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High Risk Neuroblastoma Study 1.7 of SIOP-Europe (SIOPEN)

This study is currently recruiting participants.
Verified September 2016 by St. Anna Kinderkrebsforschung
Sponsor:
ClinicalTrials.gov Identifier:
NCT01704716
First Posted: October 11, 2012
Last Update Posted: September 27, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
St. Anna Kinderkrebsforschung
  Purpose

This is a randomised 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 (R3 randomisation - Rapid COJEC vs modified N7), peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy (BuMel) followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomisation - isotretinoin and ch14.18/CHO, with or without aldesleukin (IL-2).

In the induction phase, all patients with stage 4 neuroblastoma and those with stage 4s MYCN-amplified neuroblastoma will be randomised (R3) to Rapid COJEC or modified N7; localised patients receive Rapid COJEC (Rapid COJEC is given with G-CSF support based on the results of the R0 randomisation running between 2002 and 2005).

Following induction treatment peripheral blood stem cell harvest (PBSCH) will be 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, localised patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCA) 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 (following the results of the R1 randomisation) followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.

During the immunotherapy phase, patients will be randomised (R4) to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2).


Condition Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)

Resource links provided by NLM:


Further study details as provided by St. Anna Kinderkrebsforschung:

Primary Outcome Measures:
  • 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.


  • Event Free Survival (R4: immunotherapy) [ Time Frame: Up to three years ]

    R4 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 now compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2).

    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.


  • 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

  • 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



Estimated Enrollment: 2700
Study Start Date: February 2002
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: anti GD2 antibody
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 Name: anti GD2 antibody
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 Name: anti GD2 antibody
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 Name: anti GD2 antibody

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 characterised 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 tumours 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 randomisation: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomised use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia

R1 randomisation: 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.

R2 randomisation: 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 randomisation tested the hypothesis that immunotherapy with chimeric 14.18/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.

R3 randomisation: 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.

R4 randomisation: 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 100mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1.7/SIOPEN study committee wishes to implement this more favourable immunotherapy dosing schedule for the time till the induction question R3 is answered and the HRNBL1.7/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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

  Contacts and Locations
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 116 Study Locations
Sponsors and Collaborators
St. Anna Kinderkrebsforschung
Investigators
Principal Investigator: Ruth L Ladenstein, MD, MBA, cPM St. Anna Kinderkrebsforschung
  More Information

Publications:
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-1.7 / SIOPEN
First Submitted: October 5, 2012
First Posted: October 11, 2012
Last Update Posted: September 27, 2016
Last Verified: September 2016

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