After amendment of the study protocol, bevacizumab (7.5mgkg�C1 selleck chem Nutlin-3a every third week) or placebo was added to XELOX, and bevacizumab (5mgkg�C1 every second week) or placebo to FOLFOX4. Bevacizumab or placebo was given as a 30- to 90-min intravenous infusion on day 1 of each cycle before oxaliplatin. Treatment was continued until disease progression or for 48 weeks, whichever came first (study treatment phase). Patients who completed the 48-week treatment phase without disease progression were eligible to continue treatment until progression (post-study treatment phase). Patients whose tumour became operable, and for whom resection was performed, were allowed to enter the post-study treatment phase. Assessments Tumour assessments (CT scan, MRI) were performed within 28 days before starting study treatment and repeated after every two XELOX cycles and every three FOLFOX4 cycles (i.
e., every sixth week in both arms), and at the end of treatment. After completion of study treatment, patients were followed every 3 months until disease progression and/or death. Patients were evaluated for adverse events during therapy and until 28 days after the last study drug dose. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3. Predefined adverse events of special interest for chemotherapy were: grade 3/4 neutropenia/granulocytopenia; grade 3/4 neurosensory toxicity; grade 3/4 diarrhoea; grade 3/4 vomiting/nausea; grade 3/4 stomatitis and grade 3 hand-foot syndrome.
Statistical analysis The intent-to-treat (ITT) patient population included all patients who underwent randomisation and signed the informed consent form. The eligible patient population (EPP) was the ITT population minus patients who did not receive at least one dose of study drug, and those patients who violated major protocol inclusion/exclusion criteria. As the results for the EPP population were the same as for the ITT population, ITT data only will be presented in this paper. The safety population included all patients receiving at least one dose of study drug. Overall survival was defined as the time from the date of randomisation to the date of death. Patients who were not reported as having died at the time of the analysis were censored using the date they were last known to be alive.
Overall survival was analysed using a Cox model and presented as Kaplan�CMeier estimates with hazard ratios (HRs) and 97.5% confidence intervals (CIs). The primary analysis of NO16966 was event driven and was performed on 31 January 2006 when 1200 progression-free survival events had occurred in the EPP; this approach ensured Entinostat 90% power at an �� level of 2.5 (Saltz et al, 2008). A further planned follow-up analysis of OS was performed at the time of the 4-month safety update.