Xeloda® plus oxaliplatin:rationale in colorectal cancer (CRC)

Oxaliplatin is active in CRC, especially when combined with 5-FU/leucovorin (LV)

Superior response rate and time to disease progression observed with the addition of oxaliplatin to 5-FU/leucovorin

Synergistic activity of fluoropyrimidines and oxaliplatin can partly overcome clinical resistance to fluoropyrimidines

No overlap in key toxicities

Xeloda® plus oxaliplatin phase I study: DLTs by dose level

*The first six patients were enrolled for determination of the maximum tolerated dose (MTD) and a total of eight patients were treated at this dose levelDLT = dose-limiting toxicity

Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

Xeloda(mg/m2 twice daily)

No. ofpatients

DLTs(no. of patients)

500 3 None

825 3 None

1,000 3 + 6 G3 diarrhoea (1)

1,250 6 (8)* G3 diarrhoea withthrombocytopenia (1)

G4 diarrhoea withneutropenia (1)

Xeloda® plus oxaliplatin phase I study: most common treatment-related, clinical adverse events (all cycles)

0

20

40

60

80

100

Pat

ien

ts (

%)

Nausea

Paraesth

esia

Vomiting

Dysaesthesia

Diarrhoea

Asthenia

Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

Xeloda® plus oxaliplatin phase I study:efficacy in CRC patients (n=9)

Tumour responseNo. of

patientsPrior treatment(no. of patients)

Partial response 5 5-FU (5), irinotecan (4)

Stable disease 3 5-FU (3)

Progressive disease 1 5-FU plus eniluracil (1)

Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

Xeloda® plus oxaliplatin phase I study: summary

Xeloda/oxaliplatin combination therapy is feasible and exhibited promising antitumour activity in patients with CRC

The MTD is Xeloda 1,250mg/m2 twice daily (days 1–14) with i.v. oxaliplatin 130mg/m2 (day 1), every 21 days

The recommended dosing schedule is oral Xeloda 1,000mg/m2 twice daily (days 1–14) with i.v. oxaliplatin 130mg/m2 (day 1), every 21 days

Xeloda/oxaliplatin combination therapy is being evaluated as first-line CRC therapy in phase II studies

Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

Xeloda® plus irinotecan: rationale in CRC

Single-agent antitumour efficacy of Xeloda and irinotecan as first-line chemotherapy

Superior response rate, time to disease progression and survival observed with the addition of irinotecan to 5-FU/LV

Efficacy of irinotecan in 5-FU-resistant patients

Different mechanisms of action

Partial overlap of key toxicities

In preclinical studies, Xeloda plus irinotecan demonstrated at least additive efficacy

Xeloda® plus irinotecan phase I study: treatment schedule

1 8 15 22 29 36 49

Irinotecan70/80/90mg/m2 as a 30-minute

i.v. infusion

Oral Xeloda1,000/1,250mg/m2

twice daily

Repeat cycle at day 50

Days 1–14 Rest Days 22–35 Rest

Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

Day

Xeloda® plus irinotecan phase I study: DLTs by dose level

Phase I study(no. of patents)

Extended phase I study(no. of patients)

Doselevel Treated

WithDLT Treated Total

DLTs(no. of patients)

1,000/70 3 0 9 (ongoing) 12 Too early

1,250/70 8 2 7 15 G3 neutropenia (1)G4 diarrhoea (3)

G4 diarrhoea withneutropenia/

sepsis (1)

1,250/80 6 3 – – G3 diarrhoea (1)G3 diarrhoea withG4 neutropenia (1)

G3 asthenia (1)

Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

Xeloda® plus irinotecan phase I study: preliminary antitumour activity

Among 19 evaluable patients– tumour responses (CR/PR) occurred

in 42% of patients (95% CI: 20–67)– disease was stabilised in an additional

53% of patients (95% CI: 30–76)

Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

Xeloda® plus irinotecan phase I study: conclusions

The predominant DLTs were diarrhoea and neutropenia

The MTD was identified as irinotecan 80mg/m2 with Xeloda 1,250mg/m2

DLTs occurred in five of 15 evaluable patients (33%) treated with irinotecan 70mg/m2 plus Xeloda 1,250mg/m2 twice daily

Dose level 1 (irinotecan 70mg/m2 plus Xeloda 1,000mg/m2 twice daily) is currently being evaluated in an extension of the trial

Based on preliminary data, the combination of Xeloda and irinotecan has significant antitumour activity

Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

Xeloda® plus radiotherapy:rationale in rectal cancer

Xeloda mimics continuous infusion 5-FU which as a partner for radiotherapy prolongs survival compared with bolus 5-FU1

Radiotherapy upregulates thymidine phosphorylase in tumour cells but not in healthy tissue2

Xeloda/radiotherapy treatment demonstrated highly enhanced activity compared with either treatment alone, whereas radiotherapy plus 5-FU showed no clear additive effects2

1O’Connell MJ et al. N Engl J Med 1994;331:502–72Sawada N et al. Clin Cancer Res 1999;5:2948–53

Xeloda® plus radiotherapy phase I study:dosing schedule

Radiotherapy– 1.8 Gray/day– 5 days/week up to 50.4 Gray plus boost

S2–S5 5.4 Gray

Oral Xeloda– first day until last day of radiotherapy– dose levels: 250, 375, 500, 650, 825 and

1,000 mg/m2 twice daily

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: DLTs by dose level

Dose(mg/m2 twice daily)

No. ofpatients

DLTs(no. of patients)

250 3 –

375 3 –

500 6 –

650 6 –

825 8 –

1,000 6 G3 hand-footsyndrome (2)*

*Developing on days 22 and 30 of treatment, respectively

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: incidence of adverse events (all grades) by dose level

These adverse events were all grade 1/2, except one case of grade 3 local skin toxicity (650mg/m2 dose level) and one case of grade 3 diarrhoea (1,000mg/m2 dose level)

Leucopenia Local skin toxicity Diarrhoea

100

80

60

40

20

0

250mg/m2

375mg/m2 500mg/m2

650mg/m2

825mg/m2

1,000mg/m2

Inci

den

ce (

% o

f co

ho

rt)

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: incidence of adverse events (all grades) by dose level (cont’d)

All episodes of these three adverse events were grade 1/2

Nausea Constipation Abdominal pain

100

80

60

40

20

0

Inci

den

ce (

% o

f co

ho

rt)

250mg/m2

375mg/m2 500mg/m2

650mg/m2

825mg/m2

1,000mg/m2

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: summary of safety

The majority of adverse events were mild to moderate

Grade 1/2 leucopenia was the most common toxicity

There was no significant decrease in haemoglobin concentrations

Hand-foot syndrome was dose-limiting at Xeloda 1,000mg/m2

The only other grade 3 adverse events were rash/itch (375mg/m2), local skin toxicity (650mg/m2) and diarrhoea* (1,000mg/m2) (one patient each)

There were no grade 4 toxicities

*which resolved to grade 1/2 within 2 days

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: efficacy

Ten patients were treated in the neo-adjuvant setting with three patients too early for evaluation

Preliminary data from seven patients indicate that– tumours were down-staged in six patients– there was one pathologically confirmed

complete response

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

Xeloda® plus radiotherapy phase I study: conclusions

MTD is Xeloda 1,000mg/m2 twice daily in combination with radiotherapy

The recommended dose for further phase II evaluation is Xeloda 825mg/m2 twice daily in combination with radiotherapy

Xeloda simplified chemoradiotherapy and was highly appealing to the patients

In combination with radiotherapy, Xeloda offers the potential to replace bolus or continuous infusion 5-FU as the standard treatment for rectal cancer

Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)