The original CTA listed all drugs used in this trial together with information on the companies who supply this drug. As hospitals use their own hospital stock for this trial we thought the CTA should tie in with the information in the approved protocol by allowing sites to use generic stock, hence why the CTA has been amended by omitting this information.

Amendment to Protocol, PIS, Consent form: Page 9, 22 and 18 in protocol and page 36 and 37 in PIS- clarified that stem cells can be harvested after second or third cycle of IVE chemotherapy

The amendment was for the addition of two new Principal Investigators and sites and some changes made to the CTA form. Details are as follows: 1. Dr. Claudius Rudin, Royal Devon & Exeter FT 2. Dr. Fergus Jack, Poole Hospital NHS FT The following changes were made to the CTA: - Change to sponsor & applicant identification - Changes made to section E.2.2 of the CTA - Change to exclusion criteria & primary endpoint (E.4 & 5) Change to central technical facilities

Change in information on the NRES application form A change to the ionising radiation section of the form (Part B section 3, question B2) was made. The exposure (dose constraint) of the staging CT scan was increased from 12.5 mSv to 16mSv. This was reviewed to meet the NDRL for chest/abdo/pelvis

After an audit carried out on the 17th of June 2010, it was discovered that the guidance given to patients in the PIS regarding contraception did not match the guidance contained within the SmPCs and investigator brochures, thus, it was decided that an urgent safety measure be taken to inform the Trial Subjects of the correct information. The PIS stated contraceptive should be used at least one month after treatment, while the SmPCs for ifosfamide, methotrexate and etoposide state that patients should use contraceptive measures for at least 6 months post last administration of these drugs. The following urgent safety measures were implemented: • Chief Investigator was notified of the circumstances surrounding the decision of the urgent safety measure and the actions to be taken • All relevant staff at the participating sites were notified of the urgent safety measure • The MHRA medical assessor (Dr Nagercoil) and the ethics committee coordinator were immediately informed by telephone of the urgent safety measure on 17th June 2010. • An addendum to the current Patient Information Sheet (PIS) informing patients of the correct information on contraception during and after treatment was sent out to sites for the re-consenting of patients already registered on the trial • A new version of the Patient Information Sheet with the correct information on how long contraception should be used after treatment has been sent out to sites, and should immediately supersede the information sheet currently being used • A process has also been put in place to monitor the re-consenting of the patients already on the trial

The following main changes were made to the CT application form: Section A: • Change to the Full and short titles of the trial, to reflect the inclusion of other disease subtypes • Update to the sponsor’s protocol code number • Inclusion of the US NCT number Section B: • Update of the sponsor’s contact details • Addition of the contact point designated by the sponsor Section C: • Update to the request for Authorisation to Competent Authority Section D: • Update to IMPs information • Deletion of Mesna as an IMP • Inclusion of Lomustine as an IMP (as stated in the amended protocol v4.0, pg 62) Section E: • Inclusion of subtypes of the medical condition to be investigated in the ‘inclusion criteria’ • Additional Information to the trial information – MedDRA • Change in the definition of ‘End of Trial’ • Addition of the recruitment start date Section G: • Addition of a central technical facility Section H: • Change of National Competent Authority details

Cyclophosphamide, Doxorubicin, Vincristine, Ifosfamide, Etoposide, Epirubicin, Methotrexate, Cytarabine, Carmustine and Melphalan: We proposed not to apply IMP labelling to Cyclophosphamide, Doxorubicin, Vincristine, Ifosfamide, Etoposide, Epirubicin, Methotrexate, Cytarabine, Carmustine and Melphalan given IV as their use falls under the remit of Regulation 46(2) of the Medicines for Human Use (Clinical Trials) Regulations, for the following reasons: 1) The IMPs are marketed products, used broadly within their authorisations (i.e. cancer). 2) The IMPs to be dispensed to subjects in accordance with a prescription given by an authorised health care professional 3) The IMPs to be labelled in accordance with the requirements of Schedule 5 to the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 that apply in relation to dispensed relevant medicinal products Prednisolone Abridged labels to be used for Prednisolone tablets.

This amendment concerns the change of the trial name, previously approved. The name was reverted back to the original trial name, ITCL.

Retracted labels v1.0 07.04.11 for Prednisolone. Annex 13 labels v1.0 28.10.11 for Prednisolone for sites that are packing down. Exemption from labelling Lomustine which had been recently added as an IMP – approved on 04.05.11 – as it was being used within its licensed indication and will not dispensed for patients to take at home but dispensed as inpatient treatment only. Also minor amendments made to the PIS, GP Letter and Consent from