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

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ClinicalTrials.gov Identifier: NCT01704716
Recruitment Status : Recruiting
First Posted : October 11, 2012
Last Update Posted : June 11, 2018
Sponsor:
Information provided by (Responsible Party):
St. Anna Kinderkrebsforschung

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 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.


Condition or disease Intervention/treatment Phase
Neuroblastoma 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 Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3300 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)
Study Start Date : February 2002
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
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.
Drug: Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Other Name: Paraplatin

Drug: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Other Name: VP16

Drug: Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
Other Name: CDDP

Drug: Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Other Name: Endoxan

Drug: G-CSF
G-CSF is given during Induction Treatment
Other Name: Filgrastim

Active Comparator: R0: COJEC
Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF
Drug: Vincristine
given during Rapid COJEC and modified N7 therapy

Drug: Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Other Name: Paraplatin

Drug: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Other Name: VP16

Drug: Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
Other Name: CDDP

Drug: Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Other Name: Endoxan

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)

Drug: Busulfan
In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
Other Names:
  • Busilvex
  • Myleran
  • Busulphan

Drug: Melphalan
Melphalan is given during MAT treatment
Other Name: Alkeran

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
Drug: Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Other Name: Paraplatin

Drug: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Other Name: VP16

Drug: Melphalan
Melphalan is given during MAT treatment
Other Name: Alkeran

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
Drug: ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment
Other Names:
  • anti GD2 antibody
  • Dinutuximab beta EUSA
  • Qarziba®

Experimental: R2: ch14.18/CHO plus Aldesleukin
Patients randomised to receive ch14.18/CHO plus Aldesleukin
Drug: Aldesleukin
Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
Other Name: Interleukin 2, IL-2, IL2

Drug: ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment
Other Names:
  • anti GD2 antibody
  • Dinutuximab beta EUSA
  • Qarziba®

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

Drug: Vincristine
given during Rapid COJEC and modified N7 therapy

Drug: Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
Other Name: Paraplatin

Drug: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Other Name: VP16

Drug: Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
Other Name: CDDP

Drug: Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Other Name: Endoxan

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).
Drug: Vincristine
given during Rapid COJEC and modified N7 therapy

Drug: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
Other Name: VP16

Drug: Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
Other Name: CDDP

Drug: Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
Other Name: Endoxan

Drug: Doxorubicin
Doxorubicin is given during Induction Treatment (R3 arm modified N7)
Other Name: Adriamycin

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
Drug: ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment
Other Names:
  • anti GD2 antibody
  • Dinutuximab beta EUSA
  • Qarziba®

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

Drug: Aldesleukin
Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
Other Name: Interleukin 2, IL-2, IL2

Drug: ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment
Other Names:
  • anti GD2 antibody
  • Dinutuximab beta EUSA
  • Qarziba®




Primary Outcome Measures :
  1. Event Free Survival (R1: MAT therapy) [ Time Frame: Up to three years ]

    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.


  2. Event Free Survival (immunotherapy) [ Time Frame: Up to three years ]

    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.


  3. Complete metastatic response (R3: Induction therapy) [ Time Frame: Up to 95 days ]

    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

  4. Event free survival (R3: Induction therapy) [ Time Frame: Up to three years ]

    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




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Ages Eligible for Study:   1 Month to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01704716


Contacts
Contact: Ruth L Ladenstein, MD, MBA, cPM 0043140470 ext 4750 ruth.ladenstein@ccri.at

  Show 126 Study Locations
Sponsors and Collaborators
St. Anna Kinderkrebsforschung
Investigators
Principal Investigator: Ruth L Ladenstein, MD, MBA, cPM St. Anna Kinderkrebsforschung

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: St. Anna Kinderkrebsforschung
ClinicalTrials.gov Identifier: NCT01704716     History of Changes
Other Study ID Numbers: HR-NBL-1.8 / SIOPEN
First Posted: October 11, 2012    Key Record Dates
Last Update Posted: June 11, 2018
Last Verified: June 2018

Keywords provided by St. Anna Kinderkrebsforschung:
neuroblastoma
immunotherapy
MAT
antibody treatment

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Liposomal doxorubicin
Etoposide phosphate
Aldesleukin
Cisplatin
Cyclophosphamide
Carboplatin
Doxorubicin
Etoposide
Vincristine
Melphalan
Busulfan
Interleukin-2
Antibodies
Immunoglobulins
Lenograstim
Antibodies, Monoclonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs