thymidine phosphorylase (tp) upregulation dose- and time-dependent upregulation of tp in human colon...

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


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


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


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


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)


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


Post-study treatment


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


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 (

%)


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


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


Xeloda® plus docetaxel:dose reductions


Dose reduction


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)


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


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

thymidine phosphorylase (tp) upregulation dose- and time-dependent upregulation of tp in human colon...

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