Xeloda 5-FU - Cancer de Mama

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Introduction to Xeloda
Introduction to Xeloda: contents
 1.0 Role of thymidine phosphorylase (TP) in cancer
 2.0 Rationale for the development of Xeloda: mode of action
 3.0 Pharmacokinetic studies of Xeloda
 4.0 Identification of the Xeloda monotherapy regimen
 5.0 Rational combinations with Xeloda: TP upregulation
 6.0 Rational Xeloda combinations in breast cancer
– Xeloda plus docetaxel (XT)
 7.0 Conclusions
1.0 Role of thymidine
phosphorylase in cancer
Thymidine phosphorylase (TP)
 TP = tumour-associated angiogenic factor or
platelet-derived endothelial cell growth factor
 Possesses high neovascularisation potential and
has anti-apoptotic properties1,2
 Correlates with
– fast malignant growth
– aggressive invasion potential
– poor patient prognosis
 TP activation may allow Xeloda to specifically target
aggressive cells
1Matsuura
2Kitazono
T, et al. Cancer Res 1999;59:5037–40
M, et al. Biochem Biophys Res Commun 1998;253:797–803
TP is significantly more active in
human tumour than healthy tissue
Patients (n)
Colorectal
115
115
Gastric
291
351
Breast
309
309
Liver (metastasis)
16
20
Healthy tissue
*
Tumour tissue
*
*
*
0
100
200
300
400
500
TP activity (µg 5-FU/mg protein/hour)
*p<0.05
5-FU = 5-fluorouracil
Adapted from Miwa M, et al. Eur J Cancer 1998;34:1274–81
2.0 Rationale for the development
of Xeloda: mode of action
Rationale for the development of Xeloda
 To generate 5-FU preferentially at the tumour site to
improve tolerability and maximise antitumour activity
 Oral administration
– lacks complications associated with i.v.
administration
– provides convenient therapy, reducing the amount
of time spent in hospital
Xeloda
®
NH-CO-O
F
N
N
O
HC
3
HO
O
OH
Tumour/TP-activated oral Xeloda
Intestine
Xeloda
Liver
Xeloda
Tumour >> healthy tissue
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
TPTP
5-FU
CE = carboxylesterase; 5'-DFCR = 5'-deoxy-5-fluorocytidine
CyD = cytidine deaminase; 5'-DFUR = 5'-deoxy-5-fluorouridine
More 5-FU in the tumour than healthy
tissue with TP-activated Xeloda
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
Normal tissue
x3.2*
x21.4*
Plasma
Tumour tissue
5-FU
5-FU
5-FU
5-FU
*Ratio of median values
Schüller J, et al. Cancer Chemother Pharmacol 2000;45:291–7
Mean ratio of 5-FU
Xeloda uptake results in higher 5-FU
concentrations in tumour cells
22
20
18
16
14
12
10
8
6
4
2
0
Primary tumour:healthy colon/rectum
Healthy colon/rectum:plasma
Primary tumour:plasma
Xeloda1
5-FU2
1Schüller
J, et al. Cancer Chemother Pharmacol 2000;45:291–7
JS, Beart RW Jr. Invest New Drugs 1989;7:13–25
2Kovach
Tumour growth inhibition by Xeloda
2–10-fold greater than with 5-FU
Tumour growth inhibition (%)
120
Xeloda
5-FU
100
80
60
40
20
0
ZR-75-1
MCF-7
MAXF401
MX-1
MDA-MB-231
Ishikawa T, et al. Cancer Res 1998;58:685–90
3.0 Pharmacokinetic studies
of Xeloda
Pharmacokinetic studies
 Routine plasma pharmacokinetics
 Effect of liver dysfunction
 Effect of food on bioavailability
Plasma concentrations of metabolites
following oral administration of Xeloda
Mean plasma concentration
(µg/mL)
4.5
4.0
Xeloda
3.5
5'-DFCR
3.0
5'-DFUR
2.5
5-FU
2.0
1.5
1.0
0.5
0
0
2
4
6
Time (hours)
8
10
12
 Extensive (>70%) and rapid gastrointestinal absorption
 Exponential decline of concentrations with half-life values of 0.7–1.2 hours
Reigner B, et al. Clin Pharmacokinet 2001;40:85–104
No need for Xeloda dose adjustment in patients
with mild-to-moderate hepatic dysfunction
 27 advanced/metastatic solid tumour patients
– 14 patients with mild-to-moderate hepatic dysfunction
– 13 patients with normal hepatic function
 Hepatic dysfunction increases concentrations of 5'-DFUR
and 5-FU (+15%)
 No clinically relevant effect on the bioactivation of Xeloda
in patients with hepatic dysfunction due to liver
metastases
 Recommendation: caution but no need for a priori
adjustment of the starting dose
Twelves C, et al. Clin Cancer Res 1999;5:1696–702
No difference in Xeloda metabolism between
normal and abnormal hepatic function
Mean plasma concentration
(µg/mL)
4.5
Normal hepatic function (n=14)
Abnormal hepatic function (n=13)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
0
2
4
6
Time (hours)
8
10
12
Twelves C, et al. Clin Cancer Res 1999;5:1696–702
Recommendations for Xeloda dosing
in patients with renal impairment
Renal impairment level
Recommendation for Xeloda use
Moderate (creatinine clearance
30–50mL/minute)
Reduced starting dose
recommended: 950mg/m2 b.i.d.
Severe (creatinine clearance
<30mL/minute)
Contraindicated
Elderly patients
Typically receive lower starting
dose (950mg/m2) since age drives
creatinine clearance
b.i.d. = twice daily
Effect of food on the pharmacokinetics
of Xeloda and its metabolites
 Eleven advanced/metastatic CRC patients treated in a
randomised phase II Xeloda trial
 Xeloda therapy on study days 1 and 8 after a standard
breakfast or overnight fast
 Significant impact on Cmax and AUC for Xeloda and
5'-DFCR
 No impact on AUC of 5'-DFUR, 5-FU and catabolites
 Recommendation: as all studies were conducted
after food consumption, administration after food
is recommended
CRC = colorectal cancer
Reigner BG, et al. Clin Cancer Res 1998;4:941–8
Administration after food is
recommended
Plasma concentration (µg/mL)
Plasma concentration of 5'-DFUR after Xeloda given before or after food (n=5)
Mean 5'-DFUR
Dose = 1,255mg/m2
10
9
8
After
Before
7
6
5
4
3
2
1
0
0
1
2
3
4
5
Time (hours)
6
7
8
Reigner BG, et al. Clin Cancer Res 1998;4:941–8
4.0 Identification of the Xeloda
monotherapy regimen
Xeloda dose-finding studies
 Three studies aimed to determine the MTD of Xeloda1–3
 In all studies patients were required to have
– measurable or clinically assessable histologically confirmed
solid tumours
– failed previous standard therapy
 There was a predominance of colorectal tumours
Tumour, %
Europe (n=34)1
USA (n=33)2
Europe (n=26)3
Colorectal
50
52
50
Breast
21
12
8
Other
29
36
42
1Mackean
M, et al. J Clin Oncol 1998;16:2977–85
DR, et al. J Clin Oncol 1998;16:1795–802
3Cassidy J, et al. Clin Cancer Res 1998;4:2755–61
2Budman
MTD = maximum tolerated dose
Xeloda: phase I summary
Study
Treatment
No. of patients
MTD (mg/m2 b.i.d.)
DLTs
Recommended
phase II dose
(b.i.d.)
LV = leucovorin
DLT = dose-limiting toxicity
HFS = hand-foot syndrome
NA = not applicable
Europe1
Intermittent
USA2
Europe3
Continuous Continuous/intermittent
+ LV 30mg b.i.d.
34
33
31 (6/25)
1,500
828
500/1,000
Diarrhoea
Hypotension
Leucopenia
Diarrhoea
Diarrhoea
Nausea/vomiting
HFS
1,250mg/m2
666mg/m2
(days 1–14
continuously
every 21 days)
1Mackean
NA/825mg/m2
(days 1–14 every
21 days)
M, et al. J Clin Oncol 1998;16:2977–85
DR, et al. J Clin Oncol 1998;16:1795–802
3Cassidy J, et al. Clin Cancer Res 1998;4:2755–61
2Budman
Xeloda in CRC:
phase II study design
Metastatic/advanced
CRC
No prior chemotherapy
R
A
N
D
O
M
I
S
A
T
I
O
N
Treatment of 12 weeks with
SD/PR/CR continuing up to 48 weeks
Tumour assessments after weeks 6 and 12
SD = stable disease; PR = partial response
CR = complete response
Continuous Xeloda
(n=39)
(1,331mg/m2/day orally)
Intermittent Xeloda
(2,510mg/m2/day orally (n=35)
2 weeks on/1 week off)
Intermittent Xeloda
(1,657mg/m2/day orally
(n=35)
2 weeks on/1 week off)
+ 60mg/day LV
Van Cutsem E, et al. J Clin Oncol 2000;18:1337–45
Xeloda in CRC randomised phase II
study: efficacy
Treatment arm
Continuous Intermittent
(n=39)
(n=34*)
LV
(n=35)
Overall best response
(CR+PR) (%)
21
24
23
SD (%)
51
62
63
Median TTP (months)
4.2
7.7
5.5
*One patient withdrew informed consent prior to receiving therapy
TTP = time to progression
Van Cutsem E, et al. J Clin Oncol 2000;18:1337–45
Xeloda in CRC randomised
phase II study: safety
Grade 3*
adverse events
Continuous Intermittent
(n=39)
(n=34)
LV
(n=35)
Diarrhoea (%)
5
9
20
Stomatitis (%)
–
3
3
Abdominal pain/colic (%)
–
3
9
Nausea (%)
3
–
3
Vomiting (%)
3
6
6
10
15
23
HFS (%)
*Only one patient experienced a grade 4 adverse event
Van Cutsem E, et al. J Clin Oncol 2000;18:1337–45
Selected Xeloda dose and schedule
 2,500mg/m2/day p.o. divided into two single doses
(1,250mg/m2 b.i.d.) for 14 days
– followed by 7-day rest period
 Dose adjustment in case of grade 2 or 3 toxicities
– discontinuation for grade 4 toxicity
p.o. = orally
5.0 Rational combinations with
Xeloda: TP upregulation
Agents that upregulate TP are
rational combination partners for Xeloda
mg/kg
Paclitaxel
15
Docetaxel
7.5
*
Mitomycin C
5
*
Doxorubicin
7.5
*
Cyclophosphamide 200
Methotrexate
50
Gemcitabine
90
Vinorelbine
8
*
*
*
0
1
2
3
4
5
TP upregulation (x control activity) in MX-1 xenografts
*p<0.05
Endo M, et al. Int J Cancer 1999;83:127–34
Sawada N, et al. Proc Am Assoc Cancer Res 2002 (Abst 5388)
Radiotherapy upregulates TP
MX-1 mammary cancer xenografts
Control
Xeloda
Control + 5Gy
3,500
Xeloda + 5Gy
100
3,000
80
2,500
2,000
*
60
*
1,500
40
1,000
*†
500
0
20
0
Mean tumour volume change (mm3)
*p<0.05 vs control
†p<0.05 vs control + 5Gy
Tumour growth inhibition (%)
Sawada N, et al. Clin Cancer Res 1999;5:2948–53
6.0 Rational Xeloda combinations
in breast cancer
Xeloda plus docetaxel (XT): a rational
combination in breast cancer
 Xeloda and docetaxel have considerable
single-agent activity in breast cancer
 Xeloda and docetaxel have distinct mechanisms of
action and limited overlap of key toxicities
 Taxanes further upregulate TP1
 Xeloda/taxanes are synergistic in vivo1
Sawada N, et al. Clin Cancer Res 1998;4:1013–19
1
Xeloda and docetaxel have
demonstrated preclinical synergy
Activity of fluoropyrimidines and/or docetaxel against MX-1 carcinoma xenografts
6.0
Xeloda
Tumour volume change (cm3)
Tumour volume change (cm3)
6.0
5.0
4.0
3.0
2.0
***
1.0
0
–1.0
14 18 22 26 30 34 38 42 46
Days
Control
Xeloda
*p<0.05
XT
5-FU
5.0
4.0
**
3.0
2.0
1.0
0
–1.0
14 18 22 26 30 34 38 42 46
Days
Docetaxel
Docetaxel + 5-FU
5-FU
Sawada N, et al. Clin Cancer Res 1998;4:1013–19
Xeloda plus docetaxel:
no pharmacokinetic interactions
 Two dose regimens were shown to be feasible
– 75mg/m2 docetaxel + 1,250mg/m2 Xeloda b.i.d.
– 100mg/m2 docetaxel + 825mg/m2 Xeloda b.i.d.
 No evidence of a pharmacokinetic interaction between
docetaxel and Xeloda
– p<0.05 for all kinetic parameters, indicating no
mutual kinetic interaction between the two drugs
Pronk L, et al. Br J Cancer 2000;83:22–9
7.0 Conclusions
Xeloda: the first oral fluoropyrimidine
approved for the treatment of MBC
 Unique mode of action: selectively tumour activated
– rationally designed to generate 5-FU preferentially in the tumour
– potentially improving efficacy and tolerability
 Final stage of the three-step enzymatic conversion to 5-FU
mediated by TP, which is
– significantly more concentrated in tumour versus normal tissue
– upregulated by many therapies, including taxanes
 Absorption of Xeloda is rapid and virtually complete
– Tmax: 0.3–3 hours; metabolites Cmax: ~2 hours
– metabolite half-lives 0.6–0.8 hours
 Proven preclinical synergy with other agents, including Herceptin,
translates into the clinical setting
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