Clinical Trials /

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

NCT01704716

Description:

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.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
  • Official Title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)

Clinical Trial IDs

  • ORG STUDY ID: HR-NBL-1.8 / SIOPEN
  • NCT ID: NCT01704716

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
VincristineR0: COJEC
AldesleukinInterleukin 2, IL-2, IL2R2: ch14.18/CHO plus Aldesleukin
ch14.18/CHOanti GD2 antibody, Dinutuximab beta EUSA, Qarziba®R2: ch14.18/CHO
CarboplatinParaplatinR0: COJEC plus G-CSF
EtoposideVP16R0: COJEC plus G-CSF
CisplatinCDDPR0: COJEC plus G-CSF
CyclophosphamideEndoxanR0: COJEC plus G-CSF
DoxorubicinAdriamycinR3: Modified N7
G-CSFFilgrastimR0: COJEC plus G-CSF
BusulfanBusilvex, Myleran, BusulphanR1: BuMel MAT
MelphalanAlkeranR1: BuMel MAT

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.

Detailed Description

      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®).
    

Trial Arms

NameTypeDescriptionInterventions
R0: COJEC plus G-CSFExperimentalPatients 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.
  • Carboplatin
  • Etoposide
  • Cisplatin
  • Cyclophosphamide
  • G-CSF
R0: COJECActive ComparatorInduction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF
  • Vincristine
  • Carboplatin
  • Etoposide
  • Cisplatin
  • Cyclophosphamide
R1: BuMel MATActive ComparatorThe 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)
  • Busulfan
  • Melphalan
R1: CEM MATExperimentalThe 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
  • Carboplatin
  • Etoposide
  • Melphalan
R2: ch14.18/CHOActive Comparatorch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses
  • ch14.18/CHO
R2: ch14.18/CHO plus AldesleukinExperimentalPatients randomised to receive ch14.18/CHO plus Aldesleukin
  • Aldesleukin
  • ch14.18/CHO
R3: COJEC InductionActive ComparatorRapid 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
  • Vincristine
  • Carboplatin
  • Etoposide
  • Cisplatin
  • Cyclophosphamide
R3: Modified N7ExperimentalThe 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).
  • Vincristine
  • Etoposide
  • Cisplatin
  • Cyclophosphamide
  • Doxorubicin
R4: cnt inf ch14.18/CHOActive Comparatorch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO
  • ch14.18/CHO
R4: cnt inf ch14.18/CHO plus AldesleukinExperimentalch14.18/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
  • Aldesleukin
  • ch14.18/CHO

Eligibility 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

        -
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event Free Survival (R1: MAT therapy)
Time Frame:Up to three years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Anna Kinderkrebsforschung

Trial Keywords

  • neuroblastoma
  • immunotherapy
  • MAT
  • antibody treatment

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