SIOPEN Neuroblastoma trials HR-NBL1€¦ · R2 EARLY RESULTS: Toxicities Grade 3 & 4 Odds Ratios...

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


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


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


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


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-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


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



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


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


21

Gy

21

Gy


G - CSF

2xTVD

0 28 56 84 112 140

13-cis retinoic acid PO


every 4 weeks

Ch14.18/CHO IV


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


Change and activation of R2 (ch14.18/CHO ± aldesleukin (IL-2) s.c.

(Amendment 2009 July)


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


Results R2: ? AntiGD2 +/- SC IL-2

Recommendations: DMC

Number of patients reached

In attendance of results: no SC IL2 (more toxicity)

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 .


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


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 .


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

•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


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


<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


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 .


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



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


Day 0 10 20 30 40 50 60 70 90 95 1 50 / 2xTVD:210


0 28 56 84 112 140

21 49 77 105 133

MRD TreatmentMRD Treatment

13 cis retinoic acid po


every 4 weeks

Days after Start of 13 cis RA

Ch 14.18 anti GD2 AB iv


every 4 weeks

R2B

ACTIVATED

R2A

CBDCA

VP16

VCR

CDDP

CYC

G - CSF

G -CSF

G - CSF

G - CSF

G - CSF


21G

y21

Gy


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



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


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


21G

y21

Gy


G - CSF

2xTVD

0 28 56 84 112 140

13-cis retinoic acid PO


every 4 weeks

Ch14.18/CHO IV


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


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

SIOPEN Neuroblastoma trials HR-NBL1€¦ · R2 EARLY RESULTS: Toxicities Grade 3 & 4 Odds Ratios...

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