Protocol, PIS (11-15, 16+, parents), consent form CF and dispensing labels. Main changes: Protocol: Update pre-registration investigations, Addition of informed consent section, Change of blood samples required for study, Instruction to send adult blood sample samples to the Anthony Nolan Trust and paediatric samples to NHSBT, Insertion of ANT contact details, Expansion of data collection section to clarify central monitoring processes, Inclusion of an on-site monitoring section, Updated graft failure urgent event reporting procedure, Updated acute GVHD urgent event reporting procedure, Changes and clarifications of reporting mechanism for AEs and SAEs, Inclusion of information about expected AEs for IMPs in paediatric patients, Updated table of events which do not require reporting as SAEs, Addition of ‘Death’ to list of events requiring urgent reporting, Addition of Infection reporting instruction, Insertion of criteria for assessment of chronic GVHD, Insertion of cord blood selection mechanism. PIS: PIS 11-15yr version 2.0: Inclusion of the following sentences ‘You may also need to have another bone marrow test 28 days after your transplant. Your doctor will discuss this with you.’ PIS 16y+ version 3.1: Change of ‘Lymphoma Trials Office’ to ‘Haematology Trials Group’ & ‘Cancer Trails Unit’ to ‘Cancer Trials Centre’. Inclusion of the following sentence ‘You may also need another bone marrow test at 28 days after transplantation. Your consultant will discuss this with you.’ PIS parents version 3.1:Change of ‘Lymphoma Trials Office’ to ‘Haematology Trials Group’,Inclusion of the following sentence ‘Your child may also need another bone mamarrow test 28 days after transplantation.’ CF: typographical error correction. Dispensing labels: removal of redundant/duplicated informtion,add storage info,assign space to record calculated total dose,expiry date & date of administration.

Patient information sheet: 11-15yr version 2.2 – nov09 Clarification of the number and timing of biopsy samples Patient information sheet: 16y+ version 3.3 – nov09 Clarification of the number and timing of biopsy samples Patient information sheet: parents version 3.3 – nov09 Clarification of the number and timing of biopsy samples

Main changes Protocol: Section 6.2.1: Deletion of the sentence ‘Double units must also be ≥4/6 matched to each other.’ Section 8.4: Addition of the following sentence ‘In patients in whom the infused dose of DMSO will not exceed 1g/kg UCB grafts should be thawed and infused immediately. However, where this is not possible, steps to maintain cell viability are permissible according to local practice.’ Section 11: Addition of the sentence ‘On-site monitoring and reporting will continue as described from recruitment until 2 years post-transplant, whereupon followup reporting should continue annually until death. If a patient fails to attend a clinic or cannot be followed up at site, efforts should be made to contact the patient’s GP to assess their condition. Any patients ‘lost to follow-up’ and who subsequently die will be ‘flagged’ using the NHS Information Centre.’ Appendix 4: deletion of the line ‘Sites must contact the central radiotherapy co-investigator before exceeding a dose rate of 30cGy/minute.’ Patient information sheet: 11-15yr version 2.2 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses. Patient information sheet: 16y+ version 3.3 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses. Patient information sheet: parents version 3.3 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses.

Main changes: Protocol Section 3: Deletion of the objective ‘To assess immune reconstitution at 1, 2, 3, 6, 12 and 24 months after transplant as measured by quantitative recovery of B, T and NK cells (flow cytometry), qualitative recovery of T cells (TREC and spectratyping), in vivo functional T cell responses (EBV and CMV tetramers) and quantitative immunoglobulins.’ Section 10.1: Removal of the central immune reconstitution analysis to be performed as part of the RIC UCBT trial. Insertion of the following sentence ‘Sites are strongly advised to open (and register RIC UCBT patients onto) the Anthony Nolan Trust/NHSBT Immune REconstitution Study (IRES): a nationwide study to examine immune reconstitution in cord blood transplant patients.’ Patient information sheet: 11-15yr version 3.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. Patient information sheet: 16y+ version 4.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. Patient information sheet: parents version 4.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. A ‘pregnant partner information sheet and informed consent form’ to follow up the outcome of any pregnancies occuring in female-partners of male-participants was also added.

Dispensing labels for cyclophosphamide and fludarabine: permission was requested to retract these labels as there was no requirement for their submission. IMP labels for cyclophosphamide and fludarabine: Paragraph 26 of Annex 13 of the “EU Guidelines to Good Manufacturing Practice” sets out the information that should be included on labels “... unless its absence can be justified”. We proposed not to apply IMP labelling to fludaradine or cyclophosphamide for the following reason: Both fludaradine & cyclophosphamide were taken from general hospital stocks on a per patient basis, with a very short time elapsing between dispensing and reconstitution. This procedure was carried out only in pharmacies by qualified personnel. Adding an IMP label for a very short time does not seem to add anything to protect the subjects involved in the trial that is not already satisfied by the normal pharmacy accountability and labelling procedures. However, as further processing involved reconstitution of the fludaradine and cyclophosphamide in IV bags , we required sites to affix a dispensing label to the IV bag and they were provided with minimum wording for this label. This wording ensured protection of the patient, and traceability to enable identification of the product and trial and to facilitate proper use of the IMP.

Main changes: Protocol Section 1: Study synopsis updated to reflect that the maximum age limit was increased to 70 years of age and deletion of requirement for units to match each other in double cord transplants. Section 6.1: Clarification that chest radiographs & radiotherapy planning CTs were optional, as per local practice. Section 6.3.2: Inclusion criteria section updated to reflect that the upper age limit was increased to 70 years of age in those patients that had a co-morbidity index of 0 - 1. Section 6.3.3: Additional statement that patients aged 60-70 years must had a co-morbidity index of 0-1. Section 6.4: Change of exclusion criteria from ‘5-6/6 HLA-A, B, DRB1’ to ‘a suitably matched’ sibling donor. Section 6.4: Exclusion criteria updated to indicate that patient’s aged 60-70 with a co-morbidity index of >1 were excluded. Section 9.3: Chimerism analysis section updated to clarify that whole PBMC samples should be analysed in addition to the B-cell, T-cell & granulocyte fractions. Section 22: References updated to include additional references for expected adverse events added to protocol appendix 6. Appendix 6: updated to show only AEs expectedness for the trial treatment rather than expectedness for the individual IMPs. Expectedness for individual IMPs was taken directly from SPCs at UCL CTC to ensure that data was always current.

Main changes: Protocol: changes to bring it in line with the Sponsor’s protocol template & to reflect changes to the trial monitoring plan following an update to the risk assessment for the trial in Dec2012. Reference Safety Information: appendix 6 which listed AEs expected for the treatment regimen was updated in response to discussions at the MHRA statutory GCP inspection of the UCL CTC in Jan2013. Previously, appendix 6 included AEs expected for combination conditioning chemotherapy (FluCy), radiotherapy (TBI) and infused cells as a whole. This gave rise to concerns regarding a potential for under-reporting of SUSARs if AEs that were expected for the cells but not the drugs were classified as expected in line with the protocol appendix. The RIC UCBT CI considered it was not possible to separate out the AEs expected for the ‘TBI-chemotherapy conditioning regimen’ into separate lists for TBI and chemotherapy. The published literature addressed toxicities associated with ‘TBI-chemo conditioning’ as a whole, and all conditioning was given within the 7 days prior to transplant, therefore making it extremely difficult to undertake seperate causal assessments for individual chemotherapy agents, or for the chemotherapy conditioning regimen separately to radiotherapy. However, the CI considered it appropriate to seperate AEs expected for transplanted cell infusions from the expected AE list. Therefore for RIC-UCBT these were listed separately in appendix 6 and in section 13 of the protocol, and the expected AEs for transplanted cells were identified as exempt from SAE reporting. Details of complications of the stem cell infusion were collected as Urgent Events, to ensure the safety of the cell source continued to be assessed and recorded in the trial. SAEs not included in tthe list of AEs as expected for ‘TBI-chemotherapy conditioning' ontinued to be assessed. using SmPCs for the individual IMPs.