Rationale for the development of Xeloda®

To generate 5-FU at the tumour site to improve tolerability and/or maximise antitumour activity

Oral administration– is capable of mimicking the mechanism of

action of continuous infusion 5-FU– lacks complications associated with i.v.

administration– provides convenient therapy

Patient preference

89% of patients in a questionnaire-based survey preferred oral therapy compared with i.v. infusions1

In a randomised trial

– 84% of patients preferred oral to i.v. therapy– this preference was due primarily to the ability

to take medication at home2

Self-administered therapy is associated with improved quality of life for patients compared with hospital-based care3

There is an unmet need for an effective, oral, outpatient therapy

1Liu G et al. J Clin Oncol 1997;15:110–52Borner M et al. Proc Am Soc Clin Oncol 2000;19:191a (Abst 741)

3Payne SA. Soc Sci Med 1992;35:1505–9

Enzymatic activation of Xeloda®

Intestine Liver

Xeloda

5'-DFCR

5'-DFUR

CyD

5'-DFCR

5'-DFUR

5-FU

TumourXeloda

Thymidinephosphorylase (TP)

CyD

CE

5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesterase

Thymidine phosphorylase (TP)

Also known as tumour-associated angiogenic factor or platelet-derived endothelial cell growth factor (PD-ECGF)

Possesses high neovascularisation potential and has anti-apoptotic properties1,2

Correlates with– fast malignant growth– aggressive invasion potential– poor patient prognosis

1Matsuura T et al. Cancer Res 1999;59:5037–402Kitazono M et al. Biochem Biophys Res Commun 1998;253:797–803

TP activity in human tissues

TP activity (µg 5-FU/mg protein/hour)

0 100 200 300 400 500

115115291351309309

8131718142324371311363525271620

Colorectal

Gastric

Breast

Cervical

Uterine

Ovarian

Renal

Bladder

Thyroid

Liver

Liver (metastasis)

(n=)

Healthy tissue

Tumour tissue

*

*

*

*

*

*

*

*

*

*p<0.05 Miwa M et al. Eur J Cancer 1998;34:1274–81

*

TP upregulation in tumour xenografts

0 5 10 15 20

(mg/kg)Control

Paclitaxel 100Docetaxel 15

Vincristine 1.5Vinblastine 3

Vindesine 5Mitomycin C 5Doxorubicin 7.5

Cisplatin 10

ControlMethotrexate 50

Cyclophosphamide 200

TP activity (unit/mg protein)

Gemcitabine and vinorelbine also upregulate TP

Ishitsuka H. Invest New Drugs 2000;18:343–54

Tumour growth inhibition of human breast cancer xenografts in nude mice

ZR-75-1 MCF-7 MAXF401 MX-1 MDA-MB-231

120

100

80

60

40

20

0

–20

Tu

mo

ur

gro

wth

in

hib

itio

n (

%)

Xeloda

5-FU

UFT (uracil + tegafur)

Ishikawa T et al. Cancer Res 1998;58:685–90

Mean ratios of 5-FU concentrations following administration of Xeloda® or 5-FU in humans

22

20

18

16

14

12

10

8

6

4

2

0

Mea

n r

atio

of

5-F

U

Xeloda1 5-FU2

1Schüller J et al. Cancer Chemother Pharmacol 2000;45:291–72Kovach JS, Beart RW Jr. Invest New Drugs 1989;7:13–25

Primary tumour:healthy colon/rectum

Healthy colon/rectum:plasma

Primary tumour:plasma

Xeloda® pharmacokinetic data

Time (hours)0 2 4 6 8 10 12

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Xeloda

5'-DFCR

5'-DFUR

5-FU

Mea

n p

lasm

a co

nce

ntr

atio

n(µ

g/m

L)

Reigner B et al. Clin Pharmacokinet 2001;40:85–104

Effect of hepatic dysfunction on kinetics of key Xeloda® metabolites

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Mea

n p

lasm

a co

nce

ntr

atio

n(µ

g/m

L)

0 2 4 6 8 10 12

Normal hepatic function (n=14)Abnormal hepatic function (n=13)

Time (hours)

Twelves C et al. Clin Cancer Res 1999;5:1696–702

Xeloda®: phase I summary

Study Europe1 USA2 Europe3

Treatment Intermittent Continuous Continuous/intermittent+ LV 30mg b.i.d.

No. of patients 34 33 31 (6/25)

MTD (mg/m2 b.i.d.) 1,500 828 500/1,000

DLTs DiarrhoeaHypotensionLeucopenia

Diarrhoea DiarrhoeaNausea/vomiting

HFS

Recommendedphase II dose (b.i.d.)

1,250mg/m2

(days 1–14every 21 days)

666mg/m2

continuouslyNA/825mg/m2

(days 1–14 every21days)

1Mackean M et al. J Clin Oncol 1998;16:2977–852Budman DR et al. J Clin Oncol 1998;16:1795–802

3Cassidy J et al. Clin Cancer Res 1998;4:2755–61

LV = leucovorinMTD = maximum tolerated doseDLT = dose-limiting toxicityHFS = hand-foot syndrome

Randomised, phase II study in colorectal cancer

Study objective: to identify the most appropriate regimen for phase III development

Efficacy– good response rates of 21–24% achieved with

all three regimens as first-line treatment– median time to progression: 7.5 months for the

intermittent monotherapy regimen Well tolerated with all three regimens Intermittent regimen (14 days’ treatment,

7-day rest) selected based on favourable time to progression, higher dose intensity and better therapeutic index

Van Cutsem E et al. J Clin Oncol 2000;18:1337–45