European Low and Intermediate Risk Neuroblastoma

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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

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Lines: responsibilities

•• SponsorSponsor: FUNDACION PARA LA INVESTIGACION HOSPITAL

UNIVERSITARION LA FE, SPAIN

•• Principal Principal InvestigatorInvestigator:

– Low Risk Study: MD Gudrun Schleiermacher (FRANCE)

– Intermediate Risk Study: MD Andrea di Cataldo (ITALY)

–Neonatal Suprarenal Masses Study: PhD, MD Adela Canete (SPAIN)

•• BelgianBelgian National National CoordinatorCoordinator:

–Principal Investigator: PhD, MD Bénédicte Brichard

– Study coordinators: Hilde Waterloos and Bérénice Bloc

–Contact: Tel: 0032 2 764 23 76 Fax: 0032 2 764 89 64

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LINES Study: Site initiation presentation plan

• Study Primary Objectives

• treatment strategies overview

• 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

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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

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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


alteration

With segm. Chrom.

altération

Low riskGroup

11

Low riskGroup

33


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

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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

intermixed

•Informed consent

•Follow-up warranted

•Group treatment within 6 weeks from diagnosis

•Biopsy proven neuroblastoma Tumour genomic profile

obtained in a NRL according to guidelines

•MYCN amplification

All patients

Exclusion Inclusion

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Lines, treatment groups 7 to 10: Inclusion and exclusion Criteria

• Group 7: Stage L 2, differentiated histology, MYCN non-amplified, age >18 months

• Group 8: Stage L 2, undifferentiated or poorly differentiated histology, MYCN non-amplified, age >18 months

• Group 9 :INSS Stage 1, MYCN amplified, any age

• Group 10: Stage M, MYCN non-amplified, age >12 months

•Neuroblastoma NOS•Age> 18 months

•MYCN non-amplified

•Histology differentiated, poorly differentiated,

undifferentiated

Stage L2

• Age < 12 months

•MYCN non-amplified

•Any histology

Stage M

•INSS stages 2,3,4,4s•MYCN amplification L1 INSS Stage 1

• Prior chemiotherapy or radiotherapy

• Diagnosis of ganglioneuroma or ganglioneuroblastoma

intermixed

•Informed consent

•Follow-up warranted

•Group treatment within 6 weeks from diagnosis

•Tumour material available for biological studies

according to guidelines

•Biopsy proven neuroblastoma in a NRL

All patients

Exclusion Inclusion

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Lines, Neonatal suprarenal masses: An Observational Approach

•Suprarenal reaching the midline

•Suprarenal mass measuring > 5 cm at the largest

diameter

•Evidence of positive ipsi/contralateral lymph

nodes or spread outside the suprarenal gland

•Regional involvement

•Metastatic involvement

•Inability to undertake mandatory diagnostic

studies (Biological markers, US, MRI, MIBG)

•Informed consent

•Availability to the adequate Follow-up

•Age < 90 days when suprarenal mass is discovered

•Suprarenal mass detected by Ultrasound or MRI

•Suprarenal mass may be cystic or solid

•Frozen plasma available

ExclusionInclusion

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Lines: Study treatment groups, summary

Any

>12 months>12 months

<12 months

Any

>18 months

>18 months

< 12 months

< 18 months

Any

< 90 days

Age at diagnosis

MsM

High RiskAmpL2

L1-INSS stage 1High Risknon-AmpMsHigh Risknon-AmpM

Intermediate risk10non-AmpM

Intermediate risk9AmpL1-INSS stage 1

Intermediate risk8non-AmpL2 (Poorly/Undifferentiated

Histology)

Intermediate risk7non-AmpL2 (Differentiated Histology)6yes

5noyesnon-AmpLow risk6yesMs

4nono

3yes2noyesnon-Amp

Low risk3yesL2

1nonoLNESG 2non-AmpL1 (excised)

massesNSMNeonatal suprarenal

Study eligibilityStudy groupSegm. Chrom.

Alteration

Life threat.

SymptomsMYCN

StatusDisease Stage

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Lines: Investigations for all groups (during and after treatment)

* Except for neonatal suprarenal masses

Long term follow-up period for each patient will be planned in accordance with the national local guidelines for

children cured of a paediatric cancer:

• Tumour and metastatic assessments (at last once a year)

• Physical and clinical examinations

• Toxicity assessments : Renal, Auditory and Cardiac systems follow-up (at 2 years and 5 years from diagnosis).

• Second Malignancy follow-up

XXEchocardiogram (if receiving

anthracycline)

XXAudriogram (if receving carboplatin)

XXX-ray of any bone uptake of MIBG(Stage M)

XXXScintigraphy MIBG (Tc MDP)

XXXXUltrasound, CT or MRI(Stage M)(Stage M)

X*X*XBone marrow aspirate and trephine biopsy

(MYCN, DNA index, Array-CGH/MLPA)

XXBiological studiesXXXUrine Catecholamines

X(incl. Schwart's formula)XXXXXXXXRenal function evaluationXXSerum LDH

XXXXXXXXBiochemistry

XXXXXXXXComplete blood countTherapyEnd Of654321At Diagnosis

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Lines, Group 1: treatment strategy

• 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

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• *Surgical resection in indicated only if IDRF Negative

XXSurgery if IDRF negative*XXCADO

XXVP/CarboChemotherapy:

XGenomic type assigned

XXXXXToxicity monitoringXBiopsy

XXXImagingXPre-treatment evaluation


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• *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

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not indicatedtumour isthe primaryresection ofSurgical

Observation period

XGenomic type assignedXBiopsy

XXXImaging

XPre-treatment evaluation

1713951DxWeek

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• *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




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• * 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





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• *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





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• * 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



XXXImaging


21171310741DxWeek

19


X13-CIS-RA x6XLocal Radiotherapy

XSurgical ExcisionXXXCADO

XXXVP/CarboChemotherapy:

XMYCN status ConfirmedXXXXXToxicity monitoring

XBiopsyXXXImaging


21171310741DxWeek

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• *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


XXXXXToxicity monitoring

XBiopsy

XXXXXImaging

XPre-treatment evaluation

87654321Cycle21171310741DxWeek

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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

Only at W 18, 30 and

48

catecholaminesA) Regression of mass

XInterim Evaluation:

X

X

X

X

X

4876543210Visit

XXXXXXXPhysical examination

XXXXXXXBlood sampling

XXXXXXXUltrasound

XXXX***XX***XUrines catecholamines

W9W0 and betweenTo doScintigraphy MIBG

XW9W0 and betweenTo doAbdominal MRI**

3018129630*Week

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Any questions?

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Thank you for your attention

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European Low and Intermediate Risk Neuroblastoma