Clinical Trials /

European Low and Intermediate Risk Neuroblastoma Protocol

NCT01728155

Description:

The European study, LINES 2009 (Low and Intermediate Risk Neuroblastoma European Study), groups together in a single protocol the treatment of all patients with "non high risk" neuroblastoma (NB), with stratification into two groups: low risk and intermediate risk. These two separate cohorts are included in one single protocol to enable patient data from these two groups to be entered into a common database, as the current prognostic classifications determining treatment may evolve further with subsequent more detailed molecular analysis of the tumours. 1. LOW RISK STUDY The Low Risk Study is proposed in order to: - minimise the amount of treatment (chemotherapy and surgery) for all appropriate low risk patients, who in previous studies have been shown to have an excellent long-term outcome (as in the SIOPEN 99.1-2 infant neuroblastoma studies where the overall survival was greater than 97%(H. Rubie, JCO). - improve the EFS and maintain the OS (overall survival) in L2 and Ms patients with a SCA(Segmental Cromosomal Aberration) genomic profile tumour (presence of any segmental chromosomal change (SCA)) by electively treating these patients with chemotherapy despite the absence of symptoms. 2) INTERMEDIATE RISK STUDY The Intermediate Risk Study is proposed in order to: - reduce the amount of chemotherapy for differentiating histology INRG (International Neuroblastoma Risk Group) stage L2 NB and ganglioneuroblastoma nodular patients who in previous SIOPEN study have been shown to have an excellent long-term outcome; - increase the amount of treatment (radiotherapy and 13-cis-RA (13-cis-Retinoic Acid) for poorly differentiated or undifferentiated histology INRG stage L2 NB or ganglioneuroblastoma nodular patients in order to improve the EFS registered in the previous SIOPEN study; - improve the EFS (Event Free Survival) of MYCN (V-Myc myelocytomatosis viral related oncogene, NB derived ,avian )amplified INSS (International NB Staging System) stage 1 NB patients with the introduction of adjuvant treatment; - maintain the very good results obtained in previous SIOPEN study for INRG stage M infants with a moderate treatment. NEONATAL SUPRARENAL MASSES The incidence of suprarenal tumours/masses has increased in the last decade due to the expanded use of prenatal ultrasonography in routine obstetric care and in the neonatal and early infancy care. The differential diagnosis of these masses ranges from benign (adrenal haemorrhage) to malignant processes (neuroblastoma, adrenal carcinoma). Knowledge on perinatal suprarenal masses, although based on a relatively large literature, is scattered amongst studies on very few cases with no methodical approach and often short follow up. Therefore, the optimal management of these masses has not been clearly defined. Neuroblastoma at this age is an intriguing entity with a very good prognosis in most cases. The SIOPEN Group, based on their results in the first multicenter European Trial for infants with neuroblastoma (INES) and the world-wide experience provided in the literature, is launching this European surveillance study (Multi-centre, non-blinded, one armed prospective trial) for these masses. Treatment: Observation

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: European Low and Intermediate Risk Neuroblastoma Protocol
  • Official Title: European Low and Intermediate Risk Neuroblastoma Protocol

Clinical Trial IDs

  • ORG STUDY ID: LINES
  • NCT ID: NCT01728155

Conditions

  • LOW AND INTERMEDIATE PAEDIATRIC NEUROBLASTOMA AND NEONATAL SUPRARENAL MASSES

Interventions

DrugSynonymsArms
chemotherapyGroup 1: chemotherapy

Purpose

The European study, LINES 2009 (Low and Intermediate Risk Neuroblastoma European Study), groups together in a single protocol the treatment of all patients with "non high risk" neuroblastoma (NB), with stratification into two groups: low risk and intermediate risk. These two separate cohorts are included in one single protocol to enable patient data from these two groups to be entered into a common database, as the current prognostic classifications determining treatment may evolve further with subsequent more detailed molecular analysis of the tumours. 1. LOW RISK STUDY The Low Risk Study is proposed in order to: - minimise the amount of treatment (chemotherapy and surgery) for all appropriate low risk patients, who in previous studies have been shown to have an excellent long-term outcome (as in the SIOPEN 99.1-2 infant neuroblastoma studies where the overall survival was greater than 97%(H. Rubie, JCO). - improve the EFS and maintain the OS (overall survival) in L2 and Ms patients with a SCA(Segmental Cromosomal Aberration) genomic profile tumour (presence of any segmental chromosomal change (SCA)) by electively treating these patients with chemotherapy despite the absence of symptoms. 2) INTERMEDIATE RISK STUDY The Intermediate Risk Study is proposed in order to: - reduce the amount of chemotherapy for differentiating histology INRG (International Neuroblastoma Risk Group) stage L2 NB and ganglioneuroblastoma nodular patients who in previous SIOPEN study have been shown to have an excellent long-term outcome; - increase the amount of treatment (radiotherapy and 13-cis-RA (13-cis-Retinoic Acid) for poorly differentiated or undifferentiated histology INRG stage L2 NB or ganglioneuroblastoma nodular patients in order to improve the EFS registered in the previous SIOPEN study; - improve the EFS (Event Free Survival) of MYCN (V-Myc myelocytomatosis viral related oncogene, NB derived ,avian )amplified INSS (International NB Staging System) stage 1 NB patients with the introduction of adjuvant treatment; - maintain the very good results obtained in previous SIOPEN study for INRG stage M infants with a moderate treatment. NEONATAL SUPRARENAL MASSES The incidence of suprarenal tumours/masses has increased in the last decade due to the expanded use of prenatal ultrasonography in routine obstetric care and in the neonatal and early infancy care. The differential diagnosis of these masses ranges from benign (adrenal haemorrhage) to malignant processes (neuroblastoma, adrenal carcinoma). Knowledge on perinatal suprarenal masses, although based on a relatively large literature, is scattered amongst studies on very few cases with no methodical approach and often short follow up. Therefore, the optimal management of these masses has not been clearly defined. Neuroblastoma at this age is an intriguing entity with a very good prognosis in most cases. The SIOPEN Group, based on their results in the first multicenter European Trial for infants with neuroblastoma (INES) and the world-wide experience provided in the literature, is launching this European surveillance study (Multi-centre, non-blinded, one armed prospective trial) for these masses. Treatment: Observation

Detailed Description

      1. LOW RISK STUDY

      The low risk group of patients includes NB patients without MYCN amplification with or
      without life threatening symptoms in the following clinical situations:

        -  Children aged ≤ 18 months with localised neuroblastoma associated with image defined
           risk factors precluding upfront surgery (stage INRG L2).

        -  Children aged ≤ 12 months with disseminated neuroblastoma without bone, pleura, lung or
           CNS (Central Nervous System) disease (stage INRG Ms)

           2) INTERMEDIATE RISK STUDY

      The intermediate risk group of patients includes NB patients in the following clinical
      situations:

        -  Children aged >18 months with localised neuroblastoma without MYCN amplification,
           associated with image defined risk factors precluding upfront surgery (stage INRG L2).

        -  Children aged ≤12 months with disseminated neuroblastoma involving bone, pleura, lung
           and/or CNS (stage INRG M), without MYCN amplification.

        -  Children with localised resected NB (stage INSS I) with MYCN amplification. NEONATAL
           SUPRARENAL MASSES

      The incidence of suprarenal tumours/masses has increased in the last decade due to the
      expanded use of prenatal ultrasonography in routine obstetric care and in the neonatal and
      early infancy care. The differential diagnosis of these masses ranges from benign (adrenal
      haemorrhage) to malignant processes (neuroblastoma, adrenal carcinoma). Knowledge on
      perinatal suprarenal masses, although based on a relatively large literature, is scattered
      amongst studies on very few cases with no methodical approach and often short follow up.
      Therefore, the optimal management of these masses has not been clearly defined. Neuroblastoma
      at this age is an intriguing entity with a very good prognosis in most cases. The SIOPEN
      Group, based on their results in the first multicenter European Trial for infants with
      neuroblastoma (INES) and the world-wide experience provided in the literature, is launching
      this European surveillance study (Multi-centre, non-blinded, one armed prospective trial) for
      these masses. Treatment: Observation
    

Trial Arms

NameTypeDescriptionInterventions
Group1No Interventioninitial observation (chemotherapy is only given if there is subsequent progression)
    Group 1: chemotherapyActive Comparatorchemotherapy and surgery
    • chemotherapy
    Group 2Experimentalchemotherapy and surgery
    • chemotherapy
    Group 3Experimentalchemotherapy and surgery
    • chemotherapy
    Group 4No InterventionObservation
      Group 5Experimentalchemotherapy
      • chemotherapy
      Group 6Experimentalchemotherapy and surgery
      • chemotherapy
      Group 7Experimentalchemotherapy and surgery
      • chemotherapy
      Group 8Experimentalchemotherapy, surgery, radiotherapy and 13 cis-retinoic acid
      • chemotherapy
      Group 9Experimentalchemotherapy, surgery, radiotherapy and 13 cis-retinoic acid
      • chemotherapy
      Group 10Experimentalchemotherapy, surgery,
      • chemotherapy

      Eligibility Criteria

              1. LOW RISK STUDY
      
                   Inclusion criteria for the whole low risk group:
      
                     -  informed consent and follow-up warranted; group assignment completed within 6
                        weeks from diagnosis; no prior chemotherapy or radiotherapy
      
                     -  Biopsy proven neuroblastoma
      
                     -  Tumour genomic profile obtained in a NRL according to guidelines
      
                     -  MYCN non-amplified
      
                   Exclusion criteria for the whole low risk group:
      
                   * Diagnosis of ganglioneuroma or ganglioneuroblastoma intermixed INRG Stage L2
      
                   Inclusion criteria:
      
                   *age ≤ 18 months
      
                   Exclusion criteria:
      
                     -  any metastatic site
      
                     -  MYCN amplification
      
                     -  age > 18 months INRG Stage Ms
      
                   Inclusion criteria:
      
                   * age ≤ 12 months
      
                   Exclusion criteria:
      
                     -  bone, pleura/lung and/or CNS metastasis
      
                     -  MYCN amplification
      
                     -  age > 12 months
      
                2. INTERMEDIATE RISK STUDY
      
                   Inclusion criteria for the whole intermediate risk group:
      
                     -  informed consent and follow-up warranted; group assignment completed within 6
                        weeks from diagnosis; no prior chemotherapy or radiotherapy
      
                     -  Tumour material available for biological studies according to guidelines
      
                     -  Biopsy proven neuroblastoma confirmed in a National Reference Laboratory (NRL)
      
                   Exclusion criteria for the whole intermediate risk group:
      
                   * Diagnosis of ganglioneuroma or ganglioneuroblastoma intermixed
      
                   INRG Stage L1 and INSS stage 1:
      
                   Inclusion criteria:
      
                   * MYCN amplified
      
                   Exclusion criteria:
      
                     -  MYCN non-amplified
      
                     -  INSS stages 2, 3, 4, 4s
      
                   INRG Stage L2:
      
                   Inclusion criteria:
      
                     -  Histology: differentiating, poorly differentiated, undifferentiated neuroblastoma
                        or ganglioneuroblastoma nodular
      
                     -  MYCN non-amplified
      
                     -  age >18 months
      
                   Exclusion criteria:
      
                     -  neuroblastoma NOS
      
                     -  MYCN amplification.
      
                     -  age ≤ 18 months
      
                   INRG Stage M:
      
                   Inclusion criteria:
      
                     -  Any histology
      
                     -  MYCN non-amplified
      
                     -  age ≤ 12 months
      
                   Exclusion criteria:
      
                     -  MYCN amplification
      
                     -  age > 12 months
      
                3. NEONATAL SUPRARENAL MASSES
      
              Inclusion criteria:
      
                -  Age less than or equal to 90 days when the suprarenal mass is discovered.
      
                -  Suprarenal mass detected by ultrasound and/or MRI. The suprarenal mass may be cystic
                   and/or solid, but IT CANNOT REACH THE MIDLINE AND should MEASURE ≤ 5 CM AT THE LARGEST
                   DIAMETER.
      
                -  No regional involvement: MRI scan does not show evidence of positive
                   ipsi/contralateral lymph nodes or other spread outside the suprarenal gland.
      
                -  No metastatic involvement.
      
                -  Frozen plasma available.
      
                -  Informed consent.
      
                -  Availability to do the adequate follow-up
      
              Exclusion criteria:
      
                -  Age older than 90 days.
      
                -  Suprarenal mass bigger than 5 cm.
      
                -  Regional involvement.
      
                -  Metastatic involvement.
      
                -  Inability to undertake mandatory diagnostic studies (biological markers, US, MRI,
                   MIBG).
      
                -  Follow-up not guaranteed by parents/guardians.
            
      Maximum Eligible Age:18 Years
      Minimum Eligible Age:90 Days
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Primary aim for Low Risk Neuroblastoma
      Time Frame:2 years
      Safety Issue:
      Description:To demonstrate through a randomisation between observation and chemotherapy that you can safely reduce treatment in a subgroup of L2 low risk patients (those without life threatening symptoms (LTS) and without any segmental chromosomal changes (SCA), i.e. study group 1) by giving less treatment than has been given historically while maintaining an excellent OS of 100%.

      Secondary Outcome Measures

      Measure:To maintain a 2 year EFS of at least 90% and an OS of at least 95% in L2 patients with LTS without SCA (study group 2)
      Time Frame:2 year
      Safety Issue:
      Description:
      Measure:To maintain the 2 year EFS of 85% and an OS of at least 98% in Ms patients without SCA (study groups 4 and 5)
      Time Frame:2 year
      Safety Issue:
      Description:
      Measure:To improve the 2 year EFS to at least 90% and maintain the OS of close to 100% in L2 patients with SCA (Study Group 3) and improve the 2 year EFS to over 70% in Ms patients with SCA (study group 6)
      Time Frame:2 year
      Safety Issue:
      Description:
      Measure:To evaluate adherence to the protocol recommendations regarding LTS
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To reduce surgical morbidity by promoting strict adherence to Image Defined-Risk Factors (IDRFs) to determine surgical resectability
      Time Frame:5 year
      Safety Issue:
      Description:
      Measure:To define the long term follow-up and natural history of the Stage L2 non-resected masses that have remained IDRF positive at the end of treatment (study groups 1-3).
      Time Frame:5 year
      Safety Issue:
      Description:
      Measure:To confirm in a larger patient cohort the excellent OS of 95% in stage M neuroblastoma without MYCN amplification, less than 12 months of age, when treated with moderate therapy (study group 10).
      Time Frame:3 year
      Safety Issue:
      Description:
      Measure:Maintain the results of 3yr-EFS of 90% and 3yr-OS of 100% in stage L2 patients over the age of 18 months, with differentiating neuroblastoma or differentiating ganglioneuroblastoma nodular, despite a treatment reduction (group7)
      Time Frame:3 year
      Safety Issue:
      Description:
      Measure:To improve the 3 year EFS to at least 50% and the 3 year OS to 80% in INSS stage I patients with MYCN amplified neuroblastoma by the addition of adjuvant treatment (study group 9).
      Time Frame:3 year
      Safety Issue:
      Description:
      Measure:To evaluate the impact of the tumour genomic profile on patient outcome, in order to consider its role in the treatment stratification of these intermediate risk patients (all study groups).
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To manage infants with suprarenal masses discovered ante or neonatally with a uniform approach in Europe in a multicentre setting.
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To maintain an excellent overall survival with a non-operative therapeutic approach (serial monitoring, surgery if warranted) in infants with a localised suprarenal mass discovered ante or neonatally.
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:To determine the 3-year surgery-free survival in infants with suprarenal masses discovered ante or neonatally and managed conservatively (non initial surgery).
      Time Frame:3 years
      Safety Issue:
      Description:
      Measure:To find out the natural history of perinatal suprarenal masses, according to the definitions set up for the study.
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To study the kinetics of regression in those suspected suprarenal neuroblastomas in infants with suprarenal masses discovered ante or neonatally and managed conservatively (non initial surgery).
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To collect tissue from those suprarenal masses excised in order to perform standard and investigational pathological and biological studies (INPC, MYCN, 1p, 11).
      Time Frame:5 years
      Safety Issue:
      Description:
      Measure:To collect frozen plasma from all patients included in the study in order to perform research.
      Time Frame:5 years
      Safety Issue:
      Description:

      Details

      Phase:Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Instituto de Investigacion Sanitaria La Fe

      Trial Keywords

      • NEUROBLASTOMA, LOW RISK, INTERMEDIATE RISK

      Last Updated

      June 16, 2017