Rewording or amendment of text for clarification in the Treatment Details and Translational Research sections of the protocol.

Trial Monitor contact details removed. Trials in the QA team are dealt with by various personnel within the team. Wording of exclusion criteria changed with reference to hepatitis B and C Clotting Studies clarified in text and assessment table Instructions for sites to send clinical photographs to the trial office mailbox Statistical section was redrafted for clarity.

Updated Contact Details Clarified dose cohort safety teleconference Updated information regarding the continuation of patients on treatment past 12 months Amended Inclusion criterion to provide clarity Updated the Informed Consent Procedure. Updated link for HAART drug interactions Additional text added regarding HAART regimen and interactions with CYP3A Clarified the histology assessment ECHO/MUGA, Ophthalmology assessment and tumour biopsy moved from within 2 weeks of treatment to within 4 weeks of treatment). Corrected error in Phase II assessment table Clarified abnormal laboratory findings as adverse events Updated Case Report Form table Inserted the NHYA classification

Alter eligibility criteria to include patients on Atazanavir, who have asymptomatic elevated levels of bilirubin, but normal liver function Clarify procedure for gaining approval from AstraZeneca for patient continuation past the standard 6 cycles of treatment Additional instructions added requesting that patients do not change HAART medication unless clinically necessary.

Updated Contact Details; Dr Young and Professor Dockrell named as Clinical Coordinator and Deputy Clinical Coordinator, respectively. Trial Coordinator and Trial Administrator updated accordingly. Addition to/amendment of text regarding the expedited reporting of DLTs. Additional text added regarding the prompt return of Cycle 1 CRF copies. Corrected a minor error regarding the PBMC sample collection to match the Laboratory Manual. Minor formatting of reference section

Altered eligibility criteria to exclude patients of Japanese ethnicity Metabolic side effects updated to include hypoalbuminaemia Date of Amendment 6 added to table Updated contact details for Registration of patients

Updated Trial Contact and Registration details. Amended page numbering. Clarified that progression free survival data will be collected for each patient for 6 months from commencing treatment for analysis and for 12 months from completing treatment as supportive data Removed Japanese ethnicity from exclusion criteria Amended trial duration Rearranged a sentence to clarify the conditions required to raise the dose to level 3 during phase I Additional text added to phase I section to include DLT recording window and reflect that the MTD for selumetinib has been found as part of the completion of phase I Amended exclusion criteria as per AstraZeneca’s guidance Added a section on the eligibility of Asian patients Added a section on Asian Pharmacokinetic Data Associated with Selumetinib. Amended text regarding vitamin E exposure Removed phase I assessments list and schedule table and amended text to reflect the successful completion of phase I Added windows for visits in phase II Clarified assessments patients should undergo when discontinuing selumetinib treatment Clarified definition of the follow-up period. Clarified reporting requirements for adverse events for conditions which change CTCAE grade since the previous visit Added ad hoc Haematology/ Clinical Chemistry Assessments Form and Post Treatment Adverse Event Follow-Up Form to CRF table). Clarified end of trial definition Changed Trial Steering Committee to Safety Review Committee. Added Frequency of DMC meetings and amended a spelling mistake. Correction of grammatical, formatting/ spelling errors. Added AEs of interstitial lung disease-like events and updated information regarding visual events Updated guidance for management of LVEF, dyspnoea, vision disorders, CK, diarrhoea and rashes Changed ECOG to WHO in line with IRAS form Added note to check Appendix 10 after Non-Haematologic Adverse Events section regarding elevated CK

Added bullet point to 7.9.6 Post-Treatment Follow-Up: CT scans every 12 weeks for 12 months post end of treatment if visceral or extensive disease identified on baseline CT. Added sentence to 7.11 Patient Follow Up: plus additional CT scans if visceral or extensive disease identified on baseline CT.

Removal of Co-Investigator from Trial Contacts and addition of Senior Trial Manager Removal of HIV physician from trial management team Added note clarifying reasons for discontinuation of treatment after one year: if disease progression and in opinion of Chief Investigator Added point to Concomitant medication section regarding interaction of grapefruit juice and St John’s wort with HAART and selumetinib

Change of Chief Investigator

Change of End of Trial definition