All country-specific updates were consolidated into the v2.0 protocol. In addition, the following key updates were made: • Analytes to be measured as part of PK endpoint updated. • Eligibility criteria updated to: o Be more representative of the 2nd-line patient population. o Allow patients who have relapsed on prior neoadjuvant therapy. o Ensure that patients who can no longer receive oxaliplatin due to toxicity or allergy are eligible regardless of duration of prior therapy. o Ensure that patients with benign neutropenia who are otherwise eligible are not excluded. o Allow patients who tolerated prior treatment with 5-FU but at a reduced dose level to participate and to receive 5-FU at the same reduced dose. o Clarify that dosing of prednisolone ≥10 mg is not permitted during study participation. o Allow patients with skin reactions that are due to recent anti-cancer treatment. o Allow Investigators to initially withhold bevacizumab (for a maximum of 1 cycle) to allow wound healing. o Exclude concomitant use of sorivudine or analogues. • Text added to ensure that 5-FU dose adjustments in patients with partial DPD deficiency are in accordance with standard practices on a country-by-country basis. • Text added to allow Investigators to perform an initial dose reduction of irinotecan for patients with a known mutation that may affect their ability to metabolise irinotecan. • Text added to allow patients who have previously tolerated bevacizumab infusions well to receive all infusions over 30 minutes, rather than receiving the first and second infusions over 90 and 60 minutes, respectively. • The use of levo-LV was removed. • Time that live vaccines are prohibited extended to 3 months after the last dose of study treatment. • SAE reporting requirements updated to align with latest guidelines.

The following key updates were made: • Inclusion criterion 12 updated to clarify that patients with Gilbert’s syndrome do not need to meet the threshold for bilirubin levels. • It was clarified that Investigators can perform DPD status testing by either genotyping or phenotyping as per their local standard practices.