1. HOW CAN WE TAILOR DRUG DOSES IN EWING’S SARCOMA TO MAXIMISE BENEFIT AND MINIMISE SIDE EFFECTS?

2. CANCER RESEARCH IN NEWCASTLE

3. SIR BOBBY ROBSON AND THE NEWCASTLE CANCER CENTRE Diagnosed with cancer in 1991 Malignant melanoma (1995) Brain tumour operation (2006) Opened NICR in 2004 Sir Bobby Robson Foundation >£8M raised for early cancer diagnosis and new drug trials

4. WHO ARE THE FOLLOWING CELEBRITIES AND WHAT DO THEY HAVE IN COMMON? A) D)E) B) F) C)

5. CISPLATIN CHEMOTHERAPY Testicular cancer 10 year survival rate: 98% Majority of patients cured of a disease in which some of the 30,000+ genes go wrong in some of the billions of cells in the body by a very simple platinum transition metal complex

6. ‘Perfect Drug’ Benefits all patients One dose fits all Responses in all patients No adverse effects ‘Real Drug’ Benefits some patients Variable doses for different patients Responses in some patients Adverse effects in some patients

7. THE HISTORY OF ANTICANCER DRUGS NITROGEN MUSTARD MUSTARD GAS

8. WHAT IS PHARMACOLOGY? The study of how drugs affect a biological system PHARMACOLOGY Pharmacokinetics - what the body does to the drug Pharmacodynamics - what the drug does to the body

9. PHARMACOKINETICS the study of the fate of an externally administered compound Absorption Distribution Metabolism Excretion Drug in RESPONSE Dose Drug out Drug concentration Time

10. Schematic representation of the relationship between drug exposure, toxicity and response Drug exposure (AUC)  toxicity  efficacy Therapeutic window Standard Therapy INTERPATIENT VARIATION IN PHARMACOKINETICS

11. Schematic representation of the relationship between drug exposure, toxicity and response Drug exposure (AUC)  toxicity  efficacy Therapeutic window Standard Therapy Alternative/modified Therapy

12. PHARMACOLOGICAL TREATMENT STRATIFICATION NO EFFICACY / INCREASED TOXICITY EFFICACY / ACCEPTABLE TOXICITY DECREASED EFFICACY or INCREASED TOXICITY Dose modificationAlternative treatment Standard treatment

13. ETHANOL METABOLISM Alcohol dehydrogenase CH 3 CH 2 OH + 2 NAD  CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (ethanol) (acetaldehyde) Acetaldehyde dehydrogenase 2 CH 3 CHO + H 2 O  CH 3 COOH aldehyde acid (acetaldehyde) (acetic acid or vinegar)

14. ETHANOL METABOLISM 

15. Response Plasma concentration GETTING THE DOSE RIGHT FOR CANCER PATIENTS

16. NEED FOR CLINICAL PHARMACOLOGY STUDIES IN CANCER Paediatrics Adults

17. PHARMACOKINETIC STUDIES – WHAT’S INVOLVED? Drug administered –Oral –IV –Other Blood sample taken –Whole blood sample –Separation of plasma –Samples frozen and sent to Newcastle Analysis –HPLC with UV detection (  g/ml) –HPLC with fluorescence detection (ng/ml) –LC-MS (mass specific detection – pg/ml)

18. HOW CAN WE UTILISE CLINICAL PHARMACOLOGY STUDIES TO OPTIMISE THE TREATMENT OF CHILDREN WITH CANCER? Therapeutic drug monitoring approaches: - Carboplatin - Methotrexate - Busulphan Definition of most appropriate doses and schedules in different patient populations: -Infants vs teenagers and adolescents -Children with renal or hepatic impairment - other subpopulations (e.g. obesity and malnutrition) Need for clinical pharmacology data in large numbers of patients in a paediatric oncology setting

19. NATIONAL PHARMACOLOGY STUDIES Clinical trials: >750 patients across 17 centres Therapeutic Drug Monitoring (TDM) service

20. STUDIES IN NEUROBLASTOMA < 2µM

21. IMPACT ON NEUROBLASTOMA TREATMENT

22. EWING SARCOMA PHARMACOLOGY STUDY

23. EWING SARCOMA – INCIDENCE AND TOXICITY Peak incidence during adolescence / early adulthood Chemotherapy is an essential component of treatment Significant acute chemotherapy-related toxicities

24. INT 0154 non-metastatic Granowetter, JCO 2009 Euro-Ewing 99 R3 Juergens, JCO 2010 DECREASED SURVIVAL IN TEENAGERS AND YOUNG ADULTS

25. EURO EWINGS PHARMACOLOGY STUDIES Research questions: Are there differences in the way that drugs are handled and broken down between children, adolescents and older adults that could explain age-related differences in toxicity and survival? Can biomarkers in the blood predict toxicity in order to target interventions to those at highest risk? Do genetic variations correlate with variation in drug metabolism and/or prediction of drug toxicity?

26. EURO EWING 2012 STUDY

28. Sample volume PK studies (ages 18 yrs) on any cycle of VIDE, VDC/IE1-3 ml / sample Targeted pharmacogenomics of known key polymorphisms 5 ml Early toxicity biomarkers (FLT3 and CK18) baseline2.5 ml end of course 12.5 ml prior to course 2 2.5 ml prior to last course2.5 ml PLAN OF INVESTIGATION

29. TOXICITY BIOMARKER BACKGROUND Validation of a panel of blood-borne biomarkers previously shown to predict bone marrow and mucosal toxicity in adults (FLT3 ligand – BM toxicity; CK18 – mucosal toxicity)

30. CURRENT STATUS OF STUDY MHRA approval: 06/08/2013 REC approval: 07/10/2013 First patient studied: 02/04/2014 16 centres open to date Total patients studied: 32 Funding for study: Sarcoma UK

31. CURRENT STATUS – CENTRES OPEN

32. Newcastle CCLG Pharmacology Studies National Studies Website and clinical data entry Newsletters for centre information >20 publications relating to completed clinical trials Therapeutic Drug Monitoring national service >750 patients recruited at 17 major UK clinical centres >15 clinical trials completed or ongoing in UK/Europe

33. QUESTIONS?