siopen neuroblastoma trials hr-nbl1€¦ · r2 early results: toxicities grade 3 & 4 odds...
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SIOPEN Neuroblastoma trials
HR-NBL1
BSPHO Clinical Trial Day
20 June 2014
Geneviève Laureys
SIOPEN NB (European) trials: overview
Closed:
• LNESG-1 : Low stage Neuroblastoma European Study Group:
Laureys
• INES: Infant Neuroblastoma European Study: Brichard
• LNESG-2: Low stage Neuroblastoma European Study Group:
Brichard
• EUNS: European Unresectable Neuroblastoma Study: Laureys
Open
• HR-NBL1: 2001- .. High Risk Neuroblastoma: Laureys
• LINES: Low and intermediate Neuroblastoma: Brichard
SIOPEN NB (European) trials: overview
Open, not yet in Belgium
• OMS: 2014? Opsomyoclonus Syndrome: Laureys
• LTI: Long Term Infusion for relapse NB, 2014? - amendment 3:
Laureys
• Haploidentical SCT for relapse: Peter Lange
• BEACON: ITCC study
Near Future
• SCI: retrospective (Brichard) and prospective 2014? (Laureys)
• VERITAS: Protocol for early relapse or poor response: draft
ready, PIs: Mark Gaze and Dominique Couanet-Valteau
SIOPEN NB (European) trials: overview
Closed:
• LNESG-1: Low stage Neuroblastoma European Study Group:
-2001
900 pts registered
Objectives:
• Is it possible to treat children with resectable MNA-neg
neuroblastoma with surgery only?
Results:
• excellent EFS and OS for stage 1 and stage 2 MNA negative
NB
• after relapse cure is possible with 2nd surgery/chemotherapy
• for definition of surgical risk factors, high risk groups, MYCN
amplification: common language necessary
Start of European cooperation for all NB stages, creation of SIOPEN
group
Results published in:
Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP
Europe Neuroblastoma Group, B De Bernardi et al, British Journal of Cancer (2008) 99, 1027 –
1033
SIOPEN NB (European) trials: overview
Closed:
• INES: Infant Neuroblastoma European Study: Brichard
• LNESG-2: Low stage Neuroblastoma European Study Group: -
2001: Brichard
• EUNS: European Unresectable Neuroblastoma Study: Laureys
Patients: 160, EFS and OS: 76 % and 87 %
Relapses: 30
19: local
11: 2 metastatic and 9 local and metastatic:
-> local RT: for children > 5 y
-> RA: for all children
Treatment of children over the age of one year with unresectable localised neuroblastoma without
MYCN amplification: Results of the SIOPEN study, J.A. Kohler et al, European Journal of Cancer
(2013) 49, 3671–3679
• OMS: Opsomyoclonus Syndrome
for patients with OMS, with or without neuroblastoma,
collaboration with pediatric neurologists
such patients are rare, after diagnosis there is time to
submit protocol to EC and authorities
problems Belgium: dexamethasone: study medication?
study started, few inclusions so far, international PI Gudrun
Schleiermacher and Barbara Hero
• LTI: Long Term Infusion for refractory or relapse NB,
Dose finding study, in large countries, amendment 3 open in
small countries, Laureys: centers willing to participate have
to declare interest
• Haploidentical SCT for relapse: Peter Lange
• BEACON: protocol for relapsed refractory pts with avastin
(ITCC): participation Belgium possible Lucas Moreno
SIOPEN NB (European) trials: overview
Open, not yet in Belgium
Near Future
• SCI: Spinal Channel Involvement:
retrospective study: collection of data INES (Brichard)
prospective: pretreatment registration (Laureys), 2014?
Draft forms and consents: to finalise
• VERITAS: Protocol for early relapse or poor response
proposal ready, protocol: to be finalised
PIs: Mark Gaze and Dominique Couanet-Valteau
SIOPEN NB (European) trials: overview
SIOPEN-R-NET : 25 Countries
SWITZERLAND
AUSTRALIA AUSTRIA BELGIUM CZECH
REPUBLIC
DENMARK FINLAND FRANCE
GERMANY GREECE HONG KONG HUNGARY IRELAND ISRAEL ITALY
JAPAN NEW ZEALAND NORWAY POLAND PORTUGAL SERBIA SLOVAKIA
SPAIN SWEDEN UNITED
KINGDOM
SIOPEN HR-NBL1 trial
Sex 1391 males : 973 females
Age 2.9 years (birth – 19.9 years)
111 infants
249 pts. ≥ 1 and < 1.5 years
Stages
2130 Stage 4
234 localised (stages 2&3)
MycN Amplified
Median follow-up: 4.4 years
2364 Eligible Patients Since February 2002 Belgium: 75 pts
Stage 4: 66
Stage 4S: 1
localised MNA: 8
HR-NBL1/SIOPEN
Eligibility and Distribution N
ot
nm
yc-a
mp
lifie
dM
ycN
-am
plif
ied
INSS Stage 4 Localized (Stage2&3)
No
t e
ligib
le Not eligible
N=1041median age: 3.7 (1-20 yrs)0 infants (not eligible)27pts: 1-1.5 years
N=758median age: 2.0 (0-9.2 yrs.)82 infants 123 pts: 1-1.5 years
N=234median age: 2.1 (0.1-18.5 yrs.)29 infants 35 pts:1-1.5 years
SIOPEN HR-NBL1 trialStart of Study: activated 02/2002, inclusion of Belgian
patients: 05/2002
Randomisations:
•R0: Rapid Cojec with or without G-CSF: stop 11/2005: all
patients receive G-CSF
•R1: BuMel (European conditioning regimen) versus CEM
(US regimen):
stop 10/2010: all pts receive BuMel
SIOPEN HR-NBL1 trial
Results R0 - G-CSF during Rapid
Cojec
Recommendations for G-CSF Less febrile episodes
Less days in hospital (42 vs. 32)
Less days with antibiotics (23 vs. 14)
Lower CTC scores for infections and fever (score/cycle)
Less hematological toxicity (WBC, ANC)
Less gut toxicity
(stomatitis, nausea/vomiting constipation)
No adverse effects on stem cell aphaeresis nor on the
MAT randomization rate
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 Ruth Ladenstein, et al, JCO 2010, 28, 21: 3516-3524
SIOPEN HR-NBL1 trialR1 Randomisation: Results BUMEL superiority
versus CEM maintained at 5 years
Overall survival Event free survival
Patients Deaths 5-yrs. pSU p-value Events 5-yrs. pEFS p-value
BUMEL 296 145 0.53±0.03 0.001 164 0.45±0.03 0.001
CEM 301 182 0.40±0.03 . 202 0.31±0.03
HR-NBL1/SIOPEN
Total Group: Pre-MAT Evaluation
Patients
Events 5-yrs. pEFS
p-value
CR 448 198 0.50±0.03 0.000
VGPR 488 263 0.35±0.03 .
PR 353 210 0.31±0.03 .
Not entered (possible > PR)
22 11 0.36±0.14 .
Total Group: CR - Given MAT
Patients
Events 5-yrs. pEFS
p-value
BUMEL 347 141 0.52±0.03
0.049
CEM 101 57 0.45±0.05
.
R1: Toxicities Grade 3 & 4 Odds Ratios
p<0.05 in favour of BuMel
p<0.05 in favour of CEM
1.5
1.01.3
1.11.4
1.4
2.9
1.5
3.02.1
1.61.2
4.2
2.7
4.8
2.1
0.5
1.81.4
0.2
2.7
0.0
1
0.1 1
10
100
General
Haemoglobin
WBC
Granulocytes
Platelets
Infection
Fever
Stomatitis
Nausea/Vomiting
Diarrhoea
Constipation
Skin
Cardiac_func
Hypotension
Hypertension
Central neuro
Bilirubin
SGOT/SGPT
Pulmo. tox.
VOD
Ototoxicities
BUMEL betterCEM better
Trend
Grade 0 &1* Grade 2* Grade 3*
BUMEL iv Bu 85%
oral Bu 80%
11%
16%
4%
4%
CEM 96% 3% 1%
HR-NBL1/SIOPEN
Bearman Toxicity VOD
* No prophylactic use of defibrotide
HR-NBL1/SIOPEN
R1 Multivariable Analysis EFS
p-value HazardRatio
95% CL Hazard Ratio
Age (vs. > 5 years) 0.544
< 18 mo 0.271 0.3 0.5 1.2
18 mo – 5 years 0.561 0.9 0.7 1.2
Localized Disease vs. Stage4 <0.001 0.81 0.2 0.5
BUMEL vs. CEM <0.001 0.65 0.52 0.81
RR xx
R1 R2
BuMel
CEM
INDUCTION: INDUCTION: Rapid COJEC MGT/PBSCMGT/PBSC
Sx
harvest
PBSC
CBDCA 750 mg/m²
A VP16 175 mg/m²
VCR 1.5 mg/m²
CBDCA
4x ctn iv 425mg/m²
VP16
4x ctn iv338mg/m²
L -PAM
3x short iv 70mg/m²
Staging local MRI / CT /US, mIBG, BM(aspirate/biopsy)
CYC 1050 mg/m²
CC VP16 175 mg/m²
VCR 1.5 mg/m²
CDDP 80 mg/m²
BB VCR 1.5 mg/m²
G - CSF
Neupogen ® 5µg/kg
G - CSFI.V. BU *
L -PAM
140mg/m²/d short i.v.
Day 0 10 20 30 40 50 60 70 90 95 1 50 / 2xTVD:210
A B C B A B C B Course
0 28 56 84 112 140
21 49 77 105 133
MRD TreatmentMRD Treatment
13 cis retinoic acid po
160mg/m2/day x 14 days
every 4 weeks
Days after Start of 13 cis RA
Ch 14.18 anti GD2 AB iv
20mg/m²/day x 5 days
every 4 weeks
R2B
ACTIVATED
R2A
CBDCA
VP16
VCR
CDDP
CYC
G - CSF
G -CSF
G - CSF
G - CSF
G - CSF
local MRI / CT and mIBG post surgery
21
Gy
21
Gy
BM aspirates only / local ultrasound
G - CSF
2xTVD
RR xx
R1 R2
BuMel
CEM
INDUCTION: INDUCTION: Rapid COJEC MAT/PBSCMAT/PBSC
Sx
harvest
PBSC
CBDCA 750 mg/m²
A VP16 175 mg/m²
VCR 1.5 mg/m²
CBDCA
4x ctn iv 425mg/m²
VP16
4x ctn iv338mg/m²
L -PAM
3x short iv 70mg/m²
Staging local MRI / CT /US, mIBG, BM(aspirate/biopsy)
CYC 1050 mg/m²
CC VP16 175 mg/m²
VCR 1.5 mg/m²
CDDP 80 mg/m²
BB VCR 1.5 mg/m²
G - CSF
Neupogen ® 5µg/kg
G - CSFI.V. BU*
L -PAM
140mg/m²/d short i.v.
Day 0 10 20 30 40 50 60 70 90 95 150 / 2xTVD:210
CBDCA
VP16
VCR
CDDP
CYC
G - CSF
G -CSF
G - CSF
G - CSF
G - CSF
local MRI / CT and mIBG post surgery
21
Gy
21
Gy
BM aspirates only / local ultrasound
G - CSF
2xTVD
0 28 56 84 112 140
13-cis retinoic acid PO
160mg/m2/day x 14 days
every 4 weeks
Ch14.18/CHO IV
20mg/m²/day x 5 days
every 4 weeks
R2 A
21 49 77 105 133
Days after Start of 13-cis RA
R2B
ACTIVATED
21 49 77 105 133
AldesleukinAldesleukin (IL(IL--2) Treatment: R2 B2) Treatment: R2 B
Aldesleukin (IL-2) SC6 MIU/m2/day x 5 Days
every 4 weeks
A B C B A B C B Course
Change and activation of R2 (ch14.18/CHO ± aldesleukin (IL-2) s.c.
(Amendment 2009 July)
SIOPEN HR-NBL1 trial
Start of Study: activated 02/2002, inclusion of Belgian
patients: 05/2002
•R2: maintenance phase:
RA with or without antiGD2 antibodies (12/2006)
amended to RA and antiGD2 (/2011) with or without
SC-IL2 SC
stop 8/2013 inclusion of number of randomised pts
reached: pts receive antiGD2
• R3:induction: rapid Cojec versus modified N7
04/2014: late start in Belgium for insurance reasons
(Cave: patients with MNA + NB INSS stage 2 and 3 of any age should be
enrolled in trial but are not eligible for R3 (rapid COJEC)
•R4: LTI antiGD2 with or without SC IL adapted regimen
HR-NBL1/SIOPEN R2 EARLY RESULTS: Toxicities Grade 3 & 4 Odds Ratios
0,125 0,25 0,5 1 2 4 8
General Condition
Haemoglobin
WBC
Granulocytes
Platelets
Infection
Fever
Stomatitis
Nausea/Vomiting
Diarrhoea
Skin
Allergy
Cardiac_func
Echo LV/SV
Hypotension
Creatinin
Central neuro
Periph. neuro
Bilirubin
SGOT/SGPT
Odds ratioAntiGD2 alone
worse
AntiGD2+IL2
worse
SIOPEN HR-NBL1 trial
Results R2: ? AntiGD2 +/- SC IL-2
Recommendations: DMC
Number of patients reached
In attendance of results: no SC IL2 (more toxicity)
SIOPEN HR-NBL1 trial
HR-NBL1/SIOPEN
Early Results on R2 Immunotherapy
Feasibility
AntiGD2 only AntiGD2 + IL2n % n %
All cyles completed 142 84% 89 51%Incomplete data /cycle 15 9% 29 17%Interrupted cyles 2 1% 19 11%No IL2 0% 2 1%Stopped cyles 11 6% 34 20%Evaluable 170 100% 173 100%Incompletely reported 30 33
HR-NBL1/SIOPEN Early R2 Global Results on Primary Endpoint EFS
include CR and < CR patients prior to R2 inclusion
Patients Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
AntiGD2 191 64 0.68±0.04 0.60±0.04 0.57±0.04 0.449
AntiGD2+IL2 195 71 0.69±0.04 0.58±0.04 0.54±0.04
HR-NBL1/SIOPEN Early R2 Results by Response prior to
Immunotherapy
Pts. Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
AntiGD2 87 24 0.75±0.05 0.67±0.06 0.64±0.06 0.567
AntiGD2+IL2 98 30 0.71±0.05 0.63±0.06 0.63±0.06 .
Pts. Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
75 28 0.63±0.06 0.56±0.07 0.52±0.07 0.905
72 28 0.75±0.05 0.58±0.07 0.48±0.08 .
PRE-MRD: CR PRE-MRD: VGPR/PR
HR-NBL1/SIOPEN Hypothesis: If there was manageable toxicity ?
A view on patients having completed all immunotherapy cycles
Patients Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
AntiGD2 132 37 0.72±0.04 0.63±0.05 0.63±0.05 0.076
AntiGD2+IL2 84 15 0.80±0.05 0.78±0.05 0.78±0.05
HR-NBL1/SIOPEN Hypothesis: If there was manageable toxicity ?
A view on patients having completed all IT cycles
Pts. Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
AntiGD2 71 16 0.76±0.06 0.69±0.07 0.69±0.07 0.433
AntiGD2+IL2 42 7 0.81±0.06 0.81±0.06 0.81±0.06 .
Pts. Events 1-yrs. pEFS 2-yrs. pEFS 3-yrs. pEFS p-value
53 18 0.68±0.07 0.57±0.08 0.57±0.08 0.162
39 8 0.77±0.08 0.72±0.09 0.72±0.09 .
PRE-IT: CR PRE-IT:VGPR/PR
Summary
HR-NBl1/SIOPEN 2014
R1 Results maintained at 5 yr EFS
Early ch14.18/CHO R2 Results:o The 2 years EFS rates appear comparable to 2 year NEJM 2010 results
o The primary endpoint on EFS shows no benefit for s.c. IL2 under the chosen schedule
o Major toxicities in the IL2 arm prevent full delivery of immunotherapy (interruptions a/o stop of further ch14.18/CHO cycles)
o Pain control requires high dose morphine in the 8h ch14.18/CHO setting
o A less toxic treatment schedule is needed for this late treatment phase , ideally allowing outpatient treatment
Future plan based on SIOPEN – LTI experience (Lode/Ladenstein): Switch to a long term infusion schedule and reduce dose of Il2
1 of
next
cycle
.
291 5 8 2218Day
1 of
next
cycle
Day
Continuous Infusion of ch14.18/CHO
Continuous Infusion of ch14.18/CHO with IL-2
291 5 8 2218
= ch14.18/CHO: 10mg / m ²/ day / continuous i.v. infusion
= Isotretinoin (13-cis-RA) 160 mg / m² / day b.i.d
= s.c. IL2 3 x 106 lU/m²/day (days 1-5 and 9, 11, 13, 15, and 17)
R415
15
19
1936=
36=
10 days ctn GD2 inf.
10 days ctn GD2 inf.
14 days 13-cis RA oral
14 days 13-cis RA oral
s.c.IL2 50% dose reduction: week 1=5 days / week 2 & 3:every other day starting day2
36
•To test the hypothesis that the modified N7 induction regimen will
improve the metastatic response rates or event free survival (EFS)
as compared to Rapid COJEC (R3 randomisation).
•To test the hypothesis that the addition of subcutaneous aldesleukin
(IL-2, (Proleukin®)) to immunotherapy with chimeric 14.18 anti-GD2
monoclonal antibody produced in Chinese hamster ovary (CHO)
cells (ch14.18/CHO) given as continuous infusion in addition to
differentiation therapy with isotretinoin (13-cis-RA) following
myeloablative therapy (MAT) and autologous SCR, will improve EFS
in patients with high-risk neuroblastoma (stage 4 disease or stages
2 and 3 with MYCN amplification, all over the age of one, or infants
with MYCN amplification) (R4 randomisation).
HR-NBL1-7
Amendment 1
11/2005:
R0 was closed
The time to randomise for R1 was altered from previously 120 days (from
the first day of chemotherapy) to 150 days
Amendment 2
04/2006:
Inclusion of infants with MYCN amplification
The time to randomise for R1 was extended to 210 days but only for
patients having received 2 cycles of additional TVD for insufficient
response and meeting the R1 response criteria after 2 TVD courses.
11/2006:
Activation of R2 with the use of antibody ch14.18/CHO--
Amendment 3
10/2007:
Change from oral to intravenous Busulfan (Busilvex); for R1 randomised
patients Busilvex is free of charge (Please note: Infants were not eligible
for R1, but received BUMEL. Busilvex was not free of charge for
infants.)
Amendment 4
07/2009:
Change in the R2 randomisation, new R2 randomisation therapy:
Arm A: 13-cis RA + ch14.18/CHO
Arm B: 13-cis RA + ch14.18/CHO + aldesleukin (IL-2) s.c.
To be eligible for R2 patients were allowed to receive elective MAT or
either BUMEL or CEM (with minor adjustments), so long as the time
from first induction chemotherapy to PBSCR date was less than 9
months.
Amendment 5
06/2011
Activation of R3: randomisation of two different induction treatments:
- Rapid COJEC
- Modified N7
Patients with MYCN-amplified localised disease are not eligible for R3
randomisation and will receive Rapid COJEC induction.
Recommendation that all patients receive BuMel MAT. Even patients presenting
at diagnosis with a large abdominal or large pulmonary primary. However,
careful planning of the radiotherapy fields and dose is needed with
consideration given to response, local status after surgery to the primary tumour
and neighbouring organs. This should be discussed with the current
Radiotherapy Panel.
Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no
MYCN amplification and without segmental chromosomal alterations (SCA) are
not eligible for MAT. These patients are thought to have a good prognosis and
will stop treatment after induction therapy and surgery to the primary tumour.
With the closure of the R1 randomisation, Busilvex is no longer supplied free of
charge.
Amendment 6
08/2013
Amendment 6
08/2013
Suspension of R2 randomisation
The R2 randomization between Anti-GD2 antibody vs. Anti-GD2 antibody +
IL-2 reached the desired accrual of 400 patients. The DMC was informed in
August 2013 as well as the Ethical Committee at the Coordinating Sponsor
site in Austria, Vienna. At the last analysis follow up information was
available in 328 patients. The DMC recommended suspending the
randomization until the data is more complete, and it can be decided
whether to close this randomization. The DMC has taken in the interim the
position to recommend assigning patients to the “control” arm of Anti-GD2
antibody alone due to
Amendment 7
04/2014
Activation of R4 randomisation
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/m² to 10 days of continuous infusion
in relapsed /refractory patients. Hence the HRNBL1 (1.5)/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 (1.5)/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.
Study period 02/02/2002 - 09/2016
Five years of patient follow up
Current recruitment
16.09.2013
Total registered patients
R0
R1
R2
R3 2239
Closed with 239 patients (November 2005)
closed with 598 patients (October 2010)
closed with 410 patients (August 2013)
SIOPEN HR-NBL1 trialBelgium
Outcome: 75 pts
Dead: 30, 29 dead of disease, 1 of toxicity: Lung VOD
Alive: 41; 37 OK, 4 with relapse/progression
No info: 4
SAEs:
Renal insufficiency
VOD
Relapse
Lungoedema
Pumponarys symptoms
Lymph leakage
Tumour rupture
Infection
Cerebral haemorrghage
Hypercalcemia
Summary & Conclusion
HR-NBL1/SIOPEN 2014o 5-yr EFS: Stages 2&3 MycNA (64%) > stage 4 (29%)o Age is a major factor ( < 1.5 yr / 1.5- 5 yr / > 5 yr)o Higher rate of MycNA in younger stage 4 pts (excl. infants) o Very favorable group MycN non amplified 12 to 18 moo Better response rates at younger age and in MycN amplified pts
R0: G-CSF during induction significantly reduces toxicity
R1: BUMEL is superior to CEM in high risk NBLo 5yr EFS: BUMEL (45%) vs CEM (31%)o Effect of BUMEL strongest in patients with residual diseaseo BUMEL equally effective in stage 4 and localized stage 2&3o Superiority of BUMEL regimen based on lower relapse rateo VOD rate acceptable (11- 16% grade 2; 4% grade 3 Bearman)o BUMEL significantly lower toxicity profile
Specialitycommittees HR
Strategy
New drugs ITCC/NDDS
BiologyImaging
Bone marrow
SIOPEN
Strategy
Prognostic factors
at diagnosis
at the end of induction
• Strategy
• Labs
• Samples
• Network
Perspectives
Still a lot of work to do
• Different kinds of failure : different solutions
Tools to define UHR patients
New drugs
New biomarkers
Personalized strategies
HR-NBL2
Explore data HR-NBL1
New questions in HR-NBL2, 2016
Questions on Induction, Surgery, HSCT, RT, MRD
Induction: Definition of ultra-high risk group? Impact
of ALK status, anti-GD2 as frontline?
High-riskgroups; do different methods identify same
patients?(RT-PCR, MIBG, Molecular)
Surgery: extent of surgery is important, local relapse
rate?
HR-NBL1/SIOPEN
Stage 4, Age and MycN-Amplification
115
450
697
4
57
654
22844
15
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1-1.5 yrs 1.5-5 yrs 5-10 yrs 10-14 yrs >14 yrs
Age
not amplified amplified
66%
41%
23%
14%21%
p<0.001
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5uid _R2_ compl
eteIL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2
15 incomplete /191 ptsES-0271-PA 0 -1 1 1 -1 -1 -1ES-0289-MN 0 -1 1 1 1 -1 -1FR-0503-TRA-DA 0 -1 1 1 1 1 -1FR-0527-LA 0 -1 -1 1 1 1 0FR-0600-MJ 0 -1 1 -1 -1 -1 -1FR-0630-LM 0 -1 1 1 1 -1 -1FR-0632-BH 0 -1 -1 -1 -1 -1 -1IL-0123-HJ 0 -1 1 1 -1 -1 -1IT-0381-MEC-YA 0 -1 -1 1 1 -1 -1IT-0457-BUL-OS 0 -1 1 0 1 1 -1IT-0505-PS 0 -1 -1 -1 -1 -1 -1IT-0542-NS 0 -1 -1 -1 -1 -1 -1IT-0565-BH 0 -1 1 1 -1 -1 -1IT-0566-LM 0 -1 1 -1 -1 -1 -1UK-0424-DG 0 -1 1 1 -1 -1 -1
2 interruped /191 ptsIT-0523-MG 0 0 1 0 1 1 1UK-0303-B-C 0 0 1 0 0 0 1
11 stopped /191ptsBE-0095-RY 0 0 1 1 1 1 0ES-0296-LI 0 0 1 1 1 1 0FR-0466-GAZ-LO 0 0 1 0 0 0 0FR-0529-EB 0 0 1 0 1 1 0FR-0565-BS 0 0 0 0 0 0 0IT-0655-LD 0 0 1 1 0 0 0UK-0250-ATA-SO 0 0 1 0 0 0 0UK-0302-MCK-KA 0 0 1 1 0 0 0UK-0386-MO 0 0 1 0 0 0 0UK-0390-WJ 0 0 1 1 0 0 0UK-0423-WR 0 0 1 1 0 0 0
HR-NBL1/SIOPEN: AntiGD2 alone
Green: done Grey: missingYellow: not given
HR-NBL1/SIOPENAntiGD2+ s.c. IL2: 19 pts interrupted cycles - mainly IL2!
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5uid IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2
AT-0077-AL 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1FR-0472-BEL-AY 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1FR-0473-BES-AN 1 1 1 0 0 1 1 1 1 1 1 1 1 1 1FR-0482-HER-CA 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1FR-0516-VT 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1IL-0112-GY 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1IT-0420-DE -GI 1 1 1 1 1 1 0 0 1 0 0 1 0 1 1IT-0428-BOZ-AL 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1IT-0429-BUT-FR 1 1 1 0 1 1 0 1 1 0 1 1 0 1 1IT-0524-CL 1 0 1 0 0 1 1 0 1 0 1 1 0 1 1IT-0570-CI 1 1 1 1 0 1 1 0 1 1 1 1 1 0 1UK-0251-AND-LO 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1UK-0270-FAR-IS 1 0 0 1 1 1 1 1 1 1 1 1 1 1 1UK-0327-AHM-ZA 1 1 1 0 0 1 1 1 1 1 1 1 1 1 1UK-0370-LOT-RI 1 1 1 1 1 1 1 0 1 1 0 1 1 0 1UK-0417-WC 1 1 1 1 1 1 1 0 1 1 0 1 1 0 1UK-0439-HJ 1 1 1 0 0 0 1 1 1 1 1 1 1 1 1UK-0449-HH 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1UK-0460-ES 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1
Green: done Grey: missingYellow: not given
HR-NBL1/SIOPEN:
AntiGD2+IL2: 34 pts stopped IT therapyCycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
uid _R2_ complete
IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2 IL2 IL2 GD2
AT-0069-UHL-DA 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0AT-0080-RR 1 0 1 0 1 1 1 1 1 1 1 1 0 0 0 0 0AU-0003-BON-NA 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0AU-0004-FOT-PE 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0BE-0071-VAN-SA 1 0 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0FR-0408-MES-AB 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0FR-0409-SAI-CY 1 0 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0FR-0441-ROM-HU 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0FR-0457-CAC-TH 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0FR-0470-ET-BR 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0FR-0579-SE 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0FR-0585-DN 1 0 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0FR-0602-CD 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0FR-0634-SS 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0FR-0643-PN 1 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0IL-0101-ZM 1 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0IL-0109-LI 1 0 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0IL-0113-CN 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0IL-0118-RY 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0IT-0592-RF 1 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0UK-0290-FUR-MA 1 0 1 1 1 1 1 1 1 1 0 1 1 0 1 0 0UK-0348-CLI-SA 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0UK-0366-WEB-RH 1 0 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0UK-0375-HUD-TH 1 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0UK-0396-LM 1 0 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0UK-0400-NK 1 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0
3 stopped GD2FR-0414-PET-CH 1 0 1 0 1 1 0 1 1 1 1 1 1 0 1 1 0UK-0352-DUF-LA 1 0 1 1 1 1 1 1 1 1 0 1 1 0 1 1 0UK-0356-CYG-TO 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0
5 stopped IL2ES-0226-CHA-ER 1 0 1 0 1 1 0 1 1 0 1 0 0 1 0 0 1FR-0507-IAC-HO 1 0 1 1 1 1 0 1 0 0 1 0 0 1 0 0 1UK-0415-NU 1 0 1 1 1 0 0 1 0 0 1 0 0 1 0 0 1UK-0430-AK 1 0 1 1 1 1 1 1 0 0 0 0 0 1 0 0 1FR-0474-BON-AD 1 0 1 1 1 1 1 1 1 0 0 1 1 1 0 0 1
COG ANBL0032: phase II trial design
for high risk neuroblastoma
(Yu et al, N Engl J Med. 2010; 363(14): 1324–1334)
Alice YU, et al NEJM (2010)
High Risk Patients: CR at Randomisation to Immunetherapy
2yr EFS
HRNBL1/SIOPEN: CR prior to R2
Ch14.18/CHO + s.c. IL2 + 13 cis RA 63%
Ch14.18/CHO +13 cis RA 67%
NEJM 2010, Alice Yu, et al
Ch14.18+iv IL2+GM-CSF + cis RA 66%
cis RA alone 46%
Simon T, et al.; JCO 2004; 22:3549 Simon T, et al.; BMC Cancer 2011; 11:21.
GPOH: Role of ch14.18 alone in neuroblastomaImpact of observation time (non – randomised)
NS S
GPOH: Role of ch14.18 alone in neuroblastoma
Impact of observation time (non – randomised)
Prof. Dr. med. Lode
Median observation time: 11.11 y
9y EFS 9y OS
MAB ch14.18 41 ± 4% 46 ± 4%
NB90 MT 31 ± 5% 34 ± 5% p = 0.026
no consolidation 32 ± 6% 35 ± 6% p = 0.019
Simon T, et al.; JCO 2004; 22:3549. Simon T, et al.; BMC Cancer 2011; 11:21.
Patients Events 5-yrs. pEFS p-value
BUMEL 1107 531 0.41±0.02 0.001
CEM 333 220 0.32±0.03 .
HR-NBL1/SIOPEN
Total Group: Given MAT Therapy
HR NBL1/SIOPEN
EFS and Surgical Results
PatientsEven
ts 3-yrs. pEFS p-value
Complete excision 373 146 0.53±0.03 0.024
Complete excision - possible microscopic tumour re 357 158 0.47±0.03 .
Macroscopic tumour residue 211 108 0.41±0.04 .
Resection not possible 17 11 0.37±0.12 .
Overall survival Event Free survival
Patients Evaluable* Deaths 5-yrs. pSU p-value** Events 5-yrs. pEFS p-value**
Localised 234 219 59 0.68±0.04 <0.001 66 0.64±0.04 <0.001
Stage 4 2130 1998 974 0.39±0.01 . 1173 0.29±0.01 .
* Patients with information on FU, ** log-rank test
HR-NBL1/SIOPEN
Stage
Overall Survival Event free Survival
SIOPEN HR-NBL1 trial
Patients Events 5-yrs. pEFS p-value
MNA- 998 600 0.27±0.02 0.253/0.142
MNA+ 723 434 0.31±0.02 .
HR-NBL1/SIOPEN
Stage 4, MycN-Amplification and EFS
HR-NBL1/SIOPEN
Stage 4, Age and EFS
Patients Events 5-yrs. pEFS p-value
<1 year (NMA+ only) 78 39 0.43±0.06 0.009
1-1.5 yrs 193 97 0.41±0.04
1.5-5 yrs 1301 746 0.31±0.02 .
5-10 yrs 345 236 0.16±0.02 .
10-14 yrs 59 38 0.17±0.07 .
>14 yrs 22 17 0.06±0.06 .
HR-NBL1/SIOPEN
Stage 4, No MycN Amplification, Age and EFS
Patients Events 5-yrs. pEFS p-value
1-1.5 yrs 57 14 0.72±0.06 0.000
1.5-5 yrs 654 385 0.29±0.02 .
5-10 yrs 228 159 0.16±0.03 .
10-14 yrs 44 30 0.15±0.07 .
>14 yrs 15 12 0.08±0.08 .
Patients Events 5-yrs. pEFS p-value
LN only 26 9 0.59±0.11 0.014
LN+others 810 496 0.27±0.02 .
Others only 741 455 0.30±0.02 .
HR-NBL1/SIOPEN
VGPR/PR: Given MAT Arm
HR-NBL1/SIOPEN
Stage 4 Distant Lymph Nodes only
RR xx
R1 R2
BuMel
CEM
INDUCTION: INDUCTION: Rapid COJEC MGT/PBSCMGT/PBSC
Sx
harvest
PBSC
CBDCA 750 mg/m²
A VP16 175 mg/m²
VCR 1.5 mg/m²
CBDCA
4x ctn iv 425mg/m²
VP16
4x ctn iv338mg/m²
L -PAM
3x short iv 70mg/m²
Staging local MRI / CT /US, mIBG, BM(aspirate/biopsy)
CYC 1050 mg/m²
CC VP16 175 mg/m²
VCR 1.5 mg/m²
CDDP 80 mg/m²
BB VCR 1.5 mg/m²
G - CSF
Neupogen ® 5µg/kg
G - CSFI.V. BU *
L -PAM
140mg/m²/d short i.v.
Day 0 10 20 30 40 50 60 70 90 95 1 50 / 2xTVD:210
A B C B A B C B Course
0 28 56 84 112 140
21 49 77 105 133
MRD TreatmentMRD Treatment
13 cis retinoic acid po
160mg/m2/day x 14 days
every 4 weeks
Days after Start of 13 cis RA
Ch 14.18 anti GD2 AB iv
20mg/m²/day x 5 days
every 4 weeks
R2B
ACTIVATED
R2A
CBDCA
VP16
VCR
CDDP
CYC
G - CSF
G -CSF
G - CSF
G - CSF
G - CSF
local MRI / CT and mIBG post surgery
21G
y21
Gy
BM aspirates only / local ultrasound
G - CSF
2xTVD
RR xx
R1 R2
BuMel
CEM
INDUCTION: INDUCTION: Rapid COJEC MAT/PBSCMAT/PBSC
Sx
harvest
PBSC
CBDCA 750 mg/m²
A VP16 175 mg/m²
VCR 1.5 mg/m²
CBDCA
4x ctn iv 425mg/m²
VP16
4x ctn iv338mg/m²
L -PAM
3x short iv 70mg/m²
Staging local MRI / CT /US, mIBG, BM(aspirate/biopsy)
CYC 1050 mg/m²
CC VP16 175 mg/m²
VCR 1.5 mg/m²
CDDP 80 mg/m²
BB VCR 1.5 mg/m²
G - CSF
Neupogen ® 5µg/kg
G - CSFI.V. BU*
L -PAM
140mg/m²/d short i.v.
Day 0 10 20 30 40 50 60 70 90 95 150 / 2xTVD:210
CBDCA
VP16
VCR
CDDP
CYC
G - CSF
G -CSF
G - CSF
G - CSF
G - CSF
local MRI / CT and mIBG post surgery
21G
y21
Gy
BM aspirates only / local ultrasound
G - CSF
2xTVD
0 28 56 84 112 140
13-cis retinoic acid PO
160mg/m2/day x 14 days
every 4 weeks
Ch14.18/CHO IV
20mg/m²/day x 5 days
every 4 weeks
R2 A
21 49 77 105 133
Days after Start of 13-cis RA
R2B
ACTIVATED
21 49 77 105 133
AldesleukinAldesleukin (IL(IL--2) Treatment: R2 B2) Treatment: R2 B
Aldesleukin (IL-2) SC6 MIU/m2/day x 5 Days
every 4 weeks
A B C B A B C B Course
Change and activation of R2 (ch14.18/CHO ± aldesleukin (IL-2) s.c.
(Amendment 2009 July)
Sx
DE
RE
Surgery
Irradiation
Diagnostic evaluation
Response evaluation
DE
• BM (ICH, AIPF, RT-PCR)
• Genomic profile: MLPA / a-CGH /Gent-GS• Blood (GD2, RT-PCR)
• Skeleton mIBG, PET
• Primary Site MRI , PET
Diagnostic evaluation
RE Response evaluation
•BM (ICH, AIPF,
RT-PCR /Gent GS)•TP: 1, 2(3), 6, 7, 8
• Blood (GD2, RT-PCR)•TP: 1, 2 (3), 5/6, 7, 8
• Skeleton mIBG, PET*•TP: 1/*, 2 (3)/*, 4, 5/*, 6, 8 mIBG
• Primary Site MRI , PET* •TP MRI: 2 (3)/* , 4, 5, 8
•TP PET: 2 (3) /* , 4, 5, 8
PD & NR: off study
< metast.
CR
Rapid COJEC
HD
-CA
V
HD
-CA
V
CD
PP
-VP
16
HD
-CA
V
CD
PP
-VP
16
R3
RE 2 RE 3RE 1
CR (metast! )
R2
Ch14.18/CHO + IL2 s.c.
+ 13 cis RA
CR, VGPR,
PR (metast.)
X< PR* (metast.)
BUXMEL
SCT
RE 4 RE6 RE 7
End of
treatment
After
3 cycles
RE 5 DE
( Sx ) ( Sx )Sx
105 – 120(150) days 60 days 60-90 days 140 days
9-11 months (?)
RE 8
TV
D
TV
D
Phase II
PBSC
H1
PBSC
H2
PI: A. GARAVENTA PI: R.LADENSTEIN
if Sx
Ch14.18/CHO +
13-cisRA
HDT Phase MRD Phase
INDUCTION Phase
HR-NBL 1 (Amendmend
5)/SIOPEN
SIOPEN phase I/II LTI ch 14-18 protocol