-Deletion in the EudraCT application form of the central facility in the Netherlands (section G4); the samples are sent by the sites directly to the central pathology review facility without any intermediate storage.

• Change in the drug supply chain of Shering-Plough: The Temodal will continue to be manufactured at Orion, in Finland. The bulk Temodal will the be shipped from Orion to WAG, in Switzerland, for secondary packaging and labeling. The GMP/QA releases for the packaged supplies will be performed by WAG. The drug will be shipped from WAG to Almac UK where the QP release will be performed. Once the QP release completed, the product will be shipped to the country sites directly. • The protocol and Group Specific Appendix have been amended, please note those changes are considered as non-substantial (changes are detailed in the document “GSA-26062-22061-amend 2 annex 1” and “GSA-26062-22061-amend 2”): • The first change is a number of clarifications to the protocol in regards to dose modifications for radiotherapy and the transition from concurrent to adjuvant temozolomide, as well as clarifications for supporting documentation required for radiotherapy. • The second change to the protocol involves a clarification to the eligibility criteria regarding the timing between initial surgery and the start of study therapy. • A third change to the protocol involves follow-up for patients on the temozolomide and radiotherapy arm of the trial (Arm 2 patients).

1. Changes in the IMP labels: Due to the switch of activities from Schering-Piough to Merck (MSD) and therefore changes in the standard operational procedures for IMP label design, the wording and layout of the IMP labels have changed. 2. Correction on drug supply chain: WAG has been initially declared in our covering letter but does not reflect in the Annex I. Therefore the relevant part of the Annex I has been updated accordingly.

Merck (MSD) is not able to provide a new stock of TEMOZOLOMIDE within the timelines. The batch being used for the moment on the participating site expires on 30/09/2013 and very soon some sites will be out of stock. As a consequence, we are momentarily obliged to ask participating sites to use commercial drug. The commercial drug will be reimbursed by the EORTC which will then invoice Merck. No patient will be charged for the drug costs.

Protocol and Group Specific Appendix (GSA) Previous GSA version: 2.0 dated 10AUG2009 New GSA version: 2.1 dated 21MAY2010 Previous Protocol version: 1.0 dated 16APR2007 New Protocol version: 2.0 dated 22FEB2010 Rationale: The first change is a number of clarifications to the protocol in regards to dose modifications for radiotherapy and the transition from concurrent to adjuvant temozolomide, as well as clarifications for supporting documentation required for radiotherapy. The second change to the protocol involves a clarification to the eligibility criteria regarding the timing between initial surgery and the start of study therapy. A third change to the protocol involves follow-up for patients on the temozolomide and radiotherapy arm of the trial (Arm 2 patients). These changes are described on “GSA-26062-22061-amend 2 & GSA-26062-22061-AMEND 2 annex 1” document which will allow you to clearly identify the changes. The following documents have been impacted by this amendment and have been updated: -The Clinical Trial Protocol -The Group Specific Appendix Please note that this amendment doesn’t affect the safety, physical or mental integrity of the patients, or on the scientific value of the trial.

Notification of temozolomide new safety information Merck Sharp & Dohme (MSD), the marketing authorization holder for temozolomide, informed healthcare providers of the following new safety information: • Cases of hepatic injury, including fatal hepatic failure, have been reported in patients receiving temozolomide. • Liver toxicity may occur several weeks or more after initiation of treatment or after temozolomide discontinuation. • Liver function tests should be performed:  prior to treatment initiation. If abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient;  after each treatment cycle. • For patients on a 42 day treatment cycle, liver function tests should be repeated midway during this cycle; • For patients with significant liver function abnormalities the benefits and risks of continuing treatment should be carefully considered. Recruitment for this trial has been completed. As a result there are no implications for the management of patients on treatment and thus a protocol amendment is not required. However, patients who are continuing on follow-up will be informed orally of this updated information by their Principal Investigator.