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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT01704716

Studienbeginn:
Februar 2002

Letztes Update:
23.10.2020

Wirkstoff:
Vincristine, Aldesleukin, ch14.18/CHO, Carboplatin, Etoposide, Cisplatin, Cyclophosphamide, Doxorubicin, G-CSF, Busulfan, Melphalan

Indikation (Clinical Trials):
Neuroblastoma

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
Phase 3

Sponsor:
St. Anna Kinderkrebsforschung

Collaborator:
-

Studienleiter

Ruth L Ladenstein, MD, MBA, cPM
Principal Investigator
St. Anna Kinderkrebsforschung

Kontakt

Ruth L Ladenstein, MD, MBA, cPM
Kontakt:
Phone: 0043140470
Phone (ext.): 4750
E-Mail: ruth.ladenstein@ccri.at» Kontaktdaten anzeigen

Studienlocations
(3 von 126)

Lady Cilento Children´s Hospital
Brisbane
AustraliaRekrutierend» Google-Maps
John Hunter Children's Hospital
Newcastle
AustraliaRekrutierend» Google-Maps
Royal Children's Hospital Melbourne
Parkville
AustraliaRekrutierend» Google-Maps
Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck
Innsbruck
AustriaRekrutierend» Google-Maps
Madarász Children Hospital Budapest
Budapest
HungaryRekrutierend» Google-Maps
Semmelweis University of Budapest
Budapest
HungaryRekrutierend» Google-Maps
Schneider Children's Medical Center of Israel
Petah Tiqwa
IsraelRekrutierend» Google-Maps
Ospedale Regionale per le Microcitemie
Cagliari
ItalyRekrutierend» Google-Maps
Sec. Univ. degli Studi di Napoli - Policlinico
Napoli
ItalyRekrutierend» Google-Maps
Clinica di Oncoematologia Pediatrica Padova
Padova
ItalyRekrutierend» Google-Maps
Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica
Parma
ItalyRekrutierend» Google-Maps
Casa Sollievo della Sofferenza
San Giovanni Rotondo
ItalyRekrutierend» Google-Maps
Istituto per l'Infanzia "Burlo Garofolo"
Trieste
ItalyRekrutierend» Google-Maps
Upper Silesian Centre of Child and Mother's Care
Katowice
PolandRekrutierend» Google-Maps
Children's University Hospital in Lublin
Lublin
PolandRekrutierend» Google-Maps
University of Medical Sciences Poznan
Poznan
PolandRekrutierend» Google-Maps
University Hospital F. D. Roosevelt
Banská Bystrica
SlovakiaRekrutierend» Google-Maps
H . Materno-Infantil Teresa Herrera
La Coruna
SpainRekrutierend» Google-Maps
H. de Donostia Ntra. Sra. de Aranzazu
San Sebastián
SpainRekrutierend» Google-Maps
H. General de Galicia
Santiago De Compostela
SpainRekrutierend» Google-Maps
Queen Silvia's Children's Hospital
Göteburg
SwedenRekrutierend» Google-Maps
Aberdeen: Royal Aberdeen Children's Hospital
Aberdeen
United KingdomRekrutierend» Google-Maps
Royal Belfast Hospital for Sick Children
Belfast
United KingdomRekrutierend» Google-Maps
Birmingham Children's Hospital
Birmingham
United KingdomRekrutierend» Google-Maps
Bristol Royal Hospital for Children
Bristol
United KingdomRekrutierend» Google-Maps
Edinburgh Royal Hospital for Sick Children
Edinburgh
United KingdomRekrutierend» Google-Maps
Glasgow Royal Hospital for Sick Children
Glasgow
United KingdomRekrutierend» Google-Maps
Leeds: St James's University Hospital
Leeds
United KingdomRekrutierend» Google-Maps
Leicester Royal Infirmary
Leicester
United KingdomRekrutierend» Google-Maps
Liverpool: Alder Hey Children's Hospital
Liverpool
United KingdomRekrutierend» Google-Maps
Great Ormond Street Hospital
London
United KingdomRekrutierend» Google-Maps
UCLH University College London Hospital
London
United KingdomRekrutierend» Google-Maps
Royal Manchester Children's Hospital
Manchester
United KingdomRekrutierend» Google-Maps
Newcastle: Royal Victoria Infirmary
Newcastle
United KingdomRekrutierend» Google-Maps
Nottingham: Queen's Medical Centre
Nottingham
United KingdomRekrutierend» Google-Maps
Oxford: John Radcliffe Hospital
Oxford
United KingdomRekrutierend» Google-Maps
Sheffield Children's Hospital
Sheffield
United KingdomRekrutierend» Google-Maps
Southampton General Hospital
Southhampton
United KingdomRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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®).

Ein-/Ausschlusskriterien

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

-

Studien-Rationale

Primary outcome:

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

Studien-Arme

  • 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

Geprüfte Regime

  • Vincristine:
    given during Rapid COJEC and modified N7 therapy
  • Aldesleukin (Interleukin 2, IL-2, IL2):
    Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
  • ch14.18/CHO (anti GD2 antibody / Dinutuximab beta EUSA / Qarziba® / ):
    ch14.18/CHO antibody is given during MRD treatment
  • Carboplatin (Paraplatin):
    Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
  • Etoposide (VP16):
    Etoposide is given during Induction Treatment (both R3 randomisation arms)
  • Cisplatin (CDDP):
    Cisplatin is given during Induction Treatment (both R3 randomisation arms)
  • Cyclophosphamide (Endoxan):
    Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
  • Doxorubicin (Adriamycin):
    Doxorubicin is given during Induction Treatment (R3 arm modified N7)
  • G-CSF (Filgrastim):
    G-CSF is given during Induction Treatment
  • Busulfan (Busilvex / Myleran / Busulphan / ):
    In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
  • Melphalan (Alkeran):
    Melphalan is given during MAT treatment

Quelle: ClinicalTrials.gov


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