Children’s Brain Tumour Research: translating research into practice

1. Children’s Brain Tumour Research: translating research into practice Dr David Walker, Professor of Paediatric Oncology, Children’s Brain Tumour Research Centre, Faculty of Medicines and Health Sciences, University of Nottingham

3. Childrens Brain Tumour Research Centre www.cbtrc.org • To highlight the epidemiology clinical challenges of childhood brain tumours – including Proton Beam Therapy • To illustrate two research projects within a CNS drug delivery development programme for childhood brain tumours

4. Worldwide, ~260,000 children develop cancer each year Of these, 30,000-40,000 children have CNS tumors

6. A Developmental Hypothesis for Childhood CancerNature Reviews Cancer (2005) 5; 481-488

7. Prof David Walker Professor of Pediatric Oncology

9. Cerebellar Medulloblastoma with Spinal Metastases Survival Rates: No metastases ~ 80% 5-10yr + Chemo & Cranio Spinal RT 24Gy Metastases ~ 60% 5-10 yr + Chemo & Cranio Spinal RT >36 Gy Hatch Hatch

10. IQ modelling after cranial irradiation during childhood

12. Height SDS for patients treated with: Cranial Irradiation Cranio-Spinal Irradiation

13. Improved Exec Functn SIOP PNET 4 Trial comparing Hyperfractionated RT (HFRT) versus Standard RT STRT

14. SIOP PNET 4 Trial comparing Hyperfractionated RT (HFRT) versus Standard RT STRT Height SDS Greater loss of height

15. Conventional craniospinal radiotherapy Tomotherapy Machine Similar principle to 3D / conformal Radiotherapy

22. The Therapeutic Challengeof Childhood CNS Tumour Therapies • Optimization / individualisation of therapies • Maximise efficacy against tumour • Minimise toxicity for brain and organ systems • Incorporate new therapeutics

23. HATCH, MATCH, DESPATCH and DELIVERA drug delivery programme to optimise medical therapy for brain tumours : A PROPOSAL FOR A COLLABORATIVE NETWORK Match Hatch Hatch Despatch Deliver Tumour Biology Targets Pathways Bioinformatics Drugs Chemotherapeutics Biological agents Existing or new Tumour Biology Drug/ biomodifier Delivery system testing Does it get into the brain? Does it get into the cell? Does it damage the tumour? Does it damage the brain? Clinical trials Licensing Commercialisation Clinical practice Delivery system/route Intra-CSF Interstitial Enhanced systemic Sustained release Enhanced local Enhanced Experimental Models 3D C—culture Organotypic Blood brain barrier Rotary Cell Culture System In vivo orthotopic resection model Tumour Biology Targets Pathways Bioinformatics

24. Direct CNS drug delivery Provides Needs Matching of effective drug, biology and optimal delivery system to tumour location Cytotoxic concentration to tumour bypassing blood-brain barrier (BBB)

25. Blood-brain-barrier complicates CSF entrance of systemic administered drugs 3 barrier sites to CNS 2 • Blood-brain-barrier • Arachnoid membrane (meninges) • Choroid plexus epithelium Problem tight junctions 1 3 Abbott 2006

26. Leukaemia: replace RT by intra-CSF Tx: No significant difference in outcome Clarke, 2003

27. A systematic literature and dataset review • To identify drugs most suitable for further investigation for intrathecal administration to children with brain tumours • based on physicochemical characteristics and current knowledge of use. • Conroy, Walker et al

28. Effective drug for drug delivery system Clinically Physico-chemical and pharmaceutical Characteristics that suit delivery method Active, e.g. does not need metabolisation Stable in drug delivery system Readily diffusion from drug delivery system • Non-irritant • Low/absent neurotoxicity • Evidence of tumour sensitivity Adapted from Conroy et. al 2010

29. Carboplatin Cytarabine - depot formulations Diaziquone Etoposide Floxuridine Mafosfamide Mercaptopurine Nimustine Ranimustine Temozolomide Topotecan Most promising drugs for IT use?

30. Intra-CSF administration VR: ventricular route Through Ommaya reservoir LR: lumbar route Through Port-A-Cath withlumbar line extension Blue is cerebrospinal fluid space Red is blood space

31. Mode of administration has impact on clinical outcome Intraventricular Etoposide Reduction in tumour size Postchemo Prechemo Oral Etoposide Tumour growth Postchemo Prechemo Nottingham University Hospital

32. HATCH, MATCH, DESPATCH and DELIVERA drug delivery programme to optimise medical therapy for brain tumours : A PROPOSAL FOR A COLLABORATIVE NETWORK Match Hatch Hatch Despatch Deliver Tumour Biology Targets Pathways Bioinformatics Drugs Chemotherapeutics Biological agents Existing or new Tumour Biology Drug/ biomodifier Delivery system testing Does it get into the brain? Does it get into the cell? Does it damage the tumour? Does it damage the brain? Clinical trials Licensing Commercialisation Clinical practice Delivery system/route Intra-CSF Interstitial Enhanced systemic Sustained release Enhanced local Enhanced Experimental Models 3D C—culture Organotypic Blood brain barrier Rotary Cell Culture System In vivo orthotopic resection model Tumour Biology Targets Pathways Bioinformatics

33. HD systemic administration does not yield cytotoxic CSF concentrationIntra-CSF at 1/200th systemic dose does IVC: intraventricular CIV: continuous intra- venous infusion VP16: etoposide 0.5 mg /day intraventricular etoposide bolus on 5 consecutive days vs. 400 mg/m2 continuous intravenous etoposide over 96 hours At 1/200 of dose cytotoxic concentration Fleischhack 2001, Henwood 1990

34. Clinical studies with ventricular route etoposide Fleischhack et al 2001 Slavc et al. 2003 122 courses, 2 patients etoposide, 9 patients etopose/mafosfamide 0.5 mg intraventricular, 2-6 weeks No short or long term toxicity with etoposide 3 CR, 3 PR, 5 DOD (1, 12, 23, 30, 42 months) • 59 courses, 14 patients • 0.5 mg intraventricular, 5 days, every 2-5 weeks • 2 courses headache, 2 courses bacterial meningitis • 2 CR, 1 SD, 2 MR, 7 PR, 2 PD

35. Etoposide more cytotoxic atlonger exposure than higher dose Fleischhack group

36. HATCH, MATCH, DESPATCH and DELIVERA drug delivery programme to optimise medical therapy for brain tumours : A PROPOSAL FOR A COLLABORATIVE NETWORK Match Hatch Hatch Despatch Deliver Tumour Biology Targets Pathways Bioinformatics Drugs Chemotherapeutics Biological agents Existing or new Tumour Biology Drug/ biomodifier Delivery system testing Does it get into the brain? Does it get into the cell? Does it damage the tumour? Does it damage the brain? Clinical trials Licensing Commercialisation Clinical practice Delivery system/route Intra-CSF Interstitial Enhanced systemic Sustained release Enhanced local Enhanced Experimental Models 3D C—culture Organotypic Blood brain barrier Rotary Cell Culture System In vivo orthotopic resection model Tumour Biology Targets Pathways Bioinformatics

38. Preparing InfusionalEtoposide for Despatch • CRUK New Agent Committee Funding • Selection of Etoposide formulation – ETO Gry, preservative free • Clinical risk assessment for Intra-CSF administration • Etoposide stability over prolonged periods • Surety syringe system and drug interaction requiring syringe re-design. • Neurosurgical survey of device insertion and safety • Patient acceptability reporting – see video • Ethical and R and I approval • Setting trial launch date Dec 2014

39. Selecting target CSF [Etoposide] • 3D human culture system • Previously published pharmacokinetic data • Cytotoxicity of sustained Etoposide exposure in human tumour cells • CSF route administration and clearance data in young children with different CSF volumes

40. HATCH, MATCH, DESPATCH and DELIVERA drug delivery programme to optimise medical therapy for brain tumours : A PROPOSAL FOR A COLLABORATIVE NETWORK Match Hatch Hatch Despatch Deliver Tumour Biology Targets Pathways Bioinformatics Drugs Chemotherapeutics Biological agents Existing or new Tumour Biology Drug/ biomodifier Delivery system testing Does it get into the brain? Does it get into the cell? Does it damage the tumour? Does it damage the brain? Clinical trials Licensing Commercialisation Clinical practice Delivery system/route Intra-CSF Interstitial Enhanced systemic Sustained release Enhanced local Enhanced Experimental Models 3D C—culture Organotypic Blood brain barrier Rotary Cell Culture System In vivo orthotopic resection model Tumour Biology Targets Pathways Bioinformatics

41. INTREPID protocol scheme Cohort 1 Cohort 2 Cohort 3 Cohort 4 ≥3 yr D: 0.8 μg/ml 7 days + shunt ≥ 3 yr D: 1.2 μg/ml 7 days +/- shunt ≥ 3 yr D: 1.2 μg/ml 10 days +/- shunt ≥ 3 yr D: 1.2 μg/ml 14 days +/- shunt Over three years ≥ 3 yr D: 0.8 μg/ml 7 days - shunt Dose escalation Infusion duration escalation Dose escalation Infusion duration escalation <3 yr D: 0.8 μg/ml 7 days + shunt <3 yr D: 1.2 μg/ml 7 days +/- shunt <3 yr D: 1.2 μg/ml 10 days +/- shunt <3 yr D: 1.2 μg/ml 14 days +/- shunt Under three years <3 yr D: 0.8 μg/ml 7 days - shunt Dose rate (µg/min) = clearance (ml/min) x steady state concentration x 60 (min) DR = 0.56 x 0.8 x 60

42. What have we learnt? • It is possible to bring a novel drug to trial for intra-CSF infusional administration in children • Infusional intra-CSF delivery offers strong theoretical benefits over systemic administration • Clinical risk assessment must be tackled as a specific step in planning the clinical trial • Sharing learning through collaboration would offer a route to disseminate expertise • Using experience of development of other Drug Delivery Systems in a collaborating network in rare disease is the ethically preferred method for further system development

43. INTREPID PI: David Walker Collaborators Neuro-surgery Donald Macarthur Stuart Smith Neuro-radiology Rob Dineen Tim Jaspan (central radiology review) Neuro-toxicity study Charlotte Teunissen Pharmacy: • Research pharmacist to appoint • Malcolm Partridge • Nigel Ballentine Statistician • Veronica Moroz Trial coordinator: • Elena Brodgen Co-applicants Lisethe Meijer Gareth Veal Richard Grundy Pamela Kearns

44. Childrens Brain Tumour Research Centre www.cbtrc.org • To highlight the epidemiology clinical challenges of childhood brain tumours – including Proton Beam Therapy • To illustrate two research projects within a CNS drug delivery development programme for childhood brain tumours

45. Multiplexing Three Methods for Spheroid Viability Determination in High-Throughput Delyan Ivanov

46. Inception of project Selective uptake of NPs into tumors in 3D Weina Meng (2007), PhD Thesis, University of Nottingham

47. Safety and efficacy in brain cancer therapy Stem cell neurosphere Tumor spheroid Safety Neural stem cells Human fetal brain tissue Proliferating part of brain Efficacy UW228 Tumor cells: Human medulloblastoma Invading cancer cells

48. User-friendly 3D screens Seed cell suspension Spheroid formation Ultra low attachment plate Spheroid ready for analysis Reproducible diameter from 100 to 900µm with CV 3-10% Fast form dense spheroids in 72h Analysis-friendly measure fluorescence and absorbance directly in plates Vinci M, BMC Biology 2012,10:29

49. Stem cells vs Tumors * *

50. Acknowledgements Martin Garnett Cameron Alexander David Walker Marianne Ashford Paul Gellert Terry Parker Weina Meng Beth Coyle CBTRC FRAME Lab