Transcript How can we tailor drug doses in Ewing`s sarcoma to

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?