Brief Summary
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 diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results).
The protocol consists of a rapid, dosethe amount of medication taken intensive induction chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells, peripheral bloodthe red bodily fluid that transports oxygen and other nutrients around the body stem cell harvest, attempted complete excisionto surgically remove/cut out of the primary tumoura tissue mass that forms from groups of unhealthy cells, myeloablative therapy followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapya treatment that uses a person's immune system to fight cancer (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 antibodya protein made by the immune system to fight against harmful substances (antigens), such as bacteria or viruses is recommended without scIL-2 as continuous infusionto slowly introduce/give fluid into a vein 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 prognosisto predict how a disease/condition may progress and what the outcome might be and will stop treatment after induction therapy and surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence 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.
Intervention / Treatment
- Drug: Vincristine
- Drug: Aldesleukin
- Drug: ch14.18/CHO
- Drug: Carboplatin
- Drug: Etoposide
- Drug: Cisplatin
- Drug: Cyclophosphamide
- Drug: Doxorubicin
- Drug: G-CSF
- Drug: Busulfan
- Drug: Melphalan
Inclusion Criteria
- • Established diagnosis of neuroblastoma according to the International Neuroblastoma Stagingthe process of determining how big the cancer is, where it started and if it has spread to other areas System (INSS).
- Age below 21 years.
- High riskthe possibility that something bad will happen neuroblastoma defined as either:
- INSS stage 2, 3, 4, and 4s with MYCN amplification, or
- INSS stage 4 without MYCN amplification aged > 12 months at diagnosis
- Patients who have received no previous chemotherapy except for one cycle of etoposide and carboplatin (VP16/Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).
- Written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment., 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.
- 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.
- 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.