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Perspectives from a Clinical Investigator

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.

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Perspectives from a Clinical Investigator

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  1. Perspectives from a Clinical Investigator Dr Darren Hargrave Consultant Paediatric Oncologist in Neuro-oncology & Experimental Therapeutics

  2. 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 strugglesand challenges?

  3. PAEDIATRIC ONCOLOGY UNMET needs

  4. Why do we need new therapies? Quality of Life Survival

  5. Decreasing the Burden of Rx! • Radiotherapy • Secondary malignancies • Cardiac impairment- anthracyclines • Renal impairment- platinums/ ifosfamide • Fertility

  6. PAEDIATRIC ONCOLOGY Role of networks & EXPERTS

  7. 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

  8. PAEDIATRIC ONCOLOGY Rational biology-driven drug development, preclinical models

  9. Changing Oncology Pipeline

  10. Aim: to decode the genomes of more than 600 childhood cancer patients, who have contributed tumor samples for this historic effort.

  11. High Grade Glioma of brain & brainstem

  12. GBM Genome?- 2008 CCLG CNS Division Annual Meeting

  13. Nat Rev Clin Oncol. 2012 May 29;9(7):400-13

  14. MICROARRAY STRATEGY WHOLE GENOME GENE SELECTION GENE VALIDATION BIOMARKER DEVELOPMENT

  15. Paediatric & TYA HGG

  16. Paediatric & TYA HGG

  17. Medulloblastoma

  18. Sonic Hedgehog Pathway(Shh) • Pediatric tumors • Constitutive activation (mutations) in: • Gorlin Syndrome • Medulloblastoma (MB) • Basal cell carcinoma (BCC) • Rhabdomyosarcoma

  19. Cancer Cell.6: 229-240, 2004. • HhAntag691 (Curis/Genentech) • Blocks SMO function (10x cyclopamine) • Blood-brain penetration • Assessment using PTCH (+/-) mouse MB model

  20. Cancer Cell.6: 229-240, 2004.

  21. Toxicity

  22. PAEDIATRIC ONCOLOGY Existing initiatives

  23. USA: CTEP/PPTP Scheme Stage 1 Efficacy testing at MTD Test across entire panel Stage 2 Dose-response PK/PD (target modulation) Combinations PPTP

  24. ITCC Clinical Trial Committee

  25. 42 accredited clinical and research Institutions over Europe.

  26. 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)

  27. A Network of Excellence Structuring clinical research in paediatric and adolescent oncology in Europe HEALTH.2010.2.2.1-3

  28. PAEDIATRIC ONCOLOGY clinical investigators-Challenges & future?

  29. 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

  30. 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

  31. Questions?

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