Removal of toxicity, bowel toxicity and adverse event monitoring assessments at the primary endpoint visit as this was a duplicated assessment (already performed at cycle 4 toxicity). • Change to liver function criteria. Added to inclusion criteria, removed from exclusion criteria. Liver function: Patients must have (with or without the presence of liver metastases): o A prothrombin time >70% NV (normal value) AND o Bilirubin <1.5xULN AND o Transaminases <2.5xULN AND o GGT <5xULN • Changes to Primary Endpoint Assessment visit. o Adverse events and toxicity assessment removed o Bowel toxicity monitoring removed. • Clarification that patients who father a child during the course of treatment must be reported as a SAE. SAEs are defined as events that occur after the commencement of study treatment and up to 30 days following the last dose of study drug.

Inclusion criteria revised to ensure that patients have GFR ≥ 60ml/min. GFR to be assessed according to local practice (recommended technique of eGFR using the MDRD formula (see Appendix 2). Where GFR is 55-60ml/min please contact the trials unit for a decision to be made on patient inclusion by the Chief Investigator OR Clinical Co-ordinator. The Trial Management Group (TMG) reviewed discussed the inclusion criteria that GFR should be ≥60ml/min. The TMG and Trial Steering Committee agreed to amend the inclusion criterion to consider patients for the trial with GFR 55-60ml/min as long as all other eligibility criteria are met. The decision to include such a patient must be discussed with the Chief Investigator and/or the Clinical Coordinator. Previous safety concerns raised by Pierre Fabre (drug company for Vinflunine), about inclusion of patients with a lower GFR, in relation to renal function, originate from use of Vinflunine in bladder cancer patients where disturbance of renal function would be expected; the TMG and TSC agreed that this safety concern is not applicable to this patient group. This amendment was also supported by the pharmaceutical company, Pierre-Fabre. Added requirement to forward SAEs and SARs to the pharmaceutical company, Pierre-Fabre. Change to ICR professional address in affiliations for all ICR staff: Sutton, Surrey to London to comply with new institutional guidance.

Change to the liver function criteria in line with the SmPC. Liver function parameters updated to allow patients on trial with transaminases <5xULN only in the presence of liver metastases. This accurately reflects the parameters outlined in the summary of product characteristics (SmPC). The trial management group discussed and agreed to this update on the basis that the protocol should fall in line with the SmPC recommendations for patients with hepatic impairment: Liver function: Patients must have (with or without the presence of liver metastases): o A prothrombin time >70% NV (normal value) AND o Bilirubin <1.5xULN AND o Transaminases <2.5xULN (<5xULN only in the case of liver metastases) AND o GGT <5xULN

• Change to the liver function criteria - Specifying AST and/or ALT to be consistent with the wording in section 8.3 of the protocol • Changes to the exclusion criteria: o Patients who are sexually active and unwilling to use effective contraception (if they are not already surgically sterile). New exclusion criterion linked with new section – lifestyle guidelines: Update to the protocol to provide a definition of effective contraception. o Other malignancy (other than Squamous Cell Carcinoma or Basal Cell Carcinoma of non-penile skin) that has required surgical or non-surgical treatment in the last 2 years. Change from 5 to 2 years. The 5 year window was an arbitrary timeframe and two years was felt to be a more reasonable period • If a patient’s performance status deteriorates to PS2, the decision to continue to treat the patient should be made by the local treating clinician. Where possible, discussion with the either the Chief Investigator or Clinical Co-ordinator is encouraged before the next cycle of vinflunine is administered. • Drug Dose Reduction Schedule - If any of the criteria for a dose reduction or delay are met, for example a grade 3 toxicity (considered severe or life threatening), but in the opinion of the treating clinician the event does not indicate a need to dose reduce at the expense of the patient deriving benefit from vinflunine, the case should be discussed with either the Chief Investigator or Clinical Co-ordinator prior to the start of the next cycle of treatment. • correction that IDMC, not TMG are responsible for reviewing evaluability of patients.