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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

High Risk <span class="go-doc-concept go-doc-disease">Neuroblastoma</span> Study 1.7 of SIOP-Europe (SIOPEN)

Title

  • Brief Title: High Risk Neuroblastoma Study 1.7 of SIOP-Europe (SIOPEN)
  • Official Title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)
  • Clinical Trial IDs

    NCT ID: NCT01704716

    ORG ID: HR-NBL-1.7 / SIOPEN

    Trial Conditions

    Neuroblastoma

    Trial Interventions

    Drug Synonyms Arms
    Vincristine R0: COJEC, R3: COJEC Induction, R3: Modified N7
    Aldesleukin Interleukin 2, IL-2, IL2 R2: ch14.18/CHO plus Aldesleukin, R4: cnt inf ch14.18/CHO plus Aldesleukin
    ch14.18/CHO anti GD2 antibody R2: ch14.18/CHO, R2: ch14.18/CHO plus Aldesleukin, R4: cnt inf ch14.18/CHO, R4: cnt inf ch14.18/CHO plus Aldesleukin
    Carboplatin Paraplatin R0: COJEC plus G-CSF, R0: COJEC, R1: CEM MAT, R3: COJEC Induction
    Etoposide VP16 R0: COJEC plus G-CSF, R0: COJEC, R1: CEM MAT, R3: COJEC Induction, R3: Modified N7
    Cisplatin CDDP R0: COJEC plus G-CSF, R0: COJEC, R3: COJEC Induction, R3: Modified N7
    Cyclophosphamide Endoxan R0: COJEC plus G-CSF, R0: COJEC, R3: COJEC Induction, R3: Modified N7
    Doxorubicin Adriamycin R3: Modified N7
    G-CSF Filgrastim R0: COJEC plus G-CSF
    Busulfan Busilvex, Myleran, Busulphan R1: BuMel MAT
    Melphalan Alkeran R1: BuMel MAT, R1: CEM MAT

    Trial 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).

    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/m 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.

    Trial Arms

    Name Type Description Interventions
    R0: COJEC plus G-CSF Experimental 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. Carboplatin, Etoposide, Cisplatin, Cyclophosphamide, G-CSF
    R0: COJEC Active Comparator Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF Vincristine, Carboplatin, Etoposide, Cisplatin, Cyclophosphamide
    R1: BuMel MAT Active Comparator 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) Busulfan, Melphalan
    R1: CEM MAT Experimental 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 Carboplatin, Etoposide, Melphalan
    R2: ch14.18/CHO Active Comparator ch14.18/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 Aldesleukin Experimental Patients randomised to receive ch14.18/CHO plus Aldesleukin Aldesleukin, ch14.18/CHO
    R3: COJEC Induction Active Comparator 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 Vincristine, Carboplatin, Etoposide, Cisplatin, Cyclophosphamide
    R3: Modified N7 Experimental 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). Vincristine, Etoposide, Cisplatin, Cyclophosphamide, Doxorubicin
    R4: cnt inf ch14.18/CHO Active Comparator 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 ch14.18/CHO
    R4: cnt inf ch14.18/CHO plus Aldesleukin Experimental 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 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

    Minimum Eligible Age: 1 Month

    Maximum Eligible Age: 21 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Event Free Survival (R1: MAT therapy)

    Event Free Survival (R4: immunotherapy)

    Complete metastatic response (R3: Induction therapy)

    Event free survival (R3: Induction therapy)

    Secondary Outcome Measures

    Trial Keywords

    neuroblastoma

    immunotherapy

    MAT

    antibody treatment