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

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?