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HOW CAN WE TAILOR DRUG DOSES IN EWING’S SARCOMA TO MAXIMISE BENEFIT AND MINIMISE SIDE EFFECTS? CANCER RESEARCH IN NEWCASTLE 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 WHO ARE THE FOLLOWING CELEBRITIES AND WHAT DO THEY HAVE IN COMMON? A) D) B) E) C) F) 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 ‘Perfect Drug’ ‘Real Drug’ • Benefits all patients • Benefits some patients • One dose fits all • Variable doses for different patients • Responses in all patients • Responses in some patients • No adverse effects • Adverse effects in some patients THE HISTORY OF ANTICANCER DRUGS CH2 CH2 Cl CH2 CH2 Cl S MUSTARD GAS CH3 CH2 CH2 Cl CH2 CH2 Cl N NITROGEN MUSTARD 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 PHARMACOKINETICS • the study of the fate of an externally administered compound • • • • Absorption Distribution Metabolism Excretion Drug in RESPONSE Drug concentration Dose Time Drug out INTERPATIENT VARIATION IN PHARMACOKINETICS Drug exposure (AUC) • Schematic representation of the relationship between drug exposure, toxicity and response toxicity Therapeutic window efficacy Standard Therapy INTERPATIENT VARIATION IN PHARMACOKINETICS Drug exposure (AUC) • Schematic representation of the relationship between drug exposure, toxicity and response toxicity Standard Therapy Therapeutic window efficacy Alternative/modified Therapy PHARMACOLOGICAL TREATMENT STRATIFICATION DECREASED EFFICACY or INCREASED TOXICITY EFFICACY / ACCEPTABLE TOXICITY Dose modification NO EFFICACY / INCREASED TOXICITY Alternative treatment Standard treatment ETHANOL METABOLISM Alcohol dehydrogenase CH3CH2OH + 2 NAD alcohol (ethanol) cofactor CH3CHO + 2 NADH aldehyde (acetaldehyde) cofactor Acetaldehyde dehydrogenase 2 CH3CHO aldehyde (acetaldehyde) + H2O CH3COOH acid (acetic acid or vinegar) ETHANOL METABOLISM GETTING THE DOSE RIGHT FOR CANCER PATIENTS Response Plasma concentration NEED FOR CLINICAL PHARMACOLOGY STUDIES IN CANCER Paediatrics Adults 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) 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 NATIONAL PHARMACOLOGY STUDIES • Clinical trials: >750 patients across 17 centres • Therapeutic Drug Monitoring (TDM) service STUDIES IN NEUROBLASTOMA < 2µM IMPACT ON NEUROBLASTOMA TREATMENT 12 [13-cisRA] (µM) [13-cisRA] (µM) 12 9 6 3 0 5.33 mg/kg 160 mg/m2 9 6 3 0 Swallowed Extracted 13-cisRA dosing regimen 13-cisRA dosing regimen 13-cisRA Dose <12 kg >12 kg Capsules swallowed Capsules opened Current guidelines 5.33 mg/kg 160 mg/m2 160 mg/m2 Proposed based on PK study data 160 mg/m2 160 mg/m2 200 mg/m2 EWING SARCOMA PHARMACOLOGY STUDY EWING SARCOMA – INCIDENCE AND TOXICITY • Peak incidence during adolescence / early adulthood • Chemotherapy is an essential component of treatment • Significant acute chemotherapy-related toxicities DECREASED SURVIVAL IN TEENAGERS AND YOUNG ADULTS INT 0154 non-metastatic Granowetter, JCO 2009 Euro-Ewing 99 R3 Juergens, JCO 2010 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? EURO EWING 2012 STUDY PLAN OF INVESTIGATION Sample volume 1-3 ml / sample PK studies (ages <12, 12-18, >18 yrs) on any cycle of VIDE, VDC/IE Targeted pharmacogenomics of known key polymorphisms 5 ml Early toxicity biomarkers (FLT3 and CK18) • baseline • end of course 1 • prior to course 2 • prior to last course 2.5 ml 2.5 ml 2.5 ml 2.5 ml Drug Vincristine Ifosfamide Doxorubicin Etoposide Cyclophosphamide Genotype Toxicity Biomarkers Sample Plasma Plasma Plasma Plasma / UF Plasma Saliva / DNA Plasma Assay LC/MS LC/MS LC/MS LC/MS LC/MS PCR ELISA Blood volume 2ml 2ml 1ml 1ml 2ml 3ml 2.5ml * Time points 0.25, 0.5, 4, 24h 1, 3, 6, 24h 4, 6, 8, 24h 0.5, 1, 2, 6h 1, 2, 6, 24h Pre-treatment C1 (D1/3); Pre-C2/C6 Sensitivity 0.5 ng/ml 5.0 ng/ml 5 ng/ml 0.1 µg/ml 0.025 µg/ml N/A N/A 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) 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 CURRENT STATUS – CENTRES OPEN Site Date Activated Manchester Children’s Hospital Royal Marsden Hospital Sheffield Children’s Hospital Royal Aberdeen Children’s Hospital Royal Victoria Infirmary, Newcastle Royal Hospital for Sick Children, Glasgow Queens Medical Centre, Nottingham Alder Hey Hospital, Liverpool Great Ormond Street Hospital Addenbrooke’s Hospital, Cambridge John Radcliffe Hospital, Oxford Royal Bristol Children’s Hospital Leeds Teaching Hospitals NHS Trust Christie Hospital, Manchester Royal Hospital for Sick Children, Edinburgh Children’s Hospital of Wales, Cardiff 06/03/14 20/03/14 28/03/14 24/04/14 02/05/14 02/06/14 02/06/14 12/06/14 24/06/14 25/06/14 31/07/14 18/08/14 20/10/14 29/10/14 08/01/15 09/02/15 First patient recruited 22/04/14 18/08/14 02/04/14 Number of patients recruited 5 2 1 12/05/14 4 15/10/14 28/10/14 24/06/14 21/07/14 27/10/14 02/10/14 27/10/14 13/01/15 2 3 1 1 2 1 2 5 24/02/15 3 >15 clinical trials completed or ongoing in UK/Europe >750 patients recruited at 17 major UK clinical centres >20 publications relating to completed clinical trials Newcastle CCLG Pharmacology Studies National Studies Website and clinical data entry Therapeutic Drug Monitoring national service Newsletters for centre information QUESTIONS?