Trial Information

A Randomised Study of Sequential Versus Combination Chemotherapy in Patients With Previously Untreated Advanced Colorectal Carcinoma

Objectives: Primary objective:

To assess the efficacy, defined as overall survival, of sequential versus combination
chemotherapy for advanced CRC.

Secondary objectives are to assess:

To assess Tumour response (CR, PR or SD) Progression free survival Quality of life Toxicity
profile Methodology Open, randomised multicenter phase III study. Randomisation by centre
will be centralized by IKC. Number of patients 820 Main criteria for inclusion Histology
and staging disease

- Histologically proven advanced CRC; not amenable to curative surgery;

- Of Note: In case of a single metastasis, histological or cytological proof of
colorectal carcinoma should be obtained prior to randomisation.

- Measurable or evaluable disease. Serum CEA as the only parameter for disease activity
is not allowed.

General conditions

- Written informed consent;

- Age 18 years and above;

- WHO performance status 0-2;

- Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/L, Hb > 6
mmol/L);

- Adequate hepatic function: total bilirubin < 1. 5 x upper normal limit, ASAT and ALAT <
3 x upper normal limits (in case of liver metastases < 5 x upper normal limits);

- Adequate renal function: creatinin < 1. 5 x upper normal limits. Other

- Expected adequacy of follow-up.

Main criteria for exclusion General conditions

- Pregnancy or lactation;

- Patients (M/F) with reproductive potential not implementing adequate contraceptives
measures.

Prior or current history

- Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed,
provided that the last drug administration took place more than 6 months prior to
randomisation.

- Serious concomitant diseases preventing the safe administration of chemotherapy or
likely to interfere with the study assessments;

- Serious active infections;

- Inflammatory bowel disease or other diseases associated with chronic diarrhoea;

- Previous extensive irradiation of pelvis or abdomen;

- Other malignancies in the past 5 years with the exception of adequately treated
carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin.

Concomitant treatments

- Concomitant (or within 4 weeks before randomisation) administration of any other
experimental drug under investigation;

- Concurrent treatment with any other anti-cancer therapy. Test product, dose and mode of
administration Arm A First line: capecitabine

Every 3 weeks (q 3):

capecitabine 1250 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until
progression or unacceptable toxicity. Continuation after 6 months without disease
progression and/or severe toxicity at the investigator's discretion.

Second line: irinotecan

Every 3 weeks (q 3):

irinotecan 350 mg/m2 IV infusion on day 1. This schedule will be continued until progression
or unacceptable toxicity. Continuation after 6 months without disease progression and/or
severe toxicity at the investigator's discretion.

Third line: oxaliplatin plus capecitabine oxaliplatin 130 mg/m2 IV infusion on day 1 and
capecitabine 1000 mg/m2 orally b.i.d. on day 1-14. This schedule will be continued until
progression or unacceptable toxicity. Continuation after 6 months without disease
progression and/or severe toxicity at the investigator's discretion.

Arm B First line: irinotecan plus capecitabine

Every 3 weeks (q 3):

irinotecan 250 mg/m2 IV infusion in 30 minutes on day 1 2 hours after discontinuation of the
infusion followed by capecitabine 1000 mg/m2 orally b.i.d. on day 1-14. This schedule will
be continued until progression or unacceptable toxicity. Continuation after 6 months without
disease progression and/or severe toxicity at the investigator's discretion.

Second line: oxaliplatin plus capecitabine

Every 3 weeks (q 3):

oxaliplatin 130 mg/m2 IV infusion in 2 hours on day 1 and capecitabine 1000 mg/m2 orally
b.i.d. on day 1-14. This schedule will be continued until progression or unacceptable
toxicity. Continuation after 6 months without disease progression and/or severe toxicity at
the investigator's discretion.

Duration of treatment and follow-up Treatment is continued until disease progression, or
unacceptable toxicity. Patients will be followed by CT-scan every 9 weeks for response while
on treatment, or at any other moment when progression is suspected. After cessation of
chemotherapy, patients will be followed every 3 months until death. Death or progression
should be reported whenever it occurs.

Criteria for evaluation Efficacy All patients will be included in the survival analysis
(intent-to-treat). All patients receiving > 9 weeks of treatment (i.e. 3 cycles) will be
considered evaluable for response, unless documented progression occurred earlier.

Safety profile Safety will be analysed in each treatment group. Patients having received >
treatment doses are evaluable for toxicity. Evaluation will be performed by patient and by
cycle on the intent-to-treat population. Clinical and laboratory toxicity/symptomatology
will be graded according to NCI common criteria. The adverse events which are not reported
in NCI common criteria will be graded as: mild, moderate, severe, life threatening.

Statistical methodology The expected median survival in Arm A (standard arm) is 14 months.
It is anticipated that the median survival in Arm B (experimental arm) will be 19 months.
620 patients (310 in each arm) are needed to show this increase in median survival (>=0,05
and >=0,80).

Stratification parameters Patients will be stratified for the following parameters:

- WHO performance status 0-1 vs 2

- Serum LDH normal versus above normal

- Prior adjuvant therapy versus no prior adjuvant therapy

- Predominant localisation of metastases in the liver vs extrahepatic site(s)

- Per participating institution