Trial Information

Cetuximab Added to Capecitabine, Oxaliplatin and Bevacizumab in Patients With Previously Untreated Advanced Colorectal Carcinoma, a Randomised Phase III Study

Primary objective: To assess the efficacy, defined as progression-free survival (PFS), of
adding cetuximab to capecitabine/oxaliplatin/bevacizumab for advanced CRC.

Secondary objectives: To assess tumour response (CR, PR or SD), response duration, overall
survival, toxicity profile, quality of life, translational research.

Methodology: Open, randomised multicenter phase III study. The number of patients is 750.

Test products: All cycles will be administered q 3 weeks. Oxaliplatin will be discontinued
after 6 cycles in both study arms. The dose of capecitabine will be increased to 1250 mg/m2
b.i.d. as of cycle 7.

Arm A: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles),
oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v.
infusion on day 1.

Arm B: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles),
oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v.
infusion on day 1. Cetuximab 400 mg/m2 i.v. day 1 of cycle 1, thereafter weekly 250 mg/m2
i.v.

Duration of treatment and follow-up: Treatment is continued until disease progression, or
unacceptable toxicity. Patients will be evaluated every 9 weeks for response while on
treatment, or at any other time point when progression is suspected. After cessation of
therapy for reasons other than disease progression, patients will be followed every 3 months
until progression or death. Death and/or progression should be reported whenever it occurs.

In case chemotherapy (i.e. capecitabine and/or oxaliplatin) is discontinued for reasons of
toxicity, treatment with bevacizumab (arm A) or bevacizumab + cetuximab (Arm B) should be
continued until progression or unacceptable toxicity. Also, if chemotherapy plus bevacizumab
is discontinued in Arm B for reasons of toxicity, treatment with cetuximab should be
continued until progression or unacceptable toxicity.

Criteria for evaluation:

Efficacy: All eligible patients will be included in the 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 ≥
1 treatment doses are evaluable for toxicity. Evaluation will be performed on the safety
population (having received treatment, assignment to treatment groups as treated). Clinical
and laboratory toxicity/symptomatology will be graded according to NCI common toxicity
criteria, version 3.0. The adverse events which are not reported in NCI common toxicity
criteria will be graded as: mild, moderate, severe, life threatening.

Statistical methodology: The main endpoint of the study is the progression free survival
interval (PFS). PFS curves will be constructed by means of the Kaplan Meier method.
Comparisons of PFS curves will performed by mean of the log rank test. Similar methods will
be used to analyse the duration of survival. All analyses will be done according to the
intention-to-treat principle.

The expected median PFS in Arm A (standard arm) is 11 months. The minimum increase in PFS in
Arm B (experimental arm) will be 3 months (21% hazard ratio reduction). 540 events are
required for 80% power. 740 patients are needed to show this difference (>=0.05, 2-tailed
test). To allow for ineligibility in some patients, a total of 750 patients will be
included.

Stratification parameters:

Patients will be stratified for the following parameters:

- Prior adjuvant therapy (yes versus no);

- Number of organs affected (1 versus > 1, in case the primary tumour is in situ this
will count as one organ);

- Serum LDH (normal versus above normal);

- Per participating institution.

Side studies: Side studies on prognostic factors in tumour samples from included patients
will be performed, as well as on circulating tumour cells and endothelial cells and serum
proteomics.