N/A

Protocol changes to reflect the addition of a third treatment (pazopanib in combination with paclitaxel) arm to the PACMEL trial and other additional changes are provided separately with the notification. Pazopanib is an antiangiogenic agent. Evidence suggests that antiangiogenic therapies can enhance the impact of chemotherapy by inducing vascular normalization, alleviating hypoxia and increasing the delivery of cytotoxic chemotherapies to cancer cells. Clinical trials using pazopanib in combination with paclitaxel in the treatment of melanoma have also shown promising results. However, these results could be explained by patient selection. Therefore there is a need to compare the combination against paclitaxel alone. The PACMEL study offers a means to do this very efficiently, as the required control arm is already included in the trial and the entry criteria and safety monitoring of the current study are consistent with what is required for the safety profile of pazopanib.

Removal of the inclusion criterion "Maximum 2 prior lines of treatment for advanced disease" in the Protocol, to allow patients at any point in the treatment pathway to be considered. Patients are now considering cytotoxic chemotherapy later in the treatment pathway as more agents become available. Prior therapy will not impact upon the primary endpoint and removing this inclusion criterion will make the trial available to more patients. Change to exclusion point 1 (Any systemic anticancer therapy within 28 days prior to starting treatment) to permit eligibility 42 days after prior ipilimumab treatment – in the protocol synopsis this is given as 63 days prior to starting trial treatment, however, no statement has been made previously in the main exclusion criteria with regards ipilimumab. 28 days washout period is too short for ipilimumab, however, 63 is excessive and 42 is sufficient. The Main eligibility criteria have been updated to reflect the Synopsis for consistency. Additional blood sample for genetic testing which could previously be taken at screening is changed to being taken at cycle 1 day 1. Only blood samples donated by randomised patients will be analysed, therefore patients should not be asked to donate blood prior to randomisation as this blood will not be analysed if they are not subsequently randomised. Additions to the list of adverse events which do not require to be reported: medical/surgical procedures, day-to-day fluctuations in preexisting disease or conditions, expected progression or signs of the patients’ melanoma. This is done to improve protocol clarity and avoid unnecessary reporting of events which have no impact on patient safety in the trial.

Addition of details for German sites. None sub-amendment for the UK.

We were not on target to recruit according to the milestones stated. Recruitment had been lower than expected but has picked up in Q1 2015 due to competing studies/treatments no longer causing an issue, thus we have secured an extension until January 2016. Updates and clarifications to the safety sections of protocol due to amended working practices and amendments to bring the protocol in line with the German version.

Change to recruitment end date from January 2016 to April 2016 due to slower recruitment rate than expected. Change of wording to MAX of 120 patients as fewer patients now needed according to statistical assessment. Change to definition of the end of the trial due to longer recruitment period. Updates to OCTO contact details throughout the protocol due to changes in staff and new email addresses for the trials unit.