thymidine phosphorylase (tp) upregulation dose- and time-dependent upregulation of tp in human colon...
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Thymidine phosphorylase (TP) upregulation
Dose- and time-dependent upregulation of TP in human colon cancer xenografts
20
15
10
5
0
20
15
10
5
0
Paclitaxel Docetaxel
0 2 4 6 8 10 0 2 4 6 8 10Days after administration Days after administration
TP
(u
nit
/mg
pro
tein
)
Sawada N et al. Clin Cancer Res 1998;4:1013–9
No treatmentVehiclePaclitaxel 15mg/kgPaclitaxel 100mg/kg
No treatmentVehicleDocetaxel 3.75mg/kg Docetaxel 15mg/kg
*p<0.05
**
*
**
*
***
*
*
TP
(u
nit
/mg
pro
tein
)
Xeloda® plus taxanes
Activity of the combination of Xeloda and taxanes against MX-1 carcinoma xenografts
6.0
5.0
4.0
3.0
2.0
1.0
0
–1.014 18 22 26 30 34 38 42 46 14 18 22 26 30 34 38 42 46
6.0
5.0
4.0
3.0
2.0
1.0
0
–1.0
Tu
mo
ur
volu
me
chan
ge
(cm
3)
Xeloda 5-FU
Sawada N et al. Clin Cancer Res 1998;4:1013–9
Control Docetaxel Xeloda Docetaxel + Xeloda
Docetaxel + 5-FU 5-FU
** *
**
Days Days*p<0.05
Tu
mo
ur
volu
me
chan
ge
(cm
3)
Xeloda® plus docetaxel: rationale in breast cancer
Xeloda and docetaxel have considerable single-agent activity in breast cancer
Xeloda and docetaxel have distinct mechanisms of action and no overlap of key toxicities
Synergistic interaction between Xeloda and docetaxel mediated by further taxane-induced upregulation of TP
Xeloda® plus docetaxel: phase I study summary
Two dose regimens were shown to be feasible
– 75mg/m2 docetaxel + 1,250mg/m2 Xeloda
twice daily
– 100mg/m2 docetaxel + 825mg/m2 Xeloda
twice daily
No evidence of a pharmacokinetic interaction between docetaxel and Xeloda
Pronk L et al. Br J Cancer 2000;83:22–9
Xeloda® plus docetaxel:phase III study design
Randomisation(3-weekly cycles)
Xeloda 1,250mg/m2 twice daily, days 1–14 docetaxel 75mg/m2, day 1
Docetaxel 100mg/m2, day 1
Patients responding or with stable disease after 6 weeks of treatment continued until disease progression or unacceptable toxicity
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel:study objectives
Primary
– time to disease progression*
Secondary
– objective response rate
– overall survival
– safety profile
– quality of life (EORTC QLQ-C30 and QLQ-BR23)
– medical care utilisation*or death O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel:baseline characteristics
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda/docetaxel(n=255)
Docetaxel(n=256)
Age (years): median, range 52 (26–79) 51 (25–75)KPS (%): median, range 90 (70–100) 90 (70–100)ER/PR (%)
Positive/negative/unknown 39/32/29 42/28/30Metastatic sites (%)
Lymph nodes/liver 47/45 49/48
Bone/lung 42/37 46/39
KPS = Karnofsky Performance Status
Xeloda® plus docetaxel:chemotherapy pretreatment
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Prior therapy
Xeloda/docetaxel
(n=255) (%)Docetaxel
(n=256) (%)
Anthracyclines 100 100
Alkylating agents 93 92
5-FU 77 74
Paclitaxel 10 9
Study treatment (%)
First line 35 31
Second line 48 53
Third line 17 15
Xeloda® plus docetaxel: overall tumour response
Xeloda/docetaxel(n=255)
Docetaxel(n=256)
InvestigatorPR + CR (%) 42 30 p=0.006
95% CI 35–48 24–36
Stable disease (%) 38 44
95% CI 32–44 38–51
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel : duration of response
Time (months)
1.0
0.8
0.6
0.4
0.2
0
Xeloda/docetaxel 7.2Docetaxel 6.9
Est
imat
ed p
rob
abil
ity
0 5 10 15 20 25
6.9 7.2
Median (months)
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: time to disease progression
4.2 6.1
Xeloda/docetaxelDocetaxel
Hazard ratio = 0.643(0.536–0.770)
Log-rankp=0.0001
Median (CI)6.1 (5.4–6.5)4.2 (3.4–4.5)
1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed p
rob
abil
ity
0 5 10 15 20 25
Time (months)O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: overall survival*
1.0
0.8
0.6
0.4
0.2
0.0
Est
imat
ed p
rob
abil
ity
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (months)
Median (CI) EventsXeloda/docetaxel 14.5 (12.3–16.3) 72%
Docetaxel 11.5 (9.8–12.7) 79%
11.5 14.5
Hazard ratio = 0.775
Log-rankp=0.0126
*Minimum follow up of 15 months (4-month safety update)
Xeloda® plus docetaxel:post-study treatment
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Post-study treatment
Xeloda/docetaxel(n=255)
Docetaxel(n=256)
Cytotoxic chemotherapy (%) 63 61
Endocrine therapy (%) 27 26
Xeloda (%) 3 15
Herceptin (%) 8 8
Vinorelbine (%) 26 23
Xeloda® plus docetaxel: quality of life (global health status)
80
70
60
50
40
Glo
bal
hea
lth
sta
tus
0 6 12 18 24 30 36 42 48
Time (weeks)Xeloda/docetaxeln=219 187 127 97 57 41 31 21 13
Docetaxeln=224 190 133 85 42 20 14 12 5
0
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: most common treatment-related clinical adverse events (all grades)
Xeloda/docetaxel (n=251)
Docetaxel (n=255)
Diarrh
oea
Stom
atiti
sHFS
Nause
a
Fatig
ue/
asth
enia NF
Vomiti
ng
Alopec
ia
Pyrex
ia
Mya
lgia
Arthra
lgia
HFS = hand-foot syndrome; NF = neutropenic fever
70
60
50
40
30
20
10
0
Pat
ien
ts (
%)
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: most common (>5%) grade 3/4 treatment-related toxicities
30
25
20
15
10
5
0
Pat
ien
ts (
%)
Xeloda/docetaxel (n=251)
Diarrh
oea
Stom
atiti
sHFS*
Nause
a
Fatig
ue/
asth
enia NF
Docetaxel (n=255)
Grade 3Grade 4
Grade 3Grade 4
*Grade 4 not applicable; NF = neutropenic feverO’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: grade 3/4 treatment-related adverse events over time
100
80
60
40
20
0
Ad
vers
e ev
ents
(%
)
0 6 12 18 24 30 36 42 48 54
Time (weeks)
Xeloda/docetaxel
Docetaxel
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: most common grade 3/4* laboratory abnormalities
Xeloda/docetaxel (%)
(n=251)Docetaxel (%)
(n=255)
HaematologyHaemoglobin (<8.0g/dL)Neutrophils (0.5–1.0x109/L)Neutrophils (<0.5x109/L)Platelets (<50x109/L)
9.619.444.0
2.8
5.910.262.0
2.8
ChemistryASAT (SGOT) (>5.0 x ULN)Alkaline phosphatase (>5.0 x ULN)Total bilirubin (>1.5–3 x ULN)Total bilirubin (>3 x ULN)
2.80.86.82.0
3.51.81.61.6
*NCIC common toxicity criteria; ULN = upper limit of normal
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel:dose reductions
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Dose reduction
Xeloda/docetaxel(n=251)
Docetaxel(n=255)
To 75% of initial dose (%)
Xeloda alone 4
Docetaxel alone 12 34
Both 47
To 50% of initial dose (%)
Xeloda alone 17
Docetaxel alone 2 7
Both 2
Xeloda® plus docetaxel: summary of safety
Treatment with oral Xeloda plus docetaxel compared with docetaxel alone leads to
– more gastrointestinal side effects and hand-foot syndrome
– less myalgia, arthralgia and grade 4 neutropenia with associated complications (neutropenic fever/sepsis)
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus docetaxel: conclusions
The addition of oral Xeloda to docetaxel leads to
– superior response rates
– superior time to disease progression
– superior overall survival
with a manageable safety profile
Xeloda plus docetaxel is the first and only cytotoxic combination to improve survival over docetaxel monotherapy in anthracycline-pretreated patients
O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)
Xeloda® plus paclitaxel: phase II trial
Ongoing study evaluating a 21-day cycle of– Xeloda 1,000mg/m2 twice daily, days 1–14– i.v. paclitaxel 175mg/m2, day 1
All patients had anthracycline-pretreated advanced/metastatic breast cancer
62% objective response rate including 16 complete responses (23%) in 71 evaluable patients
8.6 months median time to disease progression
Favourable safety profile, with a low incidence of severe toxicities
Pérez-Manga G et al. Breast Cancer Res Treat 2000;64:125 (Abst 535)
Xeloda® plus docetaxel plus epirubicin
Phase I study in 23 patients with advanced breast cancer
Principal dose-limiting toxicity was neutropenia, non-haematological toxicities were rare
Recommended regimen is a 21-day cycle of
– Xeloda 985mg/m2 twice daily, days 1–14– i.v. docetaxel 75mg/m2, day 1– i.v. epirubicin 75mg/m2, day 1
Objective responses occurred in 21 of 23 patients enrolled (91%)
Angiolini C et al. Breast Cancer Res Treat 2000;64:123 (Abst 529)
Xeloda® plus vinorelbine: phase I study
40 pretreated patients with advanced/metastatic breast cancer received a 21-day cycle of
– Xeloda 500–1,250mg/m2 twice daily, days 1–14
– i.v. vinorelbine 12.5–22.5mg/m2, days 1 and 3
Maximum tolerated dose not yet defined
48% response rate in 33 evaluable patients treated at all dose levels
Minimal toxicity
Nolè F et al. Breast Cancer Res Treat 2000;64:125 (Abst 539)
Xeloda® plus weekly docetaxel:phase I/II study
12 patients with anthracycline-pretreated MBC have been treated in an ongoing phase I/II study
Recommended dose identified as intermittent Xeloda 900mg/m2 twice daily plus weekly docetaxel 30mg/m2
Feasible safety profile with a low incidence of severe myelosuppression– only one grade 4 adverse event (neutropenia)– most common (>10%) grade 3 adverse events were
asthenia (five patients) and nail toxicity (four patients) Objective tumour responses in six of 11 evaluable
patients
Mackey J. 2nd International Breast Cancer International Research Group Conference, Edmonton, Canada, June 26–28, 2000
Ongoing Xeloda® combination trials
Additional trials are investigating Xeloda plus
Weekly paclitaxel/docetaxel
Vinorelbine (three studies exploring different schedules)
Docetaxel/epirubicin in untreated advanced breast cancer
Cyclophosphamide/epirubicin as neo-adjuvant therapy (EORTC)
Idarubicin
Cyclophosphamideall-oral regimens