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HOW CAN WE TAILOR DRUG DOSES IN HOW CAN WE TAILOR DRUG DOSES IN EWING’S SARCOMA TO MAXIMISE BENEFIT EWING’S SARCOMA TO MAXIMISE BENEFIT
AND MINIMISE SIDE EFFECTS?AND MINIMISE SIDE EFFECTS?
CANCER RESEARCH IN NEWCASTLE CANCER RESEARCH IN NEWCASTLE
SIR BOBBY ROBSON AND THE NEWCASTLE SIR BOBBY ROBSON AND THE NEWCASTLE CANCER CENTRE 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 WHO ARE THE FOLLOWING CELEBRITIES AND WHAT DO THEY HAVE IN COMMON? WHAT DO THEY HAVE IN COMMON?
A)
D) E)
B)
F)
C)
CISPLATIN CHEMOTHERAPY 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’
• 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
THE HISTORY OF ANTICANCER DRUGSTHE HISTORY OF ANTICANCER DRUGS
CH2S
CH2
CH2
CH2
Cl
Cl
CH2N
CH2
CH2
CH2
Cl
ClCH3
NITROGEN MUSTARD
MUSTARD GAS
WHAT IS PHARMACOLOGY?WHAT IS PHARMACOLOGY?
• The study of how drugs affect a biological system
PHARMACOLOGPHARMACOLOGYY
Pharmacokinetics- what the body does to the drug
Pharmacodynamics- what the drug does to the body
PHARMACOKINETICSPHARMACOKINETICS
• the study of the fate of an externally administered compound
• Absorption• Distribution• Metabolism• Excretion
Drug in
RESPONSE
Dose
Drug out
Dru
g co
ncen
trat
ion
Time
• Schematic representation of the relationship between drug exposure, toxicity and response
Dru
g ex
posu
re (
AU
C)
toxicity
efficacy
Therapeutic window
Standard Therapy
INTERPATIENT VARIATION IN PHARMACOKINETICSINTERPATIENT VARIATION IN PHARMACOKINETICS
INTERPATIENT VARIATION IN PHARMACOKINETICSINTERPATIENT VARIATION IN PHARMACOKINETICS
• Schematic representation of the relationship between drug exposure, toxicity and response
Dru
g ex
posu
re (
AU
C)
toxicity
efficacy
Therapeutic window
Standard Therapy
Alternative/modified Therapy
PHARMACOLOGICAL TREATMENT STRATIFICATIONPHARMACOLOGICAL TREATMENT STRATIFICATION
NO EFFICACY / INCREASED TOXICITYEFFICACY / ACCEPTABLE TOXICITY
DECREASED EFFICACY or INCREASED TOXICITY
Dose modification Alternative treatmentStandard treatment
ETHANOL METABOLISMETHANOL 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)
ETHANOL METABOLISMETHANOL METABOLISM
Response
Plasma concentration
GETTING THE DOSE RIGHT FOR CANCER PATIENTSGETTING THE DOSE RIGHT FOR CANCER PATIENTS
NEED FOR CLINICAL PHARMACOLOGY NEED FOR CLINICAL PHARMACOLOGY STUDIES IN CANCERSTUDIES IN CANCER
Paediatrics
Adults
PHARMACOKINETIC STUDIES – WHAT’S INVOLVED?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 HOW CAN WE UTILISE CLINICAL PHARMACOLOGY STUDIES TO OPTIMISE THE TREATMENT OF STUDIES TO OPTIMISE THE TREATMENT OF
CHILDREN WITH CANCER?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 STUDIESNATIONAL PHARMACOLOGY STUDIES
• Clinical trials: >750 patients across 17 centres
• Therapeutic Drug Monitoring (TDM) service
STUDIES IN NEUROBLASTOMASTUDIES IN NEUROBLASTOMA
< 2µM
IMPACT ON NEUROBLASTOMA TREATMENTIMPACT ON NEUROBLASTOMA TREATMENT
5.33 mg/kg 160 mg/m20
3
6
9
12
13-cisRA dosing regimen
[13-
cisR
A]
(µM
)
Swallowed Extracted0
3
6
9
12
13-cisRA dosing regimen
[13-
cisR
A]
(µM
)
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 STUDYEWING SARCOMA PHARMACOLOGY STUDY
EWING SARCOMA – INCIDENCE AND TOXICITYEWING SARCOMA – INCIDENCE AND TOXICITY
• Peak incidence during adolescence / early adulthood
• Chemotherapy is an essential component of treatment
• Significant acute chemotherapy-related toxicities
INT 0154 non-metastaticGranowetter, JCO 2009
Euro-Ewing 99 R3Juergens, JCO 2010
DECREASED SURVIVAL IN TEENAGERS AND YOUNG DECREASED SURVIVAL IN TEENAGERS AND YOUNG ADULTSADULTS
EURO EWINGS PHARMACOLOGY STUDIESEURO 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 STUDYEURO EWING 2012 STUDY
Sample volumePK 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
PLAN OF INVESTIGATIONPLAN OF INVESTIGATION
Drug Sample Assay Blood volume Time points* Sensitivity Vincristine Plasma LC/MS 2ml 0.25, 0.5, 4, 24h 0.5 ng/ml Ifosfamide Plasma LC/MS 2ml 1, 3, 6, 24h 5.0 ng/ml Doxorubicin Plasma LC/MS 1ml 4, 6, 8, 24h 5 ng/ml Etoposide Plasma / UF LC/MS 1ml 0.5, 1, 2, 6h 0.1 µg/ml Cyclophosphamide Plasma LC/MS 2ml 1, 2, 6, 24h 0.025 µg/ml Genotype Saliva / DNA PCR 3ml Pre-treatment N/A Toxicity Biomarkers Plasma ELISA 2.5ml C1 (D1/3); Pre-C2/C6 N/A
TOXICITY BIOMARKER BACKGROUNDTOXICITY 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 STUDYCURRENT 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 OPENCURRENT STATUS – CENTRES OPEN
Site Date Activated First patient recruited
Number of patients recruited
Manchester Children’s Hospital 06/03/14 22/04/14 5 Royal Marsden Hospital 20/03/14 18/08/14 2 Sheffield Children’s Hospital 28/03/14 02/04/14 1 Royal Aberdeen Children’s Hospital 24/04/14 Royal Victoria Infirmary, Newcastle 02/05/14 12/05/14 4 Royal Hospital for Sick Children, Glasgow 02/06/14 Queens Medical Centre, Nottingham 02/06/14 15/10/14 2 Alder Hey Hospital, Liverpool 12/06/14 28/10/14 3 Great Ormond Street Hospital 24/06/14 24/06/14 1 Addenbrooke’s Hospital, Cambridge 25/06/14 21/07/14 1 John Radcliffe Hospital, Oxford 31/07/14 27/10/14 2 Royal Bristol Children’s Hospital 18/08/14 02/10/14 1 Leeds Teaching Hospitals NHS Trust 20/10/14 27/10/14 2 Christie Hospital, Manchester 29/10/14 13/01/15 5 Royal Hospital for Sick Children, Edinburgh 08/01/15 Children’s Hospital of Wales, Cardiff 09/02/15 24/02/15 3
Newcastle CCLG Newcastle CCLG Pharmacology StudiesPharmacology 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
QUESTIONS?