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?