Innovative therapies, new agents and targeted

advertisement
Perspectives from a
Clinical Investigator
Dr Darren Hargrave
Consultant Paediatric Oncologist in
Neuro-oncology & Experimental Therapeutics
Outline
• Current paediatric unmet needs.
• Role of paediatric cancer networks & experts.
• Rational biology-driven paediatric cancer drug
development, preclinical models.
• Existing Initiatives.
• What can the clinical investigators offer?
• What do the clinical investigators need?
• What are the struggles and challenges?
PAEDIATRIC ONCOLOGY
UNMET NEEDS
Figure 2.1: Average annual number of deaths in children previously
diagnosed with cancer 0-14 years, GB, 1996-2005
Brain & CNS tumours 32%
Leukaemias 30%
SNS tumours 11%
Soft tissue sarcomas 9%
Lymphomas 5%
Bone tumours 5%
Renal tumours 4%
Hepatic tumours 1%
Gonadal & germ cell tumours 1%
Carcinomas & Melanomas 1%
Retinoblastomas 1%
Other & unspecified cancers
0
20
40
60
Average number of cases per year
80
100
120
Why do we need new therapies?
Survival
Quality
of Life
Decreasing the Burden of Rx!
•
•
•
•
•
Radiotherapy
Secondary malignancies
Cardiac impairment- anthracyclines
Renal impairment- platinums/ ifosfamide
Fertility
PAEDIATRIC ONCOLOGY
ROLE OF NETWORKS & EXPERTS
Role of Networks & Experts
• They treat the children!
– Know current therapies & outcomes
– Know where the real unmet needs are
– Best placed to prioritise
– Established national & international collaborations
– Understand treating children
• Links with tumours specific biology
– Access to tumours samples
– Accurate preclinical models
PAEDIATRIC ONCOLOGY
RATIONAL BIOLOGY-DRIVEN DRUG
DEVELOPMENT, PRECLINICAL MODELS
Changing Oncology Pipeline
Aim: to decode the genomes of more than 600 childhood cancer
patients, who have contributed tumor samples for this historic effort.
High Grade Glioma of brain & brainstem
GBM Genome?- 2008
CCLG CNS Division Annual Meeting
Nat Rev Clin Oncol. 2012 May 29;9(7):400-13
MICROARRAY STRATEGY
WHOLE GENOME
GENE SELECTION
GENE VALIDATION
BIOMARKER DEVELOPMENT
Paediatric & TYA HGG
Darren Hargrave
05/10/2012
Paediatric & TYA HGG
Darren Hargrave
05/10/2012
Medulloblastoma
Sonic Hedgehog Pathway
(Shh)
Pediatric tumors
•Constitutive activation (mutations) in:
•Gorlin Syndrome
•Medulloblastoma (MB)
•Basal cell carcinoma (BCC)
•Rhabdomyosarcoma
Cancer Cell. 6: 229-240, 2004.
• HhAntag691 (Curis/Genentech)
• Blocks SMO function (10x cyclopamine)
• Blood-brain penetration
• Assessment using PTCH (+/-) mouse MB model
Cancer Cell. 6: 229-240, 2004.
Toxicity
PAEDIATRIC ONCOLOGY
EXISTING INITIATIVES
USA: CTEP/PPTP Scheme
Stage 1
Efficacy testing at MTD
Test across entire panel
Stage 2
PPTP
Dose-response
PK/PD (target modulation)
Combinations
ITCC Clinical Trial Committee
42 accredited clinical and research Institutions over Europe.
North American Groups
• COG Phase I network
• Pediatric Brain Tumor Consortium (PBTC)
• New Approaches To Neuroblastoma Therapy
(NANT)
• Therapeutic Advances in Childhood Leukaemia
(TACL)
• Pediatric Oncology Experimental Therapeutics
Investigators' Consortium (POETIC)
A Network of Excellence
Structuring clinical research in paediatric
and adolescent oncology in Europe
HEALTH.2010.2.2.1-3
PAEDIATRIC ONCOLOGY
CLINICAL INVESTIGATORS
-CHALLENGES & FUTURE?
Challenges- Clinical Investigators
• Apparent lack of interest for paediatric specific
therapies
• Need to improve paediatric preclinical models
• Development of child appropriate valid
biomarkers
• Child friendly formulations
• Being involved in directing the agenda
• Funding for academic led international studies
• Need to be able to conduct trials of sufficient
quality for drug licensing
Future- Clinical Investigators
• More involvement in setting the unmet needs
and priorities
• Promoting biologically driven therapies
• Promote biomarkers in trials
• Early involvement in discussions with Pharma
and regulators
• Development of practical but valid trial designs
– Model PIPs
– Relevant to current practice and treatments
Questions?
Download