Defining and Prioritising Novel Targets and Strategies
for Poor Prognosis - High Risk Paediatric Tumours
Neuroblastoma
Andrew DJ Pearson
SIOP 2012 - London: Paediatric Oncology Education Day
5th October 2012
Overview
Defining & Prioritising Novel Targets and Strategies for Poor Prognosis
High Risk Paediatric Tumours
• Neuroblastoma
• The way forward - Paradigm shift-biological, hypothesis driven clinical trials





Selection of agents
Pre-clinical evaluation
Incorporation of biomarkers and selection of patients
Paediatric Drug Development Networks
Interaction academia, pharma, regulators and parents
 Novel trial design and integration Phase I – Frontline Future
Childhood Cancer
6
4
3
2
1
Year
Childhood Cancer Mortality
2005
2003
2001
1999
1997
1995
1993
1991
1989
1987
1985
1983
1981
1979
1977
0
1975
Mortality (per 100,000)
5
 In the past, improvement in survival due
to international, multidisciplinary trials
 Plateau in improvement in survival
 High risk groups remain poor prognosis
with very toxic therapy
 Rising cost of cure
 Need for introduction of agents
targeting molecular drivers
 Introduction of new drugs into the clinic
in the past has been slow, need to
accelerate drug development
Future
Faster and more efficient drug
development
Neuroblastoma
• Commonest solid tumour & variable
behaviour
• 50% present with high-risk disease (i.e.
the tumour has spread or there is genetic
evidence [MYCN amplification] that the
tumour will behave aggressively)
• Majority of patients with high-risk
neuroblastoma relapse following
treatment and die
• Neuroblastoma is a major cause of death
from cancer
100
Percentage surviving
Neuroblastoma
Neuroblastoma, age 1-14, stage 4, 1990-2005
Dec 2002 onwards
Apr 1999 - Nov 2002
Oct 1990 - Mar 1999
80
60
40
20
0
0
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 17 18
Years since diagnosis
Survival of children with Stage 4 neuroblastoma
Recent New Agents in Therapy
•
•
•
•
Topotecan
Irinotecan
Temozolomide
Anti GD2+IL2+GMCSF
Molecularly Targeted Therapy has not been introduced into frontline care of children with neuroblastoma - Paradigm
Why is Paediatric Drug Development Slow?
• Limited availability of agents for paediatric investigation
• Rare conditions that require international clinical trials
• Early clinical trials have not tested robust biological hypotheses (lack of
incorporation of biomarkers)
• Insufficient pre-clinical testing and integration of cancer biology
Overview
Defining & Prioritising Novel Targets and Strategies for Poor Prognosis
- High Risk Paediatric Tumours
• Neuroblastoma
 The way forward - Paradigm shift-biological, hypothesis driven clinical trials






Selection of agents
Pre-clinical evaluation
Incorporation of biomarkers and selection of patients
Paediatric Drug Development Networks
Interaction academia, pharma, regulators and parents
Novel trial design and integration Phase I – Frontline
• Future
Molecularly Targeted Therapeutics
Based on the understanding what drives the cancer cell
• Drugs that target the specific molecules that are
required for the growth of cancer tissue - not
present in normal tissue
• Ideally “reduced” toxicity
• Adult Targets





Glivec
– in chronic myeloid leukaemia –
2001
Lung Cancer – EGFR, EML4-ALK
GIST – c-KIT
Melanoma – BRAF V600E
Breast + Ovarian – BRACA1/2
Breast Cancer - HER2
• Used in conjunction with predictive biomarkers
- What is the best drug for an individual
patient?
The Changing Focus of Adult Anticancer Drug Development
Yap et al, Nature Reviews Cancer 2010
Phase I Development
Optimal Development of Molecularly Targeted Drugs
We want to follow the successes of adult drug development (Glivec)
• Selection based on: Biology and Molecular Pathology
 Efficacy in pre-clinical models including genetically engineered murine models
(GEMM)
 Compound availability, acknowledging high attrition rates
• Evaluation in hypothesis-driven early clinical trials employing predictive
and pharmacodynamic biomarkers
• Novel trial design and international networks
• Introduction into frontline trials through a personalised molecular
medicine approach
“From the bench to bedside and back again”
Neuroblastoma Targets
Focus on the identified molecular abnormalities that initiate and
maintain neuroblastoma
Themes
• MYCN - 20-25% amplification + 60%
protein expression
• Anaplastic lymphoma kinase (ALK) 10% mutations + 4% amplification
• p53 mutations - 2% + 15% at relapse
• MAPK/RAS/RAF pathway- 3%
• ATRX - 22%
Targeting MYCN
 Direct
 Oncoprotein stability
 Through synthetic lethal interactions by
drugging genes that modulate critical
functions of MYCN – Chk1
Anaplastic lymphoma kinase (ALK)
• Angiogenesis
• MDM2-p53 antagonists
• MAPK - RAS - RAF Pathway
Neuroblastoma: Hypothesis - Therapies targeting MYCN protein stability will
display enhanced efficacy in patients with MYCN driven neuroblastoma tumours
IGF-1R
DALO
Functional Imaging
GDC0941
GSK-’436
Vemurafenib
PI3K
Ras/Raf
AKT
BEZ235
GDC0980
mTOR
RIDA
AZD8055
GSK-’212
MEK/ERK
AT9283
CCT137690
AurK
Chesler et al. Cancer Res 2006, ANR2010, AACR2010 AACR2011, Mol Cancer Ther 2011, ANR2012, CCR2012, Cancer Cell 2012
Neuroblastoma
Hypothesis - Therapies targeting ALK will display enhanced efficacy in
patients with ALK mutated or amplified neuroblastomas
Kaplan-Meier and long rank analysis of ALK-mutated and ALKamplified tumours – F1174 mutated versus wild-type cases
• Mutations of ALK gene in 10% of neuroblastomas - F1174 & R1275
• F1174 mutation - 58.8% have MYCN amplification
Strategies
1. Direct inhibitors – crizotinib
2. Combination approach
3. Novel compounds
Brouwer et al, Clin Cancer Res 2010;16:4353-4362
Targeting ALK – Combination Approach
Teeara Berry, Louis Chesler, Rani George, Cancer Cell 2012
Incorporation of Biomarkers
Predictive - What is the best drug
for an individual patient?
Vemurafenib
MK2206
Pharmacodynamic: is the drug
working in the way we expected?
MK2206
MK2206
Yap et al, Nature Rev Cancer 2010; Yap , JCO 2011; Garrido-Laguna Nat Rev Clin Onc 2011
Predictive Biomarkers - patient selection and
pharmacodynamic biomarkers
Repeat tumour biopsies in children are problematic
Source of Tumour Cells for
Biomarker Studies
• Bone marrow
• Circulating Tumour Cells
Functional Imaging: DCE MRI angiogenesis
AUC (left) and ADC (right) maps
Ganglioneuroblastoma (7 years old)
Implemented in the Beacon – Neuroblastoma
Trial
Glioblastoma (10 years old)
Miyazaki, et al. ISMRM 2011
Overview
Defining & Prioritising Novel Targets and Strategies for Poor Prognosis
- High Risk Paediatric Tumours
• Neuroblastoma
• The way forward - Paradigm shift-biological, hypothesis driven clinical trials
 Selection of agents
 Pre-clinical evaluation
 Incorporation of biomarkers and selection of patients
 Paediatric Drug Development Networks
 Interaction academia, pharma, regulators and parents
 Novel trial design and integration Phase I – Frontline
• Future
BEACON-Neuroblastoma
Phase II, two hypotheses, randomised, open label, 4-arm factorial trial to be run in
SIOPEN/ITCC centres
Biomarker rich - DCE MRI, Circulating TH, PHOX2B, DCX mRNA, angiogenesis related
biomarkers, tumour profiling, PK
Novel statistical design
BEVACIZUMAB
RANDOMISATION
Relapsed/
Refractory
Neuroblastoma
fulfils eligibility
criteria
BACKBONE
RANDOMISATION
Temozolomide
Temozolomide +
Bevacizumab
Temozolomide +
Irinotecan
Temozolomide +
Irinotecan +
Bevacizumab
International Phase II Strategy
“Drop the Loser” – Octopus
versus
versus
Backbone + PI3K
inhibitor
Backbone + IGF-1R
Backbone
(to be decided from
randomized Phase IIb)
versus
versus
Backbone + Aurora
inhibitor
Backbone +
MEK/ALK
Integration Phase I – Frontline
ITCC –SIOPEN New Drug Development Strategy
Personalised therapy with molecular targeted drugs and
immunotherapeutics
Phase I
Phase II
Novel agents progress
Relapse/Non-responder
Frontline studies
Patients selected for novel agents based on predictive biomarkers
Frontline studies stratified by molecular characteristics
Phase I Development
Optimal Development of Molecularly Targeted Drugs
• Selection based on: Biology and Molecular Pathology
 Efficacy in pre-clinical models including genetically engineered murine models
(GEMM)
 Compound availability, acknowledging high attrition rates
• Evaluation in hypothesis-driven early clinical trials employing predictive
and pharmacodynamic biomarkers
• Novel trial design and international networks
• Introduction into frontline trials through a personalised molecular
medicine approach
“From the bench to bedside and back again”
Accelerating Drug Development in Neuroblastoma
Future
•
•
•
•
Must utilise maximally knowledge of biology – challenges
Reduce attrition through pre-clinical models
Hypothesis driven, biomarker rich clinical trials
International Phase II with novel statistical design
Acknowledgements
• Peppy Brock – President
• Dominique Valteau-Couanet - INRC
• The Royal Marsden Hospital – Paediatric
Drug Development Team
Lynley Marshall, Lucas Moreno, Giuseppe Barone,
Susanne Gatz, Dominik Schrey, Andrea Boast, Gill
James, Tracey Crowe & Research Nurse Team
• The Institute of Cancer Research
• G Vassal - Chair
• B Geoerger - Clinical Trial Committee
• H Caron - Biology Committee
• R Riccardi - Training & Education Committee
• B Morland - Accreditation & Quality
Committee
 Louis Chesler (Neuroblastoma Drug Development
Team)
 Michelle Garrett (Clinical PD Biomarker Group)
 Simon Robinson (Pre-clinical Imaging Team)
• University of Birmingham CRCTU
• Cancer Research UK Drug Development
Office