Rationale for the development of Xeloda®
To generate 5-FU at the tumour site to improvetolerability and/or maximise antitumour activity
Oral administration
–is capable of mimicking the mechanism ofaction of continuous infusion 5-FU
–lacks complications associated with i.v.administration
–provides convenient therapy
Patient preference
89% of patients in a questionnaire-based surveypreferred 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 abilityto take medication at home2
Self-administered therapy is associated withimproved quality of life for patients compared withhospital-based care3
There is an unmet need for an effective, oral,outpatient therapy
1Liu G et al. J Clin Oncol 1997;15:110–5
2Borner 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
Tumour
Xeloda
Thymidine
phosphorylase (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-associatedangiogenic factor or platelet-derivedendothelial cell growth factor (PD-ECGF)
Possesses high neovascularisationpotential and has anti-apoptotic properties1,2
Correlates with
–fast malignant growth
–aggressive invasion potential
–poor patient prognosis
1Matsuura T et al. Cancer Res 1999;59:5037–40
2Kitazono M et al. Biochem Biophys Res Commun 1998;253:797–803
TP activity in human tissues
TP activity (µg 5-FU/mg protein/hour)
0100200300400500
115
115
291
351
309
309
8
13
17
18
14
23
24
37
13
11
36
35
25
27
16
20
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
05101520
(mg/kg)
Control
Paclitaxel100
Docetaxel15
Vincristine1.5
Vinblastine3
Vindesine5
Mitomycin C5
Doxorubicin7.5
Cisplatin10
Control
Methotrexate50
Cyclophosphamide200
TP activity (unit/mg protein)
Gemcitabine and vinorelbine also upregulate TP
Ishitsuka H. Invest New Drugs 2000;18:343–54
Tumour growth inhibition of humanbreast cancer xenografts in nude mice
120
100
80
60
40
20
0
–20
Tumour growth inhibition (%)
Xeloda
5-FU
UFT (uracil + tegafur)
Ishikawa T et al. Cancer Res 1998;58:685–90
Mean ratios of 5-FU concentrations followingadministration of Xeloda® or 5-FU in humans
22
20
18
16
14
12
10
8
6
4
2
0
Mean ratio of 5-FU
Xeloda15-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)
024681012
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
Mean plasma concentration
(µg/mL)
Reigner B et al. Clin Pharmacokinet 2001;40:85–104
Effect of hepatic dysfunction onkinetics of key Xeloda® metabolites
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Mean plasma concentration
(µg/mL)
024681012
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
1Mackean M et al. J Clin Oncol 1998;16:2977–85
2Budman 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 studyin colorectal cancer
Study objective: to identify the most appropriateregimen for phase III development
Efficacy
–good response rates of 21–24% achieved withall three regimens as first-line treatment
–median time to progression: 7.5 months for theintermittent monotherapy regimen
Well tolerated with all three regimens
Intermittent regimen (14 days’ treatment,7-day rest) selected based on favourable timeto progression, higher dose intensity and bettertherapeutic index
Van Cutsem E et al. J Clin Oncol 2000;18:1337–45