A Phase 3 interventional study of Vincristine and Aldesleukin in Neuroblastoma, sponsored by St. Anna Kinderkrebsforschung. Recruiting at 126 sites in 20 countries. Open to participants aged 1 Month to 21 Years. Per ClinicalTrials.gov, last updated 2020-10-23.
Sponsored by St. Anna Kinderkrebsforschung · Phase 3, Interventional, and Treatment
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.
In this protocol the term high-risk neuroblastoma refers to children with either
Children with this type of presentation and age represent the largest neuroblastoma subgroup. Their prognosis remains poor in most cases and our ability to predict the clinical course and the outcome of the individual patient is modest.
Primary objectives:
R0 randomization: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomized use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia (Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;3516-24).
R1 randomization: R1 was opened with the study activation in February 2002 and closed in 10/2010 following the results showing significant superiority of myeloablative therapy (MAT) with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).
R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2, Proleukin®), following MAT and autologous stem cell transplantation, in addition to differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr 10500)).
R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7 induction regimen will improve the metastatic response rates or event free survival (EFS) as compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630 randomized patients as planned. There was no difference in event free survival rate between both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade 3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard induction treatment with G-CSF support based on the results of the R0 randomization open from 2002 top 2005 This change has been implemented in amendment 8 of the protocol.
R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI) ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement this more favorable immunotherapy dosing schedule for the time till the induction question R3 was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106 IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).
675 studies on the registry are indexed under Neuroblastoma; 127 are open to participants now.
This study's planned enrollment of 3,300 is above the median of 32 across 507 interventional studies indexed under Neuroblastoma.
Browse Neuroblastoma studies →St. Anna Kinderkrebsforschung is the lead sponsor of 12 studies on the registry; 2 are open to participants now.
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Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).
High risk neuroblastoma defined as either:
Exclusion Criteria:
Any negative answer concerning the inclusion criteria of the study
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Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose.
Drug: Carboplatin · Drug: Etoposide · Drug: Cisplatin · Drug: Cyclophosphamide · Drug: G-CSF
Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF
Drug: Vincristine · Drug: Carboplatin · Drug: Etoposide · Drug: Cisplatin · Drug: Cyclophosphamide
The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan. In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex)
Drug: Busulfan · Drug: Melphalan
The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course
Drug: Carboplatin · Drug: Etoposide · Drug: Melphalan
ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses
Drug: ch14.18/CHO
Patients randomised to receive ch14.18/CHO plus Aldesleukin
Drug: Aldesleukin · Drug: ch14.18/CHO
Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide
Drug: Vincristine · Drug: Carboplatin · Drug: Etoposide · Drug: Cisplatin · Drug: Cyclophosphamide
The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E).
Drug: Vincristine · Drug: Etoposide · Drug: Cisplatin · Drug: Cyclophosphamide · Drug: Doxorubicin
ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO
Drug: ch14.18/CHO
ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO. In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion
Drug: Aldesleukin · Drug: ch14.18/CHO
given during Rapid COJEC and modified N7 therapy
Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
Also known as: Interleukin 2, IL-2, IL2
Drug page: Dinutuximab
ch14.18/CHO antibody is given during MRD treatment
Also known as: anti GD2 antibody, Dinutuximab beta EUSA, Qarziba®
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Also known as: Paraplatin
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Also known as: VP16
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
Also known as: CDDP
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Also known as: Endoxan
Doxorubicin is given during Induction Treatment (R3 arm modified N7)
Also known as: Adriamycin
G-CSF is given during Induction Treatment
Also known as: Filgrastim
In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
Also known as: Busilvex, Myleran, Busulphan
Melphalan is given during MAT treatment
Also known as: Alkeran
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 years
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 years
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 days
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 years
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The record gives a start of Feb 2002, a primary completion of Sep 2021 and a completion of Sep 2026. It does not say whether these dates are actual or estimated.
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Studies of the drugs tested here: Vincristine · Dinutuximab · Carboplatin · Etoposide · Cisplatin · Cyclophosphamide · Doxorubicin · Granulocyte Colony-Stimulating Factor · Melphalan
St. Anna Kinderkrebsforschung