Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles.
After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop treatment after induction therapy and surgery to the primary tumour.
Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.
The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) is closed.
The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC approval.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
• Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).
Age below 21 years.
INSS stage 2, 3, 4, and 4s with MYCN amplification, or
INSS stage 4 without MYCN amplification aged > 12 months at diagnosis
Disqualifiers
None
Trial design
Design model
Parallel
Treatments tested in this trial
Vincristine
Druggiven during Rapid COJEC and modified N7 therapy
Aldesleukin
DrugAldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
ch14.18/CHO
Drugch14.18/CHO antibody is given during MRD treatment
Carboplatin
DrugCarboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Etoposide
DrugEtoposide is given during Induction Treatment (both R3 randomisation arms)
Cisplatin
DrugCisplatin is given during Induction Treatment (both R3 randomisation arms)
Cyclophosphamide
DrugCyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Doxorubicin
DrugDoxorubicin is given during Induction Treatment (R3 arm modified N7)
G-CSF
DrugG-CSF is given during Induction Treatment
Busulfan
DrugIn case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
Melphalan
DrugMelphalan is given during MAT treatment
Treatment groups
3,300 Participants
are divided into 10 treatment groups10
Treatment groupsSee each treatment group below.
Group A: R0: COJEC plus G-CSFExperimental treatment 5 interventions
Group B: R0: COJECActive comparator 5 interventions
Group C: R1: BuMel MATActive comparator 2 interventions
Group D: R1: CEM MATExperimental treatment 3 interventions
Group E: R2: ch14.18/CHOActive comparator 1 intervention
Group F: R2: ch14.18/CHO plus AldesleukinExperimental treatment 2 interventions
Group G: R3: COJEC InductionActive comparator 5 interventions
Group H: R3: Modified N7Experimental treatment 5 interventions
Group I: R4: cnt inf ch14.18/CHOActive comparator 1 intervention
Group J: R4: cnt inf ch14.18/CHO plus AldesleukinExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
Event Free Survival (R1: MAT therapy)
The primary endpoint was the event free survival (EFS) calculated from the date of the first R1 randomisation. The following was considered as event: * disease progression or relapse * death from any cause * second neoplasm Patients lost to follow up without event were considered at the date of their last follow up evaluation. R1 has been closed in October 2010 following the results of R1 randomisation showing significant superiority for myeloablative therapy (MAT) with busulfan and melphalan (BuMel) in patients with high risk neuroblastoma over MAT with continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT.
Time frame
Up to three years2
Event Free Survival (immunotherapy)
R2 randomisation comparing immunotherapy with ch14.18/CHO and 13-cis retinoic acid versus 13-cis retinoic acid alone was activated in November 2006. It was amended in July 2009 and compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2). Immunotherapy randomisation has been amended in 2014 (R4 randomisation). The ch14.18/CHO antibody is given as continuous Infusion and the randomisation has lasted until the necessary number of patients for R3 randomisation was reached The primary endpoint is 3-year event free survival calculated from the date of the second 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.
Time frame
Up to three years3
Complete metastatic response (R3: Induction therapy)
R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7. Complete metastatic response after induction is defined as: * no skeletal uptake on mIBG * Negative bone marrow aspirates (by cytomorphology) and trephines * Absence of other metastatic sites
Time frame
Up to 95 days4
Event free survival (R3: Induction therapy)
R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7. The primary endpoint is event free survival calculated from the date of the R3-randomisation. The following will be calculated 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
Time frame
Up to three yearsSponsors and contacts
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Source ClinicalTrials.gov