1 Study group 1: phase III, randomized prospective multi-centre trial Study group 2-10 and Neonatal Suprarenal Masses: non-blinded, one-armed, multi- centre prospective trials Initiation presentation based on the protocol Version 4.0 24th JUNE 2013 European Low and Intermediate Risk Neuroblastoma A Siopen Study EudractCT number: 2010-021396-81
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1
Study group 1: phase III, randomized prospective multi-centre trial
Study group 2-10 and Neonatal Suprarenal Masses: non-blinded, one-armed, multi-centre prospective trials
Initiation presentation based on the protocol Version 4.0
24th JUNE 2013
European Low and Intermediate Risk NeuroblastomaA Siopen StudyEudractCT number: 2010-021396-81
2
Lines: responsibilities
•• SponsorSponsor: FUNDACION PARA LA INVESTIGACION HOSPITAL
• Treatment groups 1 to 6: Inclusion and exclusion Criteria• Treatment groups 7 to 10: Inclusion and exclusion Criteria• Neonatal suprarenal masses: An Observational Approach
• Study treatment groups: summary
• Investigations for all groups (during and after treatment)• Treatment strategy for groups 1 to 10.• Neonatal suprarenal masses: observational period and follow-up
4
Lines: Study Primary Objectives
• Treatment reduction safely monitored in low risk groups
• Improve the Event-Free survival in intermediate risk groups
• Maintain a 3-years event-free survival in neonatal suprarenal
masses
• Reduce surgical morbidity
• Define the long-term follow-up of non-resected masses
• Evaluate the impact of the tumour Genomic Profile on patient
outcome
• To rise a uniform approach in Europe in a multicentre setting
• Collect tissue and frozen plasma when applicable, in order to
perform pathological and biological studies
5
Lines: treatment strategies overview
04
Titre 101
…03
Titre 202
05
06
07
Patient's age at
diagnosis
< 90 days < 12 months
>12 months
Any>18
months< 18
months
MYCNNon-
Amplified
Ms M
Without LTS With LTS
Without segm. Chrom.Altera--tion
With segm. Chrom. Altera--tion
Low riskGroup
44
With segm. Chrom.
alteration
Without segm. Chrom.
alteration
Low riskGroup
66
Low riskGroup
66
Low riskGroup
55
Neonatal Supra-renal
Masses
Observa--tion
MYCN
Non-
Amplified
Ms M
HighRisk
Interm. Risk:
Group 1010
High Risk
MYCN
Non-
Amplified
L 2
Without LTS
With LTS
Without segm. Chrom.
alteration
With segm. Chrom.
altération
Low riskGroup
11
Low riskGroup
33
Without segm. Chrom.
alteration
With segm. Chrom.
alteration
Low riskGroup
22
Low riskGroup
33
MYCN
Non-
Amplified
L2
Differen--tiated
Histology
Poorly or Undiff.
Histology
Interm. Risk
Group77
Interm. Risk
Group88
MYCN
Non-
Amplified
MYCN Amplified
Total resection
L1
LNSG 2
L1 INSS Stage 1
L1 INSS Stage 2, L 2, H,
Ms
Interm. Risk
Group99
High Risk
LTS: life threatning SymptomsM: Distant metastatic disease (except Ms)Ms: Metastatic disease in <12 months patients
with skin, liver and/or bone marrow lesionsL1 : Localised tumour not involving vital structuresL2 : Locoregional tumour with risk factors
6
Lines, treatment groups 1 to 6: Inclusion and exclusion Criteria
• Group 1: < 18 months, stage L2, MYCN non-amplified, NCA genomic profile, without life threatening symptoms
• Group 2:< 18 months, stage L2, MYCN non-amplified, NCA genomic profile, with life threatening symptoms
• Group 3:< 18 months, stage L2, MYCN non-amplified, SCA genomic profile, with / without life threatening symptoms
• Group 4: < 12 months, stage Ms , MYCN non-amplified, NCA genomic profile, without life threatening symptoms
• Group 5:< 12 months, stage Ms , MYCN non-amplified, NCA genomic profile, without life threatening symptoms
• Group 6 :< 12 months, stage Ms, MYCN non-amplified, SCA genomic profile, with/without life threatening symptoms
•Bone, pleura/lung and/or CNS metastasis• Age < 12 months Stage Ms
•Any metastatic sites• Age < 18 months
• Locoregional tumour with image defined risk factorStage L2
• Prior chemiotherapy or radiotherapy
• Diagnosis of ganglioneuroma or ganglioneuroblastoma
• Chemotherapy will start with 2 CO*:– If no response to treatment, 2VP/Carbo should be given– If there is objective response to treatment, 2 additional CO should be given
• **If IDRF positive after 4 CO therapy, 2VP/Carbo should be given• ***Surgical resection in indicated only if IDRF Negative
XSurgery at 1 year, if IDRF neg.***B) Randomised arm : Observation
XXXSurgery if IDRF negative
XX**XXVP/Carbo (2VP/Carbo max)
or:or:
XX*XXCO ( 2-4 CO max)A) Randomised arm : Chemotherapy
X
(A or B attribution)
RANDOMISATION :XGenomic type assigned
XXXXXXXToxicity monitoringXBiopsy
XXXXImaging XPre-treatment evaluation
654321Cycle1297531DxWeek
12
Lines, Group 2: treatment strategy
• *Surgical resection in indicated only if IDRF Negative
XXSurgery if IDRF negative*XXCADO
XXVP/CarboChemotherapy:
XGenomic type assigned
XXXXXToxicity monitoringXBiopsy
XXXImagingXPre-treatment evaluation
4321Cycle1310741DxWeek
13
Lines, Group 3: treatment strategy
• *4 VP/Carbo will be given in case of LTS• **CADO treatment should start if LTS persists after 2 VP/Carbo.• ***Surgical resection in indicated only if IDRF Negative
XSurgery if IDRF negative***XX
or:or:CADO**
XXXXVP/Carbo*Chemotherapy:
XGenomic type assignedXXXXXToxicity monitoring
XBiopsyXXXImaging
XPre-treatment evaluation4321Cycle
1310741DxWeek
14
Lines, Group 4: treatment strategy
not indicatedtumour isthe primaryresection ofSurgical
Observation period
XGenomic type assignedXBiopsy
XXXImaging
XPre-treatment evaluation
1713951DxWeek
15
Lines, Group 5: treatment strategy
• *If LTS persists after 2 VP/Carbo, then 2 Cado treatment should be given.
Not indicated in this groupSurgery
XXCADO*XXVP/Carbo
Chemotherapy:XGenomic type assigned
XXXXXToxicity monitoringXBiopsy
XXXImagingXPre-treatment evaluation
4321Cycle1310741DxWeek
16
Lines, Group 6: treatment strategy
• * If LTS persists after 2 VP/Carbo, then 2 CADO should be given.• **Surgical resection in indicated only if IDRF Negative
XSurgery if IDRF negative**XX
or:or:CADO*
XXXXVP/Carbo
Chemotherapy:XGenomic type assigned
XXXXXToxicity monitoringXBiopsy
XXXImagingXPre-treatment evaluation
4321Cycle1310741DxWeek
17
Lines, Group 7: treatment strategy
• *If no evidence of response after 2 VP/Carbo, then 2 CADO should be given.
• **Surgical resection in indicated only if IDRF Negative
XSurgery if IDRF negative**XX
or:or:CADO*XXXXVP/Carbo
Chemotherapy:XGenomic type assigned
XXXXXToxicity monitoringXBiopsy
XXXImagingXPre-treatment evaluation
4321Cycle1310741DxWeek
18
Lines, Group 8: treatment strategy
• * Week 13: following 2 VP/Carbo and 2 CADO cycles:
– If IDRF négative, or IDRF positive with no response: surgery and then 2 CADO chemotherapy– If IDRF positive with response:
� Response to initial VP/Carbo: 1 VP/Carbo, then 1 CADO and Surgery� No response to initial VP/Carbo: 2 CADO and then surgery
X13-CIS-RA x6XLocal Radiotherapy
XXSurgeryX
XOr * :XXCADOXXXVP/Carbo
Chemotherapy:XGenomic type assigned
XXXXXToxicity monitoringXBiopsy
XXXImaging
XPre-treatment evaluation654321Cycle
21171310741DxWeek
19
Lines, Group 9: treatment strategy
X13-CIS-RA x6XLocal Radiotherapy
XSurgical ExcisionXXXCADO
XXXVP/CarboChemotherapy:
XMYCN status ConfirmedXXXXXToxicity monitoring
XBiopsyXXXImaging
XPre-treatment evaluation654321Cycle
21171310741DxWeek
20
Lines, Group 10: treatment strategy
• *Week 7, following 2 VP/Carbo :– If response disease: 2 VP/Carbo should be given– If progression / no response disease: 2 CADO should be given
• ** If metastatic CR following cycle 4, 6 or 8: surgical resection of the primary tumour should be undertaken.
• If metastases persists after 8 cycles of chemiotherapy, consider HR-group therapy
XXXSurgery if IDRF negative**
XXXXXX
or:Or * :CADO
XXXXVP/Carbo
Chemotherapy:XGenomic type assigned
XXXXXToxicity monitoring
XBiopsy
XXXXXImaging
XPre-treatment evaluation
87654321Cycle21171310741DxWeek
21
Lines, neonatal suprarenal masses: observational period and follow-up
• Week 48: final point of observation:– If suprarenal mass still persist, pathological analysis is recommanded
– If a complete regression is observed, patient should be followed annually for 3 years
• * Day 0= Date diagnosis = date of the 1st ultrasound where the mass was visualised• **Abdominal MRI to collet size and caracteristics of the mass and to rule out metastatic or regional involvement• *** Only if positive or if the mass increases
:
:
Collected every 4
weeks
catecholaminesB) No regression or increase of mass