How can we tailor drug doses in Ewing’s sarcoma to maximise benefit and minimise side effects?

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) B) C) D) E) F)

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 MUSTARD GAS NITROGEN MUSTARD

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

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

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

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

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

13. ETHANOL METABOLISM Alcohol dehydrogenase CH3CH2OH    + 2 NAD    CH3CHO    + 2 NADH alcohol          cofactor  aldehyde cofactor (ethanol) (acetaldehyde) Acetaldehyde dehydrogenase 2 CH3CHO + H2O    CH3COOH   aldehyde acid (acetaldehyde) (acetic acid or vinegar)

14.   ETHANOL METABOLISM

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

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

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. PLAN OF INVESTIGATION Sample volume PK studies (ages <12, 12-18, >18 yrs) on any cycle of VIDE, VDC/IE 1-3 ml / sample Targeted pharmacogenomics of known key polymorphisms 5 ml Early toxicity biomarkers (FLT3 and CK18) • baseline 2.5 ml • end of course 1 2.5 ml • prior to course 2 2.5 ml • prior to last course 2.5 ml

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

33. QUESTIONS?