Xeloda 5-FU - Cancer de Mama
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Transcript Xeloda 5-FU - Cancer de Mama
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