b 10 mg/kg every 2 weeks.

c Relative to control arm.

NR = not reached.

NO16966

This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating Avastin 7.5 mg/kg in combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3-weekly schedule; or Avastin 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus, followed by 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule. The trial contained two parts: an initial unblinded 2-arm part (Part I) in which patients were randomised to two different treatment groups (XELOX and FOLFOX-4) and a subsequent 2 x 2 factorial 4-arm part (Part II) in which patients were randomised to four treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + Avastin, FOLFOX-4 + Avastin). In Part II, treatment assignment was double-blind with respect to Avastin.

Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial.

Table 5 Treatment regimens in trial N016966 (mCRC)

 Treatment
 Starting dose
 Schedule
 
FOLFOX-4

or

FOLFOX-4 + Avastin
 Oxaliplatin
 85 mg/m2 IV 2 h
 Oxaliplatin on day 1

Leucovorin on day 1 and 2

5-fluorouracil IV bolus/infusion, each on days 1 and 2
 
Leucovorin
 200 mg/m2 IV 2 h
 
5-Fluorouracil
 400 mg/m2 IV bolus, 600 mg/ m2 IV 22 h
 
Placebo or Avastin
 5 mg/kg IV 30-90 min
 Day 1, prior to FOLFOX-4, every 2 weeks
 
XELOX

or

XELOX+ Avastin
 Oxaliplatin
 130 mg/m2 IV 2 h
 Oxaliplatin on day 1

Capecitabine oral bid for 2 weeks (followed by 1 week off treatment)
 
Capecitabine
 1000 mg/m2 oral bid

Placebo or Avastin
 7.5 mg/kg IV 30-90 min
 Day 1, prior to XELOX, q 3 weeks
 
5-Fluorouracil: IV bolus injection immediately after leucovorin
The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial, there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that Avastin in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy alone. Both co-primary objectives were met:
● Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival and overall survival in the eligible per-protocol population.
● Superiority of the Avastin-containing arms versus the chemotherapy alone arms in the overall comparison was demonstrated in terms of progression-free survival in the ITT population (Table 6).
Secondary PFS analyses, based on 'on-treatment'-based response assessments, confirmed the significantly superior clinical benefit for patients treated with Avastin (analyses shown in Table 6), consistent with the statistically significant benefit observed in the pooled analysis.
Table 6 Key efficacy results for the superiority analysis (ITT population, trial NO16966)
Endpoint (months)
 FOLFOX-4 or XELOX + placebo