The REC requested some revisions to the protocol. Also, new data emerged at ASCO 2004 to suggest that capecitabine was as effective as 5-FU/FA and so the trial design was changed to incorporate capecitabine as the standard arm into Protocol v4.0, Capecitabine vs capecitabine+irinotecan vs capecitabine+irinotecan+bevacizumab As the original submission was still being considered by the REC, Protocol v4.0 was submitted using an amendment form.

The REC sent a letter confirming their approval of the v4.0 protocol and that they had received the required favourable Site Specific Assessment from at least one study site.

At ASCO 2005, results of other trials involving irinotecan were presented. These results suggested that irinotecan added no benefit to colorectal patients in the adjuvant setting and so the QUASAR 2 Trial Management Group (TMG) took the decision to amend the trial design to a two arm trial design, capecitabine vs. capecitabine+bevacizumab Recruitment was suspended on 20 May 2005 6 patients had been randomised Arm A (capecitabine) = 3 Arm B (cap + iri) = 1 Arm C (cap + iri + bev) =2 Patients randomised to receive irinotecan (n=3) were given the opportunity to discuss their treatment options with staff at their hospital. Patients were offered the chance to continue in QUASAR 2 but without irinotecan or to withdraw from the trial.

Amended trial design incorporated into Protocol v6.0 and submitted to the REC as a substantial amendment. Inclusion was limited to colon cancer patients following discussions with Roche. Protocol v6.0 received favourable ethical opinion from the REC and approval from the MHRA. Recruitment reopened on 14 Sep 2006

Protocol v7.0 submitted to Ethics. This version detailed the use of blister packs rather than bottles for capecitabine, and included improved capecitabine dose modification tables. Stratification by cancer stage was also amended from two groups (stage II or stage III) to four groups (stage II T3, stage II T4, stage III T2/T3, stage III T4) following feedback from other colorectal trials at National meetings.

The inclusion of rectal cancer patients was agreed with Roche and the protocol amended to Protocol v8.0. This version was submitted to Ethics and the MHRA. Approval for Protocol v8.0 received from MHRA and a favourable ethical opinion from the REC. Recruitment of rectal cancer patients began from 12th Feb 2007.

Protocol v9.0 submitted to the main REC and the MHRA. This version provided guidance for investigators about chest pain, bilirubinaemia and neutropenia. The Patient Information Sheet and Blood & Tissue Consent Form were also amended. Approval for Protocol v9.0 received from MHRA and a favourable ethical opinion from the REC.

Protocol v10.0 submitted to the REC and the MHRA following an urgent safety measure: On 13th October 2010, the QUASAR 2 DSMC, in collaboration with the QUASAR 2 Clinical Leads, decided to withdraw Avastin (bevacizumab) from QUASAR 2 with immediate effect. This decision was made following the review of the top-line results from the AVANT study, an open-label Phase III, multicentre, multinational, randomised, 3-arm study designed to evaluate the efficacy and safety of bevacizumab in combination with either intermittent capecitabine plus oxaliplatin (XELOX) or 5-FU/LV with oxaliplatin (FOLFOX4) versus FOLFOX4 regimen alone as adjuvant chemotherapy in chemotherapy-naïve patients (stage III or high risk stage II) who undergo surgery with curative intent for colon carcinoma. A total of 3451 patients were randomized between December 2004 and June 2007. AVANT did not meet its primary endpoint of improving disease-free survival in stage III colon cancer. Adverse events were consistent with those previously observed in pivotal trials of Avastin across tumour types for approved indications. In line with the previously reported NSABP C-08 study results that also evaluated Avastin in the early-stage setting, the AVANT study showed that standard chemotherapy plus one year of Avastin is not effective in reducing the risk of relapses in early-stage colon cancer. Unlike the C-08 results, preliminary efficacy data from AVANT numerically favour chemotherapy alone (the control arm). After careful consideration of the results of AVANT, the QUASAR 2 DSMC, in collaboration with the QUASAR 2 Clinical Leads, decided to withdraw Avastin. QUASAR 2 patients still on active treatment of bevacizumab ceased bevacizumab treatment immediately and continued with capecitabine alone if they were within the first six months treatment, or continued with follow-up alone if they had already completed capecitabine. Approval of protocol v10.0 received from MHRA and a favourable ethical opinion