Update to protocol in line with summary of product characteristics for one of the trial drugs (oxaliplatin). The changes are regarding contraception requirements and the definition of adequate haematological function required to enter the trial. Additionally: • Add a further 2 research sites to the trial (centres in Oxford & Belfast) • Correction of an oversight in the patient information sheet, whereby there was no specific mention made of the radioisotope test of kidney function which may be required for some trial patients. • Minor changes to the wording of the patient diary, to ensure clarity and quality of data collected.

The amendment consists of: 1. Amendments to the protocol: a. Only excluding patients with previous malignancies if these were within the previous 5 years. b. Allowing the Wright formula to be used as an alternative to the Cockroft-Gault formula. c. Clarifying that radioisotope determination of GFR in patients with estimated creatinine clearance <30 ml/min at screening is not mandatory d. Clarifying distribution of consent form copies e. Amendment to suggested premedication guidance relating to ondansetron f. Allowing for local variation in which coagulation tests are completed g. Allowing for pre chemotherapy assessments to be completed within 2 working A Research Ethics Committee established by the Health Research Authority days of treatment h. Other minor clarifications, spelling corrections, correction of contact details. 2. New Participant Information Sheet and informed consent form to be used in the event of a participant's partner becoming pregnant. 3. Two new sites 4. A change of Principal Investigator

The main purpose of this amendment is to:  Make a number of wording changes to the trial protocol. These are fully documented in the enclosed amendment form and amended trial protocol, but in brief they include: o Extending the timeline between radiological progression to randomisation to 6 weeks, whilst still ensuring that both randomisation and start of chemotherapy (ARM B ONLY) begin within 6 weeks of progression. o Clarifying that either Alanine Aminotransferase (ALT) and / or Aspartate Aminotransferase (AST) can be performed. o Allowing sites to perform a chest-abdo scan and a pelvic scan separately. o Clarification of the hypertension grading. Patients are only eligible if the hypertension grading is < grade 3 according to CTCAE v4.03, unless controlled with medication and/or diet. o Other minor clarifications, spelling corrections, correction of contact details.  Make a number of wording changes to the trial consent form. These are fully documented in the enclosed amendment form and amended informed consent form, but in brief they include: o Clarifying that the screening ID must be recorded on the consent form copies as well as the participant ID. o Amendment to the consent form in order to ensure that NHS sites can adhere to the MHRA GCP inspections by ensuring that patients consent for sections of their medical notes and data collected during the study may be looked at by authorised individuals. o Clarification that a copy of the consent form can be provided to the patient rather than the original

Addition on one study site.

• Reclassifying Calcium Folinate and L-Folinic Acid as Non Investigational Medicinal Products (NIMPs) as they were incorrectly classified as Investigational Medicinal Products (IMPs) at set-up. o Change to inclusion criteria 6 to reduce the absolute neutrophil count to reflect the clinical cut-out level for treatment with FOLFOX. o Change to inclusion criteria 12 to clarify wording only. o Change to exclusion criteria 9 to permit patients who do not have a history of other invasive cancers within the last 5 years to enter the trial. • Clarifying platinum sensitivity definitions; a factor controlled for at randomisation: o Confirmed ‘progressive disease’ is ‘radiologically confirmed progressive disease’. o Confirmed the three month cut off in days (three months = 90 days) to enable sites to make precise calculations for platinum sensitivity. o Clarified the date of ‘completion of last cycle of first line chemotherapy’ is defined as the day 1 date of the last cycle given. • Confirming the patient diary at screening must be completed retrospectively for the previous 2 weeks prior to randomisation, if the screening period is over a short time. • Clarifying a 6 week timeframe is allowed from staging CT and optional MR liver scan, to randomisation. • Clarifying baseline and subsequent CT scans must be reported in accordance with RECIST v1.1. • Adding in guidance to ensure translational research samples are not taken from patients with HIV or Hep C or other transmissible human disease; or from patients who are in high risk groups such as intravenous drug users. • Clarifying what needs to be collected when patients are on survival follow-up only. • Clarifying timing for the end of treatment visit (ensuring it is clear this should be carried out within 30 days of the last treatment dose). Changes have also been to the Patient Diary, to make it less onerous to complete and to assist with data interpretation, and to the GP letter as a date field for comp

Changes made within this amendment are as follows: • Change in PI at St James’s University Hospital, Leeds. • Change in PI at Nottingham University Hospital, Nottingham (Dr Victoria Brown to Dr Michelle Cunnell) for the period Feb 2016 – Jun 2016 • Change in PI at Nottingham University Hospital, Nottingham (Dr Michelle Cunnell to Dr Arvind Arora) for the period Jun 2016 – present

Changes made within this amendment are as follows:  Removal of Great Western Hospitals NHS Foundation Trust, Swindon  Removal of Cheltenham General Hospital  Extension to trial end date from 30/04/2017 to 30/11/2018  Change of Principal Investigator at St James Hospital, Leeds  Minor clarification added to inclusion criteria 2 – refer to summary of protocol changes document

This amendment concerns changes to the Reference Safety Information, Section 4.8 Undesirable Effects of Fluorouracil SmPC updated 27-APR-2016 (from version dated 25-MAR-2014) and to the Reference Safety Information, Section 4.8 Undesirable Effects of Oxaliplatin SmPC updated 06-NOV- 2016 (from version dated 30-DEC-2013). The Chief Investigator has reviewed the updated SmPCs and confirmed there is no impact to the riskbenefit ratio

· All references to the MAHSC-CTU have been updated to the Manchester Clinical Trials Unit (MCTU) · MCTU contact details updated – Project Manager, Statistician and generic e-mail address · Randomisation line details updated · Safety reporting contact details updated