High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	1 Month - 21 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- • Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).

- Age below 21 years.

- High risk neuroblastoma defined as either: 1.

INSS stage 2, 3, 4, and 4s with MYCN amplification, or. 2. 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 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.

- 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.

Exclusion Criteria:

Any negative answer concerning the inclusion criteria of the study. -

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT01704716
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	St. Anna Kinderkrebsforschung
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Ruth L Ladenstein, MD, MBA, cPM
Principal Investigator Affiliation	St. Anna Kinderkrebsforschung
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Australia, Austria, Belgium, Czechia, Denmark, France, Greece, Hungary, Ireland, Israel, Italy, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Neuroblastoma

Additional Details

In this protocol the term high-risk neuroblastoma refers to children with either.

- disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age of one or.

- INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and 20% of children with stage 3 and occasional patients with stage 2 disease are characterized by amplification of the MycN gene in their tumours.

This biological characteristic has clearly been shown to be associated with a greater risk of relapse and death from disease progression. These patients may benefit from very aggressive treatment and, based on this hypothesis, they are included in this protocol. Infants (< 12 months at diagnosis) with MYCN amplified tumors are included. 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®).

Arms & Interventions

Arms

Experimental: R0: COJEC plus G-CSF

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.

Active Comparator: R0: COJEC

Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF

Active Comparator: R1: BuMel MAT

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)

Experimental: R1: CEM MAT

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

Active Comparator: R2: ch14.18/CHO

ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses

Experimental: R2: ch14.18/CHO plus Aldesleukin

Patients randomised to receive ch14.18/CHO plus Aldesleukin

Active Comparator: R3: COJEC Induction

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

Experimental: R3: Modified N7

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).

Active Comparator: R4: cnt inf 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

Experimental: R4: cnt inf ch14.18/CHO plus Aldesleukin

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

Interventions

Drug: - Vincristine

given during Rapid COJEC and modified N7 therapy

Drug: - Aldesleukin

Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2

Drug: - ch14.18/CHO

ch14.18/CHO antibody is given during MRD treatment

Drug: - Carboplatin

Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)

Drug: - Etoposide

Etoposide is given during Induction Treatment (both R3 randomisation arms)

Drug: - Cisplatin

Cisplatin is given during Induction Treatment (both R3 randomisation arms)

Drug: - Cyclophosphamide

Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)

Drug: - Doxorubicin

Doxorubicin is given during Induction Treatment (R3 arm modified N7)

Drug: - G-CSF

G-CSF is given during Induction Treatment

Drug: - Busulfan

In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.

Drug: - Melphalan

Melphalan is given during MAT treatment

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International Sites

Women and Children´s Hospital, Adelaide, Australia

Status

Recruiting

Address

Women and Children´s Hospital

Adelaide, ,

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